Targeting FcRH5 in MM: Rationale and emerging dual-targeting strategies

The Multiple Myeloma Hub was pleased to speak with Adam Cohen, University of Pennsylvania, Philadelphia, US. We asked about the rationale for targeting FcRH5 in multiple myeloma and emerging dual-targeting strategies. 

In this interview, Cohen discusses Fc receptor-homolog 5 (FcRH5) as a therapeutic target in multiple myeloma (MM) and its potential role following antigen loss associated with B-cell maturation antigen (BCMA)- or G protein-coupled receptor class C group 5 member D (GPRC5D)-directed therapy. Cohen outlines the rationale for targeting multiple antigens, the potential benefits and challenges of dual-targeting, and which patients may benefit most from these approaches. Cohen also reviews emerging data on the FcRH5-targeted bispecific antibody cevostamab, including its evaluation as monotherapy and as part of combination and sequential treatment strategies. 

Key points 

• FcRH5 is expressed exclusively in the B-cell lineage, including malignant plasma cells, independently of BCMA and GPRC5D expression.^1,2 
• FcRH5 may provide an alternative target following loss or downregulation of BCMA or GPRC5D expression after antigen-directed therapy.^2‒4 
• Dual-antigen targeting may help address antigen loss and heterogeneity in antigen expression.⁵ 
• Simultaneous and sequential dual-targeting strategies are being evaluated, including combinations of bispecific antibodies and sequential targeting following chimeric antigen receptor (CAR) T-cell therapy.⁵ 
• Patients with high-risk features, extramedullary disease, or prior BCMA-directed therapy may benefit from dual-targeting approaches, although further data are needed to define optimal patient selection.⁵ 
• Cevostamab is an FcRH5-directed bispecific antibody that has demonstrated monotherapy activity in heavily pretreated MM, including in patients previously treated with T-cell redirecting therapies.⁶  
• In the phase I GO39775 trial (NCT03275103), the overall response rate was 44.3% at the 160 mg target dose and 42.1% in the overall cohort, with a median duration of response of 11.2 months among patients with partial response or better.⁶ 
• FcRH5-directed and dual-targeting strategies may provide additional treatment approaches in MM, with ongoing studies helping to define their role, optimal sequencing, and patient selection. 

This educational resource is independently supported by Roche. All content is developed by SES in collaboration with an expert steering committee. Funders are allowed no influence.