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The translocation t(11;14), occurring in around 15-20% of Multiple Myeloma (MM) patients, has been linked with higher than average levels of BCL2 mRNA expression levels, in comparison with MCL1 and BCL-XL. These patients are good candidates for targeted therapy with venetoclax (ABT-199), a selective BCL-2 inhibitor leading to cell death in MM cells.
In a phase I trial to treat Relapsed and Refractory Multiple Myeloma (RRMM) patients, venetoclax monotherapy was assessed - the primary objective to evaluate the safety profile and pharmacokinetics, and to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives were to assess the overall response rate (ORR), time to progression (TTP), duration of response (DOR), and exploratory biomarkers.
The results of the study, conducted by Shaji Kumar, from the Mayo Clinic, Rochester, MN, USA, and in collaboration with a large group of researchers, were reported in Blood in October 2017. The Phase I M13-367 study recruited patients with RRMM from October 2012; data cut-off was 19 August 2016.
A daily dose of 1,200 mg of venetoclax was well-tolerated in heavily pre-treated RRMM patients, and in particular promising efficacy data was observed for t(11;14) positive patients. Analysis of baseline BM aspirates also indicated that patients with high BCL-2 expression and lower levels of BCL-XL/MCL responded more effectively to venetoclax, and as predicted this profile of expression was more frequent in the t(11;14) sub-group. Although this monotherapy was effective, it is more commonly used with dexamethasone, which increases the BCL-2 dependency of myeloma cells. Ongoing trials are testing this combination, along with a PI as a triplet regimen, and it will be interesting to see sub-group analyses for t(11;14) positive patients. Overall, this research beckons further patient pre-screening ahead of drug selection, as targeted therapy slowly becomes mainstream.