ASCO 2017: Multiple Myeloma Highlights

August 2017, Vol 10, Special Issue: Payers’ Perspectives in Oncology: ASCO 2017 Highlights - Multiple Myeloma

In This Article


Cost-Effectiveness of Carfilzomib, Ixazomib, Elotuzumab, or Daratumumab with Lenalidomide and Dexamethasone versus Lenalidomide and Dexamethasone in Relapsed/Refractory MM

Lenalidomide-based triplet combinations have become a standard of care in the treatment of relapsed/refractory multiple myeloma (MM). Carfilzomib, ixazomib, elotuzumab, or daratumumab (DAR) in triplet combination with lenalidomide (LEN) plus dexamethasone (DEX) have shown superior efficacy over LEN+DEX in patients with relapsed/refractory MM.

This study examines the comparative efficacy and cost-effectiveness of these agents.

Efficacy as measured by progression-free survival (PFS) was indirectly estimated through a network meta-analysis and Bücher method of indirect comparison. Incremental cost-effectiveness and cost-utility ratios were calculated for PFS life-years and quality-adjusted life-years (QALYs) gained in base-case and probabilistic sensitivity analyses.

The inputs that were assessed included cost of chemotherapy, administration, adverse-event management, disease monitoring, utilities for health states, and disutilities for adverse events.

The PFS hazard ratios were similar across all the agents studied. The network analysis and indirect comparison showed the superiority of DAR+LEN+DEX over other triplet therapies in terms of PFS.

The cost-effectiveness analysis indicated that all 4 triplet regimens were associated with additional PFS life-years and QALYs gained over LEN+DEX, but at an additional cost. DAR+LEN+DEX was associated with the greatest number of PFS life-years and QALYs gained at the lowest relative cost.

The superior PFS efficacy of DAR+LEN+DEX is associated with positive cost-effectiveness and cost utility in patients with relapsed/refractory MM.

In terms of limitations, it should be noted that the network analysis in this study was limited to 1 clinical trial per triplet regimen.

Source: Alsaid N, McBride A, Agarwal AM, et al. Cost effectiveness of carfilzomib (CAR), ixazomib (IXA), elotuzumab (ELO), or daratumumab (DAR) with lenalidomide and dexamethasone (LEN+DEX) vs LEN+DEX in relapsed/refractory multiple myeloma (R/R MM). J Clin Oncol. 2017;35(15 suppl). Abstract 8030.

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ELOQUENT-2: Extended 4-Year Follow-Up of Elotuzumab plus Lenalidomide and Dexamethasone versus Lenalidomide and Dexamethasone in Relapsed/Refractory MM

Elotuzumab, an immunostimulatory monoclonal antibody, has a dual mechanism of action, directly activating natural killer cells and tagging myeloma cells for recognition and death through antibody-dependent, cell-mediated cytotoxicity. In a 3-year follow-up, the ELOQUENT-2 study showed a sustained 27% risk reduction in disease progression or death, and overall survival (OS), with elotuzumab plus lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) alone. This study reports the extended 4-year follow-up data of the ELOQUENT-2 study.

Patients with relapsed/refractory multiple myeloma (MM) were randomized 1:1 to receive either ELd or Ld in 28-day cycles until disease progression or unacceptable toxicity. The primary end points tested were progression-free survival (PFS) and overall response rate (ORR). OS was also studied as a secondary end point.

A total of 646 patients with relapsed/refractory MM were enrolled in this study, with 321 randomized to the ELd group and 325 to the Ld group. At study end, twice as many patients remained on therapy in the ELd group versus the Ld group (17% vs 9%, respectively). The major cause of treatment discontinuation in both treatment arms was disease progression (54%).

The ORR was 79% in the ELd group versus 66% in the Ld group. PFS was 19.4 months in the ELd group and 14.9 months in the Ld group. Likewise, there was a sustained OS benefit with ELd versus Ld (4-year OS, 48.3 months vs 39.6 months). At 4-year follow-up, the ELd group showed a 29% risk reduction for disease progression or death versus the Ld group (hazard ratio, 0.71; 95% confidence interval, 0.59-0.86).

Adverse event rates were similar for the 2 arms and were consistent with previous 2- and 3-year follow-up data.

ELd consistently met its efficacy end points at the 4-year follow-up—the longest median follow-up reported for an immuno-oncology agent in MM. ELd showed durable, clinically relevant improvement in PFS, with a 29% risk reduction for disease progression or death. No new safety signals were seen at 4 years of follow-up.

