Venetoclax for multiple myeloma: effective but some safety concerns

Despite promising progression-free survival (PFS) and response data with venetoclax in combination with bortezomib and dexamethasone, roughly twice the number of deaths due to infection in the experimental arm cast fears over the overall survival findings in patients with relapsed/refractory multiple myeloma, according to results of the double-blind, multicentre, randomised, phase 3 BELLINI trial [1].

In BELLINI, patients were treated with bortezomib/dexamethasone with venetoclax or placebo; the FDA has now called for a halt in enrolment because of increased risk of death (not applicable for approved indications of venetoclax).

In the late-breaking abstracts session, the trial data showed a median follow-up of 18.7 months; the median PFS was nearly doubled at 22.4 months with the venetoclax combination compared with 11.5 months with the placebo arm (HR 0.630; P=0.01). More patients demonstrated a response with venetoclax than placebo; the overall response rate was 82% vs 68%, respectively (P<0.01), and a very good partial or better response (≥VGPR) was seen in 59% vs 36% of patients (P<0.01). Regarding the parameter of undetectable minimal residual disease (uMRD [10-5]), the uMRD rates were 13% compared with 1% with the respective treatments. The median duration of response was not reached with venetoclax, compared with 12.8 months with placebo.

However, at the interim analysis, the FDA found that for overall survival, there were 41/194 (21.1%) deaths in the venetoclax arm compared with 11/97 deaths in the placebo arm (HR 2.03; 95% CI 1.04-3.94), “increasing the relative risk of death by approximately 2-fold compared with the placebo arm,” according to the FDA. The FDA noted, however, that this alert does not apply to indications for which venetoclax is currently FDA-approved, including chronic lymphocytic leukaemia, small lymphocytic lymphoma, and as part of a combination treatment for acute myeloid leukaemia. Additionally, patients currently enrolled in the BELLINI clinical trial who are receiving clinical benefit may continue the treatment after reconsenting.

“Novel therapies targeting disease biology are key to continuing the survival gains achieved in multiple myeloma,” lead study author Dr Shaji Kumar (Mayo Clinic, USA) said in his presentation. “The decrease in overall survival in the experimental arm was a surprise; it appears to be related to infection in patients with worse overall survival.”

Venetoclax targets BCL-2, a protein that prevents apoptosis in cancer cells, and had previously demonstrated activity in this patient population. BELLINI enrolled patients with relapsed/refractory multiple myeloma who had received 1 to 3 prior therapies and were either sensitive or naïve to proteasome inhibitors. Patients were randomised 2:1 to receive venetoclax at 800 mg daily or placebo plus bortezomib at 1.3 mg/m2 on days 1, 4, 8, 11 and dexamethasone at 20 mg on days 1, 2, 8, 9, 15, 16, 22, 23 of 28-day cycles for 8 cycles. The primary endpoint was PFS by an independent review committee.

As of the data cut-off on 26 November 2018, 194 patients were randomised to the venetoclax arm and 97 to the placebo arm. The median age was 66 years (range 36-87), 53% had International Staging System (ISS) II/III disease, and 54% of patients had received 2 or 3 prior lines of therapy. Prior treatments included proteasome inhibitors in most patients (70%), and immunotherapy in 68%; 41% of patients had received both. Most patients (59%) underwent prior stem cell transplant. High-risk cytogenetics were reported in 18% of patients, and 13% had translocation t(11;14). Immunohistochemistry testing revealed that 79% of patients were BCL-2 high.

An overall survival analysis in key subgroups indicated that low BCL-2 expression, high-risk cytogenetics, or ISS III disease were associated with both decreased PFS and overall survival in the venetoclax arm. However, patients with translocation t(11;14) derived more benefit from venetoclax and the median PFS was not reached, compared with 9.5 months in those who received placebo (HR 0.11; 95% CI 0.022-0.560; P=0.002). Also, the overall survival in this subgroup was not reached in either arm (HR 0.343; P=0.363).

Regarding safety, the most common adverse events of any grade with the venetoclax combination vs the placebo arm were diarrhoea (58% vs 48%, respectively), constipation (34% vs 31%), and nausea (36% vs 22%). The most common haematological adverse events in the respective arms were thrombocytopenia (39% vs 52%), neutropenia (32% vs 10%), and anaemia (25% vs 25%).

Dr Kumar said, “Five deaths occurred in the context of concomitant infection and disease progression and most of the deaths occurred within the first 6 months of treatment.”

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   1. Kumar S, et al. Abstract LB2601, 24th Congress of the EHA, 13-16 June 2019, Amsterdam, the Netherlands.

 



Posted on 9 August 201911 March 2021