Venetoclax Combo Improves PFS But May Lead to Early Death in Multiple Myeloma

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Adding venetoclax to bortezomib and dexamethasone led to early deaths among patients with relapsed or refractory multiple myeloma (MM), but overall survival (OS) improved over time, according to final results from the phase 3 BELLINI trial.1

The hazard ratio (HR) for OS improved with longer follow-up, said Shaji K. Kumar, MD, of Mayo Clinic in Rochester, Minnesota. He also noted that venetoclax improved progression-free survival (PFS), particularly in patients with t(11;14) or high BCL2 expression.

Dr Kumar presented these results at the 2021 American Society of Hematology (ASH) Annual Meeting.

The BELLINI trial (ClinicalTrials.gov Identifier: NCT02755597) included 291 patients with relapsed/refractory MM who had received 1-3 prior lines of therapy and were either sensitive or naïve to proteasome inhibitors. 

The patients were randomly assigned 2:1 to receive venetoclax plus bortezomib and dexamethasone (194 patients) or placebo plus bortezomib and dexamethasone (97 patients). Baseline characteristics were well-balanced between the treatment arms. 

Prior results from this trial showed improved PFS in the venetoclax arm (HR, 0.63; 95% CI, 0.44-0.90; P =.010).2 An increase in mortality was observed in the venetoclax arm as well, mostly due to an increased rate of infections, according to researchers.

Updated Survival Results

At the data cutoff (March 15, 2021), 33 patients were still receiving study treatment — 28 in the venetoclax arm and 5 in the placebo arm.

At a median follow-up of 45.6 months, the death rate was still slightly higher in the venetoclax arm than in the placebo arm — 40% and 38%, respectively. 

However, the difference in OS was not significant with continued follow-up. The median OS was not reached in either treatment arm (HR, 1.19; 95% CI, 0.80-1.77; P =.3857).

Conversely, the median PFS was significantly longer in the venetoclax arm than in the placebo arm — 23.4 months and 11.4 months, respectively (HR, 0.58; 95% CI, 0.43-0.78; P =.0003).

Subgroup Analyses

Dr Kumar noted that the greatest improvements in PFS were seen in patients with t(11;14) or high BCL2 expression.

Among patients with t(11;14), the median PFS was 36.8 months in the venetoclax arm and 9.3 months in the placebo arm (HR, 0.12; 95% CI, 0.03-0.44; P =.0014). The median OS was not reached in either arm (HR, 0.61; 95% CI, 0.16-2.32; P =.4654).

Among patients with high BCL2 expression, the median PFS was 30.1 months in the venetoclax arm and 9.9 months in the placebo arm (HR, 0.37; 95% CI, 0.21-0.64; P =.0005). The median OS was not reached in either arm (HR, 0.70; 95% CI, 0.32-1.51; P =.3624).

“The data from this trial, as well as additional data from other ongoing venetoclax studies, all point toward the need for us to have a biomarker-driven development strategy for this particular drug, which is what is currently being done,” Dr Kumar said.

Safety

Rates of adverse events (AEs) were generally similar across the treatment arms, Dr Kumar noted. 

The most common treatment-emergent AEs (in the venetoclax and placebo arms, respectively) were diarrhea (60% vs 50%), nausea (38% vs 23%), constipation (35% vs 31%), and fatigue (33% vs 32%). 

Infections occurred in 82% of patients in the venetoclax arm and 78% of those in the placebo arm. Serious infections occurred in 35% and 29%, respectively. 

The rate of treatment discontinuation was 26% in the venetoclax arm and 11% in the placebo arm. 

After an additional 17.0 months of follow-up since the last report,2 there were no further treatment-emergent deaths in the venetoclax arm, Dr Kumar noted. 

AEs led to 1 death in the placebo arm and 12 deaths in the venetoclax arm, 9 of which were related to serious infection. 

Disclosures: This research was supported by AbbVie and Genentech. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Read more of Cancer Therapy Advisor’s coverage of the ASH 2021 meeting by visiting the conference page.

References

1. 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 ASH 2021; December 11-14, 2021. Abstract 84.

2. Kumar SK, Harrison SJ, Cavo M, et al. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): A randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1630-1642. doi:10.1016/S1470-2045(20)30525-8



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