Programming Myeloma Cell Death With Venetoclax

While there has been significant progress in multiple myeloma (MM) with immunomodulatory drugs, proteasome inhibitors, and now anti-CD38 monoclonal antibodies like daratumumab, MM remains an incurable malignancy where relapse becomes more difficult to treat over time. To meet this challenge, there is an ongoing effort to identify new pathways as therapeutic targets. Dysregulation of the apoptotic pathway mediated by anti-apoptotic proteins such as BCL-2, BCL-X_L, and MCL-1 plays an important role across a range of malignancies.¹  Venetoclax (ABT-199) is an oral selective inhibitor of BCL-2, and is the first drug approved by the U.S. Food and Drug Administration, with an indication in patients with chronic lymphocytic leukemia (CLL) with 17p deletion and one or more prior lines of treatment.²  In MM, targeting BCL-2 began with preclinical work showing activity of venetoclax in MM cell lines, especially in cell lines with the t(11;14) translocation or a high BCL-2/MCL-1 ratio.³  The increased activity in t(11;14) MM may reflect a higher BCL-2/MCL-1 ratio compared to other subgroups, based on gene expression profiling.⁴  Additionally, in a xenograft model, the proteasome inhibitor bortezomib can enhance the activity of venetoclax by upregulating NOXA, a pro-apoptotic factor that neutralizes MCL-1.⁵  Furthermore, in vitro, dexamethasone promotes the binding of the pro-apoptotic protein BIM to BCL-2, increasing the sensitivity of MM cell lines to venetoclax.⁶ 

With this background, Dr. Philippe Moreau and colleagues evaluated the combination of venetoclax, bortezomib, and dexamethasone in a phase Ib trial in relapsed/refractory MM.⁷  Venetoclax was given orally daily at doses ranging from 100 to 1,200 mg combined with bortezomib given subcutaneously and dexamethasone. For the first eight cycles, bortezomib and dexamethasone were given according to the conventional 21-day, twice-per-week schedule. For cycles nine to 11, bortezomib and dexamethasone were given weekly according to a 35-day cycle. From cycles 12 onward, venetoclax was given as monotherapy. In the initial cohort, to assess for the risk of tumor lysis syndrome (which was seen in clinical trials in CLL), there was a one-week lead-in period of 50 mg alone prior to starting the combination. The study enrolled 66 patients, with a median of three prior lines of treatment (range 1-13); 39 percent were refractory to bortezomib and 53 percent were refractory to lenalidomide. The combination was tolerated well, with grade 3 to 4 adverse events reflecting mainly myelosuppression: thrombocytopenia (29%), anemia (15%), and neutropenia (14%). Gastrointestinal adverse events were common but low grade, with 6 percent grade 3 to 4 diarrhea. Tumor lysis syndrome was not seen. The maximum tolerated dose of venetoclax was not reached.

The combination was effective, with an overall response rate (ORR) of 67 percent, and 42 percent with a very good partial response or better. The median time to progression was 9.5 months (95% CI, 5.7-10.4). In patients who were not refractory to bortezomib, the ORR was 90 percent; responses were also seen in patients who were refractory to bortezomib (ORR, 31%) or lenalidomide (ORR, 60%). Importantly, patients with higher expression of BCL2 had the best responses to the combination, with an ORR of 94 percent compared to an ORR of 59 percent in patients with low BCL2 expression. Based on efficacy and safety, a venetoclax dose of 800 mg was chosen as a recommended dose going forward.