Elotuzumabplus pomalidomide/dexamethasone for relapsed/refractory multiple myeloma: final overall survival from the phase 2 ELOQUENT-3 trial

Background In the randomized phase 2 ELOQUENT-3 trial (NCT02654132), elotuzumab in combination with pomalidomide/dexamethasone (EPd) significantly improved progression-free survival (PFS) versus pomalidomide/dexamethasone (Pd) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) (Dimopoulos MA et al. N Engl J Med 2018). A preliminary analysis of overall survival (OS) (minimum follow-up of 9.1 mo) showed a trend favoring EPd over Pd (hazard ratio [HR] 0.62; 95% CI, 0.30–1.28). Here we present the final OS analysis from ELOQUENT-3. Methods 117 pts with RRMM, ≥2 prior lines of therapy (LoTs), and disease refractory to last therapy, and either refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor (PI), were randomized (1:1) to receive EPd or Pd in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was PFS. OS was a secondary endpoint. Final OS analysis was pre-specified to occur after 78 deaths, giving the study 75% power at an a=0.2 level to show a statistically significant difference when the true HR is 0.64. OS was also analyzed within patient subgroups. Results At the January 11, 2021 data cutoff (minimum follow-up of 45 mo), 3 pts remained on treatment (2 on EPd and 1 on Pd). Pts received a median of 9.0 cycles of EPd or 5.0 cycles of Pd. In all, 76.9% of pts (EPd 70.0%, Pd 84.2%) discontinued from the study mainly due to death (EPd 61.7%, Pd 71.9%). At final analysis, there were 37 (61.7%) deaths in the EPd group and 41 (74.5%) in the Pd group, most commonly due to disease progression (EPd 41.7%, Pd 49.1%). The median (95% CI) OS was significantly improved with EPd (29.8 mo [22.9–45.7]) versus Pd (17.4 mo [13.8–27.7]), with an HR of 0.59 (95% CI, 0.37–0.93; 2-sided stratified log-rank P=0.0217). The OS benefit of EPd was consistently observed across key subgroups. In pts with lenalidomide as their most recent prior LoT (n=65), HR for OS was 0.55 (95% CI, 0.29–1.04) in favor of EPd. Overall, 70.0% (EPd) and 68.4% (Pd) of pts received subsequent systemic therapy; the most common in both groups (other than dexamethasone) was daratumumab (EPd 43.3%, Pd 43.9%). The safety profile of EPd was consistent with prior reports and no new safety signals were detected. Anemia, neutropenia, and thrombocytopenia were less common with EPd (28.3%, 26.7%, 16.7%) versus Pd (38.2%, 30.9%, 20.0%). Grade 3/4 infections occurred in 25.0% (EPd) and 21.8% (Pd) of pts; grade 5 infections occurred in 6.7% (EPd) and 5.5% (Pd). Adverse events led to discontinuation in 18.3% (EPd) and 23.6% (Pd) of pts. Conclusion EPd demonstrated a statistically significant and clinically meaningful reduction (41%) in the risk of death versus Pd in pts with RRMM previously treated with lenalidomide and a PI. ELOQUENT-3 is the first randomized controlled study of a triplet regimen incorporating a monoclonal antibody and Pd in this setting to show both significant PFS and OS benefits.