Abstract The success of BCMA- and GPRC5D-directed immunotherapies has transformed multiple myeloma (MM) treatment, yet relapse remains inevitable. Fc receptor-like 5 (FcRL5) has emerged as a promising target linked to chromosome 1q21 gain, showing high prevalence on malignant plasma cells and expression independent of BCMA/GPRC5D. In this Critical Review, we evaluate FcRL5-directed strategies including bispecific antibodies, ADCs, CAR-T, and mRNA-encoded engagers.
