Michèle Cavo

This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition.

Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments.

Purpose The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). Patients and Methods Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. Results ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum β 2 -microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III (n = 295), including ISS stage III (serum β 2 -microglobulin level > 5.5 mg/L) and high-risk CA or high LDH level; and R-ISS II (n = 1,894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively. Conclusion The R-ISS is a simple and powerful prognostic staging system, and we recommend its use in future clinical studies to stratify patients with NDMM effectively with respect to the relative risk to their survival.

Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma.

Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma.

Thalidomide plus dexamethasone (TD) is a standard induction therapy for myeloma. We aimed to assess the efficacy and safety of addition of bortezomib to TD (VTD) versus TD alone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma.Patients (aged 18-65 years) with previously untreated symptomatic myeloma were enrolled from 73 sites in Italy between May, 2006, and April, 2008, and data collection continued until June 30, 2010. Patients were randomly allocated (1:1 ratio) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily for the first 14 days and 200 mg daily thereafter) plus dexamethasone (40 mg daily on 8 of the first 12 days, but not consecutively; total of 320 mg per cycle), either alone or with bortezomib (1·3 mg/m(2) on days 1, 4, 8, and 11). The randomisation sequence was computer generated by the study coordinating team and was stratified by disease stage. After double autologous stem-cell transplantation, patients received two 35-day cycles of their assigned drug regimen, VTD or TD, as consolidation therapy. The primary endpoint was the rate of complete or near complete response to induction therapy. Analysis was by intention to treat. Patients and treating physicians were not masked to treatment allocation. This study is still underway but is not recruiting participants, and is registered with ClinicalTrials.gov, number NCT01134484, and with EudraCT, number 2005-003723-39.480 patients were enrolled and randomly assigned to receive VTD (n=241 patients) or TD (n=239). Six patients withdrew consent before start of treatment, and 236 on VTD and 238 on TD were included in the intention-to-treat analysis. After induction therapy, complete or near complete response was achieved in 73 patients (31%, 95% CI 25·0-36·8) receiving VTD, and 27 (11%, 7·3-15·4) on TD (p<0·0001). Grade 3 or 4 adverse events were recorded in a significantly higher number of patients on VTD (n=132, 56%) than in those on TD (n=79, 33%; p<0·0001), with a higher occurrence of peripheral neuropathy in patients on VTD (n=23, 10%) than in those on TD (n=5, 2%; p=0·0004). Resolution or improvement of severe peripheral neuropathy was recorded in 18 of 23 patients on VTD, and in three of five patients on TD.VTD induction therapy before double autologous stem-cell transplantation significantly improves rate of complete or near complete response, and represents a new standard of care for patients with multiple myeloma who are eligible for transplant.Seràgnoli Institute of Haematology at the University of Bologna, Bologna, Italy.

The incidence of venous thromboembolism (VTE) is more than 1 per thousand annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with < or = 1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.

The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma.

Background Few effective treatments exist for patients with refractory or relapsed and refractory multiple myeloma not responding to treatment with bortezomib and lenalidomide. Pomalidomide alone has shown limited efficacy in patients with relapsed multiple myeloma, but synergistic effects have been noted when combined with dexamethasone. We compared the efficacy and safety of pomalidomide plus low-dose dexamethasone with high-dose dexamethasone alone in these patients. Methods This multicentre, open-label, randomised phase 3 trial was undertaken in Australia, Canada, Europe, Russia, and the USA. Patients were eligible if they had been diagnosed with refractory or relapsed and refractory multiple myeloma, and had failed at least two previous treatments of bortezomib and lenalidomide. They were assigned in a 2:1 ratio with a validated interactive voice and internet response system to either 28 day cycles of pomalidomide (4 mg/day on days 1–21, orally) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally) or high-dose dexamethasone (40 mg/day on days 1–4, 9–12, and 17–20, orally) until disease progression or unacceptable toxicity. Stratification factors were age (≤75 years vs >75 years), disease population (refractory vs relapsed and refractory vs bortezomib intolerant), and number of previous treatments (two vs more than two). The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01311687, and with EudraCT, number 2010-019820-30. Findings The accrual for the study has been completed and the analyses are presented. 302 patients were randomly assigned to receive pomalidomide plus low-dose dexamethasone and 153 high-dose dexamethasone. After a median follow-up of 10·0 months (IQR 7·2–13·2), median PFS with pomalidomide plus low-dose dexamethasone was 4·0 months (95% CI 3·6–4·7) versus 1·9 months (1·9–2·2) with high-dose dexamethasone (hazard ratio 0·48 [95% CI 0·39–0·60]; p<0·0001). The most common grade 3–4 haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups were neutropenia (143 [48%] of 300 vs 24 [16%] of 150, respectively), anaemia (99 [33%] vs 55 [37%], respectively), and thrombocytopenia (67 [22%] vs 39 [26%], respectively). Grade 3–4 non-haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups included pneumonia (38 [13%] vs 12 [8%], respectively), bone pain (21 [7%] vs seven [5%], respectively), and fatigue (16 [5%] vs nine [6%], respectively). There were 11 (4%) treatment-related adverse events leading to death in the pomalidomide plus low-dose dexamethasone group and seven (5%) in the high-dose dexamethasone group. Interpretation Pomalidomide plus low-dose dexamethasone, an oral regimen, could be considered a new treatment option in patients with refractory or relapsed and refractory multiple myeloma. Funding Celgene Corporation.

The serum immunoglobulin-free light chain (FLC) assay measures levels of free κ and λ immunoglobulin light chains. There are three major indications for the FLC assay in the evaluation and management of multiple myeloma and related plasma cell disorders (PCD). In the context of screening, the serum FLC assay in combination with serum protein electrophoresis (PEL) and immunofixation yields high sensitivity, and negates the need for 24-h urine studies for diagnoses other than light chain amyloidosis (AL). Second, the baseline FLC measurement is of major prognostic value in virtually every PCD. Third, the FLC assay allows for quantitative monitoring of patients with oligosecretory PCD, including AL, oligosecretory myeloma and nearly two-thirds of patients who had previously been deemed to have non-secretory myeloma. In AL patients, serial FLC measurements outperform PEL and immunofixation. In oligosecretory myeloma patients, although not formally validated, serial FLC measurements reduce the need for frequent bone marrow biopsies. In contrast, there are no data to support using FLC assay in place of 24-h urine PEL for monitoring or for serial measurements in PCD with measurable disease by serum or urine PEL. This paper provides consensus guidelines for the use of this important assay, in the diagnosis and management of clonal PCD.

Lenalidomide has tumoricidal and immunomodulatory activity against multiple myeloma. This double-blind, multicenter, randomized study compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo in patients 65 years of age or older with newly diagnosed multiple myeloma.We randomly assigned patients who were ineligible for transplantation to receive MPR-R (nine 4-week cycles of MPR followed by lenalidomide maintenance therapy until a relapse or disease progression occurred [152 patients]) or to receive MPR (153 patients) or MP (154 patients) without maintenance therapy. The primary end point was progression-free survival.The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P<0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P=0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P=0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P<0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP.MPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age. (Funded by Celgene; MM-015 ClinicalTrials.gov number, NCT00405756.).

The combination melphalan-prednisone-thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches.We randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide-dexamethasone versus MPT.The median progression-free survival was 25.5 months with continuous lenalidomide-dexamethasone, 20.7 months with 18 cycles of lenalidomide-dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide-dexamethasone vs. MPT and 0.70 for continuous lenalidomide-dexamethasone vs. 18 cycles of lenalidomide-dexamethasone; P<0.001 for both comparisons). Continuous lenalidomide-dexamethasone was superior to MPT for all secondary efficacy end points, including overall survival (at the interim analysis). Overall survival at 4 years was 59% with continuous lenalidomide-dexamethasone, 56% with 18 cycles of lenalidomide-dexamethasone, and 51% with MPT. Grade 3 or 4 adverse events were somewhat less frequent with continuous lenalidomide-dexamethasone than with MPT (70% vs. 78%). As compared with MPT, continuous lenalidomide-dexamethasone was associated with fewer hematologic and neurologic toxic events, a moderate increase in infections, and fewer second primary hematologic cancers.As compared with MPT, continuous lenalidomide-dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. (Funded by Intergroupe, Francophone du Myélome and Celgene; FIRST ClinicalTrials.gov number, NCT00689936; European Union Drug Regulating Authorities Clinical Trials number, 2007-004823-39.).

This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan–prednisone–lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma.

Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T0). The median age at diagnosis was 58 years, and time from diagnosis to T0 was 3.3 years. Following T0, 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0–8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (44%) including ⩾partial response in 69 (32%). The median overall survival and event-free survival from T0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.

Most studies of amyloidotic cardiomyopathy consider as a single entity the 3 main systemic cardiac amyloidoses: acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). In this study, we compared the diagnostic/clinical profiles of these 3 types of systemic cardiac amyloidosis.We conducted a longitudinal study of 233 patients with clear-cut diagnosis by type of cardiac amyloidosis (AL, n=157; ATTRm, n=61; ATTRwt, n=15) at 2 large Italian centers providing coordinated amyloidosis diagnosis/management facilities since 1990. Average age at diagnosis was higher in AL than in ATTRm patients; all ATTRwt patients except 1 were elderly men. At diagnosis, mean left ventricular wall thickness was higher in ATTRwt than in ATTRm and AL. Left ventricular ejection fraction was moderately depressed in ATTRwt but not in AL or ATTRm. ATTRm patients less often displayed low QRS voltage (25% versus 60% in AL; P<0.0001) or low voltage-to-mass ratio (1.1+/-0.5 versus 0.9+/-0.5; P<0.0001). AL patients appeared to have greater hemodynamic impairment. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events.AL, ATTRm, and ATTRwt should be considered 3 different cardiac diseases, probably characterized by different pathophysiological substrates and courses. Awareness of the diversity underlying the cardiac amyloidosis label is important on several levels, ranging from disease classification to diagnosis and clinical management.

