The BET Bromodomain Inhibitor OTX015 Synergizes with Targeted Agents in Multiple Myeloma

Treatment failure remains a main challenge in the management of high-risk multiple myeloma (MM) even with the expanding repertoire of new drugs. Combinatorial therapy is considered an encouraging strategy that can overcome the compensatory mechanisms and undesirable off-target effects that limit the benefits of many prospective agents. Preliminary results of a current phase I trial have indicated that the new BET bromodomain inhibitor OTX015 has favorable activity and tolerability. However, OTX015 is not efficacious enough as a monotherapy. Here, we provide evidence that synergistic drug combinations with OTX015 were generally more specific to particular cellular contexts than single agent activities. In addition, pairing OTX015 with three classes of drugs dramatically enhanced the antitumor activity in mouse models of disseminated human myeloma. Our studies further underscored that the BET inhibitor OTX015 sensitized MM cells by interrupting several pathways and genes critical for MM cell proliferation and drug response, which provided the rationale for multiple myeloma therapy with OTX015 combined with conventional chemotherapeutic drugs. Thus, the context specificity of synergistic combinations not only provide profound insights into therapeutically relevant selectivity but also improve control of complex biological systems.