Targeting FcRL5 in multiple myeloma: biological rationale and strategic sequencing beyond BCMA and GPRC5D

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. Cevostamab (FcRL5×CD3) has demonstrated clinically meaningful activity in heavily pretreated relapsed/refractory MM, including patients previously exposed to BCMA-targeted therapies, although responses may be influenced by prior treatment modality and T-cell fitness. Importantly, FcRL5 targeting avoids the skin and nail toxicities characteristic of GPRC5D therapies. Beyond mature plasma cells, FcRL5 is expressed on a CD24⁻FCRL5⁺ B-cell subset proposed as a myeloma-initiating cell population, offering the potential to target disease precursors. We further discuss resistance mechanisms and evolving strategies, such as dual-targeting CAR-Ts and co-stimulatory bispecifics, to improve durability. Collectively, this review provides a clinical framework for sequencing FcRL5-directed therapies after BCMA or GPRC5D failure, highlighting its role as a stable, lineage-restricted anchor in the MM landscape.