Multiple myeloma (MM) accounts for 1% of all cancers and ∼ 10% of all haematological malignancies. The incidence in Europe is 4.5–6.0/100 000/year with a median age at diagnosis of 72 years; the mortality is 4.1/100 000/year [1.Palumbo A. Bringhen S. Ludwig H. et al.Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN).Blood. 2011; 118: 4519-4529Crossref PubMed Scopus (274) Google Scholar]. Almost all patients with MM evolve from an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to MM at a rate of 1% per year. In some patients, an intermediate asymptomatic but more advanced pre-malignant stage termed smouldering (or indolent) MM (SMM) can be recognised. SMM progresses to myeloma at a rate of 10% per year over the first 5 years following diagnosis, 3% per year over the following 5 years, and 1.5% per year thereafter [2.Rajkumar S.V. Dimopoulos M.A. Palumbo A. et al.International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.Lancet Oncol. 2014; 15: e538-e548Abstract Full Text Full Text PDF PubMed Scopus (2559) Google Scholar]. Diagnosis of MM should be based on the following tests [3.Rajkumar S.V. Updated diagnostic criteria and staging system for multiple myeloma.Am Soc Clin Oncol Educ Book. 2016; 35: e418-e423Crossref PubMed Scopus (140) Google Scholar, 4.Terpos E. Kleber M. Engelhardt M. et al.European Myeloma Network guidelines for the management of multiple myeloma-related complications.Haematologica. 2015; 100: 1254-1266Crossref PubMed Scopus (240) Google Scholar]•Detection and evaluation of the monoclonal (M) component by serum and/or urine protein electrophoresis (concentrate of 24h urine collection); nephelometric quantification of IgG, IgA and IgM immunoglobulins; characterisation of the heavy and light chains by immunofixation; and serum-free light-chain (FLC) measurement.•Evaluation of bone marrow (BM) plasma cell infiltration: BM aspiration and/or biopsies are the standard options to evaluate the number and characteristics of plasma cells in BM. Moreover, the BM sample should be used for cytogenetic/flurorescent in situ hybridisation (FISH) studies on immunologically recognised or sorted plasma cells and also has the potential for immunophenotypic and molecular investigations.•Evaluation of lytic bone lesions: whole-body low-dose computed tomography (WBLD-CT) is the new standard for the diagnosis of lytic disease. Conventional radiography can also be used if WBLD-CT is not available. Magnetic resonance imaging (MRI) provides greater details and is recommended whenever spinal cord compression is suspected. Either whole-body MRI or MRI of the spine and the pelvis may be used, according to their availability, to assess the BM plasma cell infiltration, in particular the presence of bone focal lesions. 18F-fluorodeoxyglucose positron emission tomography with CT (PET-CT) can be done to evaluate bone lesions, according to availability and resources.•Complete blood cell count, with differential serum creatinine, creatinine clearance and calcium level. These tests can allow for the differential diagnosis between MM, SMM and MGUS. The criteria for diagnosis of MM were updated in 2014 by the International Myeloma Working Group (IMWG) [2.Rajkumar S.V. Dimopoulos M.A. Palumbo A. et al.International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.Lancet Oncol. 2014; 15: e538-e548Abstract Full Text Full Text PDF PubMed Scopus (2559) Google Scholar]. The diagnosis requires ≥ 10% clonal BM plasma cells or biopsy-proven bony or extra-medullary plasmacytoma and any of the following myeloma-defining events (Table 1):Table 1Diagnostic criteria for plasma cell disordersAdapted from [2.Rajkumar S.V. Dimopoulos M.A. Palumbo A. et al.International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.Lancet Oncol. 2014; 15: e538-e548Abstract Full Text Full Text PDF PubMed Scopus (2559) Google Scholar] with permission from Elsevier; permission conveyed through Copyright Clearance Center, Inc.Plasma cell disorderDefinitionSmouldering multiple myelomaBoth criteria must be met:•Serum M protein (IgG or IgA) ≥ 30 g/L or urinary M protein ≥ 500 mg per 24 h and/or clonal BM plasma cells 10%–60%•Absence of myeloma-defining events or amyloidosisMultiple myelomaClonal BM plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma-defining events:•Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:-Hypercalcaemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal or > 2.75 mmol/L (> 11 mg/dL)-Renal insufficiency: CrCl < 40 mL/min or serum creatinine > 177 μmol/L (> 2 mg/dL)-Anaemia: haemoglobin value of > 20 g/L below the lower limit of normal or a haemoglobin value < 100 g/L-Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or PET-CT•Any one or more of the following biomarkers of malignancy:-≥ 60% clonal BM plasma cells-Involved/uninvolved serum-free light chain ratio ≥ 100-> 1 focal lesion on MRI studies (each focal lesion must be ≥ 5 mm in size)BM, bone marrow; CrCl, creatinine clearance; CT, computed tomography; M protein, monoclonal protein; MRI, magnetic resonance imaging; PET-CT, positron emission tomography-computed tomography. Open table in a new tab BM, bone marrow; CrCl, creatinine clearance; CT, computed tomography; M protein, monoclonal protein; MRI, magnetic resonance imaging; PET-CT, positron emission tomography-computed tomography. • Evidence of end-organ damage (the so-called CRAB criteria: hypercalcaemia, renal insufficiency, anaemia or bone lesions) that is felt to be related to the underlying plasma cell disorder. Of note, renal insufficiency can be defined not only by creatinine > 2 mg/dL but also by creatinine clearance < 40 mL/min [measured by validated equations such as the Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] [4.Terpos E. Kleber M. Engelhardt M. et al.European Myeloma Network guidelines for the management of multiple myeloma-related complications.Haematologica. 2015; 100: 1254-1266Crossref PubMed Scopus (240) Google Scholar]. Moreover, lytic lesions can also be defined by CT and not only by conventional X-ray.•Any biomarkers of malignancy:- ≥ 60% clonal BM plasma cells- Involved/uninvolved serum FLC ratio ≥ 100- > 1 focal lesion on MRI studies (each focal lesion must be ≥ 5 mm in size). The course of MM is highly variable, and the clinical behaviour is remarkably heterogeneous. Many studies have identified prognostic factors capable of predicting this heterogeneity in survival: serum β2-microglobulin, albumin, C-reactive protein and lactate dehydrogenase (LDH). The International Staging System (ISS), a powerful and reproducible three-stage classification (Table 2), relies on the combination of serum levels of β2-microglobulin and albumin. ISS stage III is associated with the poorest outcome [5.Greipp P.R. San Miguel J. Durie B.G. et al.International staging system for multiple myeloma.J Clin Oncol. 2005; 23: 3412-3420Crossref PubMed Scopus (2119) Google Scholar].Table 2International staging system for MMStageCriteriaISerum β2M < 3.5 mg/mL and serum albumin ≥ 3.5 g/dLIINot stage I or IIIaThere are two possibilities for stage II:IIISerum β2M ≥ 5.5 mg//mL• Serum β2M < 3.5 mg/L but serum albumin < 3.5 g/dLor• Serum β2M 3.5–5.5 mg/L irrespective of the serum albumin.β2M, β2 microglobulin; MM, multiple myeloma.Reprinted from [5.Greipp P.R. San Miguel J. Durie B.G. et al.International staging system for multiple myeloma.J Clin Oncol. 2005; 23: 3412-3420Crossref PubMed Scopus (2119) Google Scholar] with permission. © 2005 American Society of Clinical Oncology. All rights reserved.a There are two possibilities for stage II: Open table in a new tab • Serum β2M < 3.5 mg/L but serum albumin < 3.5 g/dL or • Serum β2M 3.5–5.5 mg/L irrespective of the serum albumin.β2M, β2 microglobulin; MM, multiple myeloma. Reprinted from [5.Greipp P.R. San Miguel J. Durie B.G. et al.International staging system for multiple myeloma.J Clin Oncol. 2005; 23: 3412-3420Crossref PubMed Scopus (2119) Google Scholar] with permission. © 2005 American Society of Clinical Oncology. All rights reserved. Cytogenetics, evaluated by FISH, is a major prognostic factor. Three recurrent genetic abnormalities, t(4;14), deletion(17p) and t(14;16), are mostly associated with a poorer outcome. Chromosome 1 abnormalities are also adverse prognostic factors [6.Sonneveld P. Avet-Loiseau H. Lonial S. et al.Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group.Blood. 2016; 127: 2955-2962Crossref PubMed Scopus (542) Google Scholar]. It has recently been demonstrated that combining FISH and LDH, along with the ISS stage, could significantly improve the prognostic assessment in terms of progression-free survival (PFS) and overall survival (OS), according to this new and revised ISS (R-ISS) (Table 3) [7.Palumbo A. Avet-Loiseau H. Oliva S. et al.Revised international staging system for multiple myeloma: a report from International Myeloma Working Group.J Clin Oncol. 2015; 33: 2863-2869Crossref PubMed Scopus (1108) Google Scholar]. Median PFS was 66 months for patients with R-ISS stage I, 42 months for patients with R-ISS stage II and 29 months for patients with R-ISS stage III. The 5-year OS was 82% for R-ISS stage I, 62% for R-ISS stage II and 40% for R-ISS stage III. Median OS time was not reached for patients with R-ISS stage I and was of 83 and 43 months for R-ISS stage II and R-ISS stage III patients, respectively [7.Palumbo A. Avet-Loiseau H. Oliva S. et al.Revised international staging system for multiple myeloma: a report from International Myeloma Working Group.J Clin Oncol. 2015; 33: 2863-2869Crossref PubMed Scopus (1108) Google Scholar].Table 3Standard risk factors for MM and the revised ISSReprinted from [7.Palumbo A. Avet-Loiseau H. Oliva S. et al.Revised international staging system for multiple myeloma: a report from International Myeloma Working Group.J Clin Oncol. 2015; 33: 2863-2869Crossref PubMed Scopus (1108) Google Scholar] with permission. © 2015 American Society of Clinical Oncology. All rights reserved.Prognostic factorCriteriaISS stageISerum β2M < 3.5 mg/L, serum albumin ≥ 3.5 g/dLIINot ISS stage I or IIIIIISerum β2M ≥ 5.5 mg/LCA by iFISHHigh riskPresence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16)Standard riskNo high-risk CALDHNormalSerum LDH < the upper limit of normalHighSerum LDH > the upper limit of normalA new model for risk stratification for MMR-ISS stageIISS stage I and standard-risk CA by iFISH and normal LDHIINot R-ISS stage I or IIIIIIISS stage III and either high-risk CA by iFISH or high LDHβ2M, β2 microglobulin; CA, chromosomal abnormalities; iFISH, interphase fluorescent in situ hybridisation; ISS, International Staging System; LDH, lactate dehydrogenase; MM, multiple myeloma; R-ISS, revised International Staging System. Open table in a new tab β2M, β2 microglobulin; CA, chromosomal abnormalities; iFISH, interphase fluorescent in situ hybridisation; ISS, International Staging System; LDH, lactate dehydrogenase; MM, multiple myeloma; R-ISS, revised International Staging System. Gene-expression profiling may segregate patients with standard or high-risk disease, but this test is not yet established in routine practice. Elderly patients with myeloma are heterogeneous and assessment strategies should be considered before starting therapy to define the frailty profile of the patient. The IMWG has proposed a frailty score (an additive scoring system based on age, comorbidities and cognitive and physical conditions) that predicts mortality and the risk of toxicity in this group of patients [8.Palumbo A. Bringhen S. Mateos M.V. et al.Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report.Blood. 2015; 125: 2068-2074Crossref PubMed Scopus (477) Google Scholar]. The definition of response established by the IMWG in 2006 has been updated twice, in 2011 [9.Rajkumar S.V. Harousseau J.L. Durie B. et al.Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1.Blood. 2011; 117: 4691-4695Crossref PubMed Scopus (764) Google Scholar] and in 2016 [10.Kumar S. Paiva B. Anderson K.C. et al.International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.Lancet Oncol. 2016; 17: e328-e346Abstract Full Text Full Text PDF PubMed Scopus (1361) Google Scholar] (Tables 4 and 5). The quality and the depth of response have improved over the last 5 years in the context of novel agent-based therapies, allowing for the introduction of new response grades, namely minimal residual disease (MRD) criteria including sequencing MRD negativity, flow MRD negativity, imaging plus negativity and sustained MRD negativity. Nevertheless, MRD evaluation is not yet a reimbursed procedure, does not lead to treatment decisions, and is currently being evaluated in the context of clinical trials.Table 42011 response criteriaAdapted from [9.Rajkumar S.V. Harousseau J.L. Durie B. et al.Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1.Blood. 2011; 117: 4691-4695Crossref PubMed Scopus (764) Google Scholar] with permission of the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc.Response subcategoryResponse criteriaMolecular CRCR plus negative ASO-PCR, sensitivity 10-5Immunophenotypic CRStringent CR plusAbsence of phenotypically aberrant PCs (clonal) in BM with a minimum of 1 million total BM cells analysed by multiparametric flow cytometry (with > 4 colours)Stringent CRCR as defined below plusNormal FLC ratio andAbsence of clonal PCs by immunohistochemistry or 2- to 4-colour flow cytometryCRNegative immunofixation on the serum and urine andDisappearance of any soft tissue plasmacytomas and≤ 5% PCs in BMVGPRSerum and urine M protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M protein plus urine M protein level <100 mg per 24 hPR≥ 50% reduction of serum M protein and reduction in 24h urinary M protein by ≥ 90% or to < 200 mg per 24 hIf the serum and urine M protein are unmeasurable, a ≥ 50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M protein criteriaIf serum and urine M protein are unmeasurable, and serum-free light assay is also unmeasurable, ≥ 50% reduction in PCs is required in place of M protein, provided baseline BM PC percentage was ≥ 30%In addition to the above listed criteria, if present at baseline, a ≥ 50% reduction in the size of soft tissue plasmacytomas is also requiredProgressive diseaseIncrease of 25% from lowest confirmed response value in one of the following criteria:Serum M protein (absolute increase must be ≥ 0.5 g/dL)Serum M protein increase ≥ 1 g/dL, if the lowest M component was ≥ 5 g/dLUrine M protein (absolute increase must be ≥ 200 mg/24 h)ASO-PCR, allele-specific polymerase chain reaction; BM, bone marrow; CR, complete response; FLC, free light chain; M protein, monoclonal protein; PCs, plasma cells; PR, partial response; VGPR, very good partial response. Open table in a new tab Table 52016 response criteriaAdapted from [10.Kumar S. Paiva B. Anderson K.C. et al.International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.Lancet Oncol. 2016; 17: e328-e346Abstract Full Text Full Text PDF PubMed Scopus (1361) Google Scholar] with permission from Elsevier; permission conveyed through Copyright Clearance Center, Inc.Response subcategoryResponse criteriaIMWG MRD negativity criteriaSustained MRD-negativeMRD-negative in the marrow (next-generation flow and/or NGS) and by imaging as defined below, confirmed one year apart. Subsequent evaluations can be used to further specify the duration of negativity (e.g. MRD-negative at 5 years)Flow MRD-negativeAbsence of phenotypically aberrant clonal plasma cells by next-generation flow cytometry on BM aspirates using the EuroFlow standard operation procedure for MRD detection in MM (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higherSequencing MRD-negativeAbsence of clonal plasma cells by NGS on BM aspirates in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of BM aspirates using the Lymphosight® platform (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higherImaging + MRD-negativeMRD-negative as defined by next-generation flow cytometry or NGS plusDisappearance of every area of increased tracer uptake found at baseline or a preceding PET-CT or decrease to < mediastinal blood pool SUV or decrease to less than that of surrounding normal tissueBM, bone marrow; IMWG, International Myeloma Working Group; MM, multiple myeloma; MRD, minimal residual disease; NGS, next-generation sequencing; PET-CT, positron emission tomography-computed tomography; SUV, standardised uptake value. Open table in a new tab ASO-PCR, allele-specific polymerase chain reaction; BM, bone marrow; CR, complete response; FLC, free light chain; M protein, monoclonal protein; PCs, plasma cells; PR, partial response; VGPR, very good partial response. BM, bone marrow; IMWG, International Myeloma Working Group; MM, multiple myeloma; MRD, minimal residual disease; NGS, next-generation sequencing; PET-CT, positron emission tomography-computed tomography; SUV, standardised uptake value. There is a statistical relationship between the achievement of complete response (CR), MRD negativity and PFS or OS. Immediate treatment is not recommended at the present time for patients with indolent myeloma. Clinical trials for high-risk smouldering myeloma are strongly encouraged. Treatment should be initiated in all patients with MM according to the updated definition proposed by the IMWG in 2014 [2]. Major treatment regimens in MM are shown in Table 6. Front-line treatment regimens are shown in Figure 1.Table 6Major treatment regimens in multiple myelomaRegimenUsual dosing scheduleFront-line:Bortezomib/melphalan/prednisone (VMP) [11.San Miguel J.F. Schlag R. Khuageva N.K. et al.Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.N Engl J Med. 2008; 359: 906-917Crossref PubMed Scopus (1632) Google Scholar]Bortezomib 1.3 mg/m2 subcutaneously days 1, 8, 15, 22; melphalan 9 mg/m2 orally days 1–4; prednisone 60 mg/m2 orally days 1–4; repeated every 35 daysLenalidomide/low-dose dexamethasone (Rd) [12.Benboubker L. Dimopoulos M.A. Dispenzieri A. et al.Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma.N Engl J Med. 2014; 371: 906-917Crossref PubMed Scopus (603) Google Scholar]Lenalidomide 25 mg orally days 1–21; dexamethasone 40 mg orally days 1, 8, 15, 22; repeated every 28 daysMelphalan/prednisone/thalidomide (MPT) [13.Fayers P.M. Palumbo A. Hulin C. et al.Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials.Blood. 2011; 118: 1239-1247Crossref PubMed Scopus (225) Google Scholar]Melphalan 0.25 mg/kg orally days 1–4 (use 0.20 mg/kg/day orally days 1–4 in patients over the age of 75); prednisone 2 mg/kg orally days 1–4; thalidomide 100–200 mg orally days 1–28 (use 100 mg dose in patients >75); repeated every 6 weeksBortezomib/cyclophosphamide/dexamethasone (VCD) [14.Moreau P. Attal M. Facon T. Frontline therapy of multiple myeloma.Blood. 2015; 125: 3076-3084Crossref PubMed Scopus (216) Google Scholar]Cyclophosphamide 300 mg/m2 orally days 1, 8, 15 and 22; bortezomib 1.3 mg/m2 i.v. on days 1, 8, 15, 22; dexamethasone 40 mg orally on days 1, 8, 15, 22; repeated every 4 weeksBortezomib/thalidomide/dexamethasone (VTD) [14.Moreau P. Attal M. Facon T. Frontline therapy of multiple myeloma.Blood. 2015; 125: 3076-3084Crossref PubMed Scopus (216) Google Scholar]Bortezomib 1.3 mg/m2 subcutaneously days 1, 8, 15, 22; thalidomide 100–200 mg orally days 1–21; dexamethasone 20 mg on day of and day after bortezomib (or 40 mg days 1, 8, 15, 22); repeated every 4 weeks × 4 cycles as pre-transplant induction therapyBortezomib/lenalidomide/dexamethasone (VRd) [14.Moreau P. Attal M. Facon T. Frontline therapy of multiple myeloma.Blood. 2015; 125: 3076-3084Crossref PubMed Scopus (216) Google Scholar]Bortezomib 1.3 mg/m2 subcutaneously days 1, 8, 15; lenalidomide 25 mg orally days 1–14; dexamethasone 20 mg on day of and day after bortezomib (or 40 mg days 1, 8, 15, 22); repeated every 3 weeksRelapse/refractory disease:Carfilzomib/lenalidomide/dexamethasone (KRd) [24.Korde N. Roschewski M. Zingone A. et al.Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma.JAMA Oncol. 2015; 1: 746-754Crossref PubMed Scopus (229) Google Scholar, 32.Stewart A.K. Rajkumar S.V. Dimopoulos M.A. et al.Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.N Engl J Med. 2015; 372: 142-152Crossref PubMed Scopus (988) Google Scholar]Carfilzomib 20 mg/m2 (cycle 1) and 27 mg/m2 (subsequent cycles) i.v. on days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg orally days 1–21; dexamethasone 40 mg on days 1, 8, 15, 22; 28-day cyclesBortezomib/dexamethasone/panobinostat (VD-Pano) [31.San-Miguel J.F. Hungria V.T. Yoon S.S. et al.Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial.Lancet Oncol. 2014; 15: 1195-1206Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar]Bortezomib 1.3 mg/m2 subcutaneously days 1, 8, 15, 22; dexamethasone 20 mg on day of and day after bortezomib; panobinostat 20 mg orally days 1, 3, 5 week 1 and 2; repeated every 3 weeks (cycles 1–8)Carfilzomib/dexamethasone (Kd) [33.Dimopoulos M.A. Moreau P. Palumbo A. et al.Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study.Lancet Oncol. 2016; 17: 27-38Abstract Full Text Full Text PDF PubMed Scopus (644) Google Scholar]Carfilzomib 56 mg/m2 i.v. days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only); dexamethasone 20 mg days 1, 2, 8, 9, 15, 16, 22, 23; 28-day cyclesLenalidomide/dexamethasone/elotuzumab (Rd-Elo) [34.Lonial S. Dimopoulos M. Palumbo A. et al.Elotuzumab therapy for relapsed or refractory multiple myeloma.N Engl J Med. 2015; 373: 621-631Crossref PubMed Scopus (994) Google Scholar]Lenalidomide 25 mg orally days 1–21; dexamethasone 40 mg weekly; elotuzumab 10 mg/kg i.v. weekly cycle 1 and 2, every other week cycles 3+; repeated every 28 daysLenalidomide/dexamethasone/ixazomib (IRd) [35.Moreau P. Masszi T. Grzasko N. et al.Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med. 2016; 374: 1621-1634Crossref PubMed Scopus (755) Google Scholar]Lenalidomide 25 mg orally days 1–21; dexamethasone orally 40 mg days 1, 8, 15, 22; ixazomib 4 mg orally days 1, 8, 15; repeated every 28 daysBortezomib/dexamethasone/daratumumab (DVd) [38.Palumbo A. Chanan-Khan A. Weisel K. et al.Daratumumab, bortezomib, and dexamethasone for multiple myeloma.N Engl J Med. 2016; 375: 754-766Crossref PubMed Scopus (1018) Google Scholar]Bortezomib 1.3 mg/m2 subcutaneously days 1, 4, 8, 11 (cycles 1–8); dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11, 12 (cycles 1–8); daratumumab 16 mg/kg i.v. every week (cycles 1–3), every 3 weeks (cycles 4–8), every 4 weeks (cycles 9+); cycles 1–8: repeated every 21 days; cycles 9+: repeated every 28 daysLenalidomide/dexamethasone/daratumumab (DRd) [39.Dimopoulos M.A. Oriol A. Nahi H. et al.Daratumumab, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med. 2016; 375: 1319-1331Crossref PubMed Scopus (1011) Google Scholar]Lenalidomide 25 mg orally days 1–21; dexamethasone 40 mg orally weekly; daratumumab 16 mg/kg i.v. weekly (cycles 1-2), every other week (cycles 3-6), every 4 weeks (cycles 7+) Open table in a new tab The two following options are recommended based on data from randomised phase III trials [I, A]: bortezomib (administered subcutaneously)/melphalan/prednisone (VMP) [11.San Miguel J.F. Schlag R. Khuageva N.K. et al.Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.N Engl J Med. 2008; 359: 906-917Crossref PubMed Scopus (1632) Google Scholar] or lenalidomide plus low-dose dexamethasone (Rd) [12.Benboubker L. Dimopoulos M.A. Dispenzieri A. et al.Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma.N Engl J Med. 2014; 371: 906-917Crossref PubMed Scopus (603) Google Scholar]; both VMP and Rd are approved in this setting by the European Medicines Agency (EMA). Rd is approved until progression of the disease. Melphalan/prednisone/thalidomide (MPT) [13.Fayers P.M. Palumbo A. Hulin C. et al.Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials.Blood. 2011; 118: 1239-1247Crossref PubMed Scopus (225) Google Scholar] is also approved by the EMA, but is inferior to Rd in terms of PFS and OS [12.Benboubker L. Dimopoulos M.A. Dispenzieri A. et al.Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma.N Engl J Med. 2014; 371: 906-917Crossref PubMed Scopus (603) Google Scholar]. Bortezomib-cyclophosphamide and dexamethasone (VCD) is not EMA-approved (no controlled data), but is widely used and induces high response rates and prolonged PFS [III, A] [14.Moreau P. Attal M. Facon T. Frontline therapy of multiple myeloma.Blood. 2015; 125: 3076-3084Crossref PubMed Scopus (216) Google Scholar]. Rd has recently been compared prospectively with Rd plus bortezomib (VRd), and the addition of bortezomib resulted in significantly improved PFS and OS and had an acceptable risk–benefit profile [15.Durie B.G. Hoering A. Abidi M.H. et al.Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.Lancet. 2017; 389: 519-527Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]. Nevertheless, this triplet combination is not yet approved by the EMA. Bendamustine plus prednisone is also approved by the EMA in patients who have clinical neuropathy at time of diagnosis, precluding the use of thalidomide according to the MPT regimen or bortezomib according to the VMP regimen [II, C] [16.Pönisch W. Mitrou P.S. Merkle K. et al.Treatment of bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone – a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO).J Cancer Res Clin Oncol. 2006; 132: 205-212Crossref PubMed Scopus (163) Google Scholar]. Melphalan/prednisone/lenalidomide (MPR) has been evaluated in two prospective randomised studies versus melphalan and prednisone (MP) [17.Palumbo A. Hajek R. Delforge M. et al.Continuous lenalidomide treatment for newly diagnosed multiple myeloma.N Engl J Med. 2012; 366: 1759-1769Crossref PubMed Scopus (637) Google Scholar] and versus MPT [18.Zweegman S. van der Holt B. Mellqvist U.H. et al.Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma.Blood. 2016; 127: 1109-1116Crossref PubMed Scopus (85) Google Scholar], but MPR was not superior to the other combinations with a fixed number of cycles [II, C]. This triplet combination is approved by the EMA but is not routinely used and cannot be considered as a standard of care. Cyclophosphamide/thalidomide/dexamethasone (CTD) has also been compared with MP and is superior in terms of response rates, but does not induce a clear survival advantage over MP [II, C] [19.Morgan G.J. Davies F.E. Gregory W.M. et al.Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation.Blood. 2011; 118: 1231-1238Crossref PubMed Scopus (163) Google Scholar]. For patients in good clinical condition (e.g. fit patients), induction followed by high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard treatment [II, B] [14.Moreau P. Attal M. Facon T. Frontline therapy of multiple myeloma.Blood. 2015; 125: 3076-3084Crossref PubMed Scopus (216) Google Scholar]. Two recent phase III trials comparing front-line ASCT versus ASCT at the time of first relapse showed that PFS was improved in the front-line ASCT arm (in the context of triplet novel agent-based induction) [20.Attal M. Lauwers-Cances V. Hulin C. et al.Autologous transplantation for multiple myelo

Abstract We prospectively analyzed the prognostic relevance of positron emission tomography–computed tomography (PET/CT) at diagnosis, after thalidomide-dexamethasone (TD) induction therapy and double autotransplantation (ASCT) in 192 newly diagnosed multiple myeloma (MM) patients. Presence at baseline of at least 3 focal lesions (FLs; 44% of cases), a standardized uptake value (SUV) &gt; 4.2 (46%), and extramedullary disease (EMD; 6%) adversely affected 4-year estimates of progression-free survival (PFS; ≥ 3 FLs: 50%; SUV &gt; 4.2: 43%; presence of EMD: 28%). SUV &gt; 4.2 and EMD were also correlated with shorter overall survival (OS; 4-year rates: 77% and 66%, respectively). Persistence of SUV &gt; 4.2 after TD induction was an early predictor for shorter PFS. Three months after ASCT, PET/CT was negative in 65% of patients whose 4-year rates of PFS and OS were superior to those of PET-positive patients (PFS: 66% and OS: 89%). In a multivariate analysis, both EMD and SUV &gt; 4.2 at baseline and persistence of fluorodeoxyglucose (FDG) uptake after ASCT were independent variables adversely affecting PFS. PET/CT involvement at diagnosis, after novel agent-based induction and subsequent ASCT is a reliable predictor of prognosis in MM patients. This study is registered at www.clinicaltrials.gov as NTC01341262.

Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma.We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2-3 vs >3) and age (<75 years vs ≥75 years). Treatments were assigned based on a permuted blocked randomisation scheme with a block size of four. The isatuximab-pomalidomide-dexamethasone group received isatuximab intravenously on days 1, 8, 15, and 22 in the first 28-day cycle, then on days 1 and 15 in subsequent cycles. Both groups received oral pomalidomide on days 1 to 21 in each cycle, and oral or intravenous dexamethasone on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. Dose reductions for adverse reactions were permitted for pomalidomide and dexamethasone, but not for isatuximab. The primary endpoint was progression-free survival, determined by an independent response committee and assessed in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. This study is registered at ClinicalTrials.gov, number NCT02990338.Between Jan 10, 2017, and Feb 2, 2018, we randomly assigned 307 patients to treatment: 154 to isatuximab-pomalidomide-dexamethasone, and 153 to pomalidomide-dexamethasone. At a median follow-up of 11·6 months (IQR 10·1-13·9), median progression-free survival was 11·5 months (95% CI 8·9-13·9) in the isatuximab-pomalidomide-dexamethasone group versus 6·5 months (4·5-8·3) in the pomalidomide-dexamethasone group; hazard ratio 0·596, 95% CI 0·44-0·81; p=0·001 by stratified log-rank test. The most frequent treatment-emergent adverse events (any grade; isatuximab-pomalidomide-dexamethasone vs pomalidomide-dexamethasone) were infusion reactions (56 [38%] vs 0), upper respiratory tract infections (43 [28%] vs 26 [17%]), and diarrhoea (39 [26%] vs 29 [20%]). Adverse events with a fatal outcome were reported in 12 patients (8%) in the isatuximab-pomalidomide-dexamethasone group and 14 (9%) in the pomalidomide-dexamethasone group. Deaths due to treatment-related adverse events were reported for one patient (<1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection).The addition of isatuximab to pomalidomide-dexamethasone significantly improves progression-free survival in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor.Sanofi. VIDEO ABSTRACT.

Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19.This multicentre, retrospective, cohort study included adult patients (aged ≥18 years) with diagnosis of a WHO-defined haematological malignancy admitted to 66 Italian hospitals between Feb 25 and May 18, 2020, with laboratory-confirmed and symptomatic COVID-19. Data cutoff for this analysis was June 22, 2020. The primary outcome was mortality and evaluation of potential predictive parameters of mortality. We calculated standardised mortality ratios between observed death in the study cohort and expected death by applying stratum-specific mortality rates of the Italian population with COVID-19 and an Italian cohort of 31 993 patients with haematological malignancies without COVID-19 (data up to March 1, 2019). Multivariable Cox proportional hazards model was used to identify factors associated with overall survival. This study is registered with ClinicalTrials.gov, NCT04352556, and the prospective part of the study is ongoing.We enrolled 536 patients with a median follow-up of 20 days (IQR 10-34) at data cutoff, 85 (16%) of whom were managed as outpatients. 440 (98%) of 451 hospitalised patients completed their hospital course (were either discharged alive or died). 198 (37%) of 536 patients died. When compared with the general Italian population with COVID-19, the standardised mortality ratio was 2·04 (95% CI 1·77-2·34) in our whole study cohort and 3·72 (2·86-4·64) in individuals younger than 70 years. When compared with the non-COVID-19 cohort with haematological malignancies, the standardised mortality ratio was 41·3 (38·1-44·9). Older age (hazard ratio 1·03, 95% CI 1·01-1·05); progressive disease status (2·10, 1·41-3·12); diagnosis of acute myeloid leukaemia (3·49, 1·56-7·81), indolent non-Hodgin lymphoma (2·19, 1·07-4·48), aggressive non-Hodgkin lymphoma (2·56, 1·34-4·89), or plasma cell neoplasms (2·48, 1·31-4·69), and severe or critical COVID-19 (4·08, 2·73-6·09) were associated with worse overall survival.This study adds to the evidence that patients with haematological malignancies have worse outcomes than both the general population with COVID-19 and patients with haematological malignancies without COVID-19. The high mortality among patients with haematological malignancies hospitalised with COVID-19 highlights the need for aggressive infection prevention strategies, at least until effective vaccination or treatment strategies are available.Associazione italiana contro le leucemie, linfomi e mieloma-Varese Onlus.

Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy. Indeed, bortezomib is an established component of induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. In addition, a new route of bortezomib administration, subcutaneous infusion, has recently been approved. Recently, several new agents have been introduced into the clinic, including carfilzomib, marizomib, and MLN9708, and trials investigating these "second-generation" PIs in patients with relapsed/refractory MMs have demonstrated positive results. This review provides an overview of the role of PIs in the treatment of MM, focusing on developments over the past decade.

The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of 18fluorodeoxyglucose (18F-FDG) PET/CT in patients with multiple myeloma and other plasma cell disorders, including smouldering multiple myeloma and solitary plasmacytoma. 18F-FDG PET/CT can be considered a valuable tool for the work-up of patients with both newly diagnosed and relapsed or refractory multiple myeloma because it assesses bone damage with relatively high sensitivity and specificity, and detects extramedullary sites of proliferating clonal plasma cells while providing important prognostic information. The use of 18F-FDG PET/CT is mandatory to confirm a suspected diagnosis of solitary plasmacytoma, provided that whole-body MRI is unable to be performed, and to distinguish between smouldering and active multiple myeloma, if whole-body X-ray (WBXR) is negative and whole-body MRI is unavailable. Based on the ability of 18F-FDG PET/CT to distinguish between metabolically active and inactive disease, this technique is now the preferred functional imaging modality to evaluate and to monitor the effect of therapy on myeloma-cell metabolism. Changes in FDG avidity can provide an earlier evaluation of response to therapy compared to MRI scans, and can predict outcomes, particularly for patients who are eligible to receive autologous stem-cell transplantation. 18F-FDG PET/CT can be coupled with sensitive bone marrow-based techniques to detect minimal residual disease (MRD) inside and outside the bone marrow, helping to identify those patients who are defined as having imaging MRD negativity.

In contrast to autologous bone marrow transplants for hematologic cancers, allogeneic transplants contain no tumor cells that might cause a relapse. We report the results of such allogeneic bone marrow transplantation using HLA-compatible sibling donors in 90 patients with multiple myeloma performed in 26 European centers between 1983 and 1989.