Source: Lonial S, Dimopoulos MA, Weisel KC, et al. Phase 3 ELOQUENT-2 study: extended four year follow-up (FU) of elotuzumab plus lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2017;35(15 suppl). Abstract 8028.

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Trends in Survival and Cost Among US Patients with Multiple Myeloma

Survival among patients with multiple myeloma (MM) has improved over time as a result of new therapy advancements, but not much is known about parallel changes in healthcare costs. This study examined trends in survival and healthcare costs from 2006 to 2014 in US patients with MM.

The MarketScan Commercial and Medicare claims data set was used to identify 5199 adults diagnosed with MM from January 2006 to December 2014. Patients had no previous evidence of cancer, were continuously enrolled for >12 months before diagnosis, and were followed through the earliest event (ie, death, end of enrollment, or end of the study period). Patients were assessed from 2006 to 2010 and from 2011 to 2014. Healthcare costs and survival probabilities were estimated by multivariate generalized linear model and Cox proportional hazards models, while controlling for demographic and clinical characteristics. The recycled prediction method was used to calculate the incremental cost estimates between the time periods.

Of the patients included in the study, 2597 were diagnosed from 2006 to 2010, and 2602 patients were diagnosed from 2011 to 2014. A 35% lower risk for death was reported in patients diagnosed from 2011 to 2014 compared with those diagnosed from 2006 to 2010 (hazard ratio, 0.65; 95% confidence interval [CI], 0.57-0.74). Patients diagnosed from 2011 to 2014 had 18% (95% CI, 6-31) higher all-cause and 26% (95% CI, 6-50) higher MM-related per-patient per-month costs compared with those diagnosed from 2006 to 2010.

Researchers concluded that among patients with MM, survival has improved at a greater rate than the increase in healthcare costs. In addition to improvements in treatments for MM, changes in overall disease management may have contributed to the MM-related increased expenditures and reduced mortality in this study.

Source: Maiese EM, Evans K, Chu BC, et al. Trends in survival and costs among US multiple myeloma patients. J Clin Oncol. 2017;35(15 suppl). Abstract 8046.

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First-in-Human Study of bb2121 Anti-BCMA CAR T-Cell Therapy for Relapsed/Refractory MM: Updated Results

To examine the safety and efficacy of the chimeric antigen receptor (CAR) T-cell in relapsed/refractory multiple myeloma (MM), Berdeja and colleagues designed a second-generation CAR construct targeting B-cell maturation antigen (BCMA) to redirect T-cells to MM cells. bb2121 consists of autologous T-cells transduced with a lentiviral vector encoding a novel CAR with an anti-BCMA single-chain variable fragment, a 4-1BB costimulatory motif, and a CD3-zeta T-cell activation. This study reports the updated results of this novel therapy.

CRB-401 is a multicenter phase 1 dose-escalation trial of bb2121 in patients with relapsed/refractory MM who have received ≥3 previous regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have ≥50% BCMA expression on plasma cells. Peripheral blood mononuclear cells were collected via leukapheresis. Patients underwent lymphodepletion with fludarabine/cytarabine daily for 3 days, then received 1 infusion of bb2121. The study follows a standard 3 + 3 design, with planned dose levels of 5, 15, 45, 80, and 120 × 107 CAR+ T-cells.

A total of 21 patients were infused with bb2121 in the first 4 dose cohorts, with a mean follow-up of 15.4 weeks. All patients were refractory to bortezomib and lenalidomide; the majority were also refractory to pomalidomide, carfilzomib, and daratumumab. As of May 2017, no dose-limiting toxicities occurred, and the maximum tolerated dose of 80 × 107 CAR+ T-cells was identified. Grade 1/2 cytokine release syndrome was reported in 15 patients. In the 15 evaluable patients, the overall response rate was 100%; very good partial response or better was 73%. CAR+ T-cell expansion was consistent.

This study demonstrates that bb2121 shows promising efficacy, with mild and manageable adverse events in heavily pretreated patients. These initial data support CAR T-cell therapy with bb2121 as a new treatment paradigm in patients with relapsed/­refractory MM.

Source: Berdeja JG, Lin Y, Raje NS, et al. First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: updated results. J Clin Oncol. 2017;35(15 suppl). Abstract 3010.

