Belantamab mafodotin does not induce B-cell maturation antigen loss or systemic immune dysfunction in multiple myeloma.

Various drug classes target B-cell maturation antigen (BCMA) including chimeric antigen receptor T-cell (CAR T) therapies, bispecific antibodies (bsAb), and antibody-drug conjugates (ADC). Outcomes with CAR T and bsAb therapies in multiple myeloma (MM) have been affected by T-cell exhaustion, and abrogated expression/mutation of the BCMA target has been observed with anti-BCMA therapies. Optimal anti-BCMA sequencing strategies are needed to improve long-term clinical outcomes. We used data from multiple clinical studies of the ADC belantamab mafodotin (as monotherapy and combination regimens) to explore its impact on BCMA levels and binding (using electrochemiluminescence methodology) and T-cell/ natural killer (NK) cell fitness (including cell counts, expression of functional markers), to determine whether belantamab mafodotin could be sequenced ahead of other BCMA-targeting therapies for MM. Levels of free soluble BCMA (sBCMA), measured at the best-confirmed response (BCR) and at progression, dropped at BCR but returned to near baseline at time of disease progression. There was no apparent impact on the binding epitope of BCMA, as indicated by the retention of belantamab mafodotin binding to sBCMA. No significant changes in cell counts or expression of T-cell exhaustion markers (PD-1, TIGIT, TIM-3 [except NK cells], or CTLA-4) and co-stimulatory markers (ICOS [except CD4+ T cells], OX40, 4-1BB) were observed at relevant time points (up to 4 or 21+ months depending on the marker). No negative impact was observed on expression of proliferation (Ki67) and antitumor activity (granzyme B, CD107a) markers. Pending confirmatory studies, our results indicate potential for utilizing belantamab mafodotin ahead of other anti-BCMA therapies in MM.