Pieter Sonneveld

There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification.Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies.Serum beta2-microglobulin (Sbeta2M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sbeta2M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sbeta2M less than 3.5 mg/L plus serum albumin > or = 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sbeta2M > or = 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and > or = 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system. CONCLUSION) The new ISS is simple, based on easy to use variables (Sbeta2M and serum albumin), and recommended for early adoption and widespread use.

This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies.

High-dose chemotherapy followed by autologous bone marrow transplantation is a therapeutic option for patients with chemotherapy-sensitive non-Hodgkin's lymphoma who have relapses. In this report we describe a prospective randomized study of such treatment.

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.

Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma.In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival.A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion.Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).

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.

A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area.Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter every 12 hours [DOSAGE ERROR CORRECTED] for 6 days. The primary end point was event-free survival.The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%).In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.)

Purpose We investigated whether bortezomib during induction and maintenance improves survival in newly diagnosed multiple myeloma (MM). Patients and Methods In all, 827 eligible patients with newly diagnosed symptomatic MM were randomly assigned to receive induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD) followed by high-dose melphalan and autologous stem-cell transplantation. Maintenance consisted of thalidomide 50 mg (VAD) once per day or bortezomib 1.3 mg/m 2 (PAD) once every 2 weeks for 2 years. The primary analysis was progression-free survival (PFS) adjusted for International Staging System (ISS) stage. Results Complete response (CR), including near CR, was superior after PAD induction (15% v 31%; P &lt; .001) and bortezomib maintenance (34% v 49%; P &lt; .001). After a median follow-up of 41 months, PFS was superior in the PAD arm (median of 28 months v 35 months; hazard ratio [HR], 0.75; 95% CI, 0.62 to 0.90; P = .002). In multivariate analysis, overall survival (OS) was better in the PAD arm (HR, 0.77; 95% CI, 0.60 to 1.00; P = .049). In high-risk patients presenting with increased creatinine more than 2 mg/dL, bortezomib significantly improved PFS from a median of 13 months to 30 months (HR, 0.45; 95% CI, 0.26 to 0.78; P = .004) and OS from a median of 21 months to 54 months (HR, 0.33; 95% CI, 0.16 to 0.65; P &lt; .001). A benefit was also observed in patients with deletion 17p13 (median PFS, 12 v 22 months; HR, 0.47; 95% CI, 0.26 to 0.86; P = .01; median OS, 24 months v not reached at 54 months; HR, 0.36; 95% CI, 0.18 to 0.74; P = .003). Conclusion Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS.

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.

Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein <15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2–3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1–2% per year for the next 10 years. Testing should be done 2–3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4–6 months for 1 year and, if stable, every 6–12 months.

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.

Abstract The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification.

Background Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma. Methods In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383. Findings Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21–2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10−5 sensitivity threshold, assessed by multiparametric flow cytometry; both p<0·0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0·47, 95% CI 0·33–0·67, p<0·0001). 46 deaths on study were observed (14 vs 32, 0·43, 95% CI 0·23–0·80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%). Interpretation D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma. Funding The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.

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.

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

Purpose This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma. Patients and Methods Six hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m 2 on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m 2 on day 4. Results Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant. Median duration of response was increased from 7.0 to 10.2 months (P = .0008) with PLD + bortezomib. Grade 3/4 adverse events were more frequent in the combination group (80% v 64%), with safety profiles consistent with the known toxicities of the two agents. An increased incidence in the combination group was seen of grade 3/4 neutropenia, thrombocytopenia, asthenia, fatigue, diarrhea, and hand-foot syndrome. Conclusion PLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients with relapsed or refractory multiple myeloma. The combination therapy is associated with a higher incidence of grade 3/4 myelosuppression, constitutional symptoms, and GI and dermatologic toxicities.

Key Points Elderly patients with myeloma are heterogeneous and assessment strategies are needed to define the frailty profile. The proposed frailty score aims to better assess patients and provide them with more suitable therapies.

Abstract Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a 6-month benefit, despite substantial crossover from dexamethasone to bortezomib. Overall and complete response rates with bortezomib were 43% and 9%, respectively; among responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy. This study is registered at http://clinicaltrials.gov (Study ID NCT00048230).

The European Myeloma Network (EMN) organized two flow cytometry workshops. The first aimed to identify specific indications for flow cytometry in patients with monoclonal gammopathies, and consensus technical approaches through a questionnaire-based review of current practice in participating laboratories. The second aimed to resolve outstanding technical issues and develop a consensus approach to analysis of plasma cells. The primary clinical applications identified were: differential diagnosis of neoplastic plasma cell disorders from reactive plasmacytosis; identifying risk of progression in patients with MGUS and detecting minimal residual disease. A range of technical recommendations were identified, including: 1) CD38, CD138 and CD45 should all be included in at least one tube for plasma cell identification and enumeration. The primary gate should be based on CD38 vs. CD138 expression; 2) after treatment, clonality assessment is only likely to be informative when combined with immunophenotype to detect abnormal cells. Flow cytometry is suitable for demonstrating a stringent complete remission; 3) for detection of abnormal plasma cells, a minimal panel should include CD19 and CD56. A preferred panel would also include CD20, CD117, CD28 and CD27; 4) discrepancies between the percentage of plasma cells detected by flow cytometry and morphology are primarily related to sample quality and it is, therefore, important to determine that marrow elements are present in follow-up samples, particularly normal plasma cells in MRD negative cases.

Sensitization of leukemic cells with hematopoietic growth factors may enhance the cytotoxicity of chemotherapy in acute myeloid leukemia (AML).In a multicenter randomized trial, we assigned patients (age range, 18 to 60 years) with newly diagnosed AML to receive cytarabine plus idarubicin (cycle 1) and cytarabine plus amsacrin (cycle 2) with granulocyte colony-stimulating factor (G-CSF) (321 patients) or without G-CSF (319). G-CSF was given concurrently with chemotherapy only. Idarubicin and amsacrin were given at the end of a cycle to allow the cell-cycle-dependent cytotoxicity of cytarabine in the context of G-CSF to have a greater effect. The effect of G-CSF on disease-free survival was assessed in all patients and in cytogenetically distinct prognostic subgroups.After induction chemotherapy, the rates of response were not significantly different in the two groups. After a median follow-up of 55 months, patients in complete remission after induction chemotherapy plus G-CSF had a higher rate of disease-free survival than patients who did not receive G-CSF (42 percent vs. 33 percent at four years, P=0.02), owing to a reduced probability of relapse (relative risk, 0.77; 95 percent confidence interval, 0.61 to 0.99; P=0.04). G-CSF did not significantly improve overall survival (P=0.16). Although G-CSF did not improve the outcome in the subgroup with an unfavorable prognosis, the 72 percent of patients with standard-risk AML benefited from G-CSF therapy (overall survival at four years, 45 percent, as compared with 35 percent in the group that did not receive G-CSF [relative risk of death, 0.75; 95 percent confidence interval, 0.59 to 0.95; P=0.02]; disease-free survival, 45 percent vs. 33 percent [relative risk, 0.70]; 95 percent confidence interval, 0.55 to 0.90; P=0.006).Sensitization of leukemic cells with growth factors is a clinically applicable means of enhancing the efficacy of chemotherapy in patients with AML.

