Concerning Mortality Increase Seen With Venetoclax/Bortezomib Combo in Phase III Trial

The combination of venetoclax and bortezomib lead to an increased number of deaths by infection in patients with multiple myeloma in the phase III BELLINI trial, according to data presented at the 2019 EHA Congress. Deaths increased in spite of promising responses data and a high progression-free survival rate.

Shaji Kumar, MD

The combination of venetoclax (Venclexta) and bortezomib (Velcade) lead to an increased number of deaths by infection in patients with multiple myeloma in the phase III BELLINI trial, according to data presented at the 2019 European Hematology Association Congress. Deaths increased in spite of promising responses data and a high progression-free survival (PFS) rate.

In BELLINI, patients were treated either with venetoclax or placebo, each in combination with bortezomib/dexamethasone. At 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= .01).

More patients demonstrated a response with venetoclax than placebo; the overall response rate (ORR) was 82% versus 68%, respectively (P <.01), and a very good partial or better response (≥VGPR) was seen in 59% versus 36% of patients (P<.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.

At the interim analysis, an increased risk of death was detected in the venetoclax plus bortezomib/dexamethasone arm. Although the median overall survival (OS) in the overall population was not reached in either arm, OS favored the placebo combination (HR, 2.027; 95% CI, 1.042-3.945).

“Novel therapies targeting disease biology are key to continuing the survival gains achieved in multiple myeloma,” lead study author Shaji Kumar MD, professor of medicine, Mayo Clinic, said in a presentation during the meeting. “The decrease in OS in the experimental arm was a surprise; it appears to be related to infection in patients with worse OS. In March, the FDA suspended venetoclax in multiple myeloma based on data from the BELLINI trial, and development remains on hold awaiting further instruction from the FDA.”

In March 2019, the FDA has placed a partial clinical hold on all clinical trials examining venetoclax in multiple myeloma, halting enrollment of new patients on the studies, due to the safety data from the BELLINI study.

Venetoclax targets BCL-2, a protein that prevents apoptosis in cancer cells, and had previously demonstrated activity in this patient population.

In the double-blind, multicenter, randomized phase III BELLINI trial (NCT02755597), investigators compared the efficacy and safety of venetoclax plus bortezomib/dexamethasone with placebo plus bortezomib/dexamethasone in patients with relapsed/refractory multiple myeloma.

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 (PIs). Patients were randomized 2:1 to receive venetoclax at 800 mg daily or placebo plus bortezomib at 1.3 mg/m2on 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 November 26, 2018, 194 patients were randomized 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 PIs in most patients (70%), and immunotherapy in 68%; 41% of patients had received both. The majority of patients (59%) underwent prior stem cell transplant. High-risk cytogenetics were reported in 18% of patients, and 13% had t(11,14). Immunohistochemistry testing revealed that 79% of patients were BCL-2 high.

An OS analysis in key subgroups indicated that low BCL-2 expression, high-risk cytogenetics, or ISS III disease were associated with both decreased PFS and OS in the venetoclax arm. However, patients with 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= .002). Also in this subgroup, the OS was not reached in either arm (HR, 0.343; P= .363.).

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

However, the increase in deaths was noted in the venetoclax arm.

“Treatment emergent deaths mainly occurred early on during treatment and were commonly due to infection and in the context of disease progression,” 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.”

Moreover, a review of OS and safety data indicated that 40 (21%) deaths occurred on the venetoclax arms compared with 11 (11%) in the placebo arm; of these 14 (7%) versus 2 (2%) were due to infection, 17 (9%) versus 8 (8%) due to progressive disease, and 9 (5%) versus 1 (1%) were due to other causes, respectively.

In both arms, the majority of deaths occurred after 30 days of the last dose, with 27 (14%) on the venetoclax arm compared with 10 (10%) in the placebo group. Of these, 3% versus 2% were due to infection, 8% versus 7% were due to progressive disease, and 3% versus 1% were due to other causes, respectively.

“Long-term biomarker strategy may be used to select patients that would benefit from venetoclax; the best marker may be the ratio of BCL-2 to BCL-X expression,” said Kumar. “The next steps are to focus on the t(11;14) subgroup for future development and to implement additional risk measures in multiple myeloma studies.”


Kumar S, Harrison S, Cavo M, et al. A phase 3 study of venetoclax or placebo in combination with n combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract LB2601.