The treatment of Multiple myeloma (MM) has been revolutionized by the advent of immunotherapies. Monoclonal antibodies targeting specific markers greatly contributed to patients’ outcome improvement. Antibodies can be conjugated with a toxic payload to exert anti-tumor efficacy (antibody–drug conjugates, ADCs). ADCs combine direct cytotoxicity with immune-mediated effects, potentially sustaining antimyeloma activity even with prolonged dosing intervals. B-cell maturation antigen (BCMA) is selectively expressed on plasma cells, including malignant clones and represents a validated target in MM. Belantamab-mafodotin is the first in class anti-BCMA ADC approved in MM. The drug demonstrated single agent activity in heavily pretreated MM patients enrolled in the phase II DREAMM-2 trial. However, the confirmatory phase III DREAMM-3 trial failed to show superiority over standard therapy, leading to a temporary withdrawal of its approval by regulatory agencies. Despite this setback, recent data from the DREAMM-7 and DREAMM-8 trials have renewed interest in Belantamab-mafodotin, showing a benefit over standard of care treatments when evaluated in earlier lines of therapy and in combination with known therapeutic backbones. Recently, other ADCs against BCMA or other targets are being developed. This review aims to explore the current clinical positioning of ADCs within MM therapeutic landscape and their possible future development.
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