•This EHA-ESMO Clinical Practice Guideline provides key recommendations on the management of multiple myeloma.•Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe.•Key treatment recommendations are provided for both newly diagnosed myeloma patients and patients with relapsed/refractory disease.•Recommendations for the treatment of plasma cell leukaemia, solitary plasmacytoma and smouldering myeloma are also provided.•Key recommendations for myeloma complications, including bone disease and renal impairment, are included. Incidence and epidemiologyMultiple myeloma (MM) is a plasma cell neoplasm that accounts for 1%-1.8% of all cancers and is the second most common haematological malignancy with an estimated incidence in Europe of 4.5-6.0/100 000/year. Despite the significant improvement in patients' survival over the past 20 years, only 10%-15% of patients achieve or exceed expected survival compared with the matched general population.1Usmani S.Z. Hoering A. Cavo M. et al.Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research Project.Blood Cancer J. 2018; 8: 123Crossref PubMed Scopus (55) Google ScholarDiagnosis and stagingIn 2017, ESMO published clinical practice guidelines for the diagnosis, staging and definitions of progressive disease, relapse and refractoriness to therapy, which have not changed and are summarised in Supplementary Tables S1-S3, available at https://doi.org/10.1016/j.annonc.2020.11.014.2Moreau P. San Miguel J. Sonneveld P. et al.Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv52-iv61Abstract Full Text Full Text PDF PubMed Scopus (451) Google ScholarThe recommendations for the tests that are required for the diagnosis, determination of prognosis and follow-up of MM are described in Table 1.Table 1Recommendations on examinations at diagnosis, response assessment, during follow-up and at relapse of MMAdapted with permission from Caers et al.85Caers J. Garderet L. Kortum K.M. et al.European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when.Haematologica. 2018; 103: 1772-1784Crossref PubMed Scopus (62) Google ScholarToolDiagnosisAt responseAt follow-upAt relapseBloodBlood count and blood smearObligatoryObligatoryObligatoryObligatorySerum electrophoresis and IFObligatoryObligatory (IF for CR confirmation)Obligatory (IF for CR patients)ObligatorySerum-free light chainObligatoryObligatory to confirm sCRObligatoryObligatorySerum immunoglobulin levelsObligatoryObligatoryObligatoryObligatoryRenal and liver function testsObligatoryObligatoryObligatoryObligatoryCalciumObligatoryObligatoryObligatoryObligatoryLactate dehydrogenaseObligatoryObligatoryObligatoryObligatoryAlbumin, β2mObligatoryNot requiredOptionalObligatoryFlow cytometryOptionalNot requiredNot requiredOptionalUrineUrine sample from 24 h urine collection to check for proteinuria and light-chain proteinuriaObligatoryObligatoryObligatoryObligatoryUrine electrophoresis and IF electrophoresisObligatoryObligatory (IF for CR confirmation)Obligatory (IF for CR patients)ObligatoryBone marrowBM cytology and biopsy to confirm plasmacytosis and monoclonalityObligatoryObligatory to confirm CR or for non-secretory MMNot requiredOptional (obligatory for non-secretory disease)NGF or NGS to detect clonal plasma cellsObligatoryObligatory to confirm MRD negativity in CR or sCR patientsEvery 12 months in CR and/or MRD-negative patientsaSustained MRD negativity is supported by IMWG guidelines,3 although it is not fully reimbursed in several countries. In a recent ‘Real-World’ study, MRD assessments were carried out in 139 patients before starting lenalidomide maintenance after ASCT and/or at the achievement of CR, while additional assessments were subsequently carried out on an annual basis until sustained MRD negativity was confirmed. In total, 34.3% of patients who were MRD-positive after induction treatment achieved MRD-negative status during maintenance and ultimately had improved PFS. Sequential MRD assessments identified patients with progressively decreasing MRD levels who also had better PFS outcomes, compared with patients not showing a decreasing pattern of MRD.90OptionalCytogenetics: karyotype and FISH for detection of del17p, t(4;14), t(14;16), ampl 1q/ gain 1q, t(11;14)ObligatoryNot requiredNot requiredObligatory for del17p, ampl 1q/ gain 1q and t(11;14)Advanced techniques: GEP, NGSFor clinical trials use onlyFor clinical trials use onlyFor clinical trials use onlyFor clinical trials use onlyImagingWBLD-CTObligatoryNot requiredWhen symptomatic (or CT of the symptomatic area)ObligatoryPET-CTOptional (it may be carried out instead of WBLD-CT if available)Obligatory to confirm imaging MRDEvery 12 months in bone marrow MRD-negative patientsbRecommended based on panel consensus in order to confirm extramedullary MRD negativity in patients who are MRD-negative in the bone marrow.OptionalWhole-body MRIObligatory in WBLD-CT-negative cases and if PET-CT is not carried outNot requiredWhen symptomaticOptionalASCT, autologous stem cell transplantation; β2m, beta-2 microglobulin; BM, bone marrow; CR, complete response; CT, computed tomography; FISH, fluorescent in situ hybridisation; GEP, gene expression profiling; IF, immunofixation; IMWG, International Myeloma Working Group; MM, multiple myeloma; MRD, minimal residual disease; MRI, magnetic resonance imaging; NGF, next-generation flow cytometry; NGS, next-generation sequencing; PET, positron emission tomography; PFS, progression-free survival; sCR, stringent complete response; WBLD-CT, whole-body low-dose computed tomography.a Sustained MRD negativity is supported by IMWG guidelines,3Kumar S. Paiva B. Anderson K.C. et al.International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.Lancet Oncol. 2016; 17: e328-e346Abstract Full Text Full Text PDF PubMed Scopus (1265) Google Scholar although it is not fully reimbursed in several countries. In a recent ‘Real-World’ study, MRD assessments were carried out in 139 patients before starting lenalidomide maintenance after ASCT and/or at the achievement of CR, while additional assessments were subsequently carried out on an annual basis until sustained MRD negativity was confirmed. In total, 34.3% of patients who were MRD-positive after induction treatment achieved MRD-negative status during maintenance and ultimately had improved PFS. Sequential MRD assessments identified patients with progressively decreasing MRD levels who also had better PFS outcomes, compared with patients not showing a decreasing pattern of MRD.90Alonso R. Cedena M.T. Wong S. et al.Prolonged lenalidomide maintenance therapy improves the depth of response in multiple myeloma.Blood Adv. 2020; 4: 2163-2171Crossref PubMed Scopus (12) Google Scholarb Recommended based on panel consensus in order to confirm extramedullary MRD negativity in patients who are MRD-negative in the bone marrow. Open table in a new tab Response criteria to anti-myeloma therapyOne of the most significant improvements in the response criteria is the introduction of minimal residual disease (MRD) both in the bone marrow (BM) [using either next-generation sequencing or next-generation flow cytometry (NGF)] and outside the BM [using positron emission tomography-computed tomography (PET-CT); imaging MRD].3Kumar S. Paiva B. Anderson K.C. et al.International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.Lancet Oncol. 2016; 17: e328-e346Abstract Full Text Full Text PDF PubMed Scopus (1265) Google Scholar MRD negativity in the BM in patients who have achieved conventional complete response (CR) consistently correlates with prolonged progression-free survival (PFS) and overall survival (OS) in both newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients.4Perrot A. Lauwers-Cances V. Corre J. et al.Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma.Blood. 2018; 132: 2456-2464Crossref PubMed Scopus (216) Google Scholar,5Munshi N.C. Avet-Loiseau H. Rawstron A.C. et al.Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis.JAMA Oncol. 2017; 3: 28-35Crossref PubMed Scopus (325) Google ScholarMRD negativity in the BM, defined as the absence of tumour plasma cells within 1 000 000 BM cells (<10−6) shows the best results for the prediction of both PFS and OS compared with higher cut-off values (i.e. 10−5).4Perrot A. Lauwers-Cances V. Corre J. et al.Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma.Blood. 2018; 132: 2456-2464Crossref PubMed Scopus (216) Google Scholar Outside the BM, PET-CT is able to recognise hypermetabolic areas in approximately 15%-20% of patients with MRD negativity in the BM and is considered the best method for imaging MRD to date.6Cavo M. Terpos E. Nanni C. et al.Role of (18)F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group.Lancet Oncol. 2017; 18: e206-e217Abstract Full Text Full Text PDF PubMed Scopus (286) Google ScholarMRD has been found to be a surrogate endpoint for PFS in patients receiving first-line treatment.7Avet-Loiseau H. Ludwig H. Landgren O. et al.Minimal residual disease status as a surrogate endpoint for progression-free survival in newly diagnosed multiple myeloma studies: a meta-analysis.Clin Lymphoma Myeloma Leuk. 2020; 20: e30-e37Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Therefore, MRD may be used as an endpoint to accelerate drug development. The use of MRD to drive treatment decisions is under investigation, e.g. whether maintenance/continuous therapy in MRD-negative patients can be stopped or whether treatment needs to be changed in MRD-positive patients, especially in high-risk MM. The results of several phase III trials in the field will clarify the role of MRD in making decisions about therapy in MM.Front-line therapySmouldering MMPatients with standard- or intermediate-risk smouldering MM (SMM; see Supplementary Table S4, available at https://doi.org/10.1016/j.annonc.2020.11.014) do not need immediate therapy. Myeloma treatment should be initiated according to the International Myeloma Working Group (IMWG) recommendations.8Rajkumar S.V. Dimopoulos M.A. Palumbo A. et al.International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.Lancet Oncol. 2014; 15: e538-548Abstract Full Text Full Text PDF PubMed Scopus (2424) Google Scholar Regarding high-risk SMM, which is recently defined by the ‘20-20-20’ rule (Supplementary Table S4, available at https://doi.org/10.1016/j.annonc.2020.11.014),9Rajkumar S.V. Landgren O. Mateos M.V. Smoldering multiple myeloma.Blood. 2015; 125: 3069-3075Crossref PubMed Scopus (159) Google Scholar two randomised, phase III studies have shown that lenalidomide plays a significant role in prolonging PFS. In the first study, 119 patients with high-risk SMM (before the introduction of the new criteria for the definition of myeloma)8Rajkumar S.V. Dimopoulos M.A. Palumbo A. et al.International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.Lancet Oncol. 2014; 15: e538-548Abstract Full Text Full Text PDF PubMed Scopus (2424) Google Scholar were randomly assigned either to receive treatment with the combination of lenalidomide plus dexamethasone (Rd) for 9 cycles followed by lenalidomide maintenance or to observation. At a median follow-up of 75 months, Rd improved both PFS [median PFS (mPFS) not reached versus 23 months; P < 0.0001] and OS compared with observation [hazard ratio (HR) 0.43; P = 0.024].10Mateos M.V. Hernandez M.T. Giraldo P. et al.Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma.N Engl J Med. 2013; 369: 438-447Crossref PubMed Scopus (371) Google Scholar,11Mateos M.V. Hernandez M.T. Giraldo P. et al.Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial.Lancet Oncol. 2016; 17: 1127-1136Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar However, this study was conducted several years ago and enrolled a number of patients who are considered as having MM according to the revised definition. In the second study,12Lonial S. Jacobus S. Fonseca R. et al.Randomized trial of lenalidomide versus observation in smoldering multiple myeloma.J Clin Oncol. 2020; 38: 1126-1137Crossref PubMed Scopus (98) Google Scholar 182 patients with intermediate- or high-risk SMM were randomly assigned either to receive lenalidomide monotherapy or to observation. At a median follow-up of 35 months, PFS was longer with lenalidomide (HR 0.28; P = 0.002); this result was driven mainly by the high-risk SMM group.12Lonial S. Jacobus S. Fonseca R. et al.Randomized trial of lenalidomide versus observation in smoldering multiple myeloma.J Clin Oncol. 2020; 38: 1126-1137Crossref PubMed Scopus (98) Google Scholar This study has not reported OS advantage for the lenalidomide arm to date. Several phase II studies using daratumumab (Dara) monotherapy,13Landgren C.O. Chari A. Cohen Y.C. et al.Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS).Leukemia. 2020; 34: 1840-1852Crossref PubMed Scopus (40) Google Scholar isatuximab (Isa) monotherapy or other Rd-based regimens [with elotuzumab (EloRd), or with ixazomib] have shown encouraging results.All the above data suggest that high-risk SMM patients should be encouraged to participate in randomised phase III trials to reveal the best treatment that offers OS advantage. To date, no treatment has been approved for SMM.Newly diagnosed patients who are eligible for high-dose therapy and autologous transplantationFor fit NDMM patients, aged <70 years, without comorbidities, induction followed by high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) and lenalidomide maintenance is the recommended treatment. Two recent phase III trials comparing the use or not of upfront ASCT, after triplet novel agent-based induction, showed that PFS was improved in the upfront ASCT arm.14Cavo M. Gay F. Patriarca F. et al.Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/HO95 study.Blood. 2017; 130: 401Google Scholar, 15Attal M. Lauwers-Cances V. Hulin C. et al.Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.N Engl J Med. 2017; 376: 1311-1320Crossref PubMed Scopus (668) Google Scholar, 16Cavo M. Gay F. Beksac M. et al.Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study.Lancet Haematol. 2020; 7: e456-e468Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar The first study was conducted by the French Myeloma Study Group and included 700 patients who were randomised to receive induction therapy with 3 cycles of bortezomib, lenalidomide and dexamethasone (VRd) and then consolidation therapy with either 5 additional cycles of VRd or high-dose melphalan (HDM) plus ASCT followed by 2 additional cycles of VRd. Patients in both groups received maintenance therapy with lenalidomide for 1 year. After a median follow-up of 44 months in the VRd-alone group and 43 months in the ASCT group, the mPFS was longer in the ASCT group (50 versus 36 months; P < 0.001). This benefit was observed across all patient subgroups, including advanced Revised International Staging System (R-ISS) and high-risk cytogenetics. OS at 4 years was not different between the ASCT and the non-ASCT groups.15Attal M. Lauwers-Cances V. Hulin C. et al.Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.N Engl J Med. 2017; 376: 1311-1320Crossref PubMed Scopus (668) Google ScholarThe second study was conducted by the European Myeloma Network (EMN)—EMN02/HO95 trial—and included 1503 patients who received an induction therapy with 3-4 cycles of bortezomib, cyclophosphamide and dexamethasone (VCD) followed by the first randomisation between bortezomib, melphalan and prednisone (VMP) versus ASCT. A second randomisation to consolidation therapy (2 cycles of VRd) versus no consolidation was carried out after intensification therapy, to be followed by lenalidomide maintenance until progression or toxicity in both arms. With a median follow-up from the first randomisation of 60.3 months, the mPFS was improved with ASCT compared with VMP (56.7 versus 41.9 months; P = 0.0001).16Cavo M. Gay F. Beksac M. et al.Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study.Lancet Haematol. 2020; 7: e456-e468Abstract Full Text Full Text PDF PubMed Scopus (142) Google ScholarInduction regimenA three-drug combination, including at least bortezomib and dexamethasone, has been the standard of care.2Moreau P. San Miguel J. Sonneveld P. et al.Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv52-iv61Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar,17Sonneveld P. Goldschmidt H. Rosinol L. et al.Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials.J Clin Oncol. 2013; 31: 3279-3287Crossref PubMed Scopus (203) Google Scholar Bortezomib, thalidomide, dexamethasone (VTD) induction showed better response rates over VCD at the expense of a higher rate of peripheral neuropathy.18Moreau P. Hulin C. Macro M. et al.VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial.Blood. 2016; 127: 2569-2574Crossref PubMed Scopus (187) Google Scholar VCD and bortezomib, doxorubicin and dexamethasone (PAd) were equally effective in terms of response but VCD was less toxic.19Mai E.K. Bertsch U. Durig J. et al.Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma.Leukemia. 2015; 29: 1721-1729Crossref PubMed Scopus (109) Google Scholar In single-arm studies, VRd produced high very good partial response (VGPR), CR and MRD negativity rates, as well as prolonged PFS.4Perrot A. Lauwers-Cances V. Corre J. et al.Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma.Blood. 2018; 132: 2456-2464Crossref PubMed Scopus (216) Google Scholar,15Attal M. Lauwers-Cances V. Hulin C. et al.Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.N Engl J Med. 2017; 376: 1311-1320Crossref PubMed Scopus (668) Google Scholar,20Rosinol L. Oriol A. Rios R. et al.Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma.Blood. 2019; 134: 1337-1345Crossref PubMed Scopus (106) Google Scholar, 21Voorhees P.M. Kaufman J.L. Laubach J.P. et al.Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial.Blood. 2020; 136: 936-945Crossref PubMed Scopus (235) Google Scholar, 22Joseph N.S. Kaufman J.L. Dhodapkar M.V. et al.Long-term follow-up results of lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance approach in newly diagnosed multiple myeloma.J Clin Oncol. 2020; 38: 1928-1937Crossref PubMed Scopus (75) Google Scholar However, there is no direct comparison between VTD with VRd induction before ASCT. There is only an integrated analysis of three randomised trials, presented in abstract form, which showed that VRd produces higher VGPR and MRD negativity rates compared with VTD.23Rosinol L. Hebraud B. Oriol A. et al.Integrated analysis of bortezomib- lenalidomide-dexamethasone vs bortezomib-thalidomide-dexamethasone in transplant-eligible newly diagnosed myeloma.Clin Lymphoma Myeloma Leuk. 2019; 19: E1-E2Abstract Full Text Full Text PDF PubMed Google ScholarThe introduction of monoclonal antibodies (mAbs), and especially of Dara, in the front-line setting has changed the treatment landscape in MM. In the phase III CASSIOPEIA trial, 4 cycles of induction with VTD (n = 542) were compared with 4 cycles of VTD plus Dara (DaraVTD) (n = 543); patients then received a single ASCT followed by consolidation and maintenance.24Moreau P. Attal M. Hulin C. et al.Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study.Lancet. 2019; 394: 29-38Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar PFS at 18 months showed the superiority of DaraVTD over VTD (93% versus 85%, P < 0.0001).25Moreau P. Attal M. Hulin C. et al.Phase 3 randomized study of daratumumab + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible newly diagnosed multiple myeloma: CASSIOPEIA Part 1 results.J Clin Oncol. 2019; 37: 8003Crossref Google Scholar The combination of Dara with VRd (DaraVRd) had better results. In the randomised phase II GRIFFIN study, 207 patients were randomly assigned to receive VRd ± Dara induction (4 cycles), ASCT, VRd ± Dara consolidation (2 cycles) and lenalidomide ± Dara maintenance (26 cycles). The 24-month PFS rates were 95.8% for DaraVRd and 89.8% for VRd.21Voorhees P.M. Kaufman J.L. Laubach J.P. et al.Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial.Blood. 2020; 136: 936-945Crossref PubMed Scopus (235) Google ScholarThe substitution of bortezomib with the second-generation proteasome inhibitor (PI) carfilzomib (K) resulted in high sustained MRD negativity rate in carfilzomib, lenalidomide and dexamethasone (KRd) compared with VRd, especially in patients with advanced R-ISS.26Gay F. Cerrato C. Petrucci M. et al.Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial.J Clin Oncol. 2019; 37: 8002Crossref Google Scholar There is no direct comparison between VRd and KRd in NDMM patients who are eligible for ASCT; however, in the ENDURANCE trial (see Elderly patients' section), which included <30% of patients who received an ASCT, there was no PFS difference between the two regimens.Based on the above data, VRd is likely to offer the best risk-benefit profile to date among triplet combinations [II, B]. The four-drug combination DaraVTD is more efficacious than VTD [I, A] but comparisons are lacking versus DaraVRd or VRd [these regimens have not been approved by the European Medicines Agency (EMA)]. The EMA approval of DaraVTD makes it a new standard of care for induction before ASCT. Novel studies that are ongoing compare DaraVRd versus VRd, DaraVCD versus VTD, or combinations with novel mAbs such as IsaVRd, IsaKRd or EloVRd will reveal the best induction regimen in the future.Conditioning regimen before ASCTHDM (200 mg/m2) remains the standard conditioning regimen before ASCT for NDMM patients. The addition of busulfan to melphalan has not shown OS benefit over HDM.27Blanes M. Lahuerta J.J. Gonzalez J.D. et al.Intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: a matched comparison to a melphalan-only approach.Biol Blood Marrow Transplant. 2013; 19: 69-74Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar,28Blanes M. Lorenzo J.I. Ribas P. et al.Intravenous busulfan plus melphalan versus melphalan alone as conditioning regimen for patients with multiple myeloma.Ann Hematol. 2019; 98: 2013-2015Crossref PubMed Scopus (8) Google Scholar The addition of bortezomib to HDM did not improve the efficacy of the conditioning regimen and had higher toxicity.29Roussel M. Hebraud B. Lauwers-Cances V. et al.Bortezomib and high-dose melphalan vs. high-dose melphalan as conditioning regimen before autologous stem cell transplantation in de novo multiple myeloma patients: a phase 3 study of the Intergroupe Francophone Du Myelome (IFM 2014-02).Blood. 2017; 130: 398Google ScholarConsolidation therapyThe EMN02/HO95 study showed that at a median follow-up of 42 months, consolidation therapy with 2 cycles of VRd improved mPFS compared with no consolidation (58.9 versus 45.5 months; P = 0.014).16Cavo M. Gay F. Beksac M. et al.Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study.Lancet Haematol. 2020; 7: e456-e468Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar It must be noted that induction treatment in this study included 4 cycles of VCD and not VRd or DaraVTD.The use of a second planned ASCT as consolidation has also been tested in clinical trials. In the EMN02/HO95 study, in centres with a policy of double ASCT, patients were assigned to receive VMP, single ASCT (ASCT-1) or two planned ASCTs (administered 2-3 months apart; ASCT-2) to prospectively compare ASCT-1 with ASCT-2. Patients who received ASCT-2 had a prolonged PFS compared with those who received ASCT-1: the 3-year PFS probability was 53.5% for ASCT-2 versus 44.9% for ASCT-1 group (P = 0.036), which represented a 26% reduced risk of progression or death in the ASCT-2 group. Importantly, ASCT-2 significantly improved the outcome of patients with high-risk cytogenetics (mPFS: 46 and 26.7 months for ASCT-2 and ASCT-1, respectively; HR 0.59; P = 0.062).14Cavo M. Gay F. Patriarca F. et al.Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/HO95 study.Blood. 2017; 130: 401Google Scholar In the same study, OS from the first randomisation was significantly prolonged with ASCT-2 compared with ASCT-1 (3-year rate: 89% versus 82%; HR 0.52; P = 0.011); this benefit was also reported in patients with R-ISS II + III (HR 0.48; P = 0.013) and with high-risk cytogenetics (HR 0.52; P = 0.042).14Cavo M. Gay F. Patriarca F. et al.Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/HO95 study.Blood. 2017; 130: 401Google ScholarThe phase III StaMINA study randomised 758 patients who received induction therapy for up to 12 cycles, followed by one ASCT versus tandem ASCT versus ASCT-1 followed by 4 subsequent cycles of VRd; all treatment groups received lenalidomide maintenance until disease progression.30Stadtmauer E.A. Pasquini M.C. Blackwell B. et al.Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 trial.J Clin Oncol. 2019; 37: 589-597Crossref PubMed Scopus (128) Google Scholar The 6-year PFS in high-risk patients was 43.6% and 26% for tandem ASCT and ASCT-1, respectively (P = 0.03).31Hari P. Pasquini M. Stadtmauer E. et al.Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM).J Clin Oncol. 2020; 38: 8506Crossref Google ScholarFinally, a study which compared tandem ASCTs with ASCT-1 followed by allogeneic SCT (allo-SCT) has recently reported the 10-year median follow-up results. In both standard-risk (n = 625) and high-risk patients (n = 85), there was no PFS or OS difference.32Giralt S. Costa L.J. Maloney D. et al.Tandem autologous-autologous versus autologous-allogeneic hematopoietic stem cell transplant for patients with multiple myeloma: long-term follow-up results from the Blood and Marrow Transplant Clinical Trials Network 0102 Trial.Biol Blood Marrow Transplant. 2020; 26: 798-804Abstract Full Text Full Text PDF PubMed Scopus (21) Google ScholarMaintenance therapyTreatment with lenalidomide maintenance after ASCT offers PFS and OS benefits over placebo as reported in two large randomised trials.33Attal M. Lauwers-Cances V. Marit G. et al.Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.N Engl J Med. 2012; 366: 1782-1791Crossref PubMed Scopus (888) Google Scholar,34McCarthy P.L. Owzar K. Hofmeister C.C. et al.Lenalidomide after stem-cell transplantation for multiple myeloma.N Engl J Med. 2012; 366: 1770-1781Crossref PubMed Scopus (898) Google Scholar A meta-analysis including more than 1200 patients, with a median follow-up of

Renal impairment is a common complication of multiple myeloma (MM). The estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula is the recommended method for the assessment of renal function in patients with MM with stabilized serum creatinine. In acute renal injury, the RIFLE (risk, injury, failure, loss and end-stage kidney disease) and Acute Renal Injury Network criteria seem to be appropriate to define the severity of renal impairment. Novel criteria based on eGFR measurements are recommended for the definition of the reversibility of renal impairment. Rapid intervention to reverse renal dysfunction is critical for the management of these patients, especially for those with light chain cast nephropathy. Bortezomib with high-dose dexamethasone is considered as the treatment of choice for such patients. There is limited experience with thalidomide in patients with myeloma with renal impairment. Thus, thalidomide can be carefully administered, mainly in the context of well-designed clinical trials, to evaluate if it can improve the rapidity and probability of response that is produced by the combination with bortezomib and high-dose dexamethasone. Lenalidomide is effective in this setting and can reverse renal insufficiency in a significant subset of patients, when it is given at reduced doses, according to renal function. The role of plasma exchange in patients with suspected light chain cast nephropathy and renal impairment is controversial. High-dose melphalan (140 mg/m(2)) and autologous stem-cell transplantation should be limited to younger patients with chemosensitive disease.

Abstract In a recent phase 3 trial, bortezomib-melphalan-prednisone-thalidomide followed by maintenance treatment with bortezomib-thalidomide demonstrated superior efficacy compared with bortezomib-melphalan-prednisone. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions: 372 patients received once-weekly and 139 twice-weekly bortezomib. In this post-hoc analysis we assessed the impact of the schedule change on clinical outcomes and safety. Long-term outcomes appeared similar: 3-year progression-free survival rate was 50% in the once-weekly and 47% in the twice-weekly group (P &gt; .999), and 3-year overall survival rate was 88% and 89%, respectively (P = .54). The complete response rate was 30% in the once-weekly and 35% in the twice-weekly group (P = .27). Nonhematologic grade 3/4 adverse events were reported in 35% of once-weekly patients and 51% of twice-weekly patients (P = .003). The incidence of grade 3/4 peripheral neuropathy was 8% in the once-weekly and 28% in the twice-weekly group (P &lt; .001); 5% of patients in the once-weekly and 15% in the twice-weekly group discontinued therapy because of peripheral neuropathy (P &lt; .001). This improvement in safety did not appear to affect efficacy. This study is registered at http://www.clinicaltrials.gov as NCT01063179.

The aim of the present study was to compare thalidomide-dexamethasone (Thal-Dex) and vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous peripheral blood stem-cell (PBSC) transplantation for multiple myeloma (MM). For this purpose, we performed a retrospective matched case-control analysis of 200 patients who entered 2 consecutive studies from 1996 to 2004 and received Thal-Dex (n = 100) or VAD (n = 100) administered for 4 months before collection of PBSCs and autologous transplantation. Matching criteria included age, clinical stage, and serum β2-microglobulin levels. In comparison with VAD, Thal-Dex resulted in a significantly higher response rate (52% versus 76%, respectively; P &amp;lt; .001) and effected more profound reduction in myeloma cell mass of both immunoglobulin G (IgG; P = .02) and IgA (P = .03) type. More frequent toxicities included nonfatal deep vein thrombosis with Thal-Dex (15%) and granulocytopenia with VAD (12%). In each of the 2 treatment groups, 91% of patients proceeded to PBSC mobilization. The median number of collected CD34+ cells was 7.85 × 106/kg in the Thal-Dex group and 10.5 × 106/kg in the control group. Thal-Dex may be considered an effective and relatively well-tolerated oral alternative to the more complex VAD regimen as front-line therapy for MM patients who are candidates for subsequent autologous transplantation.