•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 The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of bortezomib in multiple myeloma and to develop predictive classifiers of response and survival with bortezomib. Patients with relapsed myeloma enrolled in phase 2 and phase 3 clinical trials of bortezomib and consented to genomic analyses of pretreatment tumor samples. Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and these samples were used for gene expression profiling using DNA microarrays. Data quality and correlations with trial outcomes were assessed by multiple groups. Gene expression in this dataset was consistent with data published from a single-center study of newly diagnosed multiple myeloma. Response and survival classifiers were developed and shown to be significantly associated with outcome via testing on independent data. The survival classifier improved on the risk stratification provided by the International Staging System. Predictive models and biologic correlates of response show some specificity for bortezomib rather than dexamethasone. Informative gene expression data and genomic classifiers that predict clinical outcome can be derived from prospective clinical trials of new anticancer agents.

Cytarabine (ara-C) is an important drug in the treatment of acute myeloid leukemia (AML). High-dose cytarabine (2000 to 3000 mg per square meter of body-surface area) is toxic but results in higher rates of relapse-free survival than does the conventional dose of 100 to 400 mg per square meter. Intermediate dose levels have not been thoroughly evaluated.We compared two induction regimens in patients 18 to 60 years of age (median, 49) who had newly diagnosed AML. The intermediate-dose group, totaling 431 patients, received cytarabine at a dose of 200 mg per square meter given by continuous intravenous infusion for 24 hours during cycle 1 of induction therapy and 1000 mg per square meter by infusion for 3 hours twice daily during cycle 2 of induction therapy. The high-dose group, totaling 429 patients, received a dose-escalated regimen of 1000 mg of cytarabine per square meter every 12 hours in cycle 1 and 2000 mg per square meter twice daily in cycle 2. Patients with a complete response did not receive additional cytarabine but received consolidation therapy in a third cycle of chemotherapy (mitoxantrone-etoposide) or underwent autologous or allogeneic stem-cell transplantation. Complete remission rates, survival rates, and toxic effects were assessed for each treatment group.At a median follow-up of 5 years, no significant differences were noted between the intermediate-dose group and the high-dose group with respect to complete remission rates (80% and 82%, respectively), probability of relapse, event-free survival at 5 years (34% and 35%), or overall survival (40% and 42%). High-dose cytarabine provided no clear advantage in any prognostic subgroup. The high-dose treatment resulted in higher incidences of grade 3 and grade 4 toxic effects (in cycle 1), prolonged hospitalization, and delayed neutrophil recovery (in cycle 2) and platelet recovery (in cycles 2 and 3).Induction therapy with cytarabine at the lower dose already produced maximal antileukemic effects for all response end points, suggesting a plateau in the dose-response relationship above this dose level. High-dose cytarabine results in excessive toxic effects without therapeutic benefit. (Netherlands Trial Register number, NTR230.).

Key Points Using the largest set of patients with newly diagnosed myeloma, we identified 63 mutated driver genes. We identified oncogenic dependencies, particularly relating to primary translocations, indicating a nonrandom accumulation of genetic hits.

Abstract In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For allanalyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P = .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P = .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P &lt; .0001) and OS (P &lt; .0001) in arm A, whereas no statistically significant effect on PFS (P = .28) or OS (P = .12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13). This trial is registered at the International Standard Randomised Controlled Trial Number Register as ISRCTN64455289.

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.

Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.

Resistance to chemotherapy in refractory multiple myeloma is frequently associated with expression of multidrug resistance (MDR). In resistant cells, intracellular accumulation of doxorubicin and vincristine does not occur because the MDR- 1 gene product, a membrane glycoprotein (PgP), is an energy-dependent efflux pump. Cyclosporin is one of several non-cytotoxic drugs that can block the function of PgP. In a prospective study, we assessed the possibility that cyclosporin could be used clinically to modulate MDR. We studied 21 patients with multiple myeloma; disease had progressed during primary chemotherapy in 6 and was resistant to VAD (vincristine, doxorubicin, dexamethasone) in 15. The patients received cyclosporin by continuous infusion during VAD treatment; there were three cyclosporin dosage groups (5, 7·5, 10 mg/kg daily). Serum cyclosporin concentrations adequate for MDR modulation were reached in all patients receiving 7·5 or 10 mg/kg daily. 47% (7) of the VAD-refractory patients and 48% (10) of the whole group responded to VAD. Before treatment, MDR-1expression was present in 12 patients. After VAD plus cyclosporin, no MDR- 1-positive plasma cells were present in 6 of 8 patients tested. The response rate in MDR- 1-positive patients was 58% compared with 33% in all our patients. Toxic effects were mild and reversible and did not include nephrotoxic or serious cardiovascular side-effects. 12 months after the start of treatment, survival was 85%, and disease-free survival at a median of 9 months after the response was 65%. Thus, in multiple myeloma clinical resistance to VAD can be circumvented by cyclosporin, which enables the cytotoxic drugs to eliminate resistant myeloma cells.

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).

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.

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.

The frequency, characteristics and reversibility of bortezomib-associated peripheral neuropathy were evaluated in the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial in patients with relapsed myeloma, and the impact of a dose-modification guideline on peripheral neuropathy severity and reversibility was assessed. Patients received bortezomib 1.3 mg/m(2) (days 1, 4, 8, 11, eight 21-d cycles, then days 1, 8, 15, 22, three 35-d cycles); bortezomib was held, dose-reduced or discontinued depending on peripheral neuropathy severity, according to a protocol-specified dose-modification guideline. Overall, 124/331 patients (37%) had treatment-emergent peripheral neuropathy, including 30 (9%) with grade >or=3; incidence and severity were not affected by age, number/type of prior therapies, baseline glycosylated haemoglobin level, or diabetes history. Grade >or=3 incidence appeared lower versus phase II trials (13%) that did not specifically provide dose-modification guidelines. Of patients with grade >or=2 peripheral neuropathy, 58/91 (64%) experienced improvement or resolution to baseline at a median of 110 d, including 49/72 (68%) who had dose modification versus 9/19 (47%) who did not. Efficacy did not appear adversely affected by dose modification for grade >or=2 peripheral neuropathy. Bortezomib-associated peripheral neuropathy is manageable and reversible in most patients with relapsed myeloma. Dose modification using a specific guideline improves peripheral neuropathy management without adversely affecting outcome.

