The final overall survival results from the phase 3 BELLINI trial found that adding venetoclax to bortezomib and dexamethasone significantly improved response rates and progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (RRMM) but also led to increased mortality; these data were presented at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition. 

“Multiple myeloma (MM) is a heterogeneous cancer of terminally differentiated plasma cells that typically express elevated levels of antiapoptotic proteins, such as BCL­­­-2. Venetoclax (Ven), a highly selective, potent, oral BCL-2 inhibitor, induces apoptosis in MM cells, and when combined with bortezomib and dexamethasone showed promising efficacy in patients (pts) with relapsed/refractory (Blood; 130:2392-2400),” explained Shaji K Kumar, MD, Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, and colleagues.

BELLINI is a randomized, double-blind, multicenter study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with RRMM who received 1-3 prior lines of therapy and were either sensitive or naive to proteasome inhibitors. Patients were randomized 2:1 to receive venetoclax 800mg/day or placebo with bortezomib and dexamethasone.

The primary endpoint was PFS as assessed by an independent review committee. Secondary endpoints included overall response rate (ORR) and overall survival (OS). 

A total of 291 patients were included, with 194 randomized to venetoclax and 97 to placebo. At the final OS analysis data cutoff (March 2021), 33 patients were receiving ongoing treatment (28 with venetoclax, 5 with placebo). 

At the median follow-up of 45.6 months, the median PFS per investigator amongst all patients was 23.4 months in the venetoclax arm versus 11.4 months in the placebo arm (HR, 0.58 [95% CI, 0.43–0.78]), while there were 78 (40%) and 36 (37%) deaths in both arms, respectively.

Furthermore, in patients with t(11;14), the median PFS was 36.8 months in the venetoclax arm, compared to 9.3 months in the placebo arm (HR, 0.12 [95% CI, 0.03–0.44]). In patients with high BCL2, the median PFS was 30.1 months v.s 9.9 months in the venetoclax and placebo arms, respectively (HR, 0.37 [95% CI, 0.21–0.64]). The median OS amongst all patients was not reached in either the venetoclax or placebo arm (HR, 1.19 [95% CI, 0.80–1.77]).

The most common treatment-related adverse events (AEs) with venetoclax versus placebo were diarrhea (60% versus 50%), nausea (38% versus 23%), and constipation (35% versus 31%). Common AEs of grades 3/4 included thrombocytopenia, neutropenia, pneumonia, anemia, and diarrhea. 57% of Venetoclax patients had serious AEs compared to 55% of placebo-treated patients, with serious infections and infestations occurring in 35% and 29% of patients, respectively. 

Additionally, 26% of patients in the venetoclax arm and 11% of patients in the placebo arm discontinued treatment due to AE’s. AE’s resulted in 12 deaths in the venetoclax arm, 9 due to serious infection; AE’s led to 1 death in the placebo arm. Of the 16 treatment-related deaths (14 in venetoclax arm, 2 in placebo arm), 3 were due to disease progression (2 with venetoclax, 1 with placebo).

“In the final OS analysis, the addition of Ven to bortezomib and dexamethasone showed significantly improved PFS but resulted in increased mortality versus Pbo in the total population. Consistent with results from previous analyses, Ven added to bortezomib and dexamethasone showed the greatest PFS improvement in pts with t(11;14) or high BCL2, with a favorable benefit-risk profile,” concluded Dr Kumar et al.—Alexandra Graziano

Kumar SK, Harrison SJ, Cavo M, et al. Final Overall Survival Results from BELLINI, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma. Presented at: the 63rd ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 84.