Selective B-cell subset depletion underlies increased infection risk in patients with MM treated with anti-BCMA vs anti-GPRC5D bsAbs
Tomas Jelinek, David Žihala, Aintzane Zabaleta, Ioannis V. Kostopoulos, Ondřej Souček, Ondrej Venglár, Cristina Moreno, Despina Fotiou, Eva Radova, Luis‐Esteban Tamariz‐Amador, Foteini Theodorakakou, Ludmila Muroňová, Andrea Manubens, Ourania Tsitsilonis, Tereza Popková, Carmen González, Anjana Anilkumar Sithara, Francesco Corrado, Nayda Bidikian, Camila Guerrero, Veronika Kapustová, Daniel Bilek, Patrick R. Hagner, Marta Larráyoz, José A. Martinez‐Climent, Lucie Broskevičová, Jana Mihályová, Maximilian Merz, Tereza Ševčíková, Irene M. Ghobrial, Jesús F. San Miguel, Meletios Α. Dimopoulos, Paula Rodríguez‐Otero, Jakub Radocha, Efstathios Kastritis, Bruno Paiva, Roman Hájek
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.