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 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.

Key Points Response to the CD38-targeting antibody daratumumab is significantly associated with CD38 expression levels on the tumor cells. Resistance to daratumumab is accompanied by increased expression of complement-inhibitory proteins.

Abstract Thalidomide, bortezomib, and lenalidomide have recently changed the treatment paradigm of myeloma. In young, newly diagnosed patients, the combination of thalidomide and dexamethasone has been widely used as induction treatment before autologous stem cell transplantation (ASCT). In 2 randomized studies, consolidation or maintenance with low-dose thalidomide has extended both progression-free and overall survival in patients who underwent ASCT at diagnosis. In elderly, newly diagnosed patients, 3 independent randomized studies have reported that the oral combination of melphalan and prednisone plus thalidomide (MPT) is better than the standard melphalan and prednisone (MP). These studies have shown better progression-free survival, and 2 have shown improved overall survival for patients assigned to MPT. In refractory-relapsed disease, combinations including thalidomide with dexamethasone, melphalan, doxorubicin, or cyclophosphamide have been extensively investigated. The risks of side effects are greater when thalidomide is used in combination with other drugs. Thromboembolism and peripheral neuropathy are the major concern. The introduction of anticoagulant prophylaxis has reduced the rate of thromboembolism to less than 10%. Immediate thalidomide dose reduction or discontinuation when paresthesia is complicated by pain or motor deficit has decreased the severity of neuropathy. Future studies will define the most effective or the best sequence of combinations which could improve life expectancy.

Abstract To identify molecularly defined subgroups in multiple myeloma, gene expression profiling was performed on purified CD138+ plasma cells of 320 newly diagnosed myeloma patients included in the Dutch-Belgian/German HOVON-65/GMMG-HD4 trial. Hierarchical clustering identified 10 subgroups; 6 corresponded to clusters described in the University of Arkansas for Medical Science (UAMS) classification, CD-1 (n = 13, 4.1%), CD-2 (n = 34, 1.6%), MF (n = 32, 1.0%), MS (n = 33, 1.3%), proliferation-associated genes (n = 15, 4.7%), and hyperdiploid (n = 77, 24.1%). Moreover, the UAMS low percentage of bone disease cluster was identified as a subcluster of the MF cluster (n = 15, 4.7%). One subgroup (n = 39, 12.2%) showed a myeloid signature. Three novel subgroups were defined, including a subgroup of 37 patients (11.6%) characterized by high expression of genes involved in the nuclear factor kappa light-chain-enhancer of activated B cells pathway, which include TNFAIP3 and CD40. Another subgroup of 22 patients (6.9%) was characterized by distinct overexpression of cancer testis antigens without overexpression of proliferation genes. The third novel cluster of 9 patients (2.8%) showed up-regulation of protein tyrosine phosphatases PRL-3 and PTPRZ1 as well as SOCS3. To conclude, in addition to 7 clusters described in the UAMS classification, we identified 3 novel subsets of multiple myeloma that may represent unique diagnostic entities.

Abstract The phase 3 trial HOVON-50 was designed to evaluate the effect of thalidomide during induction treatment and as maintenance in patients with multiple myeloma who were transplant candidates. A total of 556 patients was randomly assigned to arm A: 3 cycles of vincristine, adriamycin, and dexamethasone, or to arm B: thalidomide 200 mg orally, days 1 to 28 plus adriamycin and dexamethasone. After induction therapy and stem cell mobilization, patients were to receive high-dose melphalan, 200 mg/m2, followed by maintenance with α-interferon (arm A) or thalidomide 50 mg daily (arm B). Thalidomide significantly improved overall response rate as well as quality of the response before and after high dose melphalan. Best overall response rate on protocol was 88% and 79% (P = .005), at least very good partial remission 66% and 54% (P = .005), and complete remission 31% and 23% (P = .04), respectively, in favor of the thalidomide arm. Thalidomide also significantly improved event-free survival from median 22 months to 34 months (P &lt; .001), and prolonged progression free from median 25 months to 34 months (P &lt; .001). Median survival was longer in the thalidomide arm, 73 versus 60 months; however, this difference was not significant (P = .77). Patients randomized to thalidomide had strongly reduced survival after relapse. This trial was registered on www.controlled-trials.com as ISRCTN06413384.

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.

Abn: abnormal; *ND/R = not done or not recorded; **excluding case(s) scored as normal; § results from 21 laboratories and 10 cases means 210 possible results for each of the 6 probes.

Purpose For several decades, the treatment of elderly patients with multiple myeloma (MM) has consisted of melphalan and prednisone (MP). The Dutch-Belgium Hemato-Oncology Cooperative Group (HOVON) investigated the efficacy of thalidomide added to MP (MP-T) in a randomized phase III trial. The objective of this study was to investigate the efficacy, toxicity, and effects on quality of life of MP-T. Patients and Methods A randomized phase III trial compared standard MP with MP-T (thalidomide 200 mg/d) in newly diagnosed patients with multiple myeloma older than age 65 years. Maintenance therapy with thalidomide 50 mg/d was administered to patients after MP-T until relapse. The primary end point was event-free survival (EFS); response rate, overall survival (OS), and progression-free survival (PFS) were secondary end points. Results An intent-to-treat analysis of 333 evaluable patients showed significantly higher response rates in MP-T–treated patients compared with MP-treated patients a response (≥ partial response: 66% v 45%, respectively; P &lt; .001; and ≥ very good partial response [VGPR]: 27% v 10%, respectively; P &lt; .001). EFS was 13 months with MP-T versus 9 months with MP (P &lt; .001). OS was 40 months with MP-T versus 31 months with MP (P = .05). Conclusion This study demonstrates that thalidomide improves the response rate and VGPR in elderly patients with newly diagnosed MM. MP-T also results in a better EFS, PFS, and OS.