A retrospective case-matched analysis was performed comparing 189 myeloma patients treated with allogeneic bone marrow transplantation (allo-BMT) with an equal number of patients who received autologous stem cell transplantation (ASCT). Matching was performed with respect to gender and number of treatment lines before transplantation. The groups were comparable with the exception of median age (43 years for allo-BMT v 49 years for ASCT, P = .0001) and median posttransplant follow-up (46 months for allo-BMT v 30 months for ASCT, P = .0003). The overall survival was significantly better for ASCT than for allo-BMT, with a median survival of 34 months and 18 months, respectively (P = .001). However, this survival advantage was only observed in men, but not in women. The statistically significant survival advantage for ASCT was seen in most subgroups, ie, chemotherapy-responsive patients, patients who had received two or more treatment lines before transplantation, patients in partial remission, patients with an IgG-subtype, patients older than 46 years of age, patients with stage II disease, and patients with a low or high serum-beta-2-microglobulin at diagnosis. The main reason for the poorer survival in allo-BMT patients was higher transplant-related mortality (41% v 13% for ASCT, P = .0001), which was not compensated for by a lower rate of relapse and progression. However, in patients alive at 1 year posttransplant, there was a trend for better long-term survival (P = .09) and significantly better progression-free survival (P = .02) for allo-BMT as compared with ASCT. We conclude that the median survival is superior for ASCT. However, allo-BMT has a lower relapse rate, which results in a similar long-term outcome for both approaches, but a longer follow-up is needed to assess the final outcome.

We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM).A total of 321 patients were enrolled onto the study and were randomly assigned to receive either a single course of high-dose melphalan at 200 mg/m2 (arm A) or melphalan at 200 mg/m2 followed, after 3 to 6 months, by melphalan at 120 mg/m2 and busulfan at 12 mg/kilogram (arm B).As compared with assignment to the single-transplantation group (n = 163 patients), random assignment to receive double ASCT (n = 158 patients) significantly increased the probability to attain at least a near complete response (nCR; 33% v 47%, respectively; P = .008), prolonged relapse-free survival (RFS) duration of 18 months (median, 24 v 42 months, respectively; P < .001), and significantly extended event-free survival (EFS; median, 23 v 35 months, respectively; P = .001). Administration of a second transplantation and of novel agents for treating sequential relapses in up to 50% of patients randomly assigned to receive a single ASCT likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplantation group (43%; P = .90). Transplantation-related mortality was 3% in arm A and 4% in arm B (P = .70).In comparison with a single ASCT as up-front therapy for newly diagnosed MM, double ASCT effected superior CR or nCR rate, RFS, and EFS, but failed to significantly prolong overall survival. Benefits offered by double ASCT were particularly evident among patients who failed at least nCR after one autotransplantation.

Abstract The initial analysis of the oral combination melphalan, prednisone, and thalidomide (MPT) in newly diagnosed patients with myeloma showed significantly higher response rate and longer progression-free survival (PFS) than did the standard melphalan and prednisone (MP) combination and suggested a survival advantage. In this updated analysis, efficacy and safety end points were updated. Patients were randomly assigned to receive oral MPT or MP alone. Updated analysis was by intention to treat and included PFS, overall survival (OS), and survival after progression. After a median follow-up of 38.1 months, the median PFS was 21.8 months for MPT and 14.5 months for MP (P = .004). The median OS was 45.0 months for MPT and 47.6 months for MP (P = .79). In different patient subgroups, MPT improved PFS irrespective of age, serum concentrations of β2-microglobulin, or high International Staging System. Thalidomide or bortezomib administration as salvage regimens significantly improved survival after progression in the MP group (P = .002) but not in the MPT group (P = .34). These data confirm activity of MPT for PFS but failed to show any survival advantage. New agents in the management of relapsed disease could explain this finding. The study is registered at www.clinicaltrials.gov as #NCT00232934.

Purpose The aim of International Myeloma Working Group was to develop practical recommendations for the use of magnetic resonance imaging (MRI) in multiple myeloma (MM). Methods An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations for the value of MRI based on data published through March 2014. Recommendations MRI has high sensitivity for the early detection of marrow infiltration by myeloma cells compared with other radiographic methods. Thus, MRI detects bone involvement in patients with myeloma much earlier than the myeloma-related bone destruction, with no radiation exposure. It is the gold standard for the imaging of axial skeleton, for the evaluation of painful lesions, and for distinguishing benign versus malignant osteoporotic vertebral fractures. MRI has the ability to detect spinal cord or nerve compression and presence of soft tissue masses, and it is recommended for the workup of solitary bone plasmacytoma. Regarding smoldering or asymptomatic myeloma, all patients should undergo whole-body MRI (WB-MRI; or spine and pelvic MRI if WB-MRI is not available), and if they have &gt; one focal lesion of a diameter &gt; 5 mm, they should be considered to have symptomatic disease that requires therapy. In cases of equivocal small lesions, a second MRI should be performed after 3 to 6 months, and if there is progression on MRI, the patient should be treated as having symptomatic myeloma. MRI at diagnosis of symptomatic patients and after treatment (mainly after autologous stem-cell transplantation) provides prognostic information; however, to date, this does not change treatment selection.

To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation.A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized.Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care.These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice.

The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) -related bone disease.An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members.Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.

Bone lesions in multiple myeloma (MM) have been traditionally detected by whole body X-ray (WBXR) survey although magnetic resonance imaging (MRI) has become the gold standard for detecting MM involvement of the spine and pelvis. The aim of this study was to compare a new technique, positron emission tomography (PET) with 18F fluorodeoxyglucose (FDG) integrated with computed tomography (18F-FDG PET-CT), with MRI and WBXR for baseline assessment of bone disease in MM.We prospectively compared 18F-FDG PET-CT, MRI of the spine-pelvis and WBXR in a series of 46 patients with newly diagnosed MM. In 23 patients who received up front autologous transplantation, we also compared post-treatment PET-CT scans with MR images of the spine and pelvis.Overall, PET-CT was superior to planar radiographs in 46% of patients, including 19% with negative WBXR. In 30% of patients, PET-CT scans of the spine and pelvis failed to show abnormal findings in areas in which MRI revealed an abnormal pattern of bone marrow involvement, more frequently of diffuse type. In contrast, in 35% of patients PET-CT enabled the detection of myelomatous lesions in areas which were out of the field of view of MRI. By combining MRI of the spine- pelvis and 18F-FDG PET-CT, the ability to detect sites of active MM, both medullary and extramedullary, was as high as 92%. Following transplantation, 15 patients had negative PET-CT scans (including 13 with a very good partial response or at least a near complete response), but only 8 had normal MRI.MRI of the spine and pelvis still remains the gold standard imaging technique for the detection of bone marrow involvement in MM. 18F-FDG PET-CT provides additional and valuable information for the assessment of myeloma bone disease in areas not covered by MRI.

The aim of the International Myeloma Working Group was to develop practical recommendations for the diagnosis and management of multiple myeloma-related renal impairment (RI).Recommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group.All patients with myeloma at diagnosis and at disease assessment should have serum creatinine, estimated glomerular filtration rate, and electrolytes measurements as well as free light chain, if available, and urine electrophoresis of a sample from a 24-hour urine collection (grade A). The Chronic Kidney Disease Epidemiology Collaboration, preferably, or the Modification of Diet in Renal Disease formula should be used for the evaluation of estimated glomerular filtration rate in patients with stabilized serum creatinine (grade A). International Myeloma Working Group criteria for renal reversibility should be used (grade B). For the management of RI in patients with multiple myeloma, high fluid intake is indicated along with antimyeloma therapy (grade B). The use of high-cutoff hemodialysis membranes in combination with antimyeloma therapy can be considered (grade B). Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B). Thalidomide is effective in patients with myeloma with RI, and no dose modifications are needed (grade B). Lenalidomide is effective and safe, mainly in patients with mild to moderate RI (grade B); for patients with severe RI or on dialysis, lenalidomide should be given with close monitoring for hematologic toxicity (grade B) with dose reduction as needed. High-dose therapy with autologous stem cell transplantation (with melphalan 100 mg/m(2) to 140 mg/m(2)) is feasible in patients with RI (grade C). Carfilzomib can be safely administered to patients with creatinine clearance > 15 mL/min, whereas ixazomib in combination with lenalidomide and dexamethasone can be safely administered to patients with creatinine clearance > 30 mL/min (grade A).

Background Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. Methods ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. Findings 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4–43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46–0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2–82·0) in the D-VMP group and 67·9% (62·6–72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34–0·51]; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [15%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28 [10%]). Interpretation D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns. Funding Janssen Research & Development.

Abstract Most patients with newly diagnosed multiple myeloma (MM) are aged &gt; 65 years with 30% aged &gt; 75 years. Many elderly patients are also vulnerable because of comorbidities that complicate the management of MM. The prevalence of MM is expected to rise over time because of an aging population. Most elderly patients with MM are ineligible for autologous transplantation, and the standard treatment has, until recently, been melphalan plus prednisone. The introduction of novel agents, such as thalidomide, bortezomib, and lenalidomide, has improved outcomes; however, elderly patients with MM are more susceptible to side effects and are often unable to tolerate full drug doses. For these patients, lower-dose-intensity regimens improve the safety profile and thus optimize treatment outcome. Further research into the best treatment strategies for vulnerable elderly patients is urgently needed. Appropriate screening for vulnerability and an assessment of cardiac, pulmonary, renal, hepatic, and neurologic functions, as well as age &gt; 75 years, at the start of therapy allows treatment strategies to be individualized and drug doses to be tailored to improve tolerability and optimize efficacy. Similarly, occurrence of serious nonhematologic adverse events during treatment should be carefully taken into account to adjust doses and optimize outcomes.

In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens.A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment.Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, -3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, -1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded.In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH.

Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥ 20%) and absolute number (≥ 2 × 10(9)/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.

Recent advances in the treatment of multiple myeloma have increased the need for accurate diagnosis of the disease. The detection of bone and bone marrow lesions is crucial in the investigation of multiple myeloma and often dictates the decision to start treatment. Furthermore, detection of minimal residual disease is important for prognosis determination and treatment planning, and it has underscored an unmet need for sensitive imaging methods that accurately assess patient response to multiple myeloma treatment. Low-dose whole-body CT has increased sensitivity compared with conventional skeletal survey in the detection of bone disease, which can reveal information leading to changes in therapy and disease management that could prevent or delay the onset of clinically significant morbidity and mortality as a result of skeletal-related events. Given the multiple options available for the detection of bone and bone marrow lesions, ranging from conventional skeletal survey to whole-body CT, PET/CT, and MRI, the International Myeloma Working Group decided to establish guidelines on optimal use of imaging methods at different disease stages. These recommendations on imaging within and outside of clinical trials will help standardise imaging for monoclonal plasma cell disorders worldwide to allow the comparison of results and the unification of treatment approaches for multiple myeloma.

The European Myeloma Network provides recommendations for the management of the most common complications of multiple myeloma. Whole body low-dose computed tomography is more sensitive than conventional radiography in depicting osteolytic disease and thus we recommend it as the novel standard for the detection of lytic lesions in myeloma (grade 1A). Myeloma patients with adequate renal function and bone disease at diagnosis should be treated with zoledronic acid or pamidronate (grade 1A). Symptomatic patients without lytic lesions on conventional radiography can be treated with zoledronic acid (grade 1B), but its advantage is not clear for patients with no bone involvement on computed tomography or magnetic resonance imaging. In asymptomatic myeloma, bisphosphonates are not recommended (grade 1A). Zoledronic acid should be given continuously, but it is not clear if patients who achieve at least a very good partial response benefit from its continuous use (grade 1B). Treatment with erythropoietic-stimulating agents may be initiated in patients with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other causes of anemia have been excluded (grade 1B). Erythropoietic agents should be stopped after 6-8 weeks if no adequate hemoglobin response is achieved. For renal impairment, bortezomib-based regimens are the current standard of care (grade 1A). For the management of treatment-induced peripheral neuropathy, drug modification is needed (grade 1C). Vaccination against influenza is recommended; vaccination against streptococcus pneumonia and hemophilus influenza is appropriate, but efficacy is not guaranteed due to suboptimal immune response (grade 1C). Prophylactic aciclovir (or valacyclovir) is recommended for patients receiving proteasome inhibitors, autologous or allogeneic transplantation (grade 1A).

A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4;14) and del17p, and detection by fluorescence in situ hybridization of t(4;14), t(14;16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serum β(2)-microglobulin level and International Staging System stages II and III, incorporating high β(2)-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations.

Abstract In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.

Abstract The role of high-dose therapy followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional chemotherapy to newer regimens incorporating the immunomodulatory derivatives thalidomide or lenalidomide and the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various doublet, triplet, and quadruplet regimens. Up-front use of these induction treatments, in particular 3-drug combinations, has affected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the depth of response, a gain that translates into extended progression-free survival and, potentially, overall survival. High activity shown by immunomodulatory derivatives and bortezomib before ASCT has recently led to their use as consolidation and maintenance therapies after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This article reviews the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current management of younger, transplantation-eligible MM patients.

As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide.We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β2 microglobulin at screening. Bortezomib (1·3 mg/m2) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled.Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9-21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66-13·73] vs 7·10 months [5·88-8·48]; hazard ratio 0·61, 95% CI 0·49-0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had febrile neutropenia), infections (86 [31%] vs 48 [18%]), and thrombocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]).Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide.Celgene.

The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib-melphalan-prednisone (VMP) as intensification therapy, and bortezomib-lenalidomide-dexamethasone (VRD) consolidation therapy with no consolidation.In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18-65 years, had symptomatic multiple myeloma stage 1-3 according to the International Staging System (ISS), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0-2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1·3 mg/m2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m2 administered orally on days 1-4) and prednisone (60 mg/m2 administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m2), stratified by site and ISS disease stage. In centres with a double HSCT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1·3 mg/m2 either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1-21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment.Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60·3 months (IQR 52·2-67·6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56·7 months [95% CI 49·3-64·5] vs 41·9 months [37·5-46·9]; hazard ratio [HR] 0·73, 0·62-0·85; p=0·0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42·1 months (IQR 32·3-49·2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58·9 months [54·0-not estimable] vs 45·5 months [39·5-58·4]; HR 0·77, 0·63-0·95; p=0·014). The most common grade ≥3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%]).This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone.Janssen and Celgene.

Abstract Lenalidomide plus dexamethasone is effective in the treatment of multiple myeloma (MM) but is associated with an increased risk of venous thromboembolism (VTE). This prospective, open-label, randomized substudy of a phase 3 trial compared the efficacy and safety of thromboprophylaxis with low-dose aspirin (ASA) or low-molecular-weight heparin (LMWH) in patients with newly diagnosed MM, treated with lenalidomide and low-dose dexamethasone induction and melphalan-prednisone-lenalidomide consolidation. Overall, 342 patients who did not have clinical indications or contraindications to antiplatelet or anticoagulant therapy were randomly assigned to receive ASA 100 mg/d (n = 176) or LMWH enoxaparin 40 mg/d (n = 166). The incidence of VTE was 2.27% in the ASA group and 1.20% in the LMWH group. Compared with LMWH, the absolute difference in the proportion of VTE was 1.07% (95% confidence interval, −1.69-3.83; P = .452) in the ASA group. Pulmonary embolism was observed in 1.70% of patients in the ASA group and none in the LMWH group. No arterial thrombosis, acute cardiovascular events, or sudden deaths were reported. No major hemorrhagic complications were reported. In previously untreated patients with MM receiving lenalidomide with a low thromboembolic risk, ASA could be an effective and less-expensive alternative to LMWH thromboprophylaxis. This study was registered at www.clinicaltrials.gov as #NCT00551928.

<h2>Summary</h2><h3>Background</h3> Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. <h3>Methods</h3> In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from 90 hospitals in 16 countries. Eligible patients were randomly assigned (2:1) centrally using an interactive response technology system and a block size of three to receive venetoclax (800 mg per day orally) or placebo with bortezomib (1·3 mg/m² subcutaneously or intravenously and dexamethasone (20 mg orally). Treatment was given in 21-day cycles for the first eight cycles and 35-day cycles from the ninth cycle until disease progression, unacceptable toxicity, or patient withdrawal. Randomisation was stratified by previous exposure to a proteasome inhibitor and the number of previous therapies. Sponsors, investigators, study site personnel, and patients were masked to the treatment allocation throughout the study. The primary endpoint was independent review committee-assessed progression-free survival in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02755597. <h3>Findings</h3> Between July 19, 2016, and Oct 31, 2017, 291 patients were randomly assigned to receive venetoclax (n=194) or placebo (n=97). With a median follow-up of 18·7 months (IQR 16·6–21·0), median progression-free survival according to independent review committee was 22·4 months (95% CI 15·3–not estimable) with venetoclax versus 11·5 months (9·6–15·0) with placebo (hazard ratio [HR] 0·63 [95% CI 0·44–0·90]; p=0·010). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (35 [18%] of 193 patients in the venetoclax group <i>vs</i> seven [7%] of 96 patients in the placebo group), pneumonia (30 [16%] <i>vs</i> nine [9%]), thrombocytopenia (28 [15%] <i>vs</i> 29 [30%]), anaemia (28 [15%] <i>vs</i> 14 [15%]), and diarrhoea (28 [15%] <i>vs</i> 11 [11%]). Serious treatment-emergent adverse events occurred in 93 (48%) patients in the venetoclax group and 48 (50%) patients in the placebo group, with eight (4%) treatment-emergent fatal infections reported in the venetoclax group and none reported in the placebo group. Three deaths in the venetoclax group (two from pneumonia and one from septic shock) were considered treatment-related; no deaths in the placebo group were treatment-related. <h3>Interpretation</h3> The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option. <h3>Funding</h3> AbbVie and Genentech.

