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Treatment of relapsed/refractory multiple myeloma (RRMM) is challenging as patients exhaust all available therapies and the disease becomes refractory to standard drug classes. Here we report the final results of LocoMMotion, the first prospective study of real-world clinical practice (RWCP) in triple-class exposed (TCE) patients with RRMM, with a median follow-up of 26.4 months (range, 0.1-35.0). Patients (N  =  248) had received median 4 prior LOT (range, 2-13) at enrollment. 91 unique regimens were used in index LOT. Overall response rate was 31.9% (95% CI, 26.1-38.0), median progression-free survival (PFS) was 4.6 months (95% CI, 3.9-5.6) and median overall survival was 13.8 months (95% CI, 10.8-17.0). 152 patients (61.3%) had subsequent LOTs with 134 unique regimens, of which 78 were used in first subsequent LOT. Median PFS2 (from start of study through first subsequent LOT) was 10.8 months (95% CI, 8.4-13.0). 158 patients died on study, 67.7% due to progressive disease. Additional subgroup analyses and long-term safety summaries are reported. The high number of RWCP treatment regimens utilized and poor clinical outcomes confirm a lack of standardized treatment for TCE patients with RRMM, highlighting the need for new treatments with novel mechanisms., Competing Interests: Competing interests: M-VM has received honoraria from or served on the board of directors/advisory committees for AbbVie, Adaptive Biotechnologies, Amgen, BMS/Celgene, GSK, Janssen, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Seagen, and Takeda. KW has served as a consultant and received honoraria from Adaptive Biotechnologies, Karyopharm, and Takeda; has received honoraria from Roche; and has received honoraria and served as a member on boards of directors and/or advisory committees for Amgen, BMS, Celgene, GSK, Janssen, Oncopeptides, and Sanofi. VDS has served on an advisory board or speakers’ bureaus and received honoraria from AbbVie, Alexion, AOP Health, argenx, BMS, GSK, Grifols, Leo Pharma, Novartis, Novo Nordisk, Sanofi, SOBI, and Takeda. HG has served as a consultant for Amgen, Novartis, and Takeda; has served as a consultant and received honoraria, grants, and/or provision of investigational medicinal product and research funding from Amgen, BMS, Celgene, Chugai, Janssen, and Sanofi; has received research funding from Incyte, Molecular Partners, MSD, Mundipharma, and Novartis; and has received other grants from Dietmer Hopp Foundation. MD has received honoraria from Amgen, BMS, GSK, and Janssen; and has served on the speakers’ bureau for Janssen. MM has received honoraria from Adaptive Biotech, Amgen, Astellas, BMS, Gilead, Novartis, Pfizer, and Takeda; and has received honoraria/research funding from Celgene and Sanofi. JL-H has no relationships to disclose. DD is an employee/consultant/honoraria/member of board of directors/advisory committees for Janssen Cilag; and a member of the board of directors/advisory committees/received research funding from Celgene. EA has no relationships to disclose. LV has served on the advisory board of BMS, Janssen, and Takeda. AP has received honoraria from or has served in a consulting/advisory role for AbbVie, Amgen, BMS, Janssen, Pfizer, Sanofi, and Takeda. RB has received honoraria/research funding from Allogene, BMS, Gilead, Janssen, and Servier. NWCJvdD has received research funding from AbbVie, Amgen, BMS, Celgene, Cellectis, Janssen Pharmaceuticals, and Novartis; and has served in a consulting/advisory role for Adaptive, Amgen, Bayer, BMS, Celgene, Janssen, Novartis, Pfizer, Roche, Sanofi, Servier, and Takeda. EMO has received honoraria from or has served in a consulting/advisory role for AbbVie, Amgen, BMS, GSK, Janssen, Karyopharm, Menarini, Oncopeptides, Pfizer, Sanofi, and Takeda. TR is a former Janssen employee. JMS is a Janssen employee. SK is a Janssen employee. IH is a Janssen employee. VS is a Janssen employee. LM is a Janssen employee. JB is a Janssen employee. OCF is an employee of Legend Biotech USA Inc. HE has received research funding or honoraria and has served in a consulting/advisory role for Amgen, BMS/Celgene, GSK, Janssen, and Sanofi. PM has received honoraria and/or served on advisory boards for AbbVie, Amgen, Celgene, Janssen, Sanofi, and Takeda., (© 2024. The Author(s).)

Background: Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM., Methods: FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders., Results: Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores., Conclusion: The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach., Trial Registration: This trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015., (© 2021. The Author(s).)

