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BACKGROUND: Elotuzumab plus lenalidomide and dexamethasone has shown improved progression-free and overall survival versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. We aimed to assess these regimens in patients with newly diagnosed multiple myeloma who are ineligible for haematopoietic stem-cell transplantation (HSCT). METHODS: ELOQUENT-1 is an open-label, multicentre, randomised, phase 3 trial conducted at 185 hospitals, oncology practices, and research centres in 19 countries. Eligible patients were aged 18 years or older with newly diagnosed, untreated, symptomatic myeloma and not candidates for high-dose therapy plus HSCT, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower. Patients were randomly assigned (1:1) to receive elotuzumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone using an interactive voice response system, stratified by the International Staging System (ISS; stage I-II vs III), age (

Background: Despite recent advances in therapeutic options, there remains an unmet need for treating patients with relapsed or refractory multiple myeloma, especially in those previously exposed or refractory to lenalidomide. This updated efficacy and safety analysis from the phase 3 CANDOR study compared carfilzomib, daratumumab, and dexamethasone (KdD) with carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma. Methods: In this updated analysis of the randomised, multicentre, open-label, phase 3 CANDOR study, patients (aged ≥18 years) with relapsed or refractory multiple myeloma, at least a partial response to between one and three previous therapies, and Eastern Cooperative Oncology Group performance status of 0–2, were recruited from 102 medical centres globally and randomly assigned (2:1) by interactive voice or web response software to receive KdD or Kd. Participants were stratified by disease stage, previous proteasome inhibitor or anti-CD38 antibody exposure, and number of previous therapies. All patients received intravenous infusions of carfilzomib twice per week at 56 mg/m2 (20 mg/m2 on days 1 and 2 during cycle 1) on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3–6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients >75 years old). This analysis was a preplanned interim analysis for overall survival; however, at the time of data cutoff, overall survival data were not mature. The primary endpoint was progression-free survival. Here, we provide updated progression-free survival data, assessed centrally by Onyx Response Computer Algorithm in the intention-to-treat population, with 11 months additional follow-up. Adverse events were assessed in the safety population, which included all participants who received at least one dose of trial treatment. CANDOR is registered with ClinicalTrials.gov, NCT03158688, and is active but not recruiting. Findings: Between June 13, 2017, and June 25, 2018, 466 patients were enrolled, of whom 312 received KdD and 154 received Kd. At data cutoff (June 15, 2020), median follow-up was 27·8 months (IQR 25·6–29·5) for KdD and 27·0 months (13·2–28·6) for Kd. Median progression-free survival was 28·6 months (95% CI 22·7–not estimable [NE]) in the KdD group and 15·2 months (11·1–19·9) in the Kd group (hazard ratio 0·59 [95% CI 0·45–0·78], log-rank p

BACKGROUND: Despite recent advances in therapeutic options, there remains an unmet need for treating patients with relapsed or refractory multiple myeloma, especially in those previously exposed or refractory to lenalidomide. This updated efficacy and safety analysis from the phase 3 CANDOR study compared carfilzomib, daratumumab, and dexamethasone (KdD) with carfilzomib and dexamethasone (Kd) in patients with relapsed or refractory multiple myeloma. METHODS: In this updated analysis of the randomised, multicentre, open-label, phase 3 CANDOR study, patients (aged =18 years) with relapsed or refractory multiple myeloma, at least a partial response to between one and three previous therapies, and Eastern Cooperative Oncology Group performance status of 0-2, were recruited from 102 medical centres globally and randomly assigned (2:1) by interactive voice or web response software to receive KdD or Kd. Participants were stratified by disease stage, previous proteasome inhibitor or anti-CD38 antibody exposure, and number of previous therapies. All patients received intravenous infusions of carfilzomib twice per week at 56 mg/m(2) (20 mg/m(2) on days 1 and 2 during cycle 1) on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients >75 years old). This analysis was a preplanned interim analysis for overall survival; however, at the time of data cutoff, overall survival data were not mature. The primary endpoint was progression-free survival. Here, we provide updated progression-free survival data, assessed centrally by Onyx Response Computer Algorithm in the intention-to-treat population, with 11 months additional follow-up. Adverse events were assessed in the safety population, which included all participants who received at least one dose of trial treatment. CANDOR is registered with ClinicalTrials.gov, NCT03158688, and is active but not recruiting. FINDINGS: Between June 13, 2017, and June 25, 2018, 466 patients were enrolled, of whom 312 received KdD and 154 received Kd. At data cutoff (June 15, 2020), median follow-up was 27·8 months (IQR 25·6-29·5) for KdD and 27·0 months (13·2-28·6) for Kd. Median progression-free survival was 28·6 months (95% CI 22·7-not estimable [NE]) in the KdD group and 15·2 months (11·1-19·9) in the Kd group (hazard ratio 0·59 [95% CI 0·45-0·78], log-rank p