Lenalidomide has been linked to second primary malignancies in myeloma. We aimed to pool and analyse available data to compare the incidence of second primary malignancies in patients with and without lenalidomide exposure.We identified relevant studies through a search of PubMed and abstracts from the American Society of Clinical Oncology, American Society of Hematology, and the International Myeloma Workshop. Randomised, controlled, phase 3 trials that recruited patients with newly diagnosed multiple myeloma between Jan 1, 2000, and Dec 15, 2012, and in which at least one group received lenalidomide were eligible for inclusion. We obtained individual patient data (age, sex, date of diagnosis, allocated treatment and received treatment, duration of treatment and cause of discontinuation, maintenance treatment, date of first relapse, date of second primary malignancy diagnosis, type of second primary malignancy, date of death or last contact, and cause of death) by direct collaboration with the principal investigators of eligible trials. Primary outcomes of interest were cumulative incidence of all second primary malignancies, solid second primary malignancies, and haematological second primary malignancies, and were analysed by a one-step meta-analysis.We found nine eligible trials, of which seven had available data for 3254 patients. 3218 of these patients received treatment (2620 had received lenalidomide and 598 had not), and were included in our analyses. Cumulative incidences of all second primary malignancies at 5 years were 6·9% (95% CI 5·3-8·5) in patients who received lenalidomide and 4·8% (2·0-7·6) in those who did not (hazard ratio [HR] 1·55 [95% CI 1·03-2·34]; p=0·037). Cumulative 5-year incidences of solid second primary malignancies were 3·8% (95% CI 2·7-4·9) in patients who received lenalidomide and 3·4% (1·6-5·2) in those that did not (HR 1·1 [95% CI 0·62-2·00]; p=0·72), and of haematological second primary malignancies were 3·1% (95% CI 1·9-4·3) and 1·4% (0·0-3·6), respectively (HR 3·8 [95% CI 1·15-12·62]; p=0·029). Exposure to lenalidomide plus oral melphalan significantly increased haematological second primary malignancy risk versus melphalan alone (HR 4·86 [95% CI 2·79-8·46]; p<0·0001). Exposure to lenalidomide plus cyclophosphamide (HR 1·26 [95% CI 0·30-5·38]; p=0·75) or lenalidomide plus dexamethasone (HR 0·86 [95% CI 0·33-2·24]; p=0·76) did not increase haematological second primary malignancy risk versus melphalan alone.Patients with newly diagnosed myeloma who received lenalidomide had an increased risk of developing haematological second primary malignancies, driven mainly by treatment strategies that included a combination of lenalidomide and oral melphalan. These results suggest that alternatives, such as cyclophosphamide or alkylating-free combinations, should be considered instead of oral melphalan in combination with lenalidomide for myeloma.Celgene Corporation.

Summary With increasing number of therapies available for the treatment of multiple myeloma, it is timely to examine the course of patients' journeys. We investigated patient characteristics, treatment durations and outcomes, and symptom burden across the treatment pathway in Belgium, France, Germany, Italy, Spain, Switzerland and the UK . In total, 435 physicians retrospectively reviewed 4997 patient charts. Profiles of patients diagnosed with multiple myeloma during the last 12 months were similar across countries; bone pain was the most common presentation. Median duration of first‐line therapy was 6 months, followed by a median treatment‐free interval of 10 months; both these decreased with increasing lines of therapy, as did time to progression. Depth of response, as assessed by the treating physician, also decreased with each additional line of therapy: 74% of patients achieved at least a very good partial response at first line, compared with only 11% at fifth line. Deeper responses were associated with longer time to progression, although these were physician‐judged. Toxicities and co‐morbidities increased with later treatment lines, and were more likely to have led to discontinuation of treatment. These real‐world data provide an insight into patient outcomes and treatment decisions being made in clinical practice.

Purpose To characterize efficacy and safety of bortezomib-based versus nonbortezomib-based induction regimens through an integrated analysis of data from phase III studies in transplantation-eligible patients with previously untreated myeloma. Patients and Methods Patient-level data from the IFM 2005-01 (bortezomib-dexamethasone v vincristine-doxorubicin-dexamethasone [VAD] induction), HOVON-65/GMMG-HD4 (bortezomib-doxorubicin-dexamethasone v VAD), and PETHEMA GEM05MENOS65 (bortezomib-thalidomide-dexamethasone v thalidomide-dexamethasone) studies were pooled in an integrated analysis of efficacy and safety. Study-level data from the GIMEMA MM-BO2005 study (bortezomib-thalidomide-dexamethasone v thalidomide-dexamethasone) supplemented the integrated patient-level analysis. Key efficacy end points were post-transplantation complete plus near-complete response (CR+nCR) rate and progression-free survival (PFS). Results Patient-level data for 1,572 patients (bortezomib-based induction, n = 787; nonbortezomib-based induction, n = 785) were included. Post-transplantation CR+nCR rate was significantly higher following bortezomib-based versus nonbortezomib-based induction (38% v 24%; odds ratio, 2.05; P &lt; .001); the benefit remained similar (pooled odds ratio, 1.96) when GIMEMA MM-BO2005 data were included. Median PFS was 35.9 months versus 28.6 months with bortezomib-based versus nonbortezomib-based induction, respectively (hazard ratio, 0.75; P &lt; .001); 3-year overall survival (OS) rates were 79.7% and 74.7%, respectively (hazard ratio for OS, 0.81; P = .0402). Median duration of induction treatment was 11 weeks in both treatment groups. Rates of peripheral neuropathy during induction were 34% versus 17% (grade ≥ 3, 6% v 1%). Overall, 3% and 4% of patients died during bortezomib-based and nonbortezomib-based induction, respectively. Conclusion Bortezomib-based induction results in significant improvements in response and PFS/OS compared with nonbortezomib-based induction and is generally well tolerated, with a higher rate of peripheral neuropathy but no apparent increase in risk of death during induction.

Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow up is presented. After 19.4 (range: 0-27.7) months of median follow up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P<0.0001) and improved the overall response rate (83.8% versus 63.2%; P<0.0001) compared with bortezomib and dexamethasone alone. The progression-free survival benefit of daratumumab plus bortezomib and dexamethasone was most apparent in patients with 1 prior line of therapy (median: not reached versus 7.9 months; hazard ratio, 0.19; 95% con fidence interval, 0.12-0.29; P<0.0001). Daratumumab plus bortezomib and dexamethasone was also superior to bortezomib and dexamethasone alone in subgroups based on prior treatment exposure (bortezomib, thalidomide, or lenalidomide), lenalidomide-refractory status, time since last therapy (≤12, >12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease-negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse. Trial registration: clinicaltrials.gov identifier: 02136134.

Key Points Rd continuous significantly extended OS compared with MPT and resulted in comparable OS to that with Rd18 in patients with multiple myeloma. Patients achieving complete or very good partial response with Rd benefited greatly from continuous vs fixed treatment in terms of PFS.

Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.

Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma.This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m2 once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m2 twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020.Of 457 patients screened for eligibility, 402 were randomly allocated-195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group-and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2-19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4-19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73-not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11-10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53-0·93], p=0·0075). The most frequent grade 3-4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32-0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died.A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy.Karyopharm Therapeutics.

Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma.We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance).In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients.Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).

Background In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma. Methods In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0–2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1–21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736. Findings Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60–72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4–20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3–19·3] vs 6·9 months [5·5–9·3]; hazard ratio 0·63 [95% CI 0·47–0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group. Interpretation Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting. Funding European Myeloma Network and Janssen Research and Development.

Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA).KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual.Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5-10·9). Median progression-free survival was 5·6 months (95% CI 3·7-7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05-2·22; p=0·98). Median overall survival was not reached (95% CI 12·9-not reached) versus 15·2 months (12·7-not reached; HR 1·61; 95% CI 0·91-2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group.The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma.Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).

<h2>Summary</h2><h3>Background</h3> Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit–risk of the combination at the request of the US Food and Drug Administration (FDA). <h3>Methods</h3> KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1–21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual. <h3>Findings</h3> Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6·6 months (IQR 3·4–9·6), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82·0% (95% CI 73·2–88·1) versus 85·0% (76·8–90·5; hazard ratio [HR] 1·22; 95% CI 0·67–2·22; p=0·75). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure). <h3>Interpretation</h3> The results from this unplanned, FDA-requested, interim analysis showed that the benefit–risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing. <h3>Funding</h3> Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).

Intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and infusion-related reactions are common. Subcutaneous daratumumab is thought to be easier to administer and to cause fewer administration-related reactions. In this study (COLUMBA), we tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab.In this ongoing, multicentre (147 sites in 18 countries), open-label, non-inferiority, randomised, phase 3 trial, we recruited adult patients (age ≥18 years) if they had confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria; received at least three previous lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or were double refractory to both a proteasome inhibitor and immunomodulatory drug; and had an Eastern Cooperative Oncology Group performance status score of 2 or lower. Patients were randomly assigned (1:1) by a computer-generated randomisation schedule and balanced using randomly permuted blocks to receive daratumumab subcutaneously (subcutaneous group) or intravenously (intravenous group). Randomisation was stratified on the basis of baseline bodyweight (≤65 kg, 66-85 kg, >85 kg), previous therapy lines (≤four vs >four), and myeloma type (IgG vs non-IgG). Patients received 1800 mg of subcutaneous daratumumab co-formulated with 2000 U/mL recombinant human hyaluronidase PH20 or 16 mg/kg of intravenous daratumumab once weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks thereafter (28-day cycles) until progressive disease or toxicity. The co-primary endpoints were overall response and maximum trough concentration (Ctrough; cycle 3, day 1 pre-dose). The non-inferiority margin for overall response was defined using a 60% retention of the lower bound (20·8%) of the 95% CI of the SIRIUS trial. Efficacy analyses were done by intention-to-treat population. The pharmacokinetic-evaluable population included all patients who received all eight weekly daratumumab doses in cycles 1 and 2 and provided a pre-dose pharmacokinetics blood sample on day 1 of cycle 3. The safety population included all patients who received at least one daratumumab dose. This trial is registered with ClinicalTrials.gov, NCT03277105.Between Oct 31, 2017, and Dec 27, 2018, 655 patients were screened, of whom 522 were recruited and randomly assigned (subcutaneous group n=263; intravenous group n=259). Three patients in the subcutaneous group and one in the intravenous group did not receive treatment and were not evaluable for safety. At a median follow-up of 7·5 months (IQR 6·5-9·3), overall response and Ctrough met the predefined non-inferiority criteria. An overall response was seen in 108 (41%) of 263 patients in the subcutaneous group and 96 (37%) of 259 in the intravenous group (relative risk 1·11, 95% CI 0·89-1·37). The geometric means ratio for Ctrough was 107·93% (90% CI 95·74-121·67), and the maximum Ctrough was 593 μg/mL (SD 306) in the subcutaneous group and 522 μg/mL (226) in the intravenous group. The most common grade 3 and 4 adverse events were anaemia (34 [13%] of 260 patients evaluable for safety in the subcutaneous group and 36 [14%] of 258 patients in the intravenous group), neutropenia (34 [13%] and 20 [8%]), and thrombocytopenia (36 [14%] and 35 [14%]). Pneumonia was the only serious adverse event in more than 2% of patients (seven [3%] in the subcutaneous group and 11 [4%] in the intravenous group). There was one death resulting from a treatment-related adverse event in the subcutaneous daratumumab group (febrile neutropenia) and four in the intravenous group (sepsis [n=2], hepatitis B reactivation [n=1], and Pneumocystis jirovecii pneumonia [n=1]).Subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma. These data could contribute to the approval of the subcutaneous daratumumab formulation by regulatory bodies.Janssen Research & Development.

This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.

Survival is poor among patients with triple-class–exposed relapsed and refractory multiple myeloma. Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapy, previously led to deep, durable responses in patients with heavily pretreated relapsed and refractory multiple myeloma. Download a PDF of the Research Summary. In this international, open-label, phase 3 trial involving adults with relapsed and refractory multiple myeloma who had received two to four regimens previously (including immunomodulatory agents, proteasome inhibitors, and daratumumab) and who had disease refractory to the last regimen, we randomly assigned patients in a 2:1 ratio to receive either ide-cel (dose range, 150×106 to 450×106 CAR-positive T cells) or one of five standard regimens. The primary end point was progression-free survival. Key secondary end points were overall response (partial response or better) and overall survival. Safety was assessed. A total of 386 patients underwent randomization: 254 to ide-cel and 132 to a standard regimen. A total of 66% of the patients had triple-class–refractory disease, and 95% had daratumumab-refractory disease. At a median follow-up of 18.6 months, the median progression-free survival was 13.3 months in the ide-cel group, as compared with 4.4 months in the standard-regimen group (hazard ratio for disease progression or death, 0.49; 95% confidence interval, 0.38 to 0.65; P<0.001). A response occurred in 71% of the patients in the ide-cel group and in 42% of those in the standard-regimen group (P<0.001); a complete response occurred in 39% and 5%, respectively. Data on overall survival were immature. Adverse events of grade 3 or 4 occurred in 93% of the patients in the ide-cel group and in 75% of those in the standard-regimen group. Among the 225 patients who received ide-cel, cytokine release syndrome occurred in 88%, with 5% having an event of grade 3 or higher, and investigator-identified neurotoxic effects occurred in 15%, with 3% having an event of grade 3 or higher. Ide-cel therapy significantly prolonged progression-free survival and improved response as compared with standard regimens in patients with triple-class–exposed relapsed and refractory multiple myeloma who had received two to four regimens previously. The toxicity of ide-cel was consistent with previous reports. (Funded by 2seventy bio and Celgene, a Bristol-Myers Squibb company; KarMMa-3 ClinicalTrials.gov number, NCT03651128.) QUICK TAKE VIDEO SUMMARYIde-cel in Relapsed and Refractory Multiple Myeloma 02:00

Key Points STRATUS (MM-010), the largest POM + LoDEX trial, confirms the regimen offers clinically meaningful benefit and is generally well tolerated. STRATUS supports POM + LoDEX as a standard of care for patients with RRMM who have poor prognosis and high need for effective treatments.

Deregulated activity of BCR-ABL1, a nonreceptor tyrosine kinase encoded by the fusion gene resulting from the t(9;22)(q34;q11) chromosomal translocation, is thought to be the driver event responsible for initiation and maintenance of chronic myeloid leukemia (CML). BCR-ABL1 was one of the first tyrosine kinases to be implicated in a human malignancy and the first to be successfully targeted. Imatinib mesylate, the first tyrosine kinase inhibitor (TKI) to be approved for therapeutic use, was hailed as a magic bullet against cancer and remains one of the safest and most effective anticancer agents ever developed. Second- and third-generation TKIs were later introduced to prevent or counteract the problem of drug resistance, that may arise in a small proportion of patients. They are more potent molecules, but have been associated to more serious side effects and complications. Patients achieving stable optimal responses to TKI therapy are predicted to have the same life expectancy of the general population. However, TKIs do not ‘cure’ CML. Only a small proportion of cases may attempt therapy discontinuation without experiencing subsequent relapse. The great majority of patients will have to assume TKIs indefinitely – which raises serious pharmacoeconomic concerns and is now shifting the focus from efficacy to compliance and quality of life issues. Here we retrace the steps that have led from the biological acquisitions regarding BCR-ABL1 structure and function to the development of inhibitory strategies and we discuss drug resistance mechanism and how they can be addressed.

Patients with newly diagnosed multiple myeloma (NDMM) show heterogeneous outcomes, and approximately 60% of them are at intermediate-risk according to the Revised International Staging system (R-ISS), the standard-of-care risk stratification model. Moreover, chromosome 1q gain/amplification (1q+) recently proved to be a poor prognostic factor. In this study, we revised the R-ISS by analyzing the additive value of each single risk feature, including 1q+.The European Myeloma Network, within the HARMONY project, collected individual data from 10,843 patients with NDMM enrolled in 16 clinical trials. An additive scoring system on the basis of top features predicting progression-free survival (PFS) and overall survival (OS) was developed and validated.In the training set (N = 7,072), at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, t(4;14), and 1q+ had the highest impact on PFS and OS. These variables were all simultaneously present in 2,226 patients. A value was assigned to each risk feature according to their OS impact (ISS-III 1.5, ISS-II 1, del(17p) 1, high lactate dehydrogenase 1, and 1q+ 0.5 points). Patients were stratified into four risk groups according to the total additive score: low (Second Revision of the International Staging System [R2-ISS]-I, 19.2%, 0 points), low-intermediate (II, 30.8%, 0.5-1 points), intermediate-high (III, 41.2%, 1.5-2.5 points), high (IV, 8.8%, 3-5 points). Median OS was not reached versus 109.2 versus 68.5 versus 37.9 months, and median PFS was 68 versus 45.5 versus 30.2 versus 19.9 months, respectively. The score was validated in an independent validation set (N = 3,771, of whom 1,214 were with complete data to calculate R2-ISS) maintaining its prognostic value.The R2-ISS is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk NDMM. The additive nature of this score fosters its future implementation with new prognostic variables.

