The addition of elotuzumab to bortezomib and dexamethasone induced clinical benefit without added toxicity in patients with relapsed or refractory multiple myeloma, according to the results of a phase 2 study.
The current standard of care for patients with relapsed or refractory multiple myeloma is treatment with bortezomib (Velcade; Takeda, Millennium) and dexamethasone. Elotuzumab (Empliciti, Bristol-Myers Squibb) is an immunostimulatory monoclonal antibody that targets SLAMF7, a glycoprotein highly expressed in myeloma cells. The agent was approved in November 2015 for use in combination with lenalidomide (Revlimid, Celgene) and dexamethasone.
“Elotuzumab showed enhanced activity when combined with bortezomib in a preclinical myeloma model,” Andrzej Jakubowiak, MD, PhD, professor of medicine and director of the myeloma program at The University of Chicago Medicine, and colleagues wrote. “In a phase 1 dose-escalation safety study, IV elotuzumab plus bortezomib and dexamethasone was well tolerated in patients with relapsed or refractory multiple myeloma, with an overall response rate of 48% and median time to progression of 9.5 months, which suggests improved activity compared with bortezomib alone.”
Jakubowiak and colleagues conducted an open-label, proof-of-concept study that included data from 150 patients (mean age, 65 years; range, 25-85; 52% men). More than half of patients (51%) had been treated previously with bortezomib.
The researchers randomly assigned patients to bortezomib and dexamethasone alone or with elotuzumab (n = 75 for both), until disease progression or unacceptable toxicity.
PFS served as the primary endpoint. Secondary endpoints included OS and ORR.
Patients assigned elotuzumab achieved longer median PFS (9.7 months vs. 6.9 months). These data equated to a 28% reduction in the risk for progression or death compared with the standard of care alone, and the study met its primary endpoint (HR = 0.72; 70% CI, 0.59-0.88).
Among patients assigned elotuzumab, 13 who were homozygous for the high-affinity FcRIIIa V (VV) allele demonstrated a median PFS of 22.3 months, whereas 24 who were homozygous for the low-affinity FcRIIIa F (FF) allele demonstrated a median PFS of 9.8 months.
Patients homozygous for the V allele assigned standard of care demonstrated a median PFS of 8.2 months.
The ORR for patients assigned elotuzumab was 66% (95% CI, 55-77), compared with 63% (95% CI, 51-74) among patients assigned standard of care. Thirty-six percent of patients in the elotuzumab arm and 27% of patients in the standard of care arm achieved a very good partial response or better.
Patients assigned elotuzumab had a median duration of response of 11.4 months (95% CI, 8.5-14.1), compared with 9.3 months (95% CI, 5.6-11.7) for standard of care.
The researchers reported 1-year OS based on 40 deaths (elotuzumab, n = 17; standard of care, n = 23). Rates of 1-year OS were 85% (95% CI, 75-92) in the elotuzumab arm and 74% (95% CI, 62-83) in the standard of care arm (HR = 0.61; 95% CI, 0.32-1.15).
A 2-year analysis based on 60 deaths (elotuzumab, n = 28; standard of care, n = 32) showed a 2-year OS rate of 73% (95% CI, 61-82) for elotuzumab and 66% (95% CI, 54-76) for standard of care.
Follow-up for mature OS data remains ongoing.
All patients assigned elotuzumab and 96% (n = 72) assigned standard of care experienced an adverse event, with serious adverse events occurring in 51% (n = 38) of the elotuzumab arm and 41% (n = 31) of the standard of care arm.
The most commonly observed grade 3 or higher adverse events included infections (elotuzumab, 21% vs. standard of care, 13%) and thrombocytopenia (9% vs. 17%).
Twenty-four patients (32%) assigned elotuzumab and 29 patients (39%) assigned standard of care discontinued treatment due to adverse events.
Two patients assigned elotuzumab died on study, both of disease. Six patients assigned standard of care died on study, due to disease (n = 2), cardiovascular disease (n = 2), infection (n = 1) and fatal bleeding (n = 1).
Four patients experienced a grade 1 or grade 2 infusion reaction to elotuzumab. The severity of infusion reactions could be mitigated with premedication, and there were no discontinuations due to infusion reactions.
Study limitations included the small sample size, and the use of investigator assessment — rather than independent review — to calculate PFS and ORR outcomes.
“Further investigation of elotuzumab with a proteasome inhibitor, including carfilzomib [Kyprolis, Onyx] or ixazomib [Ninlaro, Millennium], is warranted,” Jakubowiak and colleagues concluded. – by Cameron Kelsall
Bristol-Myers Squibb funded this study. Jakubowiak reports institutional research funding and personal fees from Bristol-Myers Squibb, as well as personal fees from Celgene, Karyopharm, Millennium Pharmaceuticals, Novartis, Onyx, SkylineDx and Sanofi-Aventis. Please see the full study for a list of all other researchers’ relevant financial disclosures.