Several studies demonstrate that the bromodomain inhibitor OTX015 has an antitumor activity in cancers. However, translation of these data to molecules suitable for clinical development has yet to be accomplished in multiple myeloma (MM). Here, we identified genes and biologic processes that substantiated the antimyeloma activity of OTX015 with global transcriptomics. OTX015 exerted a strong antiproliferative effect and induced cell cycle arrest in vitro. Gene expression profiling uncovered that OTX015 targeted NF-kappa B, EGFR, cell cycle regulation, and the cancer proliferation signaling pathway. Gene expression signatures displaying various levels of sensitivity to OTX015 were also identified. The data also showed that oral administration of OTX015 displayed significant antitumor activity in the mice model of disseminated human myeloma. In addition, our study provided the first evidence and rationale that OTX015 could promote osteoblast differentiation of mesenchymal stem cells (MSCs) and inhibited osteoclast formation and resorption in vivo experiments. Herein our results expanded the understanding of the mechanism for BET inhibitors OTX015 in MM. Our study provided an impressive basis for the clinical application of the novel antimyeloma agent OTX015 and uncovered signaling pathways that may play key roles in myeloma cell proliferation.