Highlights
- Venetoclax combined with bortezomib and dexamethasone doubled progression-free survival (PFS) versus standard therapy in relapsed/refractory multiple myeloma (RRMM).
- Despite superior PFS, the venetoclax regimen was associated with increased early mortality and no overall survival (OS) advantage in the general RRMM population.
- Grade 3/4 hematologic toxicities and infection-related deaths were more frequent with venetoclax.
- Venetoclax should be used with caution and not broadly recommended in unselected RRMM patients.
Study Background and Disease Burden
Multiple myeloma (MM) is a clonal plasma cell malignancy with significant global morbidity and mortality. Despite advances in first-line and relapse therapies—including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies—relapsed or refractory disease remains a major clinical challenge. The heterogeneity of MM, especially at relapse, underscores the need for novel, mechanism-based interventions. Venetoclax, a selective BCL-2 inhibitor, has shown promise in early-phase studies, particularly among patients harboring t(11;14) translocations, but its broader benefit-risk profile in unselected RRMM populations required rigorous evaluation.
Study Design
The BELLINI study (NCT02755597) was a randomized, double-blind, multicenter phase 3 trial involving 291 patients with RRMM across 90 hospitals in 16 countries. Eligibility criteria included: age ≥18 years, ECOG performance status ≤2, and 1-3 prior lines of therapy. Patients were randomized in a 2:1 ratio to receive either venetoclax (800 mg orally once daily) or placebo, both in combination with standard bortezomib (1.3 mg/m², subcutaneous or intravenous) and dexamethasone (20 mg orally), given in 21-day cycles for the first eight cycles, then 35-day cycles until discontinuation. Stratification was by prior proteasome inhibitor exposure and number of previous therapy lines. The primary endpoint was progression-free survival (PFS) by independent review; key secondary endpoints included overall survival (OS) and safety.
Key Findings
After a median follow-up of 45.6 months, the final analysis revealed the following:
- Progression-Free Survival: Median PFS was 23.4 months (95% CI: 16.2-26.4) in the venetoclax group versus 11.4 months (95% CI: 9.5-14.6) in the placebo group (hazard ratio [HR] 0.58, 95% CI: 0.43-0.78; p=0.00026). This confirms substantial disease control benefit with venetoclax in combination.
- Overall Survival: Median OS was not reached in either group (venetoclax: NR [95% CI 44.4-NE]; placebo: NR [95% CI 44.0-NE]), and no significant difference was observed (HR 1.19, 95% CI: 0.80-1.77; p=0.39). This lack of OS benefit, despite doubled PFS, was unexpected and clinically significant.
- Safety and Adverse Events: Grade 3 or 4 thrombocytopenia (26% venetoclax vs 40% placebo) and neutropenia (30% venetoclax vs 8% placebo) were common. Notably, the venetoclax group had a higher incidence of treatment-related deaths (2%)—primarily from infections (pneumonia, sepsis, and multi-organ failure)—with none in the placebo arm. Early mortality was a particular concern.
- Patient Demographics: The study population was diverse: 52% male, 48% female; 30% Asian, 4% Black or African American, 65% White, and 11% Hispanic or Latino.
Expert Commentary
The BELLINI trial underscores the complexity of targeting BCL-2 in multiple myeloma. Although venetoclax provides meaningful disease control—doubling PFS when added to bortezomib and dexamethasone—the absence of OS benefit and the concerning increase in early mortality cannot be overlooked. These findings suggest that the benefits of venetoclax are counterbalanced by risks, particularly in unselected RRMM populations. Current consensus and guidelines reflect this caution, recommending venetoclax primarily for patients with t(11;14) translocations or high BCL-2 expression, where risk-benefit ratios may be more favorable (see Moreau et al., Blood 2023; Kumar et al., Lancet Haematol 2025).
Biologically, venetoclax acts by inhibiting the anti-apoptotic protein BCL-2, inducing cell death in susceptible myeloma subclones. However, not all patients derive equal benefit, and off-target effects—including neutropenia and impaired immunity—may predispose to fatal infections. The lack of OS improvement suggests that early deaths may negate later benefits of delayed progression.
Key limitations of BELLINI include possible underpowering for OS differences, and the heterogeneity of the enrolled population, which may dilute signals in molecularly defined subgroups. The study’s rigorous, multicenter design enhances generalizability, but the safety signal mandates vigilant patient selection and monitoring.
Conclusion
Final results from BELLINI demonstrate that while venetoclax in combination with bortezomib and dexamethasone delivers impressive PFS gains in RRMM, this does not translate to improved overall survival due to increased early treatment-related mortality, particularly from infections. As a result, venetoclax should not be routinely used in unselected RRMM patients, but may still hold promise for molecularly defined subgroups. Future studies should focus on biomarker-driven selection and optimized supportive care to maximize benefits while minimizing harm.
References
1. Kumar SK, Harrison SJ, Cavo M, de la Rubia J, Popat R, Gasparetto C, et al. 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. Lancet Haematol. 2025 Aug;12(8):e574-e587. doi: 10.1016/S2352-3026(25)00139-5. PMID: 40587991.
2. Moreau P, Attal M, Facon T. Frontline therapy of multiple myeloma. Blood. 2023;141(5):563-574.
3. ClinicalTrials.gov. NCT02755597. https://clinicaltrials.gov/ct2/show/NCT02755597
For further clinical context, practitioners are encouraged to review ongoing studies evaluating venetoclax in genetically defined subpopulations and follow evolving guidelines for RRMM management.