Despite the recent introduction of new therapies for multiple myeloma (MM), it remains an incurable disease. As MM progresses, patients experience cycles of relapse and remission, with remission periods becoming increasingly shorter as the disease becomes less treatment-sensitive. The treatment of relapsed refractory MM (RRMM) remains a significant clinical challenge. Patients with RRMM are a highly heterogeneous group and choosing the most appropriate treatment requires careful consideration. Furthermore, the number of treatment options for MM is continually growing with no definitive consensus to guide treating clinicians. The emergence of second-generation proteasome inhibitors (e.g., carfilzomib and ixazomib), immunomodulatory drugs (e.g., pomalidomide) and monoclonal antibodies (e.g., isatuximab) has expanded an already complex treatment landscape. This review provides a clear summary of the available treatments for MM and discusses how to tailor treatments to individual patients' needs. Novel treatments currently under clinical development, including venetoclax, melflufen and CAR T-cell therapies, are also discussed., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov).

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse (N = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P = 0.0068), and patients with (22.0 vs 13.8 months; P = 0.0241) or without (16.5 vs 9.5 months; P = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months (P = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P < 0.001) and lenalidomide-nonrefractory (95.7% vs 60.0%; P < 0.001) patients, with similar results regardless of prior bortezomib or SCT. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments.

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: ABBV-838 is an antibody-drug conjugate targeting a unique epitope of CD2 subset 1, a cell-surface glycoprotein expressed on multiple myeloma cells. This phase I/Ib first-in-human, dose-escalation study (trial registration ID: NCT02462525) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-838 in patients with relapsed and refractory multiple myeloma (RRMM)., Patients and Methods: Eligible patients (≥18 years) received ABBV-838 (3+3 design) intravenously starting from 0.6 mg/kg up to 6.0 mg/kg for 3-week dosing intervals (Q3W). Patients could continue ABBV-838 for up to 24 months. Assessment of alternate dosing intervals (Q1W and Q2W) was conducted in parallel., Results: As of March 2017, 75 patients received at least one dose of ABBV-838. The most common any-grade treatment-emergent adverse events (TEAE) were neutropenia and anemia (28.0% each), fatigue (26.7%), and nausea (25.3%). Grade 3/4/5 TEAEs were reported in 73.3% of patients across all treatment groups; most common were neutropenia (20.0%), anemia (18.7%), and leukopenia (13.3%). Grade 3/4/5 ABBV-838-related TEAEs were reported by 40.0% of patients across all treatment groups. Overall, 4.0% of patients experienced TEAEs leading to death, none ABBV-838 related. The MTD was not reached; the selected recommended dose for the expansion cohort was 5.0 mg/kg Q3W. Pharmacokinetic analysis showed that exposure was approximately dose proportional. The overall response rate was 10.7%; very good partial responses and partial responses were achieved by 2 (2.7%) and 6 (8.0%) patients, respectively., Conclusions: These results demonstrate that ABBV-838 is safe and well-tolerated in patients with RRMM with a very limited efficacy., (©2020 American Association for Cancer Research.)

Background: 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., Methods: 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 β 2 microglobulin at screening. Bortezomib (1·3 mg/m 2 ) 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., Findings: 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])., Interpretation: 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., Funding: Celgene., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

With the introduction of new drugs with different mechanisms of action, multiple myeloma (MM) patients' outcomes have improved. However, the efficacy seen in clinical trials is often not seen in real-world settings and data on the effectiveness of MM therapies are needed. INSIGHT MM is a prospective, global, non-interventional, observational study that is enrolling approximately 4200 patients with newly diagnosed or relapsed/refractory MM, making it the largest study of its kind to date. The study aims to describe contemporary, real-world patterns of patient characteristics, clinical disease presentation, therapies chosen, clinical outcomes (response, treatment duration, time-to-next-therapy, progression-free and overall survival), safety, healthcare resource utilization and quality of life. One interim analysis has been conducted to date; current accrual is approximately 3094 patients. Trial registration number: NCT02761187.

Treatment history influences the outcomes of subsequent therapies in patients with relapsed or refractory multiple myeloma (RRMM) and needs to be considered when deciding which treatment to use next. To assess the relative merits of immunomodulatory (IMiD)-free treatments, a systematic literature review (SLR) was conducted to identify relevant randomized controlled trials in patients with RRMM. A network meta-analysis (NMA) was performed to assess various IMiD-free regimens, including bortezomib and dexamethasone (Vd)-based treatments, and to explore differences in patient outcomes. The SLR identified 52 articles, from which four trials were ultimately included in the base-case NMA. The NMA showed that daratumumab plus Vd (DVd) provided a significant advantage in prolonging progression-free survival. Similar trends were observed for overall survival and overall response. Across all outcomes, DVd had the highest probability of being the best treatment. These findings suggest that DVd may provide superior clinical outcomes for RRMM patients suitable for IMiD-free regimens.