Abstract Ofatumumab is a unique monoclonal antibody that targets a distinct small loop epitope on the CD20 molecule. Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocytic leukemia cells with low CD20-antigen density and high expression of complement inhibitory molecules. In a phase 1/2 trial evaluating safety and efficacy of ofatumumab in relapsed or refractory follicular non-Hodgkin lymphoma (FL) grade 1 or 2, 4 dose groups of 10 patients received 4 weekly infusions of 300, 500, 700, or 1000 mg. Patients had a median of 2 prior FL therapies and 13% had elevated lactate dehydrogenase. No safety concerns or maximum tolerated dose was identified. A total of 274 adverse events were reported; 190 were judged related to ofatumumab, most occurring on the first infusion day with Common Terminology Criteria grade 1 or 2. Eight related events were grade 3. Treatment caused immediate and profound B-cell depletion, and 65% of patients reverted to negative BCL2 status. Clinical response rates ranged from 20% to 63%. Median time to progression for all patients/responders was 8.8/32.6 months, and median duration of response was 29.9 months at a median/maximum follow-up of 9.2/38.6 months. Ofatumumab is currently being evaluated in patients with rituximab-refractory FL. This trial was registered at www.clinicaltrials.gov as #NCT00092274.

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.

Abstract Complete response (CR) was an uncommon event in elderly myeloma patients until novel agents were combined with standard oral melphalan-prednisone. This analysis assesses the impact of treatment response on progression-free survival (PFS) and overall survival (OS). We retrospectively analyzed 1175 newly diagnosed myeloma patients, enrolled in 3 multicenter trials, treated with melphalan-prednisone alone (n = 332), melphalan-prednisone-thalidomide (n = 332), melphalan-prednisone-bortezomib (n = 257), or melphalan-prednisone-bortezomib-thalidomide (n = 254). After a median follow-up of 29 months, the 3-year PFS and OS were 67% and 27% (hazard ratio = 0.16; P &lt; .001), and 91% and 70% (hazard ratio = 0.15; P &lt; .001) in patients who obtained CR and in those who achieved very good partial response, respectively. Similar results were observed in patients older than 75 years. Multivariate analysis confirmed that the achievement of CR was an independent predictor of longer PFS and OS, regardless of age, International Staging System stage, and treatment. These findings highlight a significant association between the achievement of CR and long-term outcome, and support the use of novel agents to achieve maximal response in elderly patients, including those more than 75 years. This trial was registered at www.clinicaltrials.gov as #NCT00232934, #ISRCTN 90692740, and #NCT01063179.

Abstract The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence interval 0.73-0.94, P = .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P &lt; .0001) and better 1-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%.

The aim of this subset analysis was to determine if bortezomib treatment is associated with increased incidence of varicella-zoster virus (VZV) reactivation in patients with relapsed multiple myeloma (MM).Incidence of herpes zoster was evaluated in 663 patients with relapsed MM from the phase III APEX trial comparing single-agent bortezomib with high-dose dexamethasone.Bortezomib was associated with a significantly higher incidence of herpes zoster compared with dexamethasone treatment (13%, 42 of 331 v 5%, 15 of 332; P = .0002). Most herpes zoster infections were grade 1/2; incidences of grade 3/4 events (1.8% v 1.5%) and infections considered serious adverse events (1.5% v 0.9%) were similar between treatment arms, and no herpes zoster-related deaths occurred. Neither the time to onset of the herpes event nor the patients' absolute lymphocyte counts at baseline differed significantly between arms. VZV reactivation was the only herpes viral event noted to be significantly elevated in the bortezomib treatment group compared with the dexamethasone treatment group (P = .0002). The incidence of non-VZV-related herpes viral infections was comparable between arms. No additional risk factors for herpes zoster reactivation were identified.Further studies are needed to explain these observations and their implications; however, for patients treated with bortezomib or bortezomib-containing regimens, the risk of VZV reactivation should be monitored and routine use of antiviral prophylaxis considered.

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.

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.

Treatment in medical oncology is gradually shifting from the use of nonspecific chemotherapeutic agents toward an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation proteasome inhibitors (PIs), immunomodulatory agents and alkylators). Next, we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAbs), cell cycle-specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors and kinase inhibitors. Among this plethora of new agents or mechanisms, some are specially promising: anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Moreover, the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, which has produced exciting results in the relapsed/refractory setting.

With growing numbers of elderly multiple myeloma patients, reliable tools to assess their vulnerability are required. The objective of the analysis herein was to develop and validate an easy to use myeloma risk score (revised Myeloma Comorbidity Index) that allows for risk prediction of overall survival and progression-free survival differences in a large patient cohort. We conducted a comprehensive comorbidity, frailty and disability evaluation in 801 consecutive myeloma patients, including comorbidity risks obtained at diagnosis. The cohort was examined within a training and validation set. Multivariate analysis determined renal, lung and Karnofsky Performance Status impairment, frailty and age as significant risks for overall survival. These were combined in a weighted revised Myeloma Comorbidity Index, allowing for the identification of fit (revised Myeloma Comorbidity Index ≤3 [n=247, 30.8%]), intermediate-fit (revised Myeloma Comorbidity Index 4–6 [n=446, 55.7%]) and frail patients (revised Myeloma Comorbidity Index >6 [n=108, 13.5%]): these subgroups, confirmed via validation analysis, showed median overall survival rates of 10.1, 4.4 and 1.2 years, respectively. The revised Myeloma Comorbidity Index was compared to other commonly used comorbidity indices (Charlson Comorbidity Index, Hematopoietic Cell Transplantation-Specific Comorbidity Index, Kaplan-Feinstein Index): if each were divided in risk groups based on 25% and 75% quartiles, highest hazard ratios, best prediction and Brier scores were achieved with the revised Myeloma Comorbidity Index. The advantages of the revised Myeloma Comorbidity Index include its accurate assessment of patients’ physical conditions and simple clinical applicability. We propose the revised Myeloma Comorbidity Index to be tested with the “reference” International Myeloma Working Group frailty score in multicenter analyses and future clinical trials. The study was registered at the German Clinical Trials Register (DRKS-00003868).

Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatment-related side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95%CI: 10-56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95%CI: 46-60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95%CI: 1.20-1.72; P<0.001), in patients with renal failure (HR 2.02, 95%CI: 1.51-2.70; P<0.001), in those who experienced grade 3-4 infections, cardiac or gastrointestinal adverse events during treatment (HR 2.53, 95%CI: 1.75-3.64; P<0.001) and in those who required drug discontinuation due to adverse events (HR 1.67, 95%CI; 1.12-2.51; P=0.01). This increased risk was restricted to the first six months after occurrence of adverse events or drug discontinuation and declined over time. More intensive approaches, such as the combination of bortezomib-thalidomide, negatively affected outcome. Bortezomib-based combinations may overcome the negative impact of renal failure. Age 75 years or over or renal failure at presentation, occurrence of infections, cardiac or gastrointestinal adverse events negatively affected survival. A detailed geriatric assessment, organ evaluation and less intense individualized approaches are suggested in elderly unfit subjects.

