Elotuzumab Combo Delays Myeloma Progression in Phase III Trial

Sagar Lonial, MD

Adding elotuzumab to lenalidomide (Revlimid) and dexamethasone reduced the risk of disease progression by 30% in patients with relapsed/refractory multiple myeloma, according to interim results from the phase III ELOQUENT-2 trial. The data, which were presented during a presscast held in advance of the 2015 ASCO Annual Meeting, showed that combining the monoclonal antibody with standard care prolonged remission by 4.5 months.

“Based on this randomized phase III trial, we hope that we will soon have a new treatment option for patients with relapsed or refractory myeloma where an immune therapy—based approach can be added with lenalidomide and dexamethasone for the management of these patients,” said lead author Sagar Lonial, MD, chief medical officer of the Winship Cancer Institute of Emory University, and professor and executive vice chair of the Department of Hematology and Medical Oncology of Emory University School of Medicine.

Elotuzumab, which is being developed by Bristol-Myers Squibb and AbbVie, binds to the SLAMF7 protein found on the surface of both myeloma cells and natural killer (NK) lymphocytes in the immune system. “One of the unique attributes of elotuzumab is that it appears to have a dual mechanism through which it targets both the myeloma cell and appears to enhance the activation of natural killer cells,” said Lonial.

The open-label phase III ELOQUENT-2 trial randomized 646 patients with relapsed/refractory multiple myeloma to lenalidomide and dexamethasone alone (n = 325) or in combination with elotuzumab (n = 321). Elotuzumab was administered at 10 mg/kg IV weekly for the first two cycles and then biweekly thereafter, and lenalidomide was dosed at 25 mg orally on days 1 to 21 of each cycle. Across the study, patients received 40 mg of oral dexamethasone in weeks without elotuzumab. In weeks in the experimental arm when elotuzumab was administered, dexamethasone was dosed at 28 mg orally plus 8 mg IV. The cycle length for all three drug regimens was 28 days, and treatment was administered until disease progression or unacceptable toxicity.

The median patient age in the trial was 66 years and patients had received a median of two prior therapies (range, 1-3) including bortezomib (70%), thalidomide (48%), and lenalidomide (6%). Thirty-five percent of patients were refractory to their most recent therapy; however, no patients were lenalidomide refractory. High-risk patient subgroups were identified, with 32% and 9% of patients having a 17p deletion (del[17p]) or t(4;14) translocation, respectively.

The primary outcome measures for the study were progression-free survival (PFS) and overall response rate (ORR). Overall survival (OS) was a secondary endpoint. Tumor response was assessed every 4 weeks and survival was assessed every 12 weeks following disease progression.

At a median follow-up of 2 years, PFS with the elotuzumab regimen was 19.4 months (95% CI, 16.6-22.2) versus 14.9 months (95% CI, 12.1-17.2) with lenalidomide and dexamethasone alone (HR = 0.70; 95% CI, 0.57-0.85; P = .0004). The 1-year PFS for the elotuzumab versus control arm was 68% versus 57%, respectively, with the difference in 2-year PFS rates increasing to 41% versus 27%.

“What I think is quite striking about this progression-free survival curve compared to many others that you may have seen or will see at the meeting, is that the two curves do not appear to come back together with longer follow-up,” said Lonial. “This idea of the maintenance of benefit over time really speaks to the power of an immune-mediated based approach when we treat cancer. We’ve seen this, for instance, with PD-1 and other immune-based approaches.”

The PFS benefit with elotuzumab in the overall study was observed across the high-risk del(17p) and t(4;14) subgroups. ORR was 79% with elotuzumab and 66% for the control group (P = .0002). The OS data for the trial are not yet mature.

Elotuzumab was well-tolerated overall, according to Lonial. “The improvement in clinical parameters occurred without a significant increase in adverse events or toxicities. In fact, there was no reduction in quality of life for the group receiving the three drugs.”

At the time of the interim analysis, 35% of patients receiving the elotuzumab regimen and 21% of patients receiving lenalidomide and dexamethasone alone remained on therapy. Disease progression was the primary cause of discontinuation, accounting for 42% and 47% of patients stopping treatment in the experimental and control arms, respectively.

Grade 3/4 adverse events occurring in ≥15% of patients in the elotuzumab arm were neutropenia (25% versus 33% in the control arm) and anemia (15% vs 16%).

Ten percent of patients receiving elotuzumab had infusion reactions, the majority of which were grade 1/2 and manageable.

Elotuzumab received a breakthrough therapy designation from the FDA in May 2014 for use in combination with lenalidomide and dexamethasone for patients with multiple myeloma following one or more prior therapies. There are currently no FDA approved monoclonal antibodies for the treatment of multiple myeloma, and the ELOQUENT-2 results are the first to demonstrate a PFS benefit in this disease in a phase III study.

The ongoing phase III ELOQUENT-1 trial is examining the elotuzumab plus lenalidomide and dexamethasone regimen in the frontline setting for relapsed/refractory multiple myeloma. Other ongoing trials are examining elotuzumab in various other combinations with existing therapies.

In a Q/A session following the ASCO presscast, Lonial was asked about the cost of a three-drug regimen if the FDA eventually approves elotuzumab. Lonial responded that the OS data for the trial require another 6 months of maturity but there are “encouraging” signals of an OS benefit, which would be critical to any assessment of economic value.

“To me it’s really about where is the plateau on that curve. If we are increasing [survival] or potentially even curing a subset of patients through the addition of an immune-based approach in combination with lenalidomide [and dexamethasone], in many ways that changes the game. Obviously cost is one of the factors, but what’s the benefit that you get at that price? That is where I think we need a little bit more follow-up.”

Lonial S, Dimopoulos MA, Palumbo A, et al. ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2015;(suppl; abstr 8508).

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