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Lenalidomide/Placebo Maintenance After Stem-Cell Transplant for Patients with MM: OS and PFS Adjusted for Treatment Crossover

Earlier phase 3 study findings showed significantly improved progression-free survival (PFS) for lenalidomide maintenance versus placebo after stem-cell transplant, and many patients in the placebo group without progressive disease crossed over to the lenalidomide maintenance therapy arm. A significantly longer overall survival (OS) was reported with patients in the lenalidomide maintenance arm.

This study examines the effect of lenalidomide versus placebo on OS and PFS from randomization, adjusting for the potentially favorable effects of crossover in patients in the placebo arm. Patients were randomized to lenalidomide maintenance (N = 231) or placebo (N = 229; intent-to-treat population). In the placebo arm, 76 patients without progressive disease crossed over to the lenalidomide maintenance arm. The median time from randomization to crossover was 11.5 months. A landmark OS analysis from the date of unblinding was performed; the treatment effect between crossover and noncrossover patients receiving placebo was relatively similar (hazard ratio, 0.53; 95% confidence interval, 0.25-1.13). As a result, researchers applied a rank-preserving structural failure time model for crossover adjustment.

After crossover adjustment, the median OS in the placebo arm decreased from 79.0 to 70.9 months, and the median PFS in the placebo arm decreased from 28.9 to 25.8 months. Furthermore, the relative treatment effect for OS and PFS increased for lenalidomide versus placebo when end points were adjusted for crossover.

These data confirm that the allowed crossover from placebo to lenalidomide before progressive disease on unblinding potentially diluted the treatment effect of lenalidomide maintenance. After adjusting for the potential effects of crossover, the improvements of OS and PFS were maintained in patients in the lenalidomide maintenance arm versus the placebo arm after stem-cell transplant.

Source: McCarthy PL, Holstein SA, Jung SH, et al. CALGB/ECOG 100104 (alliance) study: lenalidomide (LEN) vs placebo (PBO) maintenance (maint) after stem cell transplant (SCT) for patients (pts) with multiple myeloma—overall survival (OS) and progression-free survival (PFS) adjusted for treatment (tx) crossover (XO). J Clin Oncol. 2017;35(15 suppl). Abstract 8037.

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Daratumumab, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone in Relapsed/Refractory MM: Efficacy and Safety Update

Daratumumab is a human CD38-targeting monoclonal antibody that provides significantly prolonged progression-free survival (PFS) when added to standard-of-care regimens in patients with relapsed/refractory multiple myeloma (MM). POLLUX is a randomized phase 3 study of daratumumab, lenalidomide, and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in patients with relapsed/refractory MM; researchers provided an update on the safety and efficacy data from this trial.

In this study, patients with ≥1 previous lines of therapy received either intravenous daratumumab 16 mg/kg every week for cycles 1 and 2, every 2 weeks for cycles 3 to 6, and then every 4 weeks thereafter, in combination with lenalidomide 25 mg on days 1 to 21 of every 4-week cycle, and dexamethasone 40 mg once per week (DRd), or lenalidomide and dexamethasone (Rd). Patients were excluded from the study if they were refractory to lenalidomide. Minimal residual disease (MRD) was assessed the time of suspected complete response (CR), and at 3 and 6 months after suspected CR. Patient characteristics were well-balanced between the 2 arms. Patients received a median of 1 previous line of therapy, and 55% of patients had previously received immunomodulatory drugs (18% lenalidomide).

At a median follow-up of 25.4 months, DRd significantly prolonged PFS compared with Rd, with a median PFS not reached versus 17.5 months with Rd (hazard ratio, 0.41; 95% confidence interval, 0.31-0.53; P <.0001). Overall response rates (ORRs) were also significantly improved with DRd (93%) versus Rd (76%; P <.0001). Patients in the DRd group reported significantly higher CR rates versus Rd (51% vs 31%; P <.0001). MRD negativity was more than 3-fold higher for DRd versus Rd, and MRD-negative patients had longer PFS versus MRD-positive patients. At data cutoff, overall survival was not reached in either arm; follow-up is ongoing. Thus far, 63 deaths have been reported in the DRd arm versus 79 deaths in the Rd arm. No new safety or tolerability signals were identified.

DRd provided significant ORR and PFS benefits versus Rd, induces deep and durable responses, and induces more rapid accumulation of MRD negativity compared with Rd. These data further validate the clinical utility of DRd in patients with relapsed/refractory MM.

Source: Bahlis NJ, Moreau P, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone (DRd) vs lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): efficacy and safety update (POLLUX). J Clin Oncol. 2017;35(15 suppl). Abstract 8025.

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Last modified: September 11, 2017
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