Given the increasing use of frontline lenalidomide-based therapies in multiple myeloma (MM), there is an emerging need for lenalidomide-sparing regimens at relapse. Carfilzomib plus dexamethasone and daratumumab (KdD) and daratumumab plus bortezomib and dexamethasone (DVd) are lenalidomide-sparing triplet regimens that are approved for relapsed and/or refractory MM (R/RMM). In the absence of a head-to-head trial comparing these treatments, a matching-adjusted indirect treatment comparison (MAIC) was conducted to assess the efficacy and safety of KdD versus DVd. Results showed that treatment with KdD decreases the risk of progression or death versus DVd (HR 0.64; 95% confidence interval (CI): 0.46–0.90). Time-dependent analysis demonstrated a larger benefit for KdD after the first eight cycles. Unmatched subgroup analysis indicated that KdD may be particularly effective in lenalidomide-exposed and -refractory patients. The present analysis suggests that KdD improves outcomes compared with DVd in patients with R/RMM and may provide a rationale for a preferential treatment. © 2022 Informa UK Limited, trading as Taylor & Francis Group.

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

Vaccination is one of the most successful medical interventions that has saved the life of millions of people. Vaccination is particularly important in patients with multiple myeloma, who have an increased risk of infections due to the disease-inherent immune suppression, and because of the immune suppressive effects of therapy. Hence, all appropriate measures should be exploited, to elicit an effective immune response to common pathogens like influenza, pneumococci, varicella zoster virus, and to those bacteria and viruses (haemophilus influenzae, meningococci, and hepatitis) that frequently may pose a significant risk to patients with multiple myeloma. Patients after autologous, and specifically after allogeneic transplantation have severely reduced antibody titers, and therefore require a broader spectrum of vaccinations. Response to vaccination in myeloma often is less vigorous than in the general population, mandating either measurement of the postvaccination antibody titers and/or repeating the vaccination. Here, we compile the existing data on vaccination in multiple myeloma and provide recommendations for clinical practice. © 2020, The Author(s).

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. © 2020, The Author(s).

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. © 2021 Elsevier Ltd

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

In the randomized phase-3 OPTIMISMM study, the addition of pomalidomide to bortezomib and low-dose dexamethasone (PVd) resulted in significant improvement in progression-free survival (PFS) in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM), including lenalidomide refractory patients. Here, we report health-related quality of life (HRQoL) results from this trial. Patients received PVd or Vd in 21-day cycles until disease progression or discontinuation. HRQoL was assessed using the EORTC QLQ-C30, QLQ-MY20, and EQ-5D-3L instruments on day 1 of each treatment cycle. Mean score changes for global QoL, physical functioning, fatigue, side effects of treatment domains, and EQ-5D-3L index were generally stable over time across treatment arms. The proportion of patients who experienced clinically meaningful worsening in global QoL and other domains of interest was similar. These HRQoL results with PVd along with previously demonstrated improvement in PFS vs Vd continue to support its use in patients with RRMM. © 2020 Informa UK Limited, trading as Taylor & Francis Group.

