Shaji Kumar, MD, Division of Hematology, Department of Internal Medicine, Mayo Clinic speaks about the ASH 2021 Abstract – 84 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.
Link to Abstract:
https://ash.confex.com/ash/2021/webprogram/Paper145757.html
Background:
Multiple myeloma (MM) is a malignancy characterized by terminally differentiated plasma cells that produce high levels of antiapoptotic proteins such as BCLÂÂÂ-2. Venetoclax (Ven), an oral BCL-2 inhibitor that promotes apoptosis in MM cells, showed promise efficacy when coupled with bortezomib and dexamethasone in patients with relapsed/refractory MM (RRMM; Moreau et al. Blood. 2017;130:2392-2400). The primary analysis of the Phase 3 BELLINI study found that patients with RRMM treated with Ven plus bortezomib and dexamethasone had significantly better response rates and progression-free survival (PFS) than those treated with placebo (Pbo); however, the Ven group had significantly higher mortality (Kumar et al. Lancet Oncol. 2020;21:1630-1642). The PFS hazard ratio (HR) was 0.63 (95 percent CI, 0.44–0.90) and the overall survival (OS) HR was 2.03 (95 percent CI, 1.04–3.95) at the initial data cutoff (November 26, 2018). Patients with a t(11;14) translocation or high BCL2 expression had better responses and PFS without a higher mortality rate. The updated safety and efficacy data from the pre-specified final OS analysis are presented below.
Methods:
BELLINI (NCT02755597) is a Phase 3 randomized, double-blind, multicenter study of Ven or Pbo in combination with bortezomib and dexamethasone in patients with RRMM who had previously had 1–3 lines of therapy and were either proteasome inhibitor sensitive or naive. Ven 800 mg/day or Pbo plus bortezomib and dexamethasone were given to patients in a 2:1 ratio. Bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11 and dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12. Cycles 1–8 were 21-day cycles with bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11 and dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12. Bortezomib 1.3 mg/m2 on Days 1, 8, 15, and 22 and dexamethasone 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23 were used in cycles 9 and beyond. PFS, as determined by an independent review committee, was the main outcome. Overall response rate and OS were important secondary goals. The cutoff for high BCL2 was derived by bootstrapping and aggregating thresholds from trees, and BCL2 expression was assessed using quantitative polymerase chain reaction.
Results:
As of the final OS analysis data cutoff, 33 of the 291 randomized pts (194 to Ven and 97 to Pbo) were still receiving therapy (28 to Ven and 5 to Pbo) (March 15, 2021). The Ven arm had 78 (40%) deaths compared to 36 (37%) deaths in the Pbo arm after a median follow-up of 45.6 months. The Table shows updated PFS and OS for all pts as well as those with t(11;14) or high BCL2 expression. The median PFS per investigator in the Ven arm was 23.4 months compared to 11.4 months in the Pbo arm (HR, 0.58 [95 percent CI, 0.43–0.78]). The median PFS in patients with t(11;14) was 36.8 months in the Ven arm compared to 9.3 months in the Pbo arm (HR, 0.12 [95 percent CI, 0.03–0.44]). PFS was 30.1 months in the Ven arm versus 9.9 months in the Pbo arm in patients with high BCL2 (HR, 0.37 [95 percent CI, 0.21–0.64]). In the Ven or Pbo arm, median OS was not reached across all pts (HR, 1.19 [95 percent CI, 0.80–1.77]), pts with t(11;14) (HR, 0.61 [95 percent CI, 0.16–2.32]), pts with high BCL2 (HR, 0.70 [95 percent CI, 0.32–1.51]), and pts with t(11;14) or high BCL2
Diarrhea (60 percent against 50 percent), nausea (38 percent versus 23 percent), and constipation were the most common treatment-emergent adverse events (AEs) with Ven (versus Pbo) (35 percent versus 31 percent ). Thrombocytopenia (16 percent versus 30 percent), neutropenia (23 percent versus 8%), pneumonia (19 percent versus 13 percent), anemia (16 percent versus 15 percent), and diarrhea (16 percent versus 15 percent) were the most common Grade 3/4 AEs (Ven versus Pbo) (15 percent versus 11 percent ). Significant adverse events (AEs) occurred in 57% of Ven-treated patients and 55% of Pbo-treated patients, with serious infections and infestations occurring in 35% and 29% of patients, respectively. In all, 26% of pts in the Ven arm and 11% of pts in the Pbo arm had an AE, resulting in Ven or Pbo discontinuation. In the Ven arm, AEs resulted in 12 deaths, 9 of which were due to significant infection; in the Pbo arm, an AE resulted in 1 death. Treatment-emergent deaths occurred in 16 (6%) cases (14 [7%] with Ven and 2 [2%] with Pbo), with three of these deaths related to illness progression (2 [1 percent ] with Ven and 1 [1 percent ] with Pbo).
Conclusion:
In the final OS analysis, adding Ven to bortezomib and dexamethasone significantly improved PFS but increased mortality in the entire population compared to Pbo. Ven added to bortezomib and dexamethasone improved PFS the most in patients with t(11;14) or high BCL2, with a favorable benefit-risk profile, according to previous studies.