Isatuximab and Belantamab Mafodotin: A Primer to an Evolving Multiple Myeloma Landscape

Abstract

Multiple myeloma (MM) continues to be an incurable disease impacting mainly an ageing population. Comorbidities, disease characteristics, and drug toxicity profiles heavily influence treatment selections. Despite single agent activity of many anti-MM agents, opportunities to maintain responses most often include combination therapy with immunomodulator and/or proteasome inhibitor therapies. Monoclonal antibodies (moAb) have become an additional backbone to both newly diagnosed and relapsed or refractory transplant eligible and ineligible patients. Tolerability of these agents offers an additional benefit particularly to an ageing population. Two newly approved moAb targeting CD38 and B-cell maturation antigen have been added to the anti-MM arsenal. Isatuximab, a chimeric anti-CD38 moAb, is the second U.S. Food and Drug Administration (FDA)-approved CD38 targeted therapy offering unique mechanisms of action owing to differences in epitope binding and favourable side effect profiles. Belantamab mafodotin, a B-cell maturation antigen drug-antibody conjugate, is a first-in-class humanised moAb containing a distinct microtubule-disrupting agent: monomethyl auristatin-F. Its distinctive anti-MM activity includes antibody-dependent cellular cytotoxicity and phagocytosis, as well as direct cytotoxicity caused by internalisation of monomethyl auristatin-F. This review focusses primarily on the mechanisms of action, resistance patterns, and clinical utility of two recently FDA approved agents; isatuximab in combination with pomalidomide and dexamethasone for relapsed or refractory MM exposed to at least two or more lines of therapy, and belantamab mafodotin monotherapy in relapsed or refractory MM exposed to four or more lines of therapy.