Multiple myeloma is the second most common haematological cancer, and despite significant progress in the past two decades with introduction of several new therapies, the disease remains incurable.
Newer therapies targeting disease specific biology is critical for long term control of the disease and development of potentially curative strategies in the future.
Alterations in the apoptotic pathways are the hallmark of many cancers and Bcl2 family of proteins made up of anti- and proapoptotic proteins play a critical role in maintaining homeostasis in the normal state as well as enhancing cell survival in the setting of cancers.
Venetoclax is a small molecule inhibitor of Bcl2 that can induce apoptosis in cancer cells that are dependent on the pro-apoptotic protein for their
survival and is currently used in the clinic for treatment CLL.
Based on preclinical work demonstrating the ability of venetoclax to induce apoptosis in myeloma cells, phase 1 and 2 trials of venetoclax alone or in combination with dexamethasone or bortezomib were conducted and showed clinical efficacy, especially in patients with translocation t(11;14) in the
The Bellini trial, a randomised, placebo controlled trial, was designed to examine the efficacy of adding venetoclax to bortezomib and dexamethasone in patients with relapsed myeloma; 291 patients were randomised 2:1 to receive venetoclax or placebo in combination with bortezomib and dexamethasone.
The results of this study were presented at the 2019 European Hematology Association (EHA) Annual Meeting.
Higher overall response (82% vs 68%, p<0.01), very good partial response or better (59% vs 36%, p<0.01) were observed with venetoclax.
The median progression-free survival (PFS) was nearly doubled with addition of venetoclax (22.4 vs 11.5 months; HR=0.630, p=0.01).
However, there were more deaths observed in the venetoclax arm, resulting in an inferior overall survival (OS) (HR 2.027, 95% CI=1.042-3.945) at interim analysis.
Majority of excess deaths were due to infections and or progressive disease, especially during the first 6 months of the trial.
In particular, patients with high risk cytogenetics, higher disease stage, without t(11;14) or with low levels of bcl2 protein appear to have derived less benefit.
Ongoing studies are focusing on the patients with t(11;14) and identification of patient profiles most suitable for use of the drug alone and in combinations.