FcRh5: An Emerging Therapeutic Target in Multiple Myeloma

On Sep 22nd 2025, Roche announced that Cevostamab, a bispecific antibody targeting FcRH5×CD3, is advancing to Phase III clinical trials. The trial, named CEVOLUTION, is set to begin in 2026 and will investigate the drug's effectiveness in combination with pomalidomide and dexamethasone (Pd) for treating patients with second-line and later relapsed/refractory multiple myeloma (2L+/r/r MM). In addition, Roche also shared the critical data from the Phase I CAMMA1 trial. In this trial, Cevostamab showed strong results, achieving Overall Response Rates (ORR) of 86.2% and 88% at the 70 mg dose and 105 mg dose, respectively. The safety profile was also favorable, with a Grade 3 infection rate below 30% for both monotherapy and combination treatments. These results strongly suggest that Cevostamab will become the preferred candidate drug for combinatorial therapies.

Pharma Day 2025 Investor Deck - Roche. All credits to the original publisher. 

Disease Background

Multiple myeloma (MM) is a type of blood cancer that originates in the bone marrow's plasma cells. The disease is triggered by the abnormal growth of plasma cells that overproduce monoclonal immunoglobulins, resulting in severe complications like bone lesions, kidney failure, anemia, and hypercalcemia[1]. Over the past decades, the emergence of new drugs, including proteasome inhibitors and monoclonal antibodies, yielding continuously improving survival rates (which vary depending on many factors including age and pre-existing conditions). Although 82% of the low-risk Stage I patients can survive past five years, most of them will eventually develop drug resistance and convert into high-risk patients. For high-risk, Stage III patients, only 40% the patients can survive past five years and often relapse early or do not respond to initial treatment [2,3]. Given the high rate of relapse, the key strategy for MM treatment is to identify new therapeutic targets to extend the overall survival time [4].

Multiple Myeloma [5]

The Structure and Function of FcRH5

FcRH5 (also known as FcRL5, IRTA2, or CD307) is a protein encoded by the FcRH5 gene encoded on chromosome 1q21. It is exclusively expressed in the B-cell lineage starting from the pro-B cell stage, with expression increasing during B-cell maturation and eventually reaching the highest level in plasma cells[6].

FcRH5 is a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily (IgSF). Its structure includes nine Ig-like domains in its extracellular region, as well as an activating motif (ITAM) and two inhibitory motifs (ITIM) in its intracellular region[7]. This unique structure allows FcRH5 to play a dual role in B-cell activity, capable of both activating and inhibiting immune responses. When FcRH5 is cross-linked with the BCRs, its ITIM can recruit the phosphatase SHP-1 to reduce the phosphorylation level, preventing overactivation of the immune response. Conversely, FcRH5 can also promote B-cell activation and differentiation. When co-stimulated with BCRs, FcRH5 enhances pro-B cell proliferation and differentiation, with its ITAM being recruited by Lyn, a Src protein family kinase. The balance between activation and inhibition is modulated by SHP-1 and Lyn, which are crucial for maintaining immune homeostasis. Dysregulation of FcRH5 expression contributes to the development of B-cell malignancies [8]. Studies have shown that FcRH5 is expressed at significantly higher levels on the myeloma cell surface of MM patients [4]. Flow cytometry analysis of bone marrow samples from MM patients revealed that FcRH5 is more commonly expressed than other hot targets like GPRC5D and BCMA [9], making it a promising new therapeutic target for MM.

Structure of FcRH proteins [7]

FcRH5 gene has three mRNA isoforms: FcRH5a, FcRH5b, and FcRH5c (full-length transmembrane protein). FcRH5a is a secreted protein with eight Ig-like domains and a unique C-terminus harboring 13 polar amino acids. FcRH5b is a GPI-anchoring membrane protein, with the 32-amino acid GPI-tethering peptide fused after the 6 Ig-like domains. Therefore, the 9th Ig-like domain becomes the unique extracellular domain of FcRH5c [10]. Research also shows that malignant plasma cells in MM patients secrete a large amount of soluble FcRH5 (mainly FcRH5a), which can bind antibodies and potentially sequester agents that do not discriminate the membrane‑proximal/unique domain. This suggests that therapeutic antibodies should specifically target the 9th Ig-like domain of the transmembrane FcRH5c form. 

