Abstract 691: Activity of the BET inhibitor INCB054329 in models of multiple myeloma

Multiple myeloma (MM) is a disease of plasma cell transformation. Current therapy for MM is initially effective, but nearly all tumors relapse, making new therapeutic options a necessity. Due to their efficacy in MM models, small molecule inhibitors of Bromodomain and Extra Terminal (BET) proteins have generated much interest as potential therapeutic agents for MM. Efficacy from BET inhibitors in MM is thought to be driven by their ability to reduce transcript levels of the c-myc oncogene. Current MM standard of care (SoC) therapeutics include lenalidomide (Revlimid, Celgene), bortezomib (Velcade, Takeda), and Melphalan (Alkeran, GlaxoSmithKline). In preparation for potential clinical studies, these MM SoC agents were each combined with a potent pan-BET inhibitor, INCB054329, for in vitro and in vivo studies. In vitro, treatment of MM cell lines with INCB054329 inhibited expression of c-MYC, induced HEXIM1 levels and inhibited cell growth with potencies less than 200 nM. Combination of INCB054329 with SoC therapeutics showed synergistic effects in blocking MM cell proliferation. INA-6 and MM1.S mouse xenograft models of MM were utilized to study the effects of the combination of INCB054329 with the MM SoC agents in vivo. In each instance (INCB054329/lenalidomide, INCB054329/bortezomib, INCB054329/melphalan), additive to synergistic effects, as measured by inhibition of subcutaneous tumor growth, were seen in both models of MM. Since lenalidomide has recently been shown to bind the ubiquitin ligase cereblon (CRBN), leading to the degradation of two Ikaros family members, IKZF1 and IKZF3, that are essential to B cell fate and survival, we examined whether there could be functional overlap between BET inhibition and the downstream effects of lenalidomide. From MM1.S xenograft pharmacodynamic assays, we found a synergistic repression of c-MYC protein levels at 3hr post dose for the combination of INCB054329 and lenalidomide. Interestingly, the sharp decline in c-MYC protein levels in the MM1.S model appears to be independent of the IRF4 pathway, as IRF4 protein levels do not decrease until 24 hrs post dose of lenalidomide. Overall, our data indicate that INCB054329 may provide a novel combination partner with current standard of care therapies for MM, and support the clinical evaluation of the compound within the anti-myeloma treatment landscape. Citation Format: Matthew Stubbs, Xiaoming Wen, Valerie Dostalik, Sybil O'Connor, Eian Caulder, Alla Vogina, Thomas