Altres ajuts: This analysis and the development of this manuscript were funded by Amgen (Europe) GmbH. Medical writing support, funded by Amgen (Europe) GmbH, was provided by Oxford PharmaGenesis, Oxford, UK. Editorial support was provided by Carine Thual of Amgen (Europe) GmbH. In ENDEAVOR, carfilzomib and dexamethasone (Kd56) demonstrated significant improvement in progression-free survival (PFS) compared with bortezomib and dexamethasone (Vd). Both agents were administered until disease progression; the EU label for Vd, however, stipulates a maximum of eight treatment cycles. Here, matching-adjusted treatment comparison was used to compare efficacy of Kd56 with Vd, if Vd was administered for 8 cycles (Vd-8). Data from ENDEAVOR and CASTOR trials (which compared daratumumab, bortezomib, and dexamethasone with Vd-8) were used. Hazard ratios of PFS were estimated for Vd vs. Vd-8 and Kd vs. Vd-8. For cycles 1-8, risk reduction in PFS for Kd56 vs. Vd-8 was equal to that estimated in ENDEAVOR (HR: 0.53; 95% CI 0.44-0.65). Beyond eight cycles, risk reduction in PFS for Kd56 and Vd-8 was estimated to be 60% (HR: 0.40; 95% CI 0.26-0.63). The analysis suggested that PFS benefit of Kd56 over Vd increases when Vd is given for eight cycles only.

In ENDEAVOR, carfilzomib and dexamethasone (Kd56) demonstrated significant improvement in progression-free survival (PFS) compared with bortezomib and dexamethasone (Vd). Both agents were administered until disease progression; the EU label for Vd, however, stipulates a maximum of eight treatment cycles. Here, matching-adjusted treatment comparison was used to compare efficacy of Kd56 with Vd, if Vd was administered for 8 cycles (Vd-8). Data from ENDEAVOR and CASTOR trials (which compared daratumumab, bortezomib, and dexamethasone with Vd-8) were used. Hazard ratios of PFS were estimated for Vd vs. Vd-8 and Kd vs. Vd-8. For cycles 1-8, risk reduction in PFS for Kd56 vs. Vd-8 was equal to that estimated in ENDEAVOR (HR: 0.53; 95% CI 0.44-0.65). Beyond eight cycles, risk reduction in PFS for Kd56 and Vd-8 was estimated to be 60% (HR: 0.40; 95% CI 0.26-0.63). The analysis suggested that PFS benefit of Kd56 over Vd increases when Vd is given for eight cycles only.

In ENDEAVOR, carfilzomib and dexamethasone (Kd56) demonstrated significant improvement in progression-free survival (PFS) compared with bortezomib and dexamethasone (Vd). Both agents were administered until disease progression; the EU label for Vd, however, stipulates a maximum of eight treatment cycles. Here, matching-adjusted treatment comparison was used to compare efficacy of Kd56 with Vd, if Vd was administered for 8 cycles (Vd-8). Data from ENDEAVOR and CASTOR trials (which compared daratumumab, bortezomib, and dexamethasone with Vd-8) were used. Hazard ratios of PFS were estimated for Vd vs. Vd-8 and Kd vs. Vd-8. For cycles 1–8, risk reduction in PFS for Kd56 vs. Vd-8 was equal to that estimated in ENDEAVOR (HR: 0.53; 95% CI 0.44–0.65). Beyond eight cycles, risk reduction in PFS for Kd56 and Vd-8 was estimated to be 60% (HR: 0.40; 95% CI 0.26–0.63). The analysis suggested that PFS benefit of Kd56 over Vd increases when Vd is given for eight cycles only. © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM). In ELOQUENT-2 (NCT01239797), elotuzumab plus lenalidomide/dexamethasone (ERd) significantly improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd) in patients with RRMM and 1–3 prior lines of therapy (LoTs). We report results from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM. Overall, 646 patients with RRMM and 1–3 prior LoTs were randomized 1:1 to ERd or Rd. PFS and overall response rate were co-primary endpoints. OS was a key secondary endpoint, with the final analysis planned after 427 deaths. ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median, 48.3 vs 39.6 months; hazard ratio, 0.82 [95.4% Cl, 0.68–1.00]; P = 0.0408 [less than allotted α of 0.046]), which was consistently observed across key predefined subgroups. No additional safety signals with ERd at extended follow-up were reported. ERd is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1–3 prior LoTs. The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2–3 prior LoTs. © 2020, The Author(s).