Background: The randomized phase 3 ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab plus lenalidomide and dexamethasone (ELd) versus lenalidomide and dexamethasone (Ld) in relapsed/refractory multiple myeloma (RRMM), and to date, has the longest follow-up of any monoclonal antibody in patients with RRMM., Methods: In this extended 4-year follow-up of the ELOQUENT-2 trial, the coprimary endpoints of progression-free survival (PFS) and overall response rate as well as the secondary endpoint of overall survival were assessed. In the absence of head-to-head trials comparing Ld-based triplet regimens to guide treatment selection, 4 randomized controlled trials-ELOQUENT-2, ASPIRE, TOURMALINE-MM1, and POLLUX-were indirectly compared to provide insight into the relative efficacy of these regimens in RRMM., Results: Data at 4 years were consistent with 2- and 3-year follow-up data: ELd reduced the risk of disease progression/death by 29% versus Ld (hazard ratio, 0.71) while maintaining safety. The greatest PFS benefit among the assessed subgroups was observed in patients at the median time or further from diagnosis (≥3.5 years) with 1 prior line of therapy, who had a 44% reduction in the risk of progression/death, and in patients in the high-risk category, who had a 36% reduction in favor of ELd. This regimen also showed a relative PFS benefit that was maintained beyond 50 months., Conclusions: The sustained PFS benefit and long-term safety of ELd at 4 years, similar to those observed at 2 and 3 years, support ELd as a valuable therapeutic option for the long-term treatment of patients with RRMM., (© 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Background: The phase 3 ENDEAVOR trial was a head-to-head comparison of two proteasome inhibitors in patients with relapsed or refractory multiple myeloma. Progression-free survival was previously reported to be significantly longer with carfilzomib administered in combination with dexamethasone than with bortezomib and dexamethasone in an interim analysis. The aim of this second interim analysis was to compare overall survival between the two treatment groups., Methods: ENDEAVOR was a phase 3, open-label, randomised controlled trial in patients with relapsed or refractory multiple myeloma. Patients were recruited from 198 hospitals and outpatient clinics in 27 countries in Europe, North America, South America, and the Asia-Pacific region. Patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and had received between one and three previous lines of therapy. Patients were randomly assigned (1:1) to receive carfilzomib and dexamethasone (carfilzomib group) or bortezomib and dexamethasone (bortezomib group) through a blocked randomisation scheme (block size of four), stratified by International Staging System stage, previous lines of treatment, previous proteasome inhibitor therapy, and planned route of bortezomib delivery if assigned to the bortezomib group. Carfilzomib (20 mg/m 2 on days 1 and 2 of cycle 1; 56 mg/m 2 thereafter) was given as a 30-min intravenous infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles; bortezomib (1·3 mg/m 2 ) was given as an intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20 mg oral or intravenous infusion) was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in the carfilzomib group and on days 1, 2, 4, 5, 8, 9, 11, and 12 in the bortezomib group. The primary endpoint of ENDEAVOR, progression-free survival, has been previously reported. A stratified log-rank test was used to compare overall survival between treatment groups for this prospectively planned second interim analysis. Efficacy assessments were done in all randomly assigned patients (the intention-to-treat population) and the safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01568866, and is no longer enrolling patients., Findings: Between June 20, 2012, and June 30, 2014, 1096 patients were assessed for eligibility, of whom 929 were randomly assigned (464 to the carfilzomib group and 465 to the bortezomib group). The cutoff date for this prespecified interim analysis was Jan 3, 2017. Median overall survival was 47·6 months (95% CI 42·5-not evaluable) in the carfilzomib group versus 40·0 months (32·6-42·3) in the bortezomib group (hazard ratio 0·791 [95% CI 0·648-0·964], one-sided p=0·010). Grade 3 or worse adverse events were reported in 377 (81%) of 463 patients in the carfilzomib group and 324 (71%) of 456 patients in the bortezomib group, and serious adverse events in 273 (59%) patients in the carfilzomib group and 182 (40%) in the bortezomib group. The most frequent grade 3 or worse adverse events were anaemia (76 [16%] of 463 patients in the carfilzomib group vs 46 [10%] of 456 patients in the bortezomib group), hypertension (67 [15%] vs 15 [3%]), pneumonia (42 [9%] vs 39 [9%]), thrombocytopenia (41 [9%] vs 43 [9%]), fatigue (31 [7%] vs 35 [8%]), dyspnoea (29 [6%] vs ten [2%]), decreased lymphocyte count (29 [6%] vs nine [2%]), diarrhoea (18 [4%] vs 39 [9%]), and peripheral neuropathy (six [1%] vs 28 [6%]). Treatment-related deaths occurred in five (1%) of 463 patients in the carfilzomib group (pneumonia [n=2], interstitial lung disease [n=1], septic shock [n=1], and unknown [n=1]) and two (<1%) of 456 patients in the bortezomib group (cardiac arrest [n=1] and pneumonia [n=1])., Interpretation: Carfilzomib provided a significant and clinically meaningful reduction in the risk of death compared with bortezomib. To our knowledge, carfilzomib is the first and only multiple myeloma treatment that extends overall survival in the relapsed setting over the current standard of care. This study is informative for deciding which proteasome inhibitor to use for treating this disease., Funding: Onyx Pharmaceuticals Inc, an Amgen Inc subsidiary., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The role of allogeneic hematopoietic cell transplantation (HCT) for the treatment of multiple myeloma is controversial. However, the introduction of proteasome inhibitors and immunomodulatory drugs might influence outcomes in case of relapse or refractory disease after allogeneic HCT., Methods: We report 41 consecutive patients that underwent allogeneic HCT for the treatment of relapsed or refractory multiple myeloma., Results: Three-year event-free survival (EFS) and overall survival (OS) of the whole cohort were 15% and 51%, respectively. In a subgroup analysis, allogeneic HCT after a second high-dose chemotherapy with autologous stem cell support was associated with a decreased 3-year EFS (6% vs 24%, P=.04) and OS (35% vs 64%, P=.09). In case of relapse or refractory disease after allogeneic HCT, the treatment with proteasome inhibitors or immunomodulatory drugs significantly improved survival (1-year OS 79% vs 29%, P=.001)., Conclusion: The incorporation of proteasome inhibitors and immunomodulatory drugs into transplant protocols has the potential to improve outcomes and refine the role of allogeneic HCT for the treatment of multiple myeloma as a platform for long-term disease control., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The randomized phase 3 study ENDEAVOR demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (MM). We conducted a preplanned subgroup analysis of ENDEAVOR to evaluate Kd vs Vd by cytogenetic risk. Of 785 patients with known cytogenetics, 210 (27%) had high-risk cytogenetics (Kd, n=97 (25%); Vd, n=113 (28%)) and 575 (73%) had standard-risk cytogenetics (Kd, n=284 (75%); Vd, n=291 (72%)). Median PFS in the high-risk group was 8.8 months for Kd vs 6.0 months for Vd (hazard ratio (HR), 0.65; 95% confidence interval (CI), 0.45-0.92; P=0.0075). Median PFS in the standard-risk group was not estimable for Kd vs 10.2 months for Vd (HR, 0.44; 95% CI, 0.33-0.58; P<0.0001). Overall response rates were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ⩾CR. This preplanned subgroup analysis found that Kd was superior to Vd in relapsed or refractory MM, regardless of cytogenetic risk.

