Addition of Elotuzumab to Lenalidomide-Dexamethasone Improves Progression-Free Survival in Relapsed/Refractory Multiple Myeloma
In an interim analysis of the phase III ELOQUENT-2 trial reported in The New England Journal of Medicine, Lonial et al found that the addition of the investigational agent elotuzumab to lenalidomide (Revlimid)-dexamethasone significantly increased progression-free survival in patients with relapsed or refractory multiple myeloma.
Elotuzumab is an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7). Bone marrow myeloma cells (approximately 95%) express SLAMF7 independent of cytogenetic abnormalities. Elotuzumab directly activates natural killer cells and mediates antibody-dependent cell-mediated cytotoxicity via the CD16 pathway.
Study Details
In this open-label trial conducted at 168 sites worldwide, 648 patients were randomly assigned between June 2011 and November 2012 to receive elotuzumab plus lenalidomide-dexamethasone (n = 321) or lenalidomide–dexamethasone alone (n = 325). Elotuzumab was given intravenously at 10 mg/kg on days 1, 8, 15, and 22 during 28-day cycles, along with lenalidomide at 25 mg/d on days 1 to 21 and dexamethasone orally at 40 mg during the week without elotuzumab and intravenously at 8 mg plus 28 mg orally on the day of elotuzumab administration. Patients in the control group received lenalidomide at 25 mg on days 1 to 21 and oral dexamethasone at 40 mg on days 1, 8, 15, and 22.
The coprimary endpoints were progression-free survival and objective response rate. The primary analysis of progression-free survival used independent review committee assessment of tumor response and censoring of data for patients who received subsequent antimyeloma therapy or missed assessments. Intention to treat analysis was performed as a supportive analysis.
Overall, 35% of patients had resistance to the most recent line of therapy, including bortezomib (Velcade, 22%) and thalidomide (Thalomid, 10%), and 32% had the del(17p) variant. Patients had a median age of 66 years; 43% had stage I, 32% stage II, and 21% stage III disease; 54% had prior stem cell transplantation; and the median number of prior therapies was two (at least three in 16%). Prior treatment included lenalidomide in 5% of the elotuzumab group and 6% of the control group.
Improved Progression-Free Survival
After median follow-up of 24.5 months, median progression-free survival in the primary analysis was 19.4 months (95% confidence interval [CI] = 16.6–22.2 months in the elotuzumab group vs 14.9 months (95% CI = 12.1–17.2 months) in the control group (hazard ratio [HR] = 0.70, P < .001). The outcome was similar in intention-to-treat analysis (HR = 0.68, 95% CI = 0.56–0.83). Rates of progression-free survival were 68% vs 57% at 1 year and 41% vs 27% at 2 years.
The benefit of elotuzumab was consistent across subgroups, including patients aged ≥ 65 years and those with resistance to the most recent line of therapy, stage III disease, previous exposure to bortezomib or immunomodulatory drugs, previous stem cell transplantation, and those with the del(17p) variant. Multivariate analysis suggested increased benefit of elotuzumab among patients diagnosed ≥ 3.5 years before study entry (median 26.0 vs 17.3 months, HR = 0.55, P < .001).
Overall response rates were 79% vs 66% (P < .001). At the time of progression-free survival analysis, when 49% of prespecified deaths for final overall survival analysis had occurred, 30% of the elotuzumab group and 37% of the control group had died.
Adverse Events
The most common grade 3 or 4 hematologic adverse events in the elotuzumab group were lymphocytopenia (77% vs 49% in control group), neutropenia (34% vs 44%), anemia (19% vs 21%), and thrombocytopenia (19% vs 20%). The most common grade 3 or 4 nonhematologic adverse events were fatigue (8% vs 8%) and diarrhea (5% vs 4%). Serious adverse events were reported in 65% and 57% of patients.
Infections were reported in 81% vs 74% of patients, with infection rates being identical in the two groups after adjustment for drug exposure (197 events per 100 patient-years). Infusion reactions were reported in 33 elotuzumab patients (10%, grade 1 or 2 in 29 and grade 3 in 4), with 70% of reactions occurring during the first dose. Infusion was interrupted in 5% of patients. Reactions resolved in all patients except two (1%), with both discontinuing treatment due to the reaction.
The investigators concluded: “Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death.”
Sagar Lonial, MD, of Emory University School of Medicine, is the corresponding author for the New England Journal of Medicine article. Dr. Lonial and Meletios Dimopoulos, MD, of National and Kapodistrian University of Athens, contributed equally to the article
The study was funded by Bristol-Myers Squibb and AbbVie Biotherapeutics. For full disclosures of the study authors, visit www.nejm.org.
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