The phase 3 A.R.R.O.W. study demonstrated that treatment with once-weekly carfilzomib (70 mg/m2) and dexamethasone (once-weekly Kd70 mg/m2) improved progression-free survival compared with twice-weekly carfilzomib (27 mg/m2) and dexamethasone (twice-weekly Kd27 mg/m2) in patients with relapsed and refractory multiple myeloma (RRMM; median, 11.2 versus 7.6 months; hazard ratio [HR] = 0.69; 95% confidence interval, 0.54–0.88; P = 0.0029). Once-weekly dosing also improved response rates and depth of response. We performed a subgroup analysis from A.R.R.O.W. according to age (

Background: Lenalidomide and bortezomib frontline exposure has raised a growing need for novel treatments for patients with relapsed or refractory multiple myeloma. Carfilzomib in combination with daratumumab has shown substantial efficacy with tolerable safety in relapsed or refractory multiple myeloma in a phase 1 study. In this study, we aimed to compare the efficacy and safety of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods: In this randomised, multicentre, open-label, phase 3 study, 466 patients recruited from 102 sites across North America, Europe, Australia, and Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m2 (20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3–6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients ≥75 years old starting on the second week). The primary endpoint was progression-free survival assessed by intention to treat. Adverse events were assessed in the safety population. This trial (NCT03158688) is registered with ClinicalTrials.gov, and is active but not recruiting. Findings: Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed for eligibility were enrolled. After median follow-up of approximately 17 months, median progression-free survival was not reached in the KdD group versus 15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46–0·85; p=0·0027). Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) patients in the KdD group and 113 (74%) patients in the Kd group. The frequency of adverse events leading to treatment discontinuation was similar in both groups (KdD, 69 [22%]; Kd, 38 [25%]). Interpretation: KdD significantly prolonged progression-free survival versus Kd in patients with relapsed or refractory multiple myeloma and was associated with a favourable benefit–risk profile. Funding: Amgen. © 2020 Elsevier Ltd

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. © 2019 Future Medicine Ltd.

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 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. 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

Background. We aimed to develop and validate a conceptual model of multiple myeloma (MM) that characterizes the attributes affecting disease progression and patient outcomes, and the relationships between them. Methods. Systematic and targeted literature reviews identified disease- and patient-specific attributes of MM that affect disease progression and outcomes. These attributes were validated by a Delphi panel of four international MM experts, and a physician-validated model was constructed. Real-world clinical data from the Czech Registry of Monoclonal Gammopathies (RMG) was used to confirm the relationships between attributes using pairwise correlations and multiple Cox regression analysis. Results. The Delphi panel reached consensus that most cytogenetic abnormalities influenced disease activity, which results in symptoms and complications and affects overall survival (OS). Comorbidities and complications also affect OS. The entire panel agreed that quality of life was influenced by comorbidities, age, complications, and symptoms. Consensus was not reached in some cases, in particular, the influence of del(17p) on complications. The relationships between attributes were confirmed using pairwise analysis of real-world data from the Czech RMG; most of the correlations identified were statistically significant and the strength of the correlations changed with successive relapses. Czech RMG data were also used to confirm significant predictors of OS included in the model, such as age, Eastern Cooperative Oncology Group performance status, and extramedullary disease. Conclusions. This validated conceptual model can be used for economic modeling and clinical decision making. It could also inform the development of disease-based models to explore the impact of disease progression and treatment on outcomes in patients with MM. © The Author(s) 2019.

Background: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. Methods: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. Findings: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. Interpretation: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. Funding: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company. © 2019 Elsevier Ltd

Katja Weisel Department of Hematology/Oncology, University Hospital Tuebingen, Tuebingen, Germany Abstract: Despite advances in the treatment of multiple myeloma, it remains an incurable disease, with relapses and resistances frequently observed. Recently, immunotherapies, in particular, monoclonal antibodies, have become important treatment options in anticancer therapies. Elotuzumab is a humanized monoclonal antibody to signaling lymphocytic activation molecule F7, which is highly expressed on myeloma cells and, to a lower extent, on selected leukocyte subsets such as natural killer cells. By directly activating natural killer cells and by antibody-dependent cell-mediated cytotoxicity, elotuzumab exhibits a dual mechanism of action leading to myeloma cell death with minimal effects on normal tissue. In several nonclinical models of multiple myeloma, elotuzumab was effective as a single agent and in combination with standard myeloma treatments, supporting the use of elotuzumab in patients. In combination with lenalidomide and dexamethasone, elotuzumab showed a significant increase in tumor response rates and progression-free survival in patients with relapsed and/or refractory multiple myeloma. This review summarizes the nonclinical and clinical development of elotuzumab as a single agent and in combination with established therapies for the treatment of multiple myeloma. Keywords: multiple myeloma, elotuzumab, SLAMF7, CS1, antibody-based immunotherapy

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

The Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling was convened on December 1, 2016 at the American Society of Hematology meeting to discuss the emerging data and technologies for minimal residual disease assessment and immune profiling in myeloma. Particular emphasis was placed on developing strategies to incorporate these techniques into clinical trial design. This document reviews the literature, summarizes the topics discussed in the workshop, and provides recommendations for integration of these techniques into future clinical trial design.

