FDA Grants Priority Review to Elotuzumab Combination to Treat Multiple Myeloma

MINDY WAIZER
Thursday, August 23, 2018
The FDA has granted a priority review to the immunostimulatory monoclonal antibody elotuzumab (Empliciti) for use in combination with pomalidomide (Pomalyst) and low-dose dexamethasone (EPd) to treat patients with relapsed/refractory multiple myeloma (MM) who have received 2 or more prior therapies, including lenalidomide (Revlimid) and a proteasome inhibitor.

Elotuzumab, manufactured by Bristol-Myers Squibb, targets Signaling Lymphocyte Activation Molecule Family member (SLAMF7), a glycoprotein on the cell surface that is highly and uniformly expressed on myeloma cells and Natural Killer (NK) cells, but is not detected on normal solid tissues or on hematopoietic stem cells. Elotuzumab both directly activates the immune system through NK cells via the SLAMF7 pathway, and targets SLAMF7 on MM cells, tagging them so the NKs can destroy them via antibody-dependent cellular toxicity.

The FDA based its decision on data from the ELOQUENT-3 trial, a randomized phase II study designed to evaluate elotuzumab in combination with pomalidomide and low-dose dexamethasone in 117 patients with relapsed/refractory MM who had received 2 or more prior therapies, including lenalidomide and a proteasome inhibitor. Data from this study were presented at the 23rd Congress of the European Hematology Association in June 2018.

Prior therapies included bortezomib (100%), lenalidomide (99%), carfilzomib (21%), ixazomib (6%), daratumumab (3%), and stem cell transplantation (55%). Eighty-seven percent of patients were refractory to lenalidomide, 80% to a protease inhibitor, and 70% to both.

Patients received either EPd (n = 60) or pomalidomide and dexamethasone (Pd); (n = 57) in 28-day cycles until the disease progressed, or toxicity became too great to continue.
Patients in both the EPd and Pd arms received 4 mg of pomalidomide for days 1-21 of each cycle, and the weekly equivalent of 40 mg or 20 mg EPd for patients ≤75 years or >75 years, respectively. In the EPd arm, elotuzumab was administered at the dose of 10 mg/kg IV weekly for the first 2 cycles and 20 mg/kg monthly starting from cycle 3.

Patients randomized to EPd experienced a 46% reduction in risk of disease progression (HR, 0.54; 95% CI, 0.34-0.86, P = 0.0078) compared with patients randomized to Pd alone, with median progression free survival (PFS), the study’s primary endpoint, of 10.3 months (95% CI, 5.6 to not estimable) compared with 4.7 months (95% CI, 2.8-7.2) in patients given Pd.
The PFS benefit experienced among patients randomized to EPd was consistent among patients who had received 2 to 3 prior lines of therapy (HR, 0.55; 95% CI, 0.31-0.98) and 4 or more prior lines of therapy (HR, 0.51; 95% CI, 0.24-1.08).

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

Adverse Events

In the phase II ELOQUENT-3 trial, the safety profile for EPd was consistent with prior findings for elotuzumab and pomalidomide regimens.

Grade 3/4 neutropenia was experienced by 13% of patients given EPd 13% v versus 27% in the Pd arm.  Instances of anemia were 10% in the EPd arm, versus 20% in the Pd arm, despite longer exposure (median number of cycles 9 versus 5) and similar dose intensity of pomalidomide between arms. Any-grade infections occurred in 65% of patients in both arms.  Grade 1/2 infusion reactions occurred in 5% of patients who were elotuzumab.

Treatment discontinuation due to adverse events occurred 18% in the EPd arm versus 24% in the Pd arm. Deaths were mostly due to disease progression; 13% in the EPd arm, 25% in the Pd arm.

Prior Indications of Elotuzumab

Elotuzumab is currently indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received 1 to 3 prior therapies.

Reference
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. learningcenter.ehaweb.org/eha/2018/stockholm/218888/meletios.a.dimopoulos.elotuzumab.plus.pomalidomide.dexamethasone.28epd29.vs.pd.html?f=media=1; Accessed August 23, 2018.

 

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