Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM

Abstract

In this proof-of-concept, open-label, phase 2 study, patients with relapsed/refractory multiple myeloma (RRMM) received elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and dexamethasone (Bd) until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included overall response rate (ORR) and overall survival (OS). Two-sided 0.30 significance level was specified (80% power, 103 events) to detect hazard ratio (HR) of 0.69. Efficacy and safety analyses were performed on all randomized patients and all treated patients, respectively. Of 152 randomized patients (77 EBd, 75 Bd), 150 were treated (75 EBd, 75 Bd). PFS was greater with EBd vs Bd (HR, 0.72; 70% confidence interval [CI], 0.59-0.88; stratified log-rank P = .09); median PFS was longer with EBd (9.7 months) vs Bd (6.9 months). In an updated analysis, EBd-treated patients homozygous for the high-affinity FcγRIIIa allele had median PFS of 22.3 months vs 9.8 months in EBd-treated patients homozygous for the low-affinity allele. ORR was 66% (EBd) vs 63% (Bd). Very good partial response or better occurred in 36% of patients (EBd) vs 27% (Bd). Early OS results, based on 40 deaths, revealed an HR of 0.61 (70% CI, 0.43-0.85). To date, 60 deaths have occurred (28 EBd, 32 Bd). No additional clinically significant adverse events occurred with EBd vs Bd. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. In patients with RRMM, elotuzumab, an immunostimulatory antibody, appears to provide clinical benefit without added clinically significant toxicity when combined with Bd vs Bd alone. Registered to ClinicalTrials.gov as NCT01478048.

Figure 1

Survival rates. (A) PFS (primary definition) and (B) OS. Data cutoff: September 12, 2014.

Figure 2

PFS (primary definition): subgroup analysis. FISH, fluorescence in situ hybridization; ISS, International Staging System; NA, not available; PI, proteasome inhibitor. Data cutoff: September 12, 2014.

Figure 3

PFS (primary definition) in FcγRIIIa high-affinity (VV) and low-affinity (FF) subgroups. Data are based on all randomized patients with FcγRIIIa genotypes being homozygous VV or FF. Data cutoff: August 10, 2015.

Figure 4

Peripheral blood natural killer cell counts/percentage (all treated patients). Baseline natural killer cell values are reported on cycle 1 day 1 (C1D1). C2D1, cycle 2 day 1; EOT, end of treatment (discontinuation of elotuzumab). Whiskers, confidence intervals; middle line in box, median; upper and lower limit of box, range; circles, outliers.