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    Cellular and T cell engager Immunotherapy

    Category: Cellular and T cell engager Immunotherapy

    Acquired FCRL5 Mutation Leading to Cevostamab Resistance in Multiple Myeloma

    (PA-009) Acquired FCRL5 Mutation Leading to Cevostamab Resistance in Multiple Myeloma

    Friday, September 19, 2025
    Introduction: The recent expansion of immunotherapies, notably bispecific T-cell engagers and CAR T-cell therapies, has shown remarkable clinical activity for the treatment of multiple myeloma (MM). However, responses are not uniform across all patients, underscoring the need to identify predictive factors to optimize treatment strategies. In this study, we aimed to identify tumor intrinsic mechanisms of resistance to cevostamab, a bispecific T-cell engager targeting Fc receptor-homolog 5 (FcRH5) and CD3, with encouraging clinical activity and durable responses in heavily pre-treated MM.

    Methods: n/a

    Results:

    We present the case of a 63 year old male diagnosed with Kappa light chain MM harboring a Del(17p) treated with cevostamab as a single agent in the fifth line of therapy. Previous treatment lines included dexamethasone, cyclophosphamide, proteasome inhibitors (bortezomib and ixazomib), and IMiDs (lenalidomide and pomalidomide). Bone marrow aspirates were collected at baseline and progression for DNA and RNA extraction from sorted CD138+ cells. Tumor whole genome and transcriptome sequencing were performed at baseline, and whole exome sequencing and transcriptome sequencing was performed at cevostamab progression.

    The patient was initially treated with 60 mg of cevostamab for one year and then escalated to a higher dose cohort (90 mg) in the second year, achieving stringent complete response as the best response. At progression, whole exome sequencing detected a clonal FCRL5E115A missense mutation (allelic frequency = 56%) and a subclonal FCRL5G455Efs*19 frameshift deletion mutation (allelic frequency = 5%). Importantly, both FCRL5 mutations were absent at baseline. FCRL5 gene expression was marginally downregulated at progression compared to baseline (log2FC = -0.4).
    Following cevostamab progression, the patient was treated with daratumumab and a bispecific T-cell engager targeting B-cell maturation antigen (BCMA) and CD3. The patient achieved complete response and has been in remission for four years.

    Conclusions: By integrating longitudinal genomic characterization with clinical response, we present an acquired clonal FCRL5 mutation as a putative novel mechanism of resistance to cevostamab. Functional studies to characterize this mutation are ongoing. These findings provide insight into tumor intrinsic mechanisms associated with immunotherapies targeting FcRH5.