Venetoclax monotherapy for relapsed/refractory multiple myeloma

Shaji Kumar, MD, from the Mayo Clinic, Rochester, MN, discusses the safety and efficacy of the BCL-2 inhibitor venetoclax as a single agent in relapsed and refractory multiple myeloma at the American Society of Hematology (ASH) Congress 2016 in San Diego, CA. He explains that venetoclax is a BCL-2 inhibitor, and the BCL-2 class of proteins helps cells to survive in the presence of a variety of toxic stimuli, such as cancer drugs. By targeting BCL-2, cancer cells can be potentially induced to die. He explains results from the lab, which show that using BCL-2 inhibitors causes myeloma cell death. The Phase I study of venetoclax as a single agent in patients with relapsed and refractory multiple myeloma was based on this (NCT01794520), with safety expansion at the recommended Phase II dose. 66 patients were enrolled in this study, and the drug was well tolerated overall with very little toxicity, similar to the known toxicity seen in venetoclax in other cancers, with mostly hematological toxicity and some gastrointestinal toxicity which were both easily managed. A response to the treatment was seen in 20% of patients. Dr Kuman points out that this is interesting, as the patients had a median of 5 prior lines of treatment, with as many as 15 previous therapies. In this highly pre-treated group of patients, three-quarters of the patients were refractory to bortezomib or lenalidomide, and almost two-thirds of trial participants were refractory to both drugs. While the 20% response rate was surprisingly high, what was most striking was the result in those patients who were t(11;14) positive. In these 30 patients, a response rate of 40% was observed, indicating a very high activity of venetoclax in this group. Dr Kumar highlights that even more interestingly, certain biomarkers such as the BCL-2 and BCLXL ratio appears to be able to better define the myeloma that is going to respond to treatment. By using these criteria, a group can be identified where the response rate was 85%, introducing the possibility of carrying out a biomarker-driven therapy in myeloma, with a drug that is very efficacious in a particular genetic subgroup. This is now moving forward in Phase III trials.

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