BCL-2 Inhibitor Development Continues Amid Mixed Phase 3 Outcomes in RRMM

In clinical trials, multiple BCL-2 inhibitors are being developed to potentially treat patients with relapsed or refractory multiple myeloma (RRMM). Recently, the first-generation BCL-2 inhibitor venetoclax demonstrated less favorable overall survival (OS) compared with placebo plus bortezomib and dexamethasone, signaling that the future of BCL-2 inhibitors in RRMM might lie with next-generation agents.

Results come from the final analysis of the phase 3 BELLINI study by Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues. The study included 291 patients with RRMM who were treated in one of 90 centers across 16 countries. The patients were randomly assigned according to a 2:1 ratio to receive either venetoclax (n=194) or placebo (n=94).

At a median follow-up of 45.6 months (interquartile range, 43.6-48.3 months), median OS was not reached in the venetoclax group (95% CI, 44.4-not estimable [NE]) or in the placebo group (95% CI, 44.0-NE); the hazard ratio (HR) was 1.19 (95% CI, 0.80-1.77; P=0.39). However, the median progression-free survival was 23.4 months (95% CI, 16.2-26.4) with venetoclax compared with 11.4 months (95% CI, 9.5-14.6) with placebo (HR, 0.58; 95% CI, 0.43-0.78; P=0.00026).

Thrombocytopenia and neutropenia were the most common grade 3 and 4 adverse events, having occurred in 26% vs 40% and 30% vs 8% of the venetoclax and placebo groups, respectively. Four deaths resulted from treatment-related adverse events.

“The increased mortality was primarily among patients without the t(11;14) translocation and/or no elevated BCL-2, especially among those with high-risk cytogenetic abnormalities. The results suggest that BCL-2 inhibitors have a major role to play in the treatment of myeloma patients with t(11;14) and those with increased expression of BCL-2, though for the latter group, we do not have an assay we can use in the clinic yet,” Dr. Kumar, told Blood Cancers Today.

Dr. Kumar also pointed out, “Venetoclax combinations are effective in patients with relapsed myeloma who have t(11;14) and those patients should be on infectious disease prophylaxis if this option is chosen and patients should be carefully monitored.”