Background: Twice a week carfilzomib at 27 mg/m 2 is approved for treatment of relapsed or refractory multiple myeloma. Phase 1/2 CHAMPION-1, the first study exploring once-weekly carfilzomib dosing, established the maximum tolerated dose at 70 mg/m 2 in combination with dexamethasone. We aimed to compare progression-free survival in patients with relapsed and refractory multiple myeloma given once weekly carfilzomib or twice weekly carfilzomib. Methods: In this prespecified interim analysis of the randomised, open-label, phase 3 A.R.R.O.W. trial, we recruited patients (aged 18 years and older) with relapsed and refractory multiple myeloma previously treated with two or three treatments, including a proteasome inhibitor and immunomodulatory agent, from hospital, clinic, oncology or medical centres. Key eligibility criteria were refractory to most recent therapy (including bortezomib or ixazomib) with measurable disease, and Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were randomly assigned (1:1) to receive carfilzomib once a week (70 mg/m 2 ) or twice a week (27 mg/m 2 ). The randomisation sequence was generated using a validated randomisation software and implemented using an interactive response technology system that assigned patients to treatment sequentially based on the randomisation sequence as patients were enrolled at participating clinical sites. Patients were stratified by International Staging System stage at study entry or baseline, whether or not they were refractory to bortezomib treatment, and age (block size of 4). The once weekly group received carfilzomib (30 min intravenous infusion) on days 1, 8, and 15 of all cycles (20 mg/m 2 day 1 [cycle 1]; 70 mg/m 2 thereafter). The twice weekly group received carfilzomib (10 min intravenous infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m 2 days 1 and 2 during cycle 1; 27 mg/m 2 thereafter). All patients received dexamethasone (40 mg on days 1, 8, 15 [all cycles] and 22 [cycles 1–9 only]). Treatment continued until disease progression or unacceptable toxic effects. The primary objective was to compare progression-free survival between groups in the intention-to-treat population. Safety analysis was done in all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02412878, and is no longer enrolling patients. Findings: Between September, 2015, and August, 2016, 578 patients were recruited from 118 sites. 478 patients were randomly assigned and included in the efficacy analyses (240 to receive once weekly carfilzomib; 238 to receive twice weekly carfilzomib). Median progression-free survival was higher in the once weekly group than the twice weekly group (11·2 months [95% CI 8·6–13·0] vs 7·6 months [5·8–9·2]; hazard ratio [HR] 0·69, 95% CI 0·54–0·83; p=0·0029). The incidence of grade 3 or worse adverse events was higher in the once weekly group than the twice weekly group (68% [n=161] vs 62% [n=145]); the most common events were anaemia, pneumonia, and thrombocytopenia (42 [18%] vs 42 [18%], 24 [10%] vs 16 [7%], and 17 [7%] vs 16 [7%], respectively for once weekly carfilzomib vs twice weekly carfilzomib). A lower proportion of patients had grade 3 or worse cardiac failure in the once weekly group (7 [3%]) than in the twice weekly group (10 [4%]). Treatment-related deaths occurred in five (2%) of 238 patients in the once weekly group (sepsis [n=1], death [n=1], acute lung injury [n=1], acute respiratory distress syndrome [n=1], and tumour lysis syndrome [n=1]) and in two (1%) of 235 patients in the twice weekly group (plasma cell myeloma [n=1] and congestive heart failure [n=1]). There were 58 deaths in the once weekly group and 68 deaths in the twice weekly group at the time of data cutoff. Interpretation: Once weekly carfilzomib at 70 mg/m 2 significantly prolonged progression-free survival versus the twice weekly schedule. Overall safety was comparable between the groups. Once weekly carfilzomib appears safe and more effective with a convenient dosing regimen versus the twice weekly schedule for the treatment of patients with relapsed and refractory multiple myeloma. Funding: Amgen, Inc. © 2018 Elsevier Ltd

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drugs classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.353.

