Relapsed/Refractory Multiple Myeloma in 2020/2021 and Beyond

SIMPLE SUMMARY: During the last two decades, collaborative translational studies utilizing novel methodologies have dramatically advanced our understanding of multiple myeloma (MM) pathophysiology and revolutionized derived treatment strategies. Nevertheless, MM remains an incurable disease, with the vast majority of patients relapsing due to evolving genetic alterations within tumor cell clones as well as the pressure of the immunosuppressive bone marrow (BM) microenvironment. Therefore, continuous translational efforts are needed to further increase our understanding of MM biology, develop rationally derived drugs and to thereby improve patient outcome. ABSTRACT: Despite the challenges imposed by the COVID-19 pandemic, exciting therapeutic progress continues to be made in MM. New drug approvals for relapsed/refractory (RR)MM in 2020/2021 include the second CD38 monoclonal antibody, isatuximab, the first BCMA-targeting therapy and first-in-class antibody–drug conjugate (ADC) belantamab mafodotin, the first BCMA-targeting CAR T cell product Idecabtagen-Vicleucel (bb2121, Ide-Cel), the first in-class XPO-1 inhibitor selinexor, as well as the first-in-class anti-tumor peptide-drug conjugate, melflufen. The present introductory article of the Special Issue on “Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond” summarizes the most recent registration trials and emerging immunotherapies in RRMM, gives an overview on latest insights on MM genomics and on tumor-induced changes within the MM microenvironment, and presents some of the most promising rationally derived future therapeutic strategies.