Selective depletion of B-cell subsets underlies increased risk of infection in MM patients treated with anti-BCMA vs -GPRC5D bsAbs Open Access

• While GPRC5D is highly expressed on tumor plasma cells and less on normal plasma cells, BCMA is detectable throughout the B-cell lineage

• In contrast to anti-GPRC5D, anti-BCMA bispecific antibodies induce depletion of B cell precursors, mature B cells and normal plasma cells

Infections remain a key challenge during treatment of multiple myeloma (MM) patients with anti-BCMA and -GPRC5D bispecific antibodies (bsAbs). However, the underlying mechanism behind different rates and severity of infections induced by the two bsAbs remains poorly understood. Single-cell RNA-sequencing performed in bone marrow aspirates of 11 MM patients and 8 healthy donors revealed BCMA expression on mature B cells and, surprisingly, in small pre-B cells within B-cell precursors. By contrast, GPRC5D expression was restricted to normal and malignant plasma cells (PCs). Next-generation flow cytometry immune profiling showed that anti-BCMA bsAbs severely depleted bone marrow (BM) mature B cells (4.9%→0%; p<0.001) and normal PCs (0.17% → <0.0002%; p<0.001) during treatment of 62 relapsed MM patients. This was observed in early and late time points of 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, which confirmed no depletion of any B-cell subset after anti-BCMA treatment. In conclusion, we show that while GPRC5D bsAbs selectively target PCs, anti-BCMA bsAbs target both PCs and B cells from the small pre-B stage onwards. Our study provides mechanistic insight into the increased infection risk with anti-BCMA therapy and lays a foundation for 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.