Introduction: Combinations of proteasome inhibitors, immunomodulators, and monoclonal antibodies are highly active against multiple myeloma. Consequently, several combinations have moved from the relapsed to the front-line setting. In the context of lenalidomide and bortezomib being used upfront, salvage options need to be evaluated.Areas covered: This manuscript reviews available data for the treatment of patients progressing on optimal frontline strategies, with a focus on the role of second-generation proteasome inhibitors and immunomodulators, monoclonal antibodies and immunotherapy.Expert opinion: Remarkable progress has been made in myeloma treatment due to the integration of immunomodulators, proteasome inhibitors and more recently monoclonal antibodies in the front-line setting. However, we work on the assumption that most individuals will eventually relapse. Optimized upfront therapy negatively selects more resistant patients among still relapsing individuals. Bortezomib and lenalidomide-exposed patients are under-represented in trials leading to currently approved combinations. Evidence needs to be reviewed taking into account how the improvement of frontline therapy has modified the characteristics of patients at the time of relapse. Second generation immunomodulatory agents and proteasome inhibitors, monoclonal antibodies and other agents have shown efficacy in this new landscape. Immunotherapeutic agents, including CAR-T cells are promising for patients failing standard combinations, despite current data are still immature.
Keywords: Bispecific antibodies; CAR-T cells; immunoconjugates; immunotherapy; lenalidomide-resistance; monoclonal antibodies; relapsed and refractory multiple myeloma.