FDA Grants Elotuzumab Triplet Priority Review for Myeloma

The FDA has granted a priority review to a supplemental biologics license application (sBLA) for elotuzumab (Empliciti) for use in combination with pomalidomide (Pomalyst) and low-dose dexamethasone (EPd) for the treatment of patients with relapsed/refractory multiple myeloma following 2 or more prior therapies, including lenalidomide (Revlimid) and a proteasome inhibitor (PI).

The sBLA was submitted based on the phase II ELOQUENT-3 trial, in which the addition of elotuzumab to pomalidomide and dexamethasone reduced the risk of disease progression or death by 46% compared with pomalidomide and dexamethasone alone for patients with relapsed/refractory multiple myeloma. Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the sBLA by December 27, 2018.

In the ELOQUENT-3 trial, the median progression-free survival (PFS) was 10.3 months (95% CI, 5.6—not estimable) with the elotuzumab combination compared with 4.7 months (95% CI, 2.8-7.2) with pomalidomide plus dexamethasone (HR, 0.54; 95% CI, 0.34-0.86; P = .0078). The PFS benefit associated with EPd was similar, regardless of whether patients had received 2 to 3 prior lines of treatment (HR 0.55; 95% CI, 0.31-0.98), or ≥4 lines of treatment (HR 0.51; CI 95%, 0.24-1.08).

The objective response rate (ORR) was 53% (95% CI, 40%-66%) with elotuzumab compared with 26% (95% CI, 16%-40%) in the control arm (odds ratio, 3.25; 95% CI, 1.49-7.11; P = .0029). The rate of very good partial response or better was 20% versus 9%, with and without elotuzumab, respectively.

“This file acceptance is an important step in BMS’s ongoing efforts to advance treatment options for patients with relapsed/refractory multiple myeloma,” said Jeffrey Jackson, PhD, hematology development lead at Bristol-Myers Squibb, which is co-developing elotuzumab with AbbVie.

The phase II ELOQUENT-3 study enrolled 117 patients with relapsed/refractory multiple myeloma who were randomized to the elotuzumab combination (n = 60) or pomalidomide and dexamethasone alone (n = 57). Elotuzumab was administered at 10 mg/kg intravenously each week during cycles 1 and 2 and at 20 mg/kg every 4 weeks thereafter. Pomalidomide was given at 4 mg orally on days 1 to 21 of each cycle plus dexamethasone weekly at 40 mg for patients ≤75 years of age or 20 mg for those >75 years.

Eligible patients had received ≥2 prior lines of therapy, including lenalidomide and a PI; patients receiving prior pomalidomide were excluded from the study. The median age of patients was 67 years and they had received a median of 3 prior treatments (range, 2-8). Prior treatments included bortezomib (100%), lenalidomide (99%), carfilzomib (21%), ixazomib (6%), and daratumumab (3%). More than half of patients (55%) had undergone stem cell transplantation and most patients were refractory to lenalidomide (87%), a PI (80%), or both (70%).

The primary objective of the study was investigator-assessed PFS and secondary endpoints included ORR and overall survival (OS). At the February 21, 2018, database lock, the median follow-up was 9.1 months, and 40% of patients receiving the elotuzumab combination remained on treatment compared with 20% in the control arm.

Although OS results remained immature they suggested a trend favoring elotuzumab. At the analysis, there was a 38% reduction in the risk of death in the elotuzumab arm compared with the control group (HR, 0.62; 95% CI, 0.30-1.28). At the data cutoff, there were 13 deaths in the elotuzumab arm and 18 in the control arm.

Disease progression was the main cause of treatment discontinuation and occurred in 43% of patients in the elotuzumab arm compared with 56% in the control group. Discontinuation due to adverse events occurred in 18% of patients in the elotuzumab arm compared with 24% for the control group.

The rates of grade 3/4 neutropenia and anemia were lower with elotuzumab versus the control arm, despite longer exposure (median number of cycles 9 versus 5). Pomalidomide dose intensity was similar between groups. Grade 3/4 neutropenia was experienced by 13% of patients in the elotuzumab group compared with 27% for the control arm and grade 3/4 anemia occurred in 10% versus 20% of patients, respectively. All-grade infections occurred in 65% of patients in both treatment arms. Five percent of patients in the elotuzumab group experienced infusion reactions that were grade 1/2 in severity.

Elotuzumab is an immunostimulary monoclonal antibody that specifically targets the signaling lymphocyte activation molecule family member 7 (SLAMF7), which is expressed as a surface protein on myeloma cells, natural killer (NK), and plasma cells. Elotuzumab has a dual mechanism of action to directly stimulate the immune system via NK activation and to directly target SLAMF7 on myeloma cells for activated NK destruction via ADCC toxicity.

The FDA approved elotuzumab in November 2015 for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who received 1 to 3 prior therapies.

Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide/dexamethasone (EPd) vs Pd for treatment of relapsed/refractory multiple myeloma (RRMM): results from the phase 2, randomized open-label ELOQUENT-3 study. Presented at: 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract LB2606.

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“Given the need for new, effective treatment options in this patient population, we look forward to working with the FDA with the hope of bringing this combination to patients with relapsed/refractory multiple myeloma whose disease progressed on previous therapies as quickly as possible,” added Jackson.