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Disclosures (Graham Jackson, MD, MA, MB, BS): Grant/Research Support: Bristol Myers Squibb, Takeda, Onyx; Consultant: Amgen, Bristol Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Sanofi Genzyme, Takeda; Speakers' Bureau: Amgen, Bristol Myers Squibb, Johnson & Johnson, Sanofi Genzyme, Takeda.
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Mechanism of Action of Monoclonal Antibodies in Multiple Myeloma
There have been several advances in the multiple myeloma (MM) treatment landscape over the past 10 to 15 years with the introduction of proteasome inhibitors, immunomodulatory drugs, an HDAC inhibitor, the antibody-drug conjugate belantamab mafodotin, the peptide-drug conjugate melflufen, the nuclear transport inhibitor selinexor, and the particular emphasis of this article: the monoclonal antibodies. Many of these agents have been approved in relapsed/refractory myeloma and in the induction and consolidation setting. Several of these agents are now being investigated in maintenance and in smoldering MM (SMM) as well. With these advances, the median survival of patients with MM has been markedly prolonged, and the disease is evolving into a chronic illness in many patients.
There are three monoclonal antibodies that have been approved for the treatment of MM, namely daratumumab, elotuzumab, and isatuximab. A better understanding of the mechanism of action of the monoclonal antibody therapies is critical to the development of better therapeutic strategies in MM.
Monoclonal antibodies target the immune system and myeloma cells. Daratumumab and the more recently developed isatuximab both target the CD38 receptor on myeloma cells and facilitate complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and direct apoptosis of the myeloma cells. (1-5)
While daratumumab and isatuximab both target CD38 and have some overlapping mechanisms of action, there are key differences in...