Belantamab mafodotin triggers immune invigoration in multiple myeloma via inflammatory and immunogenic cell death

Objective 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 mediation of antibody-induced cell death. Long-term clinical responses were observed with monotherapy treatment, despite dose holds, suggesting adaptive immune system involvement. We aimed to explore mechanisms of belantamab mafodotin-triggered cell death and how this contributes to immune remodelling. Design Cell lines, myeloma patient bone marrow and samples from belantamab mafodotin-treated patients were used to explore belantamab mafodotin-driven cell death and their downstream influence on the tumour microenvironment. Results 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 low-density lipoprotein receptor-related protein 1 (LRP1) and toll-like receptor 2 (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 remodelling of the innate and adaptive immune system, a reduction in immune inhibitory signalling and the emergence of CD4 granzyme B-expressing cells in patients in remission versus those that relapse. Conclusion 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.