Bortezomib-based induction followed by high-dose melphalan (200 mg/m2) and autologous stem-cell transplantation (MEL200-ASCT) and maintenance treatment with lenalidomide alone is the current standard of care for young and fit patients with newly diagnosed multiple myeloma. We aimed to evaluate the efficacy and safety of different carfilzomib-based induction and consolidation approaches with or without transplantation and of maintenance treatment with carfilzomib plus lenalidomide versus lenalidomide alone in newly diagnosed multiple myeloma.UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done in 42 Italian academic and community practice centres. We enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 65 years or younger with a Karnofsky Performance Status of 60% or higher. Patients were stratified according to International Staging System stage (I vs II/III) and age (<60 years vs 60-65 years) and randomly assigned (1:1:1) to KRd plus ASCT (four 28-day induction cycles with carfilzomib plus lenalidomide plus dexamethasone [KRd], melphalan at 200 mg/m2 and autologous stem-cell transplantation [MEL200-ASCT], followed by four 28-day KRd consolidation cycles), KRd12 (12 28-day KRd cycles), or KCd plus ASCT (four 28-day induction cycles with carfilzomib plus cyclophosphamide plus dexamethasone [KCd], MEL200-ASCT, and four 28-day KCd consolidation cycles). Carfilzomib 36 mg/m2 was administered intravenously on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg administered orally on days 1-21; cyclophosphamide 300 mg/m2 administered orally on days 1, 8, and 15; and dexamethasone 20 mg administered orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23. Thereafter, patients were stratified according to induction-consolidation treatment and randomly assigned (1:1) to maintenance treatment with carfilzomib plus lenalidomide or lenalidomide alone. Carfilzomib 36 mg/m2 was administered intravenously on days 1-2 and 15-16 every 28 days for up to 2 years; lenalidomide 10 mg was administered orally on days 1-21 every 28 days until progression or intolerance in both groups. The primary endpoints were the proportion of patients with at least a very good partial response after induction with KRd versus KCd and progression-free survival with carfilzomib plus lenalidomide versus lenalidomide alone as maintenance treatment, both assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02203643. Study recruitment is complete, and all patients are in the follow-up or maintenance phases.Between Feb 23, 2015, and April 5, 2017, 474 patients were randomly assigned to one of the induction-intensification-consolidation groups (158 to KRd plus ASCT, 157 to KRd12, and 159 to KCd plus ASCT). The median duration of follow-up was 50·9 months (IQR 45·7-55·3) from the first randomisation. 222 (70%) of 315 patients in the KRd group and 84 (53%) of 159 patients in the KCd group had at least a very good partial response after induction (OR 2·14, 95% CI 1·44-3·19, p=0·0002). 356 patients were randomly assigned to maintenance treatment with carfilzomib plus lenalidomide (n=178) or lenalidomide alone (n=178). The median duration of follow-up was 37·3 months (IQR 32·9-41·9) from the second randomisation. 3-year progression-free survival was 75% (95% CI 68-82) with carfilzomib plus lenalidomide versus 65% (58-72) with lenalidomide alone (hazard ratio [HR] 0·64 [95% CI 0·44-0·94], p=0·023). During induction and consolidation, the most common grade 3-4 adverse events were neutropenia (21 [13%] of 158 patients in the KRd plus ASCT group vs 15 [10%] of 156 in the KRd12 group vs 18 [11%] of 159 in the KCd plus ASCT group); dermatological toxicity (nine [6%] vs 12 [8%] vs one [1%]); and hepatic toxicity (13 [8%] vs 12 [8%] vs none). Treatment-related serious adverse events were reported in 18 (11%) of 158 patients in the KRd-ASCT group, 29 (19%) of 156 in the KRd12 group, and 17 (11%) of 159 in the KCd plus ASCT group; the most common serious adverse event was pneumonia, in seven (4%) of 158, four (3%) of 156, and five (3%) of 159 patients. Treatment-emergent deaths were reported in two (1%) of 158 patients in the KRd plus ASCT group, two (1%) of 156 in the KRd12 group, and three (2%) of 159 in the KCd plus ASCT group. During maintenance, the most common grade 3-4 adverse events were neutropenia (35 [20%] of 173 patients on carfilzomib plus lenalidomide vs 41 [23%] of 177 patients on lenalidomide alone); infections (eight [5%] vs 13 [7%]); and vascular events (12 [7%] vs one [1%]). Treatment-related serious adverse events were reported in 24 (14%) of 173 patients on carfilzomib plus lenalidomide versus 15 (8%) of 177 on lenalidomide alone; the most common serious adverse event was pneumonia, in six (3%) of 173 versus five (3%) of 177 patients. One patient died of a treatment-emergent adverse event in the carfilzomib plus lenalidomide group.Our data show that KRd plus ASCT showed superiority in terms of improved responses compared with the other two treatment approaches and support the prospective randomised evaluation of KRd plus ASCT versus standards of care (eg, daratumumab plus bortezomib plus thalidomide plus dexamethasone plus ASCT) in transplant-eligible patients with multiple myeloma. Carfilzomib plus lenalidomide as maintenance therapy also improved progression-free survival compared with the standard-of-care lenalidomide alone.Amgen, Celgene/Bristol Myers Squibb.For the Italian translation of the abstract see Supplementary Materials section.

Like normal hematopoietic stem cells, leukemic stem cells depend on their bone marrow (BM) microenvironment for survival, but the underlying mechanisms remain largely unknown. We have studied the contribution of nestin+ BM mesenchymal stem cells (BMSCs) to MLL-AF9-driven acute myeloid leukemia (AML) development and chemoresistance in vivo. Unlike bulk stroma, nestin+ BMSC numbers are not reduced in AML, but their function changes to support AML cells, at the expense of non-mutated hematopoietic stem cells (HSCs). Nestin+ cell depletion delays leukemogenesis in primary AML mice and selectively decreases AML, but not normal, cells in chimeric mice. Nestin+ BMSCs support survival and chemotherapy relapse of AML through increased oxidative phosphorylation, tricarboxylic acid (TCA) cycle activity, and glutathione (GSH)-mediated antioxidant defense. Therefore, AML cells co-opt energy sources and antioxidant defense mechanisms from BMSCs to survive chemotherapy.

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)–directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. Download a PDF of the Research Summary. In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician’s choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell–associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T–related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.) QUICK TAKE VIDEO SUMMARYCilta-cel in Lenalidomide-Refractory Multiple Myeloma 02:05

<h2>Summary</h2> In this Policy Review, the Bone Working Group of the International Myeloma Working Group updates its clinical practice recommendations for the management of multiple myeloma-related bone disease. After assessing the available literature and grading recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method, experts from the working group recommend zoledronic acid as the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, with or without multiple myeloma-related bone disease. Once patients achieve a very good partial response or better, after receiving monthly zoledronic acid for at least 12 months, the treating physician can consider decreasing the frequency of or discontinuing zoledronic acid treatment. Denosumab can also be considered for the treatment of multiple myeloma-related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem-cell transplantation. Denosumab discontinuation is challenging due to the rebound effect. The Bone Working Group of the International Myeloma Working Group also found cement augmentation to be effective for painful vertebral compression fractures. Radiotherapy is recommended for uncontrolled pain, impeding or symptomatic spinal cord compression, or pathological fractures. Surgery should be used for the prevention and restoration of long-bone pathological fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route.

Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N = 248; ECOG performance status of 0-1, ≥3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1-20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2-36.0). Median progression-free survival (PFS) and median overall survival (OS) were 4.6 (95% CI: 3.9-5.6) and 12.4 months (95% CI: 10.3-NE). Treatment-emergent adverse events (TEAEs) were reported in 83.5% of patients (52.8% grade 3/4). Altogether, 107 deaths occurred, due to progressive disease (n = 74), TEAEs (n = 19), and other reasons (n = 14). The 92 varied regimens utilized demonstrate a lack of clear SOC for heavily pretreated, triple-class exposed patients with RRMM in real-world practice and result in poor outcomes. This supports a need for new treatments with novel mechanisms of action.

PURPOSE 18 F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is currently the standard technique to define minimal residual disease (MRD) status outside the bone marrow (BM) in patients with multiple myeloma (MM). This study aimed to define criteria for PET complete metabolic response after therapy, jointly analyzing a subgroup of newly diagnosed transplantation-eligible patients with MM enrolled in two independent European randomized phase III trials (IFM/DFCI2009 and EMN02/HO95). PATIENTS AND METHODS Two hundred twenty-eight patients were observed for a median of 62.9 months. By study design, PET/CT scans were performed at baseline and before starting maintenance (premaintenance [PM]). The five-point Deauville scale (DS) was applied to describe BM (BM score [BMS]) and focal lesion (FL; FL score [FS]) uptake and tested a posteriori in uni- and multivariable analyses for their impact on clinical outcomes. RESULTS At baseline, 78% of patients had FLs (11% extramedullary), 80% with an FS ≥ 4. All patients had BM diffuse uptake (35.5% with BMS ≥ 4). At PM, 31% of patients had visually detectable FLs (2% extramedullary), 24% and 67.7% of them with an FS of 3 and ≥ 4, respectively. At PM, 98% of patients retained residual BM diffuse uptake, which was significantly lower than at baseline (mainly between BMS 2 and 3, BMS was ≥ 4 in only 8.7% of patients). By both uni- and multivariable analysis, FS and BMS &lt; 4 were associated with prolonged progression-free survival (PFS) and overall survival (OS) at PM (OS: hazard ratio [HR], 0.6 and 0.47, respectively; PFS: HR, 0.36 and 0.24, respectively) CONCLUSION FL and BM FDG uptake lower than the liver background after therapy was an independent predictor for improved PFS and OS and can be proposed as the standardized criterion of PET complete metabolic response, confirming the value of the DS for patients with MM.

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE).

The primary analysis of the ICARIA-MM study showed significant improvement in progression-free survival with addition of isatuximab to pomalidomide-dexamethasone in relapsed and refractory multiple myeloma. Here, we report a prespecified updated overall survival analysis at 24 months after the primary analysis.In this randomised, multicentre, open-label, phase 3 study adult patients (aged ≥18 years) with relapsed and refractory multiple myeloma who had received at least two previous lines of therapy, including lenalidomide and a proteasome inhibitor, and had an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 102 hospitals in 24 countries across Europe, North America, and the Asia-Pacific regions. Patients were excluded if they had anti-CD38 refractory disease or previously received pomalidomide. Patients were randomly assigned (1:1), using an interactive response technology with permuted blocked randomisation (block size of four) and stratified by number of previous treatment lines (2-3 vs >3) and aged (<75 vs ≥75 years), to isatuximab-pomalidomide-dexamethasone (isatuximab group) or pomalidomide-dexamethasone (control group). In the isatuximab group, intravenous isatuximab 10 mg/kg was administered on days 1, 8, 15, and 22 of the first 4-week cycle, and then on days 1 and 15 of subsequent cycles. Both groups received oral pomalidomide 4 mg on days 1-21 of each cycle, and weekly oral or intravenous dexamethasone 40 mg (20 mg if aged ≥75 years) on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Here' we report a prespecified second interim analysis of overall survival (time from randomisation to any-cause death), a key secondary endpoint, in the intention-to-treat population (ie, all patients who provided informed consent and allocated a randomisation number) at 24 months after the primary analysis. Safety was assessed in all patients who received at least one dose or part dose of study treatment. The prespecified stopping boundary for the overall survival analysis was when the derived p value was equal to or less than 0·0181. This study is registered with ClinicalTrials.gov, NCT02990338, and is active, but not recruiting.Between Jan 10, 2017, and Feb 2, 2018, 387 patients were screened and 307 randomly assigned to either the isatuximab (n=154) or control group (n=153). Median follow-up at data cutoff (Oct 1, 2020) was 35·3 months (IQR 33·5-37·4). Median overall survival was 24·6 months (95% CI 20·3-31·3) in the isatuximab group and 17·7 months (14·4-26·2) in the control group (hazard ratio 0·76 [95% CI 0·57-1·01]; one-sided log-rank p=0·028, not crossing prespecified stopping boundary). The most common grade 3 or worse treatment-emergent adverse events in the isatuximab group versus the control group were neutropenia (76 [50%] of 152 patients vs 52 [35%] of 149 patients), pneumonia (35 [23%] vs 31 [21%]), and thrombocytopenia (20 [13%] vs 18 [12%]). Serious treatment-emergent adverse events were observed in 111 (73%) patients in the isatuximab group and 90 (60%) patients in the control group. Two (1%) treatment-related deaths occurred in the isatuximab group (one due to sepsis and one due to cerebellar infarction) and two (1%) occurred in the control group (one due to pneumonia and one due to urinary tract infection).Addition of isatuximab plus pomalidomide-dexamethasone resulted in a 6·9-month difference in median overall survival compared with pomalidomide-dexamethasone and is a new standard of care for lenalidomide-refractory and proteasome inhibitor-refractory or relapsed multiple myeloma. Final overall survival analysis follow-up is ongoing.Sanofi.

Abstract We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10−5 sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P &amp;lt; .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P &amp;lt; .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172.

T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, hypogammaglobulinaemia, and infections are common. This Policy Review presents a consensus from the European Myeloma Network on the prevention and management of these adverse events. Recommended measures include premedication, frequent assessing for symptoms and severity of cytokine release syndrome, step-up dosing for several BsAbs and some CAR T-cell therapies; corticosteroids; and tocilizumab in the case of cytokine release syndrome. Other anti-IL-6 drugs, high-dose corticosteroids, and anakinra might be considered in refractory cases. ICANS often arises concomitantly with cytokine release syndrome. Glucocorticosteroids in increasing doses are recommended if needed, as well as anakinra if the response is inadequate, and anticonvulsants if convulsions occur. Preventive measures against infections include antiviral and antibacterial drugs and administration of immunoglobulins. Treatment of infections and other complications is also addressed.

Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed.In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status.At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group.The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.).

Measurable residual disease (MRD) evaluation may help to guide treatment duration in multiple myeloma (MM). Paradoxically, limited longitudinal data exist on MRD during maintenance. We investigated the prognostic value of MRD dynamics in 1280 transplant-eligible and -ineligible patients from the TOURMALINE-MM3 and -MM4 randomized placebo-controlled phase 3 studies of 2-year ixazomib maintenance. MRD status at randomization showed independent prognostic value (median progression-free survival [PFS], 38.6 vs 15.6 months in MRD- vs MRD+ patients; HR, 0.47). However, MRD dynamics during maintenance provided more detailed risk stratification. A 14-month landmark analysis showed prolonged PFS in patients converting from MRD+ to MRD- status vs those with persistent MRD+ status (76.8% vs 27.6% 2-year PFS rates). Prolonged PFS was observed in patients with sustained MRD- status vs those converting from MRD- to MRD+ status (75.0% vs 34.2% 2-year PFS rates). Similar results were observed at a 28-month landmark analysis. Ixazomib maintenance vs placebo improved PFS in patients who were MRD+ at randomization (median, 18.8 vs 11.6 months; HR, 0.65) or at the 14-month landmark (median, 16.8 vs 10.6 months; HR, 0.65); no difference was observed in patients who were MRD-. This is the largest MM population undergoing yearly MRD evaluation during maintenance reported to date. We demonstrate the limited prognostic value of a single-time point MRD evaluation, because MRD dynamics over time substantially impact PFS risk. These findings support MRD- status as a relevant end point during maintenance and confirm the increased progression risk in patients converting to MRD+ from MRD- status. These trials were registered at www.clinicaltrials.gov as #NCT02181413 and #NCT02312258.

Summary Outcome of early treatment of COVID‐19 with antivirals or anti‐spike monoclonal antibodies (MABs) in patients with haematological malignancies (HM) is unknown. A retrospective study of HM patients treated for mild/moderate COVID‐19 between March 2021 and July 2022 was performed. The main composite end‐point was treatment failure (severe COVID‐19 or COVID‐19‐related death). We included 328 consecutive patients who received MABs ( n = 120, 37%; sotrovimab, n = 73) or antivirals ( n = 208, 63%; nirmatrelvir/ritonavir, n = 116) over a median of two days after symptoms started; 111 (33.8%) had non‐Hodgkin lymphoma (NHL); 89 (27%) were transplant/CAR‐T (chimaeric antigen receptor T‐cell therapy) recipients. Most infections ( n = 309, 94%) occurred during the Omicron period. Failure developed in 31 patients (9.5%). Its independent predictors were older age, fewer vaccine doses, and treatment with MABs. Rate of failure was lower in the Omicron versus the pre‐Omicron period (7.8% versus 36.8%, p &lt; 0.001). During the Omicron period, predictors of failure were age, fewer vaccine doses and diagnosis of acute myeloid leukaemia/myelodysplastic syndrome (AML/MDS). Independent predictors of longer viral shedding were age, comorbidities, hospital admission at diagnosis, NHL/CLL, treatment with MABs. COVID‐19‐associated mortality was 3.4% ( n = 11). The mortality in those who developed severe COVID‐19 after early treatment was 26% in the Omicron period. Patients with HM had a significant risk of failure of early treatment, even during the Omicron period, with high mortality rate.

Out of 690 allogeneic matched sibling donor transplants for multiple myeloma reported to the European Group for Blood and Marrow Transplantation (EBMT) registry, 334 were performed during the period 1983–93 (all with bone marrow) and 356 during 1994–98 [223 with bone marrow and 133 with peripheral blood stem cells (PBSCs)]. The median overall survival was 10 months for patients transplanted during the earlier time period and 50 months for patients transplanted with bone marrow during the later period. The use of PBSCs was associated with earlier engraftment but no significant survival benefit compared to bone marrow transplants during the same time period. The improvement in survival since 1994 was the result of a significant reduction in transplant‐related mortality, which was 38%, 21% and 25% at 6 months and 46%, 30% and 37% at 2 years during the earlier period, and the later period with bone marrow and PBSCs respectively. Reasons for the reduced transplant‐related mortality appeared to be fewer deaths owing to bacterial and fungal infections and interstitial pneumonitis, in turn a result of earlier transplantation and less prior chemotherapy. Better supportive treatment and more frequent use of cytokines may also play a role. The improvement in survival was not directly related to the increased use of PBSCs.

To analyze prognostic factors for allogeneic bone marrow transplantation (BMT) in multiple myeloma.One hundred sixty-two reports of allogeneic matched sibling-donor transplants in multiple myeloma received by the European Group for Blood and Marrow Transplantation (EBMT) registry between 1983 and early 1993 were analyzed for prognostic factors. End points were complete remission, survival, and duration of complete remission.Following BMT, 44% of all patients and 60% of assessable patients entered complete remission. The overall actuarial survival rate was 32% at 4 years and 28% at 7 years. The overall relapse-free survival rate of 72 patients who were in complete remission after BMT was 34% at 6 years. Favorable pretransplant prognostic factors for survival were female sex (41% at 4 years), stage I disease at diagnosis (52% at 4 years), one line of previous treatment (42% at 4 years), and being in complete remission before conditioning (64% at 3 years). The subtype immunoglobulin A (IgA) myeloma and a low beta 2-microglobulin level (< 4 g/L) also tended to have a favorable prognostic impact. The most important post-transplant prognostic factor was to enter a complete remission. Grade III to IV graft-versus-host disease (GVHD) was associated with poor survival.Patients with a low tumor burden who respond to treatment before BMT and are transplanted after first-line therapy have the best prognosis following BMT.

