Several studies have demonstrated constitutive activation of the JAK-STAT pathway in MM through dysregulated signaling of cytokines such as IL-6. In addition to its crucial role in promoting the growth, proliferation and survival of myeloma cells, IL-6 is also a potent stimulator of osteoclastogenesis and influences the tumor microenvironment in the bone marrow of myeloma patients by promoting an immunosuppressive milieu. Since JAK1 has been shown to be important for IL-6 signaling, studies to assess the effect of JAK1 inhibition alone and in combination with other anti-MM agents were undertaken. The human MM cell lines, RPMI8226 or U266, were cultured in the presence of the JAK1 selective inhibitor INCB052793 plus a panel of anti-MM agents including the alkylating agents, cyclophosphamide (CY), melphalan (MEL), and bendamustine, the proteasome inhibitor, carfilzomib, the corticosteroid, dexamethasone (DEX) or the immunomodulatory agents lenalidomide (LEN) and pomalidomide (POM). After 48 hours, cell viability was assessed. Combinations of INCB052793 plus the three alkylating agents or carfilzomib synergistically inhibited the viability of both cell lines in vitro. INCB052793 plus CY or MEL also significantly decreased the viability of the MM1S MM cell line. In vivo, mice bearing the human patient derived MM tumor LAGκ-1A had significantly smaller tumors when treated with INCB052793 alone when compared to vehicle control at Day 35 post implantation. This was in contrast to mice treated with single agent DEX, LEN or POM. Although the combination of INCB052793 with DEX, LEN or POM did not synergistically inhibit MM cell line growth in vitro, mice receiving the doublets of INCB052793 and DEX, LEN or POM demonstrated an effect on tumor growth that was superior to the doublets of DEX with LEN or POM. Mice receiving the triple combination of INCB052793 + DEX with LEN or POM demonstrated the most significant effect on tumor growth compared to all other combinations tested. The inhibition of tumor growth with these combinations was observed throughout the study (through Day 70) and all combinations were well tolerated. Concomitant with effects on tumor growth, a significant reduction in serum human IgG levels was also observed. Studies to further understand the mechanistic effects of these combinations on myeloma signaling and the tumor microenvironment are ongoing. In conclusion, these in vitro and in vivo studies demonstrate that the combination of INCB052793 with a broad spectrum of anti-MM agents is effective, and provide further support for the clinical evaluation of these drug combinations in MM patients.
Citation Format: Eric Sanchez, Mingjie Li, Cathy Wang, Puja Mehta, George Tang, Haiming Chen, James R. Berenson. Effects of INCB052793, a selective JAK1 inhibitor, in combination with standard of care agents in human multiple myeloma (MM) cell lines and xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1339.