Background: Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients., Methods/design: ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and--in absence of available stem cells from earlier harvesting--undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3(rd) (arm A + B) and the 5(th) lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS., Discussion: This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients., Trial Registration: ISRCTN16345835 (date of registration 2010-08-24).

Background: Health-related quality of life (HRQoL) is an important element for consideration in treatment decisions in patients with relapsed/refractory multiple myeloma (RRMM). The pivotal MM-003 (A Phase 3, Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Pomalidomide in Combination With Low-Dose Dexamethasone vs. High-Dose Dexamethasone in Patients With Refractory Multiple Myeloma or Relapsed and Refractory Multiple Myeloma and Companion Study [NIMBUS]) randomized, open-label, multicenter, phase III trial demonstrated improved progression-free survival (PFS) and prolonged overall survival (OS) with pomalidomide (POM) plus low-dose dexamethasone (POM + LoDEX) versus high-dose dexamethasone (HiDEX) in patients with RRMM in whom lenalidomide (LEN) and bortezomib (BORT) had failed. MM-003 also investigated HRQoL as a predefined secondary end point., Patients and Methods: Recruited patients (n = 455) were refractory to their last treatment and had failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination). Eight clinically relevant and validated HRQoL domains from the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-MY20, and EQ-5D questionnaires were selected for analysis. Time to symptom worsening based on minimally important differences (MIDs) was calculated., Results: Clinically meaningful improvements in HRQoL as determined by MIDs, regression analyses, and best response analyses were observed more frequently in patients receiving POM + LoDEX than in those receiving HiDEX. POM + LoDEX significantly extended median time to clinically meaningful worsening in HRQoL versus HiDEX in 4 HRQoL domains and demonstrated a trend in an additional 3 domains. Patients in the HiDEX arm experienced earlier HRQoL deterioration compared with those in the POM + LoDEX arm in each domain analyzed., Conclusion: POM + LoDEX offer good clinical outcomes that lead to improved and prolonged HRQoL compared with HiDEX in patients with RRMM and end-stage disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)