Elotuzumab, developed Bristol-Myers Squibb of New York, is a humanized monoclonal immunoglobulin G1 antibody targeting SLAMF7, which can be found on the surface of myeloma cells and natural killer lymphocytes in the immune system. It is approved on November 30, 2015 by the U.S. Food and Drug Administration for treating people with multiple myeloma who have received one to three prior medications in combination with two other therapies.
The target of this drug is SLAMF7. SLAMF7 is a glycosylated cell surface protein and a member of the SLAM (signaling lymphocyte activation molecules) family. It was first identified on NK cells, mediating their adhesion and function through a self-ligand binding interaction. Self-engagement of SLAMF7, or engagement by SLAMF7-specific antibodies, leads to association with its adaptor protein (EAT-2), resulting in enhanced activation of NK cells, promoting their ability to mediate killing of target cells through the subsequent release of cytotoxic granules. SLAMF7 is highly expressed in benign and neoplastic plasma cells, expressed at lower levels on the surface of NK cells, is infrequently expressed in the parenchyma of any major organs and is not found on hematopoietic stem cells, making it a unique protein for the therapeutic targeting of multiple myeloma cells.
Elotuzumab is applied for treating multiple myeloma. Multiple myeloma is a neoplasm that results in the accumulation of monoclonal plasma cells, predominantly in the bone marrow, which interfere with the production of normal white blood cells, red blood cells and platelets. It is the second most common hematological cancer after lymphoma, with an estimated incidence rate of 8 per 100,000 people and an estimated mortality rate of 2.2 per 100,000 people in Europe in 2012. Multiple myeloma remains largely incurable using current treatment approaches with fewer than 50% of patients surviving five years after diagnosis.
The approval of Elotuzumab was based on a multicenter, randomized, open-label, controlled trial evaluating progression-free survival (PFS) and overall response rate (ORR) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy. A total of 646 patients were randomized (1:1) to receive elotuzumab in combination with lenalidomide and dexamethasone (n=321) or lenalidomide plus dexamethasone alone (n=325). Patients continued treatment until disease progression or the development of unacceptable toxicity.
The trial demonstrated a statistically significant improvement in both PFS and ORR, the trial's co-primary endpoints. The median PFS was 19.4 months in the elotuzumab-containing arm and 14.9 months in the lenalidomide plus dexamethasone alone arm (hazard ratio 0.70, 95% CI: 0.57, 0.85; p = 0.0004). The ORR in the elotuzumab-containing arm was 78.5% (95% CI: 73.6, 82.9) compared to 65.5% (95% CI: 60.1, 70.7) in the lenalidomide plus dexamethasone alone arm (p=0.0002).
The safety data reflect exposure in 318 patients to elotuzumab in combination with lenalidomide and dexamethasone and 317 patients to lenalidomide plus dexamethasone. The most common adverse reactions (greater than or equal to 20%), with an increased rate in the elotuzumab arm compared to the control arm, were fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, and pneumonia.
Other important adverse reactions include infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with determination of complete response. As elotuzumab is an IgG kappa monoclonal antibody, it can be detected in the serum protein electrophoresis and immunofixation assays used to assess response.
Serious adverse events occurred in 65.4% of patients in the elotuzumab-containing arm compared to 56.5% in the lenalidomide plus dexamethasone alone arm. The most common serious adverse reactions were pneumonia, pyrexia, respiratory tract infection, anemia, pulmonary embolism, and acute renal failure.
Palumbo A, Sonneveld P, Palumbo A. Preclinical and Clinical Evaluation of Elotuzumab, a SLAMF7-targeted Humanized Monoclonal[J].