Selective B-cell subset depletion underlies increased infection risk in patients with MM treated with anti-BCMA vs anti-GPRC5D bsAbs

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.

Authors

Institutions

Publication Details

Journal
Blood
Published
2025-12-17
DOI
https://doi.org/10.1182/blood.2025029572
Citations
1
Primary Topic
Multiple Myeloma Research and Treatments
Type
article
Field-Weighted Citation Impact
1.77

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Selective B-cell subset depletion underlies increased infection risk in patients with MM treated with anti-BCMA vs anti-GPRC5D bsAbs

José A. Martínez-Climent, Marta Larráyoz, Jana Mihályová, Patrick R. Hagner et al.
1 citations
Blood
Multiple Myeloma Research and Treatments
1.77
article

Selective B-cell subset depletion underlies increased infection risk in patients with MM treated with anti-BCMA vs anti-GPRC5D bsAbs

José A. Martínez-Climent, Marta Larráyoz, Jana Mihályová, Patrick R. Hagner, Efstathios Kastritis, Jesús F. San Miguel, Irene M. Ghobrial, Veronika Kapustová, Luis‐Esteban Tamariz‐Amador, Meletios Α. Dimopoulos, Ioannis V. Kostopoulos, Jakub Radocha, Anjana Anilkumar Sithara, Ondřej Souček, Camila Guerrero, Bruno Paiva, Lucie Broskevičová, Andrea Manubens, Tereza Ševčíková, Foteini Theodorakakou, Ourania Tsitsilonis, Ondrej Venglár, Paula Rodríguez‐Otero, Cristina Moreno, Tereza Popková, Ludmila Muroňová, Aintzane Zabaleta, Despina Fotiou, Roman Hájek, David Žihala, Daniel Bilek, Carmen González, Maximilian Merz, Francesco Corrado, Nayda Bidikian, Tomas Jelinek, Eva Radova
article en
1 citations

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.

BloodVol. 147(10)
Memorial Sloan Kettering Cancer Center (US), University of Ostrava (CZ), Korea University (KR), National and Kapodistrian University of Athens (GR), Korea University Medical Center (KR), University Hospital Ostrava (CZ), Bristol-Myers Squibb (United States) (US), Navarre Institute of Health Research (ES), Alexandra Hospital (GR), Dana-Farber Cancer Institute (US), Clinica Universidad de Navarra (ES), University Hospital Hradec Králové (CZ), Sylvester Comprehensive Cancer Center (US), Centro de Investigación Biomédica en Red de Cáncer (ES), Universidad de Navarra (ES), Chartered Institute of Management Accountants (GB)
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
Openalex Percentile: Top 10%
Multiple Myeloma Research and Treatments
1.77
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.