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).

Key Points BDR is an active regimen and induces long-lasting responses in patients with newly diagnosed WM. Induction with single-agent bortezomib may be effective in preventing complications of hyperviscosity or rituximab-induced IgM flare.

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.

Summary This systematic review of studies compared magnetic resonance imaging ( MRI ), 18 F ‐fluorodeoxyglucose positron emission tomography ( FDG ‐ PET ), FDG ‐ PET with computerized tomography ( PET ‐ CT ) and CT with whole body X‐Ray ( WBXR ) or (whole body) CT in order to provide evidence‐based diagnostic guidelines in multiple myeloma bone disease. A comprehensive search of 3 bibliographic databases was performed; methodological quality was assessed using Q uality A ssessment of D iagnostic A ccuracy S tudies ( QUADAS ) criteria (score 1–14). Data from 32 directly comparative studies were extracted. The mean QUADAS score was 7·1 (3–11), with quality hampered mainly by a poor description of selection and execution criteria. All index tests had a higher detection rate when compared to WBXR , with up to 80% more lesions detected by the newer imaging techniques; MRI (1·12–1·82) CT (1·04–1·33), PET (1·00–1·58) and PET ‐ CT (1·27–1·45). However, the modern imaging techniques detected fewer lesions in the skull and ribs. In a direct comparison CT and MRI performed equally with respect to detection rate and sensitivity . This systematic review supports the I nternational M yeloma W orking G roup guidelines, which recommend that WBCT can replace WBXR . In our opinion, the equal performance of MRI also indicates that it is a valuable alternative. As lesions of the skull and ribs are underdiagnosed by modern imaging techniques we advise additional X ‐rays of these regions. The consequences of this approach are discussed.

Abstract Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies.

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.

The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65-0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74-1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size ⩾10%) and renal impairment at baseline (serum creatinine >2 mg dl-1) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.

Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10(-8)), 6q21 (rs9372120, P=9.09 × 10(-15)), 7q36.1 (rs7781265, P=9.71 × 10(-9)), 8q24.21 (rs1948915, P=4.20 × 10(-11)), 9p21.3 (rs2811710, P=1.72 × 10(-13)), 10p12.1 (rs2790457, P=1.77 × 10(-8)), 16q23.1 (rs7193541, P=5.00 × 10(-12)) and 20q13.13 (rs6066835, P=1.36 × 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.

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.

Patients with multiple myeloma (MM) seem to be at increased risk for more severe COVID-19 infection and associated complications due to their immunocompromised state, the older age and comorbidities. The European Myeloma Network has provided an expert consensus statement in order to guide therapeutic decisions in the era of the COVID-19 pandemic. Patient education for personal hygiene and social distancing measures, along with treatment individualization, telemedicine and continuous surveillance for early diagnosis of COVID-19 are essential. In countries or local communities where COVID-19 infection is widely spread, MM patients should have a PCR test of nasopharyngeal swab for SARS-CoV-2 before hospital admission, starting a new treatment line, cell apheresis or ASCT in order to avoid ward or community spread and infections. Oral agent-based regimens should be considered, especially for the elderly and frail patients with standard risk disease, whereas de-intensified regimens for dexamethasone, bortezomib, carfilzomib and daratumumab should be used based on patient risk and response. Treatment initiation should not be postponed for patients with end organ damage, myeloma emergencies and aggressive relapses. Autologous (and especially allogeneic) transplantation should be delayed and extended induction should be administered, especially in standard risk patients and those with adequate MM response to induction. Watchful waiting should be considered for standard risk relapsed patients with low tumor burden, and slow biochemical relapses. The conduction of clinical trials should continue with appropriate adaptations to the current circumstances. Patients with MM and symptomatic COVID-19 disease should interrupt anti-myeloma treatment until recovery. For patients with positive PCR test for SARS-CoV-2, but with no symptoms for COVID-19, a 14-day quarantine should be considered if myeloma-related events allow the delay of treatment. The need for surveillance for drug interactions due to polypharmacy is highlighted. The participation in international COVID-19 cancer registries is greatly encouraged.

PURPOSE Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016 . RESULTS A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.

CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only.CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18-65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0-2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants.Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2-39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]-NE) with daratumumab versus 46·7 months (40·0-NE) with observation only (hazard ratio 0·53, 95% CI 0·42-0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment.Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy.Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology.

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.

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.

At the primary analysis of CASTOR (median follow-up, 7.4 months), daratumumab plus bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival versus bortezomib and dexamethasone (Vd) alone in relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the final analysis for overall survival (OS).CASTOR was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned to Vd (up to eight cycles) with or without daratumumab (until disease progression). After positive primary analysis and protocol amendment, patients receiving Vd were offered daratumumab monotherapy after disease progression.At a median (range) follow-up of 72.6 months (0.0-79.8), significant OS benefit was observed with D-Vd (hazard ratio, 0.74; 95% CI, 0.59 to 0.92; P = .0075). Median OS was 49.6 months with D-Vd versus 38.5 months with Vd. Prespecified subgroup analyses demonstrated an OS advantage with D-Vd versus Vd for most subgroups, including patients age ≥ 65 years and patients with one or two prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and prior bortezomib treatment. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Vd versus Vd were thrombocytopenia (46.1% v 32.9%), anemia (16.0% v 16.0%), neutropenia (13.6% v 4.6%), lymphopenia (10.3% v 2.5%), and pneumonia (10.7% v 10.1%).D-Vd significantly prolonged OS in patients with RRMM, with the greatest OS benefit observed in patients with one prior line of therapy. To our knowledge, our results, together with the OS benefit observed with daratumumab plus lenalidomide and dexamethasone in the phase III POLLUX study, demonstrate for the first time an OS benefit with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02136134 [CASTOR]).

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.).

