preheader BJH 2019

header website

Adding venetoclax to bortezomib and dexamethasone worsens the overall survival of patients with relapsed/refractory multiple myeloma

In the phase III BELLINI trial, adding venetoclax to bortezomib and dexamethasone led to a better progression-free survival and higher response rates in patients with relapsed/refractory multiple myeloma. However, this benefit came at the cost of more deaths in the venetoclax-containing treatment arm resulting in a worse overall survival for patients treated with the experimental triplet therapy. The majority of these excess deaths were related to infections and/or progressive disease, especially during the first 6 months of the trial.

Background

Despite the significant progress in the treatment of patients with multiple myeloma (MM), the disease remains incurable and the majority of patients will ultimately become refractory to all available therapies. As such, there is still need for alternative treatment strategies in patients with relapsed/refractory (RR)MM. Alterations in the apoptotic pathways are a hallmark of many cancers. Bcl2 plays a critical role in maintaining homeostasis in the normal state as well as enhancing cell survival in the setting of cancer. Venetoclax is a small molecule inhibitor of Bcl2 which can induce apoptosis in cancer cells that are dependent on the pro-apoptotic protein for their survival. Venetoclax is currently being used in the clinic to treat certain patients with chronic lymphocytic leukemia. Based on preclinical work demonstrating the ability of venetoclax to induce apoptosis in myeloma cells, phase I and II trials of venetoclax alone or in combination with dexamethasone or bortezomib were conducted and showed clinical efficacy, especially in patients harbouring a translocation t(11;14). The randomised, placebo controlled, phase III BELLINI trial was designed to examine the efficacy of adding venetoclax to bortezomib and dexamethasone in patients with RRMM.

Results

In the trial at hand, 291 RRMM patients who received 1-3 prior lines of therapy and who were not refractory to proteasome inhibition were randomly assigned (2:1) to receive either venetoclax (800 mg/day) or placebo in combination with bortezomib and dexamethasone (Bd). Cycles 1-8 consisted of 21-days with bortezomib given at a dose of 1.3 mg/m2 on days 1, 4, 8 and 11, and dexamethasone at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12. From cycle 9 onwards the cycle duration was prolonged to 35 days with 1.3 mg/m2 of bortezomib on days 1, 8, 15 and 22, and 20 mg of dexamethasone on days 1, 2, 8, 9, 15, 16, 22 and 23. The primary endpoint of the trial was progression-free survival (PFS) by independent review committee.

The median age of patients in the trial was 66 years and 53% had ISS II/III disease. In total, 46% of patients received the study drug in second line and the median number of prior treatment lines was 2. About two-thirds of patients previously underwent a stem cell transplantation, 70% was previously treated with a proteasome inhibitor (PI), 68% received a prior immunomodulatory drug (IMiD) and 41% received both a PI and an IMiD. Eighteen percent of patients in the trial were found to harbour high-risk cytogenetics, 13% had a t(11;14) and 79% had high Bcl2 expression on immunohistochemistry (IHC).

The study met its primary endpoint by showing a doubling in the median PFS from adding venetoclax to Bd (median PFS: 22.4 vs 11.5 months; HR 0.630 [95% CI 0.443-0.897]; p=0.01). This PFS benefit of adding venetoclax was particularly pronounced in patients harbouring a t(11;14) (HR 0.110 [95% CI 0.022-0.560]). In contrast, in patients with high-risk cytogenetics no difference was seen in terms of PFS between both study arms (HR 1.206 [95% CI 0.577-2.520]). Also the objective response rate (ORR) was significantly higher with the venetoclax-containing combination than in the control arm (82% vs 68%; p<0.01) and this was also the case for the rate of very good partial or better response (≥VGPR, 59% vs 36%; p<0.01) and the percentage of patients reaching a level of undetectable minimal residual disease (MRD; 13% vs 1%).

However, there were more deaths observed in the venetoclax arm, resulting in an inferior overall survival (OS) compared to Bd (HR 2.027 [95% CI 1.042-3.945]). The negative impact of adding venetoclax on the OS was particularly pronounced in patients with high-risk cytogenetics, in patients with a more advanced disease stage, and in patients without t(11;14) or with low levels of bcl2. In contrast, among patients with a t(11;14) the investigators did notice a trend for a better OS with the venetoclax-containing combination (HR 0.343 [95% CI 0.031-3.842]). In total, there were 51 deaths in the safety population: 40 (21%) in the venetoclax-containing arm and 11 (12%) in the Bd-arm. The most common cause of death was progressive disease (PD; 40% with venetoclax and 64% in the control arm). Of the 14 treatment-emergent (TE) deaths that were reported in the study (i.e. deaths occurring on therapy or ≤30 days from the last dose), 13 occurred in the venetoclax arm (8 due to infection, 2 due to PD) as compared to 1 (PD) in the control arm.

The most common TE adverse events (TEAEs) (venetoclax-Bd vs Bd) were diarrhea (58% vs 48%), nausea (36% vs 22%), constipation (34% vs 31%), and fatigue (31% vs 32%). The most common grade 3/4 TEAEs were neutropenia (18% vs 7%), pneumonia (16% vs 9%), thrombocytopenia (15% vs 30%), and anaemia (15% vs 15%). Twice as much patients in the venetoclax arm discontinued therapy due to a TEAE.

Conclusions

Although the addition of venetoclax to bortezomib-dexamethasone significantly improved the PFS, the ORR, the rate of ≥VGPR, and the percentage of patients obtaining undetectable levels of MRD, the increased risk of death results in an unfavourable benefit-risk profile for this therapeutic strategy. In t(11;14) patients, the improvements in PFS and response rate resulting from the addition of venetoclax to bortezomib-dexamethasone were accompanied by a positive trend in OS. This suggests that a biomarker-driven approach focusing on this subgroup of patients might be the way forward for venetoclax in MM.

Reference

Kumar S, Harrison S, Cavo M, et al. A phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at EHA 2019; abstract LB2601.

Speaker Shaji Kumar

Kumar

Shaji Kumar, MD, PhD, Mayo Clinic, Rochester, MN, USA

 

See: Keyslides

 

Back to Top