Selective B-cell subset depletion underlies increased infection risk in patients with MM treated with anti-BCMA vs anti-GPRC5D bsAbs
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.
Article Details
Authors (37)
Tomas Jelinek
Department of Hemato-oncology, University Hospital Ostrava, Ostrava, Czech Republic
David Zihala
9Department of Hematooncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
Aintzane Zabaleta
Cancer Center Clinica Universidad de Navarra (CCUN), Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IdiSNA), CIBER-ONC number CB16/12/00369, Pamplona, Spain, Pamplona, Spain
Ioannis V. Kostopoulos
2Department of Biology, National and Kapodistrian University of Athens, Athens, Greece
Ondrej Soucek
Ondrej Venglar
1Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Cristina Moreno
Despina Fotiou
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Eva Radova
1Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Luis Esteban Tamariz-Amador
5Cancer Center Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
Foteini Theodorakakou
Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
Ludmila Muronova
1Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Andrea Manubens
5Cancer Center Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
Ourania Tsitsilonis
National and Kapodistrian University of Athens, Athens, Greece
Tereza Popkova
1Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Carmen González
Anjana Anilkumar Sithara
1Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Francesco Corrado
9Center for Early Detection and Interception, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Nayda Bidikian
9Center for Early Detection and Interception, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Camila Guerrero
CIMA, Pamplona, Spain
Veronika Kapustova
1Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Daniel Bilek
1Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Patrick R. Hagner
10Bristol Myers Squibb, Summit, NJ
Marta Larrayoz
Jose A. Martinez Climent
5Cancer Center Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
Lucie Broskevicova
1Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Jana Mihalyova
1Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Maximilian Merz
11Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY
Tereza Sevcikova
4Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic
Irene M. Ghobrial
Jesus San Miguel
5Cancer Center Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
Meletios A. Dimopoulos
Paula Rodriguez-Otero
Jakub Radocha
4th Department of Internal Medicine–Hematology, University Hospital Hradec Kralove, Faculty of Medicine in Hradec Kralove, Charles University, Prague, Czech Republic
Efstathios Kastritis
Bruno Paiva
Roman Hajek