The phase 3 BELLINI trial in multiple myeloma (ClinicalTrials.gov Identifier: NCT02755597), in which researchers were evaluating the safety and efficacy of bortezomib and dexamethasone with or without venetoclax, was put on hold by the US Food and Drug Administration (FDA) in March 2019.1 The hold, according to the FDA’s release, was necessary because of the increased risk of patient death associated with receipt of venetoclax rather than placebo.

While previous research suggested that venetoclax might be a promising treatment for myeloma, BELLINI showed, at its interim analysis, a 2-fold risk of death with the drug compared with placebo, with 41 out of 194 (21.1%) patients and 11 out of 97 (11.3%) patients dying in the venetoclax and placebo arms, respectively. The researchers noted these results despite also observing improved progression-free survival (PFS) and objective response rate (ORR) in other patients in the venetoclax arm.

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The unfortunate survival statistics were, in light of previous research, surprising to some, given that venetoclax trials have met with success in other therapeutic areas, including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). In the past several years, the FDA had approved the drug for both indications.2,3

Venetoclax is a selective oral inhibitor of BCL-2, and was shown in cell lines to be particularly active against myeloma cells expressing high BCL-2 levels. Phase 1 research of venetoclax monotherapy in relapsed/refractory myeloma showed an overall response rate of 21%; grade 3 or 4 adverse events, including thrombocytopenia (32%), neutropenia (27%), anemia (23%), and leukopenia (23%), were, however, noted.4

Yet it is unclear, at this point, why patients in the experimental arm in BELLINI saw a worse overall survival (OS) rate than those receiving placebo.

“The FDA placed a partial clinical trial hold following a review of data from the phase 3 BELLINI trial, a study in relapsed/refractory multiple myeloma, in which a higher proportion of deaths was observed in the venetoclax arm compared to the control arm of the trial,” said Carlos Taveras, global public affairs director for oncology at AbbVie, the company that manufactures venetoclax. “We’re currently analyzing the data to better understand the results and it would be premature and inappropriate to speculate about causality at this stage.”

Thirteen of the 41 deaths noted in the venetoclax arm in BELLINI were considered treatment-emergent, and “8 were attributed by the investigator to an event of infection,” according to a press release from AbbVie.5 “More than half [of the 13] were in the setting of refractory or progressive disease.”