Venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed or refractory multiple myeloma (BELLINI): final overall survival results from a randomised, phase 3 study.

Background: The phase 3 BELLINI primary endpoint was met, showing superior progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma as assessed by an independent review committee. However, venetoclax showed increased early mortality. Here, we report the final overall survival analysis.

Methods: The randomised, double-blind, multicentre, phase 3 BELLINI study enrolled patients aged 18 years or older with relapsed or refractory multiple myeloma, Eastern Cooperative Oncology Group performance status of 2 or less, and one to three previous therapies, across 90 hospitals in 16 countries. Eligible patients were centrally randomly assigned (2:1, stratified by previous proteasome inhibitor exposure and number of previous lines of therapies) via interactive response technology system (block size 3) to once-daily venetoclax (800 mg orally) or placebo with bortezomib (1·3 mg/m subcutaneously or intravenously) and dexamethasone (20 mg orally), administered in 21-day cycles for initial eight cycles, followed by 35-day cycles until discontinuation. The primary endpoint was progression-free survival as assessed by an independent review committee in the intention-to-treat population; this analysis reports overall survival and investigator-assessed progression-free survival in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov (NCT02755597) and is completed.

Findings: From July 19, 2016, to Oct 31, 2017, 291 patients were assigned to venetoclax (n=194) or placebo (n=97); 33 patients (28 in the venetoclax group and five in the placebo group) remained on treatment at the time of this analysis. Of the 291 patients, 152 (52%) were men and 139 (48%) were women. 87 (30%) of 291 patients were Asian, 12 (4%) were Black or African American, 190 (65%) were White, and 32 (11%) were Hispanic or Latino. At 45·6 months (IQR 43·6-48·3) median follow-up, median overall survival was not reached in the venetoclax group (not reached [NR] [95% CI 44·4-not estimable]) or in the placebo group (NR [95% CI 44·0-not estimable]; HR 1·19 [95% CI 0·80-1·77]); p=0·39). Median progression-free survival was 23·4 months (95% CI 16·2-26·4) with venetoclax versus 11·4 months (95% CI 9·5-14·6) with placebo (HR 0·58 [95% CI 0·43-0·78]; p=0·00026). The most common grade 3 or 4 adverse events were thrombocytopenia (51 [26%] of 193 in the venetoclax group vs 38 [40%] of 96 in the placebo group]) and neutropenia (58 [30%] of 193 vs eight [8%] of 96 patients). Treatment-related adverse events led to death in four (2%) of 193 patients in the venetoclax group (two patients with pneumonia, one with death, and one with both multiple organ dysfunction syndrome and septic shock) and none in the placebo group.

Interpretation: Final overall survival analysis in the BELLINI study showed overall survival favouring placebo over venetoclax and progression-free survival favouring venetoclax over placebo, indicating venetoclax usage should be avoided in the general relapsed or refractory multiple myeloma population.

Funding: AbbVie and Genentech.