The Janus kinase (JAK) pathway has been shown to play key roles in the growth and resistance to drugs that develop in multiple myeloma (MM) patients. The anti-MM effects of the selective JAK1 inhibitor INCB052793 (INCB) alone and in combination with anti-MM agents were evaluated in vitro and in vivo. Significant inhibition of cell viability of primary MM cells obtained fresh from MM patients, and the MM cell lines RPMI8226 and U266, was observed with single agent INCB and was enhanced in combination with other anti-MM agents including proteasome inhibitors and glucocorticosteroids. Single-agent INCB resulted in decrease in tumor growth of the MM xenograft LAGκ-1A growing in severe combined immunodeficient mice. Mice dosed with INCB (30 mg/kg) showed significant reductions in tumor volume on days 28, 35, 42, 49, 56, and 63. Similarly, INCB at 10 mg/kg showed anti-tumor effects on days 56 and 63. Tumor-bearing mice receiving combinations of INCB with carfilzomib, bortezomib, dexamethasone, or lenalidomide showed significantly smaller tumors when compared to vehicle control and mice treated with single agents. These results provide further support for the clinical evaluation of INCB052793 alone and in combination treatment for MM patients.