Selective B-cell subset depletion underlies increased infection risk in patients with MM treated with anti-BCMA vs anti-GPRC5D bsAbs
Year: 2025
Type: article
Abstract: ABSTRACT: Infections remain a challenge during treatment of patients with multiple myeloma (MM) with anti-B-cell maturation antigen (BCMA) and anti-G protein-coupled receptor class C group 5 member D (GPRC5D) bispecific antibodies (bsAbs). However, the mechanism underlying different rates and severity of infections induced by the 2 bsAbs remains poorly understood. Single-cell RNA sequencing of bone marrow (BM) aspirates of 11 patients with MM and 8 healthy donors revealed BCMA expression on mature B cells and, surprisingly, in small pre-B cells within B-cell precursors. GPRC5D expression was restricted to malignant and less to normal plasma cells (PCs). Next-generation flow cytometry immune profiling showed that anti-BCMA bsAbs severely depleted BM mature B cells, from 4.9% to 0% (P< .001), and normal PCs, from 0.17% to <0.0002% (P< .001), during treatment of 62 patients with relapsed MM. This was observed throughout therapy. Additional flow cytometry (n = 31) and single-cell RNA sequencing studies (n = 8) demonstrated that, in contrast to anti-GPRC5D, anti-BCMA bsAbs also depleted immature and small pre-B cells. The MIcγ1 mouse model was used as a negative control of BCMA expression in all stages of the B-cell lineage, confirming no depletion of any B-cell subset after anti-BCMA treatment. In conclusion, we show that although GPRC5D bsAbs selectively target PCs, anti-BCMA bsAbs target both PCs and B cells from the small pre-B stage onward. Our study provides mechanistic insight into the increased infection risk with anti-BCMA therapy and supports individualized bsAb strategies in MM. Moreover, dual targeting of B cells and PCs may have therapeutic potential in other B-cell malignancies or autoimmune diseases.
Source: Blood
Authors: Tomas Jelinek, David Zihala, Aintzane Zabaleta, Ioannis V. Kostopoulos, Ondrej Soucek, Ondrej Venglar, Cristina Moreno, Despina Fotiou, Eva Radova, Luis Esteban Tamariz-Amador, Foteini Theodorakakou, Ludmila Muronova, Andrea Manubens, Ourania Tsitsilonis, Tereza Popkova, Carmen Gonzalez, Anjana Anilkumar Sithara, Francesco Corrado, Nayda Bidikian, Camila Guerrero, Veronika Kapustova, Daniel Bilek, Patrick R. Hagner, Marta Larrayoz, Jose A. Martinez Climent, Lucie Broskevicova, Jana Mihalyova, Maximilian Merz, Tereza Sevcikova, Irene M. Ghobrial, Jesus San Miguel, Meletios A. Dimopoulos, Paula Rodriguez-Otero, Jakub Radocha, Efstathios Kastritis, Bruno Paiva, Roman Hajek
Institutions: University of Miami, University of Ostrava, University Hospital Ostrava, Sylvester Comprehensive Cancer Center, Navarre Institute of Health Research, Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada, National and Kapodistrian University of Athens, Charles University, University Hospital Hradec Králové, Universidad de Navarra, Alexandra Hospital, Dana-Farber Cancer Institute, Bristol-Myers Squibb (United States), Memorial Sloan Kettering Cancer Center, Centro de Investigación Biomédica en Red de Cáncer, Korea University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,500
Funders: Amgen, AstraZeneca, Sanofi, Celgene, Regeneron Pharmaceuticals, BeiGene, European Commission, Agentura Pro Zdravotnický Výzkum České Republiky, Centro de Investigación Biomédica en Red de Cáncer, CRIS Cancer Foundation, HORIZON EUROPE Framework Programme, Instituto de Salud Carlos III, National Cancer Institute
Awards: Entender y vencer la resistencia adquirida a drogas inmunomoduladoras en mieloma múltiple: de modelos experimentales a la clínica, G2153922575, G36935394, G3771185154, Elucidation of risk factors and health determinants associated with PROGRESSION of Monoclonal Gammopathies to Multiple Myeloma, G6884976715, G812786535, Cancer Center Support Grant, G941802975, G986966207
OpenAlex ID: W4417434339