In the post-pandemic COVID-19 period, human activities have returned to normal and COVID-19 cases are usually mild. However, patients with multiple myeloma (MM) present an increased risk for breakthrough infections and severe COVID-19 outcomes, including hospitalization and death. The European Myeloma Network has provided an expert consensus to guide patient management in this era. Vaccination with variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4/5 strains, is essential as novel strains emerge and become dominant in the community. Boosters should be administered every 6-12 months after the last vaccine shot or documented COVID-19 infection (hybrid immunity). Booster shots seem to overcome the negative effect of anti-CD38 monoclonal antibodies on humoral responses; however, anti-BCMA treatment remains an adverse predictive factor for humoral immune response. Evaluation of the immune response after vaccination may identify a particularly vulnerable subset of patients who may need additional boosters, prophylactic therapies and prevention measures. Pre-exposure prophylaxis with tixagevimab/cilgavimab is not effective against the new dominant variants and thus is no longer recommended. Oral antivirals (nirmatrelvir/ritonavir and molnupiravir) and remdesivir are effective against Omicron subvariants BA.2.12.1, BA.4, BA.5, BQ.1.1 and/or XBB.1.5 and should be administered in MM patients at the time of a positive COVID-19 test or within 5 days post symptoms onset. Convalescent plasma seems to have low value in the post-pandemic era. Prevention measures during SARS-CoV-2 outbreaks, including mask wearing and avoiding crowded places, seem prudent to continue for MM patients.

Optimization of remission-induction and postremission therapy in elderly individuals with acute myeloid leukemia (AML) was the subject of a randomized study in patients older than 60 years. Remission-induction chemotherapy was compared between daunomycin (DNR) 30 mg/m2 on days 1, 2, and 3 versus mitoxantrone (MTZ) 8 mg/m2 on days 1, 2, and 3, both plus cytarabine (Ara-C) 100 mg/m2 on days 1 to 7. Following complete remission (CR), patients received one additional cycle of DNR or MTZ chemotherapy and were then eligible for a second randomization between eight cycles of low-dose (LD)-Ara-C 10 mg/m2 subcutaneously every 12 hours for 1 2 days every 6 weeks or no further treatment.A total of 242 patients was randomized to DNR and 247 to MTZ. Median age of both study groups was 68 years. Secondary AML was documented in 26% and 25% of patients in either arm. The probability of attaining CR was greater (P = .069) with MTZ (47%) than with DNR (38%). Median duration of neutropenia was 19 (DNR) and 22 days (MTZ). The greater response rate to MTZ therapy correlated with reduced occurrence of chemotherapy resistance (32% v 47%, P = .001). With a median follow-up of 6 years, 5-year disease-free survival (DFS) is 8% in each arm. Overall survival estimates are not different between the groups (6% v 9% at 5 yrs). Poor performance status at diagnosis, high WBC count, older age, secondary AML, and presence of cytogenetic abnormalities all had an adverse impact on survival. Secondary AML and abnormal cytogenetics predicted for shorter duration of CR. Among complete responders, 74 assessable patients were assigned to Ara-C and 73 to no further therapy. Actuarial DFS was significantly longer (P = .006) for Ara-C-treated (13% [SE = 4.0%] at 5 years) versus nontreated patients (7% [SE = 3%]), but overall survival was similar (P = .29): 18% (SE = 4.6%) versus 15% (SE = 4.3%). Meta-analysis on the value of Ara-C postremission therapy confirms these results.In previously untreated elderly patients with AML, MTZ induction therapy produces a slightly better CR rate than does a DNR-containing regimen, but it has no significant effect on remission duration and survival. Ara-C in maintenance may prolong DFS, but it did not improve survival.

PURPOSE AND METHODS A prospective, randomized, multicenter phase III trial was performed to investigate the feasibility of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in elderly patients ( &gt; or = 60 years) with advanced non-Hodgkin's lymphoma (NHL) of intermediate- and high-grade malignancy, and to compare the tolerance and efficacy of doxorubicin versus mitoxantrone (CHOP v CNOP). RESULTS Of 157 enrolled patients, 148 were eligible and 145 were assessable for response. Thirty-one percent of CNOP and 45% of CHOP patients completed six cycles without dose reduction. The cumulative normalized dose-intensity (NDI) was 92% with CHOP and 90% with CNOP after six cycles. The overall complete response (CR) rates were 49% and 31% in CHOP- and CNOP-treated patients, respectively (P = .03). Survival with CNOP was significantly worse as compared with CHOP (P = .03). Lymphoma-specific survival was significantly better in CHOP-treated patients (P = .034) At 3 years, 42% of CHOP and 26% of CNOP patients were alive. Additional unfavorable prognostic factors at diagnosis were high serum lactate dehydrogenase (LDH) level, bulky mass, and low performance status, but not age. The median disease-free intervals of complete responders were 27 (CHOP) and 15 (CNOP) months, respectively. Considering the complete group of patients, at 3 years 17% of CHOP and 13% of CNOP patients were alive and disease-free (P = .12). Common toxicity criteria (CTC) grade &gt; or = 2 with CNOP and CHOP was not different. CONCLUSION CHOP is well tolerated in elderly patients with advanced intermediate- or high-grade NHL and its NDI is not seriously impaired. Treatment with CHOP (doxorubicin) results in better CR and survival rates than CNOP (mitoxantrone). CHOP should be recommended for elderly patients with high-risk NHL.

High-dose chemoradiotherapy combined with autologous bone marrow transplantation can cure patients with disseminated, aggressive non-Hodgkin's lymphoma in whom first-line chemotherapy has failed. In contrast, cure is rare with second-line chemotherapy. It has been suggested that patients with slow responses to the initial phase of first-line chemotherapy are at high risk for relapse. Therefore, such patients are potential candidates for early bone marrow transplantation.To investigate whether patients with slow responses, defined as only a partial response after three courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), would benefit from early transplantation, we conducted a prospective, randomized trial. The early application of high-dose chemoradiotherapy and autologous bone marrow transplantation was compared with the continuation of CHOP therapy for another five courses. Patients with complete responses after three courses of CHOP (fast responses) and patients who responded partially but still had tumor-positive marrow continued with another five courses of CHOP. The study end points were the response rate, overall survival, disease-free survival, and event-free survival.Of 286 patients who could be evaluated for the rapidity of their response after three courses of CHOP, 38 percent had fast responses, 47 percent had slow responses, and 15 percent had no response. Among 106 patients with slow responses who had lymphoma-negative marrow, 69 patients (65 percent) were randomized. Seventy-four percent of the CHOP group and 68 percent of the transplantation group had complete remissions (P = 0.54). At four years the rates of overall, disease-free, and event-free survival were 85, 72, and 53 percent, respectively, in the CHOP group and 56, 60, and 41 percent in the transplantation group (P > 0.10). The disease-free survival in both groups did not differ significantly from that of nonrandomized patients with fast responses (54 percent at four years).The early application of high-dose, marrow-ablative chemoradiotherapy with autologous bone marrow transplantation does not improve the outcome in patients with aggressive non-Hodgkin's lymphoma that responds slowly to first-line CHOP chemotherapy.