BackgroundBisphosphonates (BPs) prevent, reduce, and delay multiple myeloma (MM)-related skeletal complications. Intravenous pamidronate and zoledronic acid, and oral clodronate are used for the management of MM bone disease. The purpose of this paper is to review the current evidence for the use of BPs in MM and provide European Union-specific recommendations to support the clinical practice of treating myeloma bone disease.Design and methodsAn interdisciplinary, expert panel of specialists on MM and myeloma-related bone disease convened for a face-to-face meeting to review and assess the evidence and develop the recommendations. The panel reviewed and graded the evidence available from randomized clinical trials, clinical practice guidelines, and the body of published literature. Where published data were weak or unavailable, the panel used their own clinical experience to put forward recommendations based solely on their expert opinions.ResultsThe panel recommends the use of BPs in MM patients suffering from lytic bone disease or severe osteoporosis. Intravenous administration may be preferable; however, oral administration can be considered for patients unable to make hospital visits. Dosing should follow approved indications with adjustments if necessary. In general, BPs are well tolerated, but preventive steps should be taken to avoid renal impairment and osteonecrosis of the jaw (ONJ). The panel agrees that BPs should be given for 2 years, but this may be extended if there is evidence of active myeloma bone disease. Initial therapy of ONJ should include discontinuation of BPs until healing occurs. BPs should be restarted if there is disease progression.ConclusionsBPs are an essential component of MM therapy for minimizing skeletal morbidity. Recent retrospective data indicate that a modified dosing regimen and preventive measures can greatly reduce the incidence of ONJ.

The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells. An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization.

We analyzed the presenting features and survival in 1689 patients with multiple myeloma aged younger than 50 years compared with 8860 patients 50 years of age and older. Of the total 10 549 patients, 7765 received conventional therapy and 2784 received high-dose therapy. Young patients were more frequently male, had more favorable features such as low International Staging System (ISS) and Durie-Salmon stage as well as less frequently adverse prognostic factors including high C-reactive protein (CRP), low hemoglobin, increased serum creatinine, and poor performance status. Survival was significantly longer in young patients (median, 5.2 years vs 3.7 years; P < .001) both after conventional (median, 4.5 years vs 3.3 years; P < .001) or high-dose therapy (median, 7.5 years vs 5.7 years; P = .04). The 10-year survival rate was 19% after conventional therapy and 43% after high-dose therapy in young patients, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. A total of 5 of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy.

Abstract Maintaining results of successful induction therapy is an important goal in multiple myeloma. Here, members of the International Myeloma Working Group review the relevant data. Thalidomide maintenance therapy after autologous stem cell transplantation improved the quality of response and increased progression-free survival (PFS) significantly in all 6 studies and overall survival (OS) in 3 of them. In elderly patients, 2 trials showed a significant prolongation of PFS, but no improvement in OS. A meta-analysis revealed a significant risk reduction for PFS/event-free survival and death. The role of thalidomide maintenance after melphalan, prednisone, and thalidomide is not well established. Two trials with lenalidomide maintenance treatment after autologous stem cell transplantation and one study after conventional melphalan, prednisone, and lenalidomide induction therapy showed a significant risk reduction for PFS and an increase in OS in one of the transplant trials. Maintenance therapy with single-agent bortezomib or in combination with thalidomide or prednisone has been studied. One trial revealed a significantly increased OS with a bortezomib-based induction and bortezomib maintenance therapy compared with conventional induction and thalidomide maintenance treatment. Maintenance treatment can be associated with significant side effects, and none of the drugs evaluated is approved for maintenance therapy. Treatment decisions for individual patients must balance potential benefits and risks carefully, as a widely agreed-on standard is not established.

One advantage of the use of peripheral blood stem cells (PBSCs) over autologous bone marrow would be a reduced risk of tumor cell contamination. However, the level of neoplastic cells in the PB of multiple myeloma (MM) patients after mobilization protocols is poorly investigated. In this study, we evaluated PB samples from 27 pretreated MM patients after the administration of high dose cyclophosphamide (7 g/m2 or 4 g/m2) and granulocyte-colony stimulating factor for the detection of myeloma cells as well as hematopoietic progenitors. Plasma cells containing intracytoplasmic lg were counted by microscope immunofluorescence after incubation with appropriate antisera directed against light- and heavy-chain lg. Moreover, flow cytometry studies were performed to determine the presence of malignant B-lineage elements by using monoclonal antibodies against the CD19 antigen and the monotypic light chain. Before initiation of PBSC mobilization, circulating plasma cells were detected in all MM patients in a percentage ranging from 0.1% to 1.8% of the mononuclear cell fraction (mean value, 0.7% +/- 0.4% SD). In these patients, a higher absolute number of PB neoplastic cells was detected after chemotherapy and granulocyte colony-stimulating factor. Kinetic analysis showed a pattern of tumor cell mobilization similar to that of normal hematopoietic progenitors with a maximum peak falling within the optimal time period for the collection of PBSCs. The absolute number of plasma cells showed a 10 to 50-fold increase as compared with the baseline value. Apheresis products contained 0.7% +/- 0.2% SD of myeloma cells (range, 0.2% to 2.7%). Twenty-three MM patients were submitted to PBSC collection. In 10 patients, circulating hematopoietic CD34+ cells were highly enriched by avidin-biotin immunoabsorption, were cryopreserved, and used to reconstitute bone marrow function after myeloablative therapy. The median purity of the enriched CD34+ cell population was 89.5% (range, 51% to 94%), with a 75-fold increase as compared with the pretreatment samples. The median overall recovery of CD34+ cells and colony-forming unit-granulocyte-macrophage was 58% (range, 33% to 95%) and 45% (range, 7% to 100%), respectively. Positive selection of CD34+ cells resulted in 2.5- to 3-log depletion of plasma cells and CD19+ B-lineage cells as determined by immunofluorescence studies, although DNA analysis of CDR III region of IgH gene showed the persistence of minimal residual disease in 5 of 6 patient samples studied. Myeloma patients were reinfused with enriched CD34+ cells after myeloablative therapy consisting of total body irradiation (1,000 cGy) and highdose melphalan (140 mg/m2). They received a median of 4 x 10(6) CD34+ cells/kg and showed a rapid reconstitution of hematopoiesis; the median time to 0.5 x 10(9) neutrophils and to 20 and 50 x 10(9) platelets per liter of PB was 10, 11, and 12 days, respectively. These results, as well as other clinically significant parameters, did not significantly differ from those of patients (n = 13) receiving unmanipulated PBSCs after the same pretransplant conditioning regimen. In summary, our data show the concomitant mobilization of tumor cells and hematopoietic progenitors in the PB of MM patients. Positive selection of CD34+ cells reduces the contamination of myeloma cells from the apheresis products up to 3-log and provides a cell suspension capable of restoring a normal hematopoiesis after a total body irradiation-containing conditioning regimen.

The combination of serum β2-microglobulin and albumin levels has been shown to be highly prognostic in myeloma as the International Staging System (ISS). The aim of this study was to assess the independent contributions of ISS stage and cytogenetic abnormalities in predicting outcomes. A retrospective analysis of international studies looking at both ISS and cytogenetic abnormalities was performed in order to assess the potential role of combining ISS stage and cytogenetics to predict survival. This international effort used the International Myeloma Working Group database of 12 137 patients treated worldwide for myeloma at diagnosis, of whom 2309 had cytogenetic studies and 5387 had analyses by fluorescent in situ hybridization (iFISH). Comprehensive analyses used 2642 patients with sufficient iFISH data available. Using the comprehensive iFISH data, combining both t(4;14) and deletion (17p), along with ISS stage, significantly improved the prognostic assessment in terms of progression-free survival and overall survival. The additional impact of patient age and use of high-dose therapy was also demonstrated. In conclusion, the combination of iFISH data with ISS staging significantly improves risk assessment in myeloma.

Key Points UDS demonstrated that BCR-ABL KD mutations detectable with conventional methods may just be the tip of the iceberg. The information provided by conventional Sanger sequencing may not always be sufficient to predict responsiveness to a given TKI.

To construct and validate among patients with multiple myeloma (MM) who were treated with intensive therapy a prognostic index of early MM progression-related death.Patient-level data from the Intergroupe Francophone du Myélome (IFM) 2005-01 trial (N = 482) were used to construct the prognostic index. The event was MM progression-related death within 2 years from treatment initiation. The index was validated using data from three other trials: the Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) 26866138-MMY-3006 trial (N = 480), the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA)-GEMMENOS65 trial (N = 390), and the Hemato-Oncologie voor Volwassenen Nederland (HOVON) -65/German-Speaking Myeloma Multicenter Group (GMMG) -HD4 trial (N = 827).The risk of early MM progression-related death was related to three independent prognostic variables: lactate dehydrogenase (LDH) higher than than normal, International Staging System 3 (ISS3), and adverse cytogenetics [t(4;14) and/or del(17p)]. These three variables enabled the definition of an ordinal prognostic classification composed of four scores (0 to 3). Patients with a score of 3, defined by the presence of t(4;14) and/or del(17p) in addition to ISS3 and/or high LDH, comprised 5% (20 of 387 patients) to 8% (94 of 1,139 patients) of the patients in the learning and validation samples, respectively, and they had a very poor prognosis. When applied to the population of 855 patients who had received bortezomib-based induction therapy in the four trials, the prognostic classification was also able to segregate patients into four categories, with a very poor prognosis attributed to patients with a score of 3.Our model allows the simple definition of a subgroup of MM patients at high risk of early MM progression-related death despite the use of the most modern and effective strategies.

In contrast to the upfront setting in which the role of high-dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a first remission in patients with multiple myeloma (MM) is well established, the role of high-dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation convened a meeting of MM experts to: (1) summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy, (2) propose guidelines for the use of salvage HCT in MM, (3) identify knowledge gaps, (4) propose a research agenda, and (5) develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: (1) In transplantation-eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high-dose therapy with HCT as part of salvage therapy should be considered standard; (2) High-dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; (3) High-dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; (4) The role of postsalvage HCT maintenance needs to be explored in the context of well-designed prospective trials that should include new agents, such as monoclonal antibodies, immune-modulating agents, and oral proteasome inhibitors; (5) Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post-HCT strategies in patients with short (less than 18 months remissions) after primary therapy; and (6) Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing it to “best non-HCT” therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform 2 transplantations early in the course of the disease. Regarding allogeneic HCT, the expert committee agreed on the following consensus statements: (1) Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high-risk features (ie, cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase); (2) Allogeneic HCT should be performed in the context of a clinical trial if possible; (3) The role of postallogeneic HCT maintenance therapy needs to be explored in the context of well-designed prospective trials; and (4) Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy.

Purpose To assess the impact of age on outcome and to analyze the projected years of life lost in patients with multiple myeloma. Patients and Methods Ten thousand five hundred forty-nine patients were evaluated; 6,996 patients were treated with conventional chemotherapy, and 3,553 patients were treated with high-dose therapy with autologous stem-cell transplantation. Results Mean observed and relative overall survival times in the entire cohort were 3.7 and 3.9 years, respectively. Observed survival decreased steadily from 6.4 years in patients younger than age 50 years to 2.5 years in patients ≥ age 80 years. A similar decrease was noted for relative survival. Higher age correlated significantly with higher International Staging System (ISS) stage. Relative excess risk of death differed significantly between 10-year age cohorts beginning from age 40 years (P &lt; .001 for age 50 to 59 v age 40 to 49, P &lt; .001 for age 60 to 69 v age 50 to 59, P &lt; .001 for age 70 to 79 v age 60 to 69, and P = .009 for age ≥ 80 v 70 to 79). The average years of life lost per patient was 16.8 years in the entire patient cohort and decreased steadily from 36.1 years in patients younger than 40 years old to 4.6 years in patients ≥ age 80 years. Conclusion Age is associated with higher ISS stage and is an important risk factor for early mortality. Survival declined continuously by each decade from age 50 to age ≥ 80 from more than 6 to less than 3 years. The average of years of life lost in patients with myeloma is higher than in many other cancers and amounts to more than 30 years in patients younger than 40 years old but decreases to less than 5 years in patients age 80 years or older.

In 2005, the first guidelines were published on the management of patients with multiple myeloma (MM). An expert panel reviewed the currently available literature as the basis for a set of revised and updated consensus guidelines for the diagnosis and management of patients with MM who are not eligible for autologous stem cell transplantation. Here we present recommendations on the diagnosis, treatment of newly diagnosed non-transplant-eligible patients and the management of complications occurring during induction therapy among these patients. These guidelines will aid the physician in daily clinical practice and will ensure optimal care for patients with MM.

Purpose Continuous therapy (CT) prolongs progression-free survival 1 (PFS1; time from random assignment until the first progression or death), but chemotherapy-resistant relapse may negatively impact overall survival (OS). Progression-free survival 2 (PFS2; time from random assignment until the second progression or death) may represent an additional tool to estimate outcome. This study evaluates the benefit of novel agent–based CT versus fixed duration of therapy (FDT) in patients with newly diagnosed myeloma. Methods We included patients enrolled onto three phase III trials that randomly assigned patients to novel agent–based CT versus FDT. Primary analyses were restricted to the intent-to-treat population eligible for CT (patients progression free and alive at 1 year after random assignment). Primary end points were PFS1, PFS2, and OS. All hazard ratios (HRs) and 95% CIs were adjusted for several potential confounders using Cox models. Results In the pooled analysis of the three trials, 604 patients were randomly assigned to CT and 614 were assigned to FDT. Median follow-up was 52 months. In the intent-to-treat CT population, CT (n = 417), compared with FDT (n = 410), significantly improved PFS1 (median, 32 v 16 months, respectively; HR, 0.47; 95% CI, 0.40 to 0.56; P &lt; .001), PFS2 (median, 55 v 40 months, respectively; HR, 0.61; 95% CI, 0.50 to 0.75; P &lt; .001), and OS (4-year OS, 69% v 60%, respectively; HR, 0.69; 95% CI, 0.54 to 0.88; P = .003). Conclusion In this pooled analysis, CT significantly improved PFS1, PFS2, and OS. The improvement in PFS2 suggests that the benefit reported during first remission is not cancelled by a shorter second remission. PFS2 is a valuable end point to estimate long-term clinical benefit and should be included in future trials.

To evaluate the role of 18F-FDG PET/CT in 282 symptomatic multiple myeloma patients treated up-front between 2002 and 2012.All patients were studied by PET/CT at baseline, during posttreatment follow-up, and at the time of relapse. Their median duration of follow-up was 67 months.Forty-two percent of the patients at diagnosis had >3 focal lesions, and in 50% SUVmax was >4.2; extramedullary disease was present in 5%. On multivariate analysis, ISS stage 3, SUVmax >4.2, and failure to achieve best complete response (CR) were the leading factors independently associated with shorter progression-free survival (PFS) and overall survival (OS). These 3 variables were used to construct a prognostic scoring system based on the number of risk factors. After treatment, PET/CT negativity (PET-neg) was observed in 70% of patients, whereas conventionally defined CR was achieved in 53%. Attainment of PET-neg favorably influenced PFS and OS. PET-neg was an independent predictor of prolonged PFS and OS for patients with conventionally defined CR. Sixty-three percent of patients experienced relapse or progression; in 12%, skeletal progression was exclusively detected by systematic PET/CT performed during follow-up. A multivariate analysis revealed that persistence of SUVmax >4.2 following first-line treatment was independently associated with exclusive PET/CT progression.PET/CT combined with ISS stage and achievement or not of CR on first-line therapy sorted patients into different prognostic groups. PET/CT led to a more careful evaluation of CR. Finally, in patients with persistent high glucose metabolism after first-line treatment, PET/CT can be recommended during follow-up, to screen for otherwise unidentifiable progression.

Patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) frequently relapse on imatinib with acquisition of BCR-ABL kinase domain (KD) mutations. To analyze the changes that second-generation tyrosine kinase inhibitors (TKIs) have brought in mutation frequency and type, a database review was undertaken of the results of all the BCR-ABL KD mutation analyses performed in the authors' laboratory from January 2004 to January 2013.Interrogation of the database retrieved 450 mutation analyses in 272 patients with Ph+ ALL. Prescreening of samples was performed with denaturing high-performance liquid chromatography (D-HPLC), followed by direct sequencing of D-HPLC-positive cases.BCR-ABL KD mutations were detected in 70% of imatinib-resistant patients, with T315I, E255K, and Y253H mutations accounting for 75% of cases. Seventy-eight percent of the patients reported to be resistant to second-generation TKIs after imatinib failure were positive for mutations, and 58% of them had multiple mutations. Analysis of patients relapsing on dasatinib revealed a newly acquired T315I mutation in almost two-thirds of the cases. Direct sequencing detected no mutations at diagnosis, even in patients who relapsed after a few months.Second-generation TKIs ensure a more rapid debulking of the leukemic clone and have much fewer insensitive mutations, but long-term disease control remains a problem, and the T315I mutation is revealed to be an even more frequent enemy. BCR-ABL KD mutation screening of patients with Ph+ ALL who are receiving imatinib or second-generation TKIs would be a precious ally for timely treatment optimization. In contrast, the clinical usefulness of conventional direct sequencing at diagnosis seems to be very low. American Cancer Society.

Identification of patient sub-groups with smoldering multiple myeloma (SMM) at high risk of progression to active disease (MM) is an important goal. 18F-FDG PET/CT (positron emission tomography (PET) integrated with computed tomography (PET/CT) using glucose labelled with the positron-emitting radionuclide (18)F) allows for assessing early skeletal involvement. Identification of osteolytic lesions by this technique has recently been incorporated into the updated International Myeloma Working Group criteria for MM diagnosis. However, no data are available regarding the impact of focal lesions (FLs) without underlying osteolysis on time to progression (TTP) to MM. We hence prospectively studied a cohort of 120 SMM patients with PET/CT. PET/CT was positive in 16% of patients (1 FL: 8, 2 FLs: 3, >3 FLs: 6, diffuse bone marrow involvement: 2). With a median follow-up of 2.2 years, 38% of patients progressed to MM, in a median time of 4 years, including 21% with skeletal involvement. The risk of progression of those with positive PET/CT was 3.00 (95% confidence interval 1.58-5.69, P=0.001), with a median TTP of 1.1 versus 4.5 years for PET/CT-negative patients. The probability of progression within 2 years was 58% for positive versus 33% for negative patients. In conclusion, PET/CT positivity significantly increased the risk of progression of SMM to MM. PET/CT could become a new tool to define high-risk SMM.