Three FcRH5 Isoforms [10]

The termination of RG-7598 (DFRF4539A) supported the importance of targeting the 9th Ig-like domain. RG-7598 is an FcRH5-targeting Antibody Drug Conjugate developed by Genentech that entered Phase I clinical trials. RG-7598 showed significant therapeutic effects in the preclinical, xenograft mouse model studies. However, the trial results showed low ORR in MM patients. One of the potential reasons may be that the soluble FcRH5a level in MM patients’ blood is elevated, which binds to RG-7598, thereby reducing the binding interaction between RG-7598 and the transmembrane FcRH5c [11]. The failure of RG-7598 indicates the importance of domain selection in drug design.

Clinical Progress of FcRH5-targeting Drug Development

Current drug development efforts targeting FcRH5 are primarily focused on T-cell dependent bispecific antibodies (TDBs)/T-cell engagers (TCE), ADCs, and CAR-T therapies. Cevostamab (BFCR4350A) is the first TDB drug to advance to Phase III trials. It targets the membrane-proximal domain of the FcRH5 on myeloma cells and CD3 on T cells. During initial development, researchers designed three TDBs to target the membrane-proximal, central, and distal domains of FcRH5, respectively. Final results suggested that the membrane-proximal epitope is best for effective immune synapse formation and cell killing [1]. The initial clinical assessment of Cevostmab safety and efficacy profiles indicated significant therapeutic potential of Cevostmab monotherapy for heavily pre-treated patients with relapsed/refractory multiple myeloma (R/R MM) [4].

Cevostamab specifically recognize the membrane-proximal domain of FcRH5[1]

Empowering Antibody Discovery with KACTUS High Quality FcRH5 proteins.

As a promising therapeutic target, FcRH5 opens up new possibilities for MM treatment. KACTUS is proud to offer the full-length FcRH5 and membrane-proximal FcRH5 domain protein collection, with options for various species and tag designs, to fulfill diverse needs in antibody discovery and development. 

Product Validation

Immobilized Human FcRH5, His Tag at 1 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-FcRH5 Antibody, hFc Tag with the EC50 of 5.4 ng/ml determined by ELISA (QC Test).

Immobilized Human FcRH5 Domain, His Tag at 0.5 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-FcRH5 Antibody, hFc Tag with the EC50 of 8.1 ng/ml determined by ELISA (QC Test).

Immobilized Cynomolgus FcRH5 Domain, His Tag at 1 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-FcRH5 Antibody, hFc Tag with the EC50 of 21.3 ng/ml determined by ELISA (QC Test).

 

Product List

References:

[1] Li, Ji et al. “Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing.” Cancer cell vol. 31,3 (2017): 383-395. doi:10.1016/j.ccell.2017.02.001

[2] Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al. Revised international staging system for multiple myeloma: a report from international myeloma working group. J Clin Oncol. (2015) 33:2863-9. doi: 10.1200/JCO.2015.61.2267 

[3] Avet-Loiseau H. Ultra high-risk myeloma. Hematol Am Soc Hematol Educ Program. (2010) 2010:489–93. doi: 10.1182/asheducation-2010.1.489 

[4] Cheng, Linyan et al. “Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison.” Molecular cancer vol. 23,1 77. 16 Apr. 2024, doi:10.1186/s12943-024-01956-6

[5] Multiple Myeloma: Signs and symptoms, Causes, Stages, Types, Diagnosis and Treatment options - Page 4 of 6 – The Life Today

[6] Polson AG, Zheng B, Elkins K, Chang W, Du C, Dowd P, et al. Expression pattern of the human FcRH/IRTA receptors in normal tissue and in B-chronic lymphocytic leukemia. Int Immunol. 2006;18:1363–73.

[7] Capone, Mollie et al. “Fc Receptor-Like Proteins in Pathophysiology of B-cell Disorder.” Journal of clinical & cellular immunology vol. 7,3 (2016): 427. doi:10.4172/2155-9899.1000427

[8] What Is FcRH5? Role in Immunity, Disease, and Treatment - Biology Insights

[9] Devasia, A.J., Chari, A. & Lancman, G. Bispecific antibodies in the treatment of multiple myeloma. Blood Cancer J. 14, 158 (2024). https://doi.org/10.1038/s41408-024-01139-y

[10] US 10,435,471 B2

[11] Stewart, A.K., Krishnan, A.Y., Singhal, S. et al. Phase I study of the anti-FcRH5 antibody-drug conjugate DFRF4539A in relapsed or refractory multiple myeloma. Blood Cancer Journal 9, 17 (2019). https://doi.org/10.1038/s41408-019-0178-8