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.

Background Bortezomib-induced peripheral neuropathy is a dose-limiting toxicity in patients with multiple myeloma, often requiring adjustment of treatment and affecting quality of life. We investigated the molecular profiles of early-onset (within one treatment cycle) versus late-onset (after two or three treatment cycles) bortezomib-induced peripheral neuropathy and compared them with those of vincristine-induced peripheral neuropathy during the induction phase of a prospective phase 3 trial. Methods In the induction phase of the HOVON-65/GMMG-HD4 trial, patients (aged 18–65 years) with newly diagnosed Salmon and Durie stage 2 or 3 multiple myeloma were randomly assigned to three cycles of bortezomib-based or vincristine-based induction treatment. We analysed the gene expression profiles and single-nucleotide polymorphisms (SNPs) of pretreatment samples of myeloma plasma cells and peripheral blood, respectively. This study is registered, number ISRCTN64455289. Findings We analysed gene expression profiles of myeloma plasma cells from 329 (39%) of 833 patients at diagnosis, and SNPs in DNA samples from 369 (44%) patients. Early-onset bortezomib-induced peripheral neuropathy was noted in 20 (8%) patients, and 63 (25%) developed the late-onset type. Early-onset and late-onset vincristine-induced peripheral neuropathy was noted in 11 (4%) and 17 (7%) patients, respectively. Significant genes in myeloma plasma cells from patients that were associated with early-onset bortezomib-induced peripheral neuropathy were the enzyme coding genes RHOBTB2 (upregulated by 1·59 times; p=4·5×10−5), involved in drug-induced apoptosis, CPT1C (1·44 times; p=2·9×10−7), involved in mitochondrial dysfunction, and SOX8 (1·68 times; p=4·28×10−13), involved in development of peripheral nervous system. Significant SNPs in the same patients included those located in the apoptosis gene caspase 9 (odds ratio [OR] 3·59, 95% CI 1·59–8·14; p=2·9×10−3), ALOX12 (3·50, 1·47–8·32; p=3·8×10−3), and IGF1R (0·22, 0·07–0·77; p=8·3×10−3). In late-onset bortezomib-induced peripheral neuropathy, the significant genes were SOD2 (upregulated by 1·18 times; p=9·6×10−3) and MYO5A (1·93 times; p=3·2×10−2), involved in development and function of the nervous system. Significant SNPs were noted in inflammatory genes MBL2 (OR 0·49, 95% CI 0·26–0·94; p=3·0×10−2) and PPARD (0·35, 0·15–0·83; p=9·1×10−3), and DNA repair genes ERCC4 (2·74, 1·56–4·84; p=1·0×10−3) and ERCC3 (1·26, 0·75–2·12; p=3·3×10−3). By contrast, early-onset vincristine-induced peripheral neuropathy was characterised by upregulation of genes involved in cell cycle and proliferation, including AURKA (3·31 times; p=1·04×10−2) and MKI67 (3·66 times; p=1·82×10−3), and the presence of SNPs in genes involved in these processes—eg, GLI1 (rs2228224 [0·13, 0·02–0·97, p=1·18×10−2] and rs2242578 [0·14, 0·02–1·12, p=3·00×10−2]). Late-onset vincristine-induced peripheral neuropathy was associated with the presence of SNPs in genes involved in absorption, distribution, metabolism, and excretion—eg, rs1413239 in DPYD (3·29, 1·47–7·37, 5·40×10−3) and rs3887412 in ABCC1 (3·36, 1·47–7·67, p=5·70×10−3). Interpretation Our results strongly suggest an interaction between myeloma-related factors and the patient's genetic background in the development of treatment-induced peripheral neuropathy, with different molecular pathways being implicated in bortezomib-induced and vincristine-induced peripheral neuropathy. Funding German Federal Ministry of Education and Research, Dutch Cancer Foundation Queen Wilhelmina, European Hematology Association, International Myeloma Foundation, Erasmus MC, and Janssen-Cilag Orthobiotech.

We determined the expression levels of the mdr1 and mdr3 multidrug-resistance genes (also known as PGY1 and PGY3, respectively) in peripheral blood cells from 69 adult patients with acute and chronic leukemias, using an RNase protection assay. Expression of mdr1 was found in samples from patients with acute nonlymphocytic leukemia (13 of 17), chronic myelocytic leukemia (CML, chronic phase, 10 of 10; blast crisis, three of four), acute lymphocytic leukemia (ALL, eight of 11), B-cell chronic lymphocytic leukemia (B-CLL, 17 of 17), hairy cell leukemia (HCL, one of two), and T-cell prolymphocytic leukemia (one of one), but not in B-cell prolymphocytic leukemia (B-PLL, 0 of seven). Expression of mdr3 was only detected in samples from B-cell lymphocytic leukemias: CML, lymphoid blast crisis (one of one), B-cell ALL (two of two), B-CLL (17 of 17), B-PLL (seven of seven), and HCL (two of two). In vitro drug uptake studies by on-line flow cytometry showed that in leukemia cells expressing either mdr1 or mdr3 , the steady-state accumulation of daunorubicin could be significantly increased by addition of cyclosporine and, to a lesser extent, by verapamil. Because cyclosporine and verapamil are known as inhibitors of the mdr1 -encoded P-glycoprotein drug-efflux pump, and because the mdr1 and mdr3 genes are highly homologous, our data suggest that the mdr3 gene encodes a functional drug pump in B-cell lymphocytic leukemias. The results of this study may have implications for clinical therapy for acute or chronic leukemias expressing the mdr1 or mdr3 gene, in particular, treatment with combinations of cytotoxic drugs plus agents that reverse multidrug resistance. Since mdr1 and mdr3 are frequently expressed in untreated as well as treated leukemia, such combination therapy should be considered for untreated patients as well as treated patients.

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.

Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved outcomes for patients with multiple myeloma. As a result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological side-effect associated with thalidomide and bortezomib. Maximising treatment benefit while preserving quality of life therefore requires a careful balance between achieving optimum activity and minimising toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib.

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.

