FDA Puts Enrollment Hold on Venetoclax Myeloma Trials

A partial clinical hold has been placed on all clinical trials examining venetoclax in multiple myeloma, according to AbbVie, co-developer of the BCL-2 inhibitor with Genentech. This hold, placed by the FDA, halts enrollment of new patients on the studies.

A partial clinical hold has been placed on all clinical trials examining venetoclax (Venclexta) in multiple myeloma, according to AbbVie, co-developer of the BCL-2 inhibitor with Genentech (Roche). This hold, placed by the FDA, halts enrollment of new patients on the studies.

The FDA based its decision on safety data from the ongoing phase III BELLINI trial (M14-031; NCT02755597), according to a press release from AbbVie. Results from the trial showed a higher rate of patient deaths with venetoclax combined with bortezomib (Velcade) and dexamethasone (Vd) compared with placebo plus Vd in patients with relapsed/refractory myeloma.

Specifically, the rate of deaths was 21.1% (41 of 194 patients) in the venetoclax arm compared with 11.3% (11 of 97 patients) in the placebo arm (HR, 2.03; 95% CI, 1.042-3.945). Further, 6.7% (n = 13) versus 1.0% (n = 1) of the deaths were treatment emergent in the 2 arms, respectively. Investigators attributed 8 of the 13 treatment-emergent deaths in the venetoclax arm to infection. In the venetoclax arm common causes of death other than disease progression included sepsis, pneumonia, and cardiac arrest.

Although new enrollment on venetoclax myeloma trials is on hold, previously enrolled patients benefiting from the treatment may continue on the studies after a discussion with their physician, according to AbbVie. The company also reported that study investigators have been informed of the hold and that additional analyses are ongoing.

“We are committed to patient safety and are thoroughly analyzing the results observed in the BELLINI trial. We will continue working with the FDA and worldwide regulatory agencies to determine appropriate next steps for the multiple myeloma program,” Michael Severino, MD, vice chairman and president, AbbVie, said in a statement. "We will continue to further the research and development of venetoclax and other therapies with the potential to transform the standards of care in blood cancers."

The multicenter, double-blind BELLINI trial accrued patients with relapsed/refractory multiple myeloma who had received 1 to 3 prior lines of therapy and were sensitive or naïve to proteasome inhibitors. Patients were randomized to Vd plus either venetoclax or placebo.

The study achieved its primary endpoint of progression-free survival (PFS) with a median PFS of 22.4 months in the venetoclax arm compared with 11.5 months with Vd alone. This translated to a 37% reduction in the risk of disease progression or death (HR, 0.63; 95% CI; 0.44-0.90). The overall response rate was significantly improved with venetoclax at 82% versus 68%, respectively, as was the rate of very good partial response or better at 59% versus 36%, respectively.

The rates of grade 3-5 adverse events (AEs) at 86.5% versus 87.5% and serious AEs (SAEs) at 48.2% versus 50.0% were comparable between the venetoclax and placebo arms. Infections occurred in 79.8% of the venetoclax group compared with 77.1% of the Vd-alone cohort. The rates of pneumonia were 20.7% versus 15.6%, respectively.

Twenty-eight percent of patients receiving the venetoclax combination had an SAE of infection compared with 27.1% of the placebo group. SAEs of pneumonia occurred in 14.0% versus 12.5% of the 2 arms, respectively.

The clinical hold does not affect any of the FDA-approved indications for venetoclax, which include the treatment of patients with chronic lymphocytic leukemia and acute myeloid leukemia. The hold also does not impact clinical studies of the BCL-2 inhibitor for patients with malignancies other than myeloma.


AbbVie Provides Update on VENCLEXTA®/VENCLYXTO® (venetoclax) Multiple Myeloma Program. AbbVie. Published March 19, 2019. Accessed March 19, 2019. https://bit.ly/2Ogtt7M.