This is a secondary analysis of the phase 3 ENDEAVOR study comparing relapsed and/or refractory multiple myeloma (RRMM) patients receiving carfilzomib–dexamethasone (Kd) with those receiving subcutaneous (SC) bortezomib with dexamethasone (Vd) or intravenous (IV) Vd. Of Kd-treated patients, 356 Kd were pre-selected (by physician prior to randomization if to be randomized to Vd) for SC Vd (Kd [SC Vd]) and 108 for IV Vd (Kd [IV Vd], respectively. Of Vd-treated patients, 360 received SC Vd and 75 IV Vd. Kd (SC Vd) median PFS was not reached; SC Vd was 9.5 months. Median PFS for Kd (IV Vd) and IV Vd were 22.2 and 8.5 months, respectively. Median PFS was significantly longer and response rates were higher for Kd versus retreatment with bortezomib (SC or IV Vd) and in bortezomib naive patients. Overall, Kd was superior to Vd in RRMM regardless of route of bortezomib administration or prior bortezomib exposure. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified ‡60 months’ follow-up). Patients were randomized to Rd continuous (n 5 535), Rd18 (n 5 541), or MPT (n 5 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) and was similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P 5 .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an 30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vs MPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM. This trial was registered at www.clinicaltrials.gov as #NCT00689936 and EudraCT as 2007-004823-39. © 2018 by The American Society of Hematology.

Purpose Renal impairment (RI) limits treatment options in patients with relapsed/refractory multiple myeloma (RRMM). Here, we prospectively studied pomalidomide plus low-dose dexamethasone (LoDEX) in patients with RRMM and moderate or severe RI, including those receiving hemodialysis. Patients and Methods MM-013, a noncomparative, European phase II trial, enrolled three patient cohorts: moderate RI (cohort A; estimated glomerular filtration rate, 30 to, 45 mL/min/1.73 m2); severe RI (cohort B; estimated glomerular filtration rate,, 30 mL/min/1.73 m2); and severe RI that requires hemodialysis (cohort C). Patients received pomalidomide 4 mg/d on days 1 to 21 and LoDEX 20 or 40 mg once per week in 28-day cycles. The primary end point was overall response rate. Results Of 81 enrolled patients (33, 34, and 14 patients in cohorts A, B, and C, respectively), 13 were still receiving treatment at data cutoff (January 28, 2017). Overall response rates were 39.4%, 32.4%, and 14.3%, with a median duration of response of 14.7 months, 4.6 months, and not estimable, respectively. Of importance, 100%, 79.4%, and 78.6% of patients, respectively, achieved disease control. With a median follow-up of 8.6 months, median overall survival was 16.4 months, 11.8 months, and 5.2 months, respectively. Complete renal responses were observed only in cohort A (18.2%), and no patients in cohort C became hemodialysis independent. Grade 3 and 4 hematologic treatment-emergent adverse events and pomalidomide discontinuations as a result of treatment-emergent adverse events occurred more frequently in cohort C. Pomalidomide pharmacokinetics were comparable among the three renal cohorts. Conclusion Pomalidomide 4 mg/d plus LoDEX is efficacious in patients with RRMM with moderate or severe RI, including those who had more advanced disease and required hemodialysis. The safety profile was acceptable among the three groups, and no new safety signals were observed. © 2018 by American Society of Clinical Oncology

In newly diagnosed multiple myeloma (MM), patients ineligible for front-line autologous stem cell transplantation (ASCT), melphalan and prednisone (MP) with thalidomide (MPT) or bortezomib (VMP) are standard first-line therapeutic options. Despite new treatment regimens incorporating bortezomib or lenalidomide, MM remains incurable. The FIRST study demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) for the combination of lenalidomide and low-dose dexamethasone (Rd) until progression vs. MPT in transplant-ineligible ndMM patients. However, to date no head-to-head randomized controlled trials (RCTs) have compared Rd or MPT versus VMP. We conducted a network meta-analysis using RCTs identified through a systematic literature review to evaluate the relative efficacy of Rd versus other regimens on survival endpoints in previously untreated MM patients ineligible for ASCT. In this analysis, Rd was associated with a significant PFS and survival advantage versus other first-line treatments (VMP, MPT, MP), challenging the role of alkylators in this setting. © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

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/m2 on days 1 and 2 of cycle 1; 56 mg/m2 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/m2) 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 (