Shaji Kumar, MD
The addition of venetoclax (Venclexta) to the combination of bortezomib (Velcade) plus dexamethasone significantly improved clinical outcomes in patients with relapsed/refractory multiple myeloma in the phase III BELLINI trial, but a venetoclax regimen may be most suited for patients with t(11;14) abnormality or high BCL-2 expression, according to lead investigator Shaji K. Kumar, MD.1
Although the venetoclax combination met its primary endpoint of improved progression-free survival (PFS), it was associated with an increased risk of death. In March, the FDA suspended enrollment in BELLINI and other multiple myeloma studies in which patients were receiving venetoclax.2
The agency lifted a partial clinical hold on the phase III CANOVA study (NCT03539744) evaluating venetoclax plus dexamethasone in patients with the t(11;14) translocation in June.3
The BELLINI findings point to a potential role for venetoclax in subsets of patients with multiple myeloma and illustrate the importance of developing therapies targeted to different types of the malignancy, Kumar said in a presentation during the 17th International Myeloma Workshop (IMW). IMW was held September 12 to 15 in Boston, Massachusetts.
“The results of the BELLINI trial provide us with a blueprint of how we move this drug toward approval for patients who can benefit from it,” Kumar, a hematologist at the Mayo Clinic in Rochester, Minnesota, said in an interview with OncLive
. “… Venetoclax is part of an important class of drugs that targets an important pathway in myeloma.”
Venetoclax selectively inhibits BCL-2. During his presentation, Kumar noted that BCL-2, along with MCL-1 and BCL-XL, promotes the survival of multiple myeloma cells.
The BELLINI trial randomized 291 patients who had undergone 1 to 3 prior lines of therapy and who were refractory to a proteasome inhibitor in a 2:1 ratio to receive venetoclax, bortezomib, and dexamethasone or placebo, bortezomib, and dexamethasone.
In the intention-to-treat population, venetoclax demonstrated superior median PFS of 22.4 months versus 11.5 months with placebo (HR, 0.630; 95% CI, 0.443-0.897; P
Across the board, clinical responses for overall response rate (ORR), very good partial response (VGPR), complete response (CR), and minimal residual disease (MRD) negativity rates were positive for patients receiving venetoclax. ORR was 82% with venetoclax versus 68% with placebo (P
= .008). The VGPR was 59% versus 36% (P
<.001) in favor of venetoclax and CR was reported as 26% for venetoclax versus 5% for placebo (P
<.001). MRD negativity was 13% for patients in the venetoclax arm versus 1% in the placebo arm (P
However, at the overall survival (OS) interim analysis in November 2018, a higher risk of death was observed in the venetoclax arm compared with placebo for all patients. In an updated analysis in March 2019, 70 deaths were reported: 51 in the venetoclax arm and 19 in the placebo arm (HR, 1.474; 95% CI, 0.870- 2.498; P
= .147). In addition, 8 deaths were attributed to infection in the venetoclax arm compared with 0 deaths in the placebo arm.
Subgroup analysis for patients with t(11;14) abnormality showed that median PFS was not reached in the venetoclax group compared with 9.5 months in the placebo group (HR, 0.110; 95% CI, 0.022-0.560; P
= .002). Median OS in this subgroup was not reached in either treatment arm (HR, 0.343; 95% CI, 0.031-3.842; P
For patients identified as BCL-2 high, median PFS was 22.4 months in the venetoclax arm and 10.2 months in the placebo arm (HR, 0.341; 95% CI, 0.146-0.560; P = .011). For both the venetoclax and placebo arms, OS was not reached (HR, 1.114; 95% CI, 0.240-5.179; P
= .890) (Table1
).OncLive: Could you explain your findings from the BELLINI trial?Kumar
: We found a significant increase in the overall response rate, particularly when you look at the complete response rate. There was a significant improvement with the addition of venetoclax to bortezomib and dexamethasone.
We also examined the minimal disease negativity, which was significantly higher, about 13% versus 1%, in patients who received venetoclax versus bortezomib and dexamethasone. This also translated to a better PFS, with significant improvement. Median PFS for patients in the venetoclax arm was 22.4 months compared with 11.5 months in patients who received bortezomib and dexamethasone.