Belantamab Mafodotin Triggers Immune Invigoration in Multiple Myeloma Via Inflammatory and Immunogenic Cell Death

Belantamab mafodotin, an antibody-drug conjugate targeting B-cell maturation antigen, has demonstrated significant clinical efficacy in combination therapies for relapsed/refractory multiple myeloma. Belantamab mafodotin exerts therapeutic effects through cytotoxicity of its payload, monomethyl auristatin F, and through mediation of antibody-induced cell death. Long-term clinical responses were observed with monotherapy treatment, despite dose holds, suggesting adaptive immune system involvement. Here, we show that belantamab mafodotin induces markers of immunogenic and inflammatory cell death in vitro and ex vivo. Belantamab mafodotin monotherapy treatment triggers acute inflammation detectable in patient serum within 24 hours, with increases in granzyme B, CXCL9, CCL3, and CCL4 linked to response depth achieved. High expression of LRP1 and TLR2, receptors that mediate immunogenic cell death on patients’ monocytoid (monocyte/macrophage) cells, suggests an important function of monocytoid cells to mediate the inflammation and immunogenic cell death cascades. Inflammation is followed by remodeling of the innate and adaptive immune system, a reduction in immune inhibitory signaling and the emergence of CD4 granzyme B-expressing cells in patients in remission vs those that relapse. Belantamab mafodotin’s ability to promote adaptive immune responses and its cytotoxic activity may help explain the durable responses observed in treated patients, despite dose and schedule modifications.