Richard Pazdur, MD
The FDA approved elotuzumab (Empliciti) for use in combination with lenalidomide (Revlimid) and dexamethasone for patients with multiple myeloma following the failure of 1 to 3 prior therapies.
The approval was based on data from the phase III ELOQUENT-2 trial, in which the 3-drug elotuzumab combination reduced the risk of disease progression by 30% compared with lenalidomide/dexamethasone alone.
“We are continuing to learn about the ways the immune system interacts with different types of cancer, including multiple myeloma," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval is the second monoclonal antibody approved to treat patients with multiple myeloma and works with another approved therapy to provide additional benefit.”
The FDA approved the monoclonal antibody daratumumab (Darzalex) for multiple myeloma earlier this month.
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 2 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 3-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 2prior therapies (range, 1-3) including bortezomib (Velcade; 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
<.001). 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%.
The PFS benefit with elotuzumab in the overall study was observed across the high-risk del(17p) and t(4;14) subgroups, with HRs of 0.65 and 0.53, respectively.
“The approval of elotuzumab provides renewed hope for the multiple myeloma community who urgently need a treatment option that extends the time patients live without their disease progressing,” Sagar Lonial, MD, lead author of the ELOQUENT-2 trial and chief medical officer of the Winship Cancer Institute of Emory University, said in a statement.
ORR was 79% with elotuzumab and 66% for the control group (P
<.001). The OS data for the trial are not yet mature.
Elotuzumab was well tolerated overall. At the time of the interim analysis, 35% of patients receiving the elotuzumab regimen and 20% of patients receiving lenalidomide and dexamethasone alone remained on therapy. The most commonly reported all-grade adverse events (AEs) in the elotuzumab arm versus the control arm were lymphocytopenia (99% vs 98%) anemia (96% vs 95%), thrombocytopenia (84% vs 78%), neutropenia (82% vs 89%), fatigue (47% vs 39%), diarrhea (47% vs 36%), and pyrexia (37% vs 25%).
Serious AEs occurred in 65% versus 57% of the elotuzumab versus control arms, respectively. Grade 3/4 lymphocytopenia rates were higher with elotuzumab at 77% versus 49%; however, high-grade neutropenia rates were higher in the control arm, at 44% versus 34%. Ten percent of patients (n = 33) in the elotuzumab arm had infusion reactions, most of which were grade 1/2 (n = 29).
Elotuzumab binds to the SLAMF7 protein found on the surface of both myeloma cells and natural killer (NK) lymphocytes in the immune system. The FDA granted the drug a breakthrough therapy designation in May 2014 for use in combination with lenalidomide and dexamethasone for patients with multiple myeloma following one or more prior therapies.
"Empliciti in combination with lenalidomide and dexamethasone is an important new option for patients with multiple myeloma and healthcare providers who are treating this cancer," Michael Severino, MD, executive vice president of Research and Development and chief scientific officer at AbbVie, which codevelops elotuzumab with Bristol-Myers Squibb, said in a statement. "AbbVie is pleased to have partnered with Bristol-Myers Squibb in making this new treatment available for patients with relapsed or refractory multiple myeloma."
Bristol-Myers Squibb and AbbVie are supporting the ongoing phase III ELOQUENT-1 trial, which is examining elotuzumab plus lenalidomide and dexamethasone in the frontline setting for relapsed/refractory multiple myeloma. Other ongoing trials are examining elotuzumab in various other combinations with existing therapies.
Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621-631.