Abstract To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT. Lenalidomide was dosed 10 mg on days 1 to 21 of a 28-day schedule for a total of 24 cycles. Peripheral blood samples were taken to evaluate immune modulating effects. Thirty-five eligible patients were enrolled, and 30 started with lenalidomide. After 2 cycles, 14 patients (47%) had to stop treatment, mainly because of the development of acute graft versus host disease (GVHD). In total, 13 patients (43%) stopped treatment because of development of GVHD, 5 patients (17%) because of other adverse events, and 5 patients (17%) because of progression. Responses improved in 37% of patients, and the estimated 1-year progression-free survival from start of maintenance was 69% (90% confidence interval, 53%-81%). Lenalidomide increased the frequency of human leukocyte antigen-DR+ T cells and regulatory T cells, without correlation with clinical parameters. In conclusion, lenalidomide maintenance 10 mg daily after nonmyeloablative allo-SCT with unmanipulated graft in multiple myeloma patients is not feasible, mainly because of the induction of acute GVHD. This trial was registered at www.trialregister.nl as #NTR1645.

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.

Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) <30, 30–50, 51–80 and >80 ml min−1). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl ⩽50 ml min−1 (severe-to-moderate) and >50 ml min−1 (no/mild impairment). Response rates with bortezomib were similar (36–47%) and time to response rapid (0.7–1.6 months) across subgroups. Although the trend was toward shorter TTP/OS in bortezomib patients with severe-to-moderate vs no/mild impairment, differences were not significant. OS was significantly shorter in dexamethasone patients with CrCl ⩽50 vs >50 ml min−1 (P=0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the detrimental effect of renal impairment. Safety profile of bortezomib was comparable between subgroups. With dexamethasone, grade 3/4 adverse events (AEs), serious AEs and discontinuations for AEs were significantly elevated in patients with CrCl ⩽50 vs >50 ml min−1. These results indicate that bortezomib is active and well tolerated in patients with relapsed MM with varying degrees of renal insufficiency. Efficacy/safety were not substantially affected by severe-to-moderate vs no/mild impairment.

Vaults are ribonucleoprotein particles found in the cytoplasm of eucaryotic cells. The 13 MDa particles are composed of multiple copies of three proteins: an Mr 100 000 major vault protein (MVP) and two minor vault proteins of Mr 193 000 (vault poly-(ADP-ribose) polymerase) and Mr 240 000 (telomerase-associated protein 1), as well as small untranslated RNA molecules of approximately 100 bases. Although the existence of vaults was first reported in the mid-1980s no function has yet been attributed to this organelle. The notion that vaults might play a role in drug resistance was suggested by the molecular identification of the lung resistance-related (LRP) protein as the human MVP. MVP/LRP was found to be overexpressed in many chemoresistant cancer cell lines and primary tumor samples of different histogenetic origin. Several, but not all, clinico-pathological studies showed that MVP expression at diagnosis was an independent adverse prognostic factor for response to chemotherapy. The hollow barrel-shaped structure of the vault complex and its subcellular localization indicate a function in intracellular transport. It was therefore postulated that vaults contributed to drug resistance by transporting drugs away from their intracellular targets and/or the sequestration of drugs. Here, we review the current knowledge on the vault complex and critically discuss the evidence that links vaults to drug resistance.

To investigate whether the relative dose-intensity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy could be improved by prophylactic administration of granulocyte colony-stimulating factor (G-CSF) in elderly patients with aggressive non-Hodgkin's lymphoma (NHL).Patients aged 65 to 90 years (median, 72 years) with stage II to IV aggressive NHL were randomly assigned to receive standard CHOP every 3 weeks or CHOP plus G-CSF every 3 weeks on days 2 to 11 of each cycle.In 389 eligible patients, the relative dose intensities (RDIs) of cyclophosphamide (median, 96.3% v 93.9%; P =.01) and doxorubicin (median, 95.4% v 93.3%; P =.04) were higher in patients treated with CHOP plus G-CSF. The complete response rates were 55% and 52% for CHOP and CHOP plus G-CSF, respectively (P =.63). The actuarial overall survival at 5 years was 22% with CHOP alone, compared with 24% with CHOP plus G-CSF (P =.76), with a median follow-up of 33 months. Patients treated with CHOP plus G-CSF had an identical incidence of infections, with World Health Organization grade 3 to 4 (34 of 1,191 cycles v 36 of 1,195 cycles). Only the cumulative days with antibiotics were fewer with CHOP plus G-CSF (median, 0 v 6 days; P =.006) than with CHOP alone. The number of hospital admissions and the number of days in hospital were not different.In elderly patients, G-CSF improved the RDI of CHOP, but this did not lead to a higher complete response rate or better overall survival. G-CSF did not prevent serious infections.

Abstract The expression of the MDR-1-encoded P-170 glycoprotein (P-170) associated with clinical multidrug resistance (MDR) was investigated in 52 consecutive patients with untreated acute myeloid leukemia (AML). P- 170 expression was analyzed in correlation with CD34 expression and clinical response. Thirty of 52 patients expressed P-170 (58%). Eight of 30 P-170+ as compared with 16 of 22 P-170- patients achieved a complete remission (CR) (27% v 73%, P = .003). In 21 of 30 P-170+ patients, expression of the CD34 antigen was observed in greater than 10% of the blast cells, as compared with 14 of 22 P-170- patients (70% v 64%, P &gt; .05). The CR rate of CD34+ and CD34- patients was 31% and 76%, respectively (P = .006). In AMLs that simultaneously expressed both P-170 and CD34, the CR rate was worse as compared with those negative for P-170 and CD34 (5% v 63%, P = .004). In 12 patients (8 P- 170+, 4 P-170-) CD34 and P-170 expression were further characterized by double fluorescence studies. It was shown that P-170+ cells were largely, but not exclusively, restricted to the CD34+ cell population. For the 8 P-170+ AML samples, the median ratio of P-170+/P-170- in CD34+ cells was 4.845 (range, 0.60 to 25.00) as compared with 0.135 (range, 0.02 to 0.67) in CD34- cells. In these 12 AML samples, the presence of functional resistance as defined by reduced daunorubicin accumulation was evaluated in CD34+ and CD34- AML cells. In 8 of 8 P- 170+ patients, intracellular daunorubicin accumulation in CD34+ AML blast cells was lower than in CD34- cells, and it increased after cyclosporin addition. No difference of intracellular daunorubicin accumulation was observed between CD34+ and CD34- AML cells of 4 P-170- patients. These data indicate that P-170 expression in AML with a heterogeneous CD34+ phenotype seems predominantly present in CD34+ AML blast cells.