Depletion of Mature B Cells and of Normal Plasma Cells (PC) behind the Higher Incidence of Infections after Anti-BCMA VS Anti-GPRC5D Bispecific Antibodies (bsAb) in Relapsed Refractory Multiple Myeloma (RRMM)

Background: BsAbs have become a standard part of therapy in RRMM with three approved agents targeting BCMA (teclistamab, elranatamab) and GPRC5D (talquetamab). However, infections are a key challenge and there is increasing evidence that bsAb targeting BCMA are associated with higher infections rate compared to GPRC5D. It is postulated that the different risk of infection is caused by differential expression of BCMA vs GPRC5D in the B lineage. However, there are no comparative studies investigating the effect of the two bsAb in the B and plasma cell (PC) compartments, as well as in other cell types potentially associated with T cell exhaustion and neutropenia, which in addition to hypogammaglobinemia may also cause infections. Aims: Investigate the underlying immune mechanisms responsible for different infection rate during treatment with anti-BCMA vs GPRC5D bsAb. Methods: This multi-center study included 75 RRMM patients treated with anti-BCMA (teclistamab, elranatamab; N=28) or anti-GPRC5D bsAb (talquetamab; N=47) either as monotherapy (N=16 and N=24 in the BCMA and GPRC5D groups) or in combination with anti-CD38 mAb and/or IMiD (N=12 and N=23). Immune profiling was performed in bone marrow using next-generation flow cytometry at baseline (N=70) and at the time of MRD assessment (N=45). The immune subsets analyzed were B cell precursors, (naïve and memory) mature B cells, normal and clonal PC, T and NK cells, neutrophils and monocytes. Infections and their grade were evaluated by CTCAE 5.0. High-risk cytogenetics included t(4;14), t(14;16) and/or del(17p). Extramedullary disease (EMD) was considered if involving soft tissues. Results: Patients in both groups (BCMA vs GRPC5D) were well balanced regarding the number of previous lines of therapy (both median of 3), R-ISS distribution and presence of EMD. The frequency of any grade of infection was significantly higher in the BCMA vs GPRC5D group (82% vs. 53%; p=0.02) but the incidence of grade III or higher infections was comparable (27% vs. 31%, p=0.12) with one infectious death in each group. There was a significant decrease in IgM levels (p=0.02) and the frequency of immunoglobulin replacement was higher (74% vs. 32%; p=0.001) in patients treated with anti-BCMA bsAb. Immune profiling at baseline revealed no significant differences between groups. By contrast, during MRD assessment (BCMA: N=19 vs. GRPC5D: N=26) there were differences observed in mature B cells, normal PC and neutrophils. The percentage of total B cells was significantly lower in patients treated with anti-BCMA vs GPRC5D bsAb (mean 2% vs. 9%; p=0.001). Of note, the percentage of B cell precursors within the B cell compartment remained unchanged (p=0.7), while mature B cells were depleted in the BCMA group (0% vs. 5.7%; p<0.001). Similarly, the percentage of normal PC was significantly lower in the BCMA group (0% vs. 0.01%; p<0.001), with no difference in clonal PCs (p=0.16). In addition, neutrophils were also significantly reduced in patients treated with anti-BCMA vs. GPRC5D bsAb (mean: 55% vs. 67%; p=0.015). Next, we analyzed immune dynamics by comparing baseline and MRD profiles in 40 paired samples (BCMA: N=16 vs. GPRC5D: N=24). In the BCMA group there was a significant reduction of mature B cells from 7.2% at baseline to 0% at MRD (p<0.001), while in the GPRC5D group mature B cells remained unchanged (6.8 vs. 5.4%; p=0.66). Normal PCs were significantly reduced in both groups, but in patients treated with anti-BCMA bsAb these became undetectable (0.16% vs. <0.0001%, p<0.001) while anti-GPRC5D bsAb induced a less profound reduction (0.17% vs. 0.01%, p=0.03). Importantly, we noticed a trend linking a decreased number of mature B-cells and increased rate of infections in patients treated with anti-BCMA or GPRC5D in monotherapy (p=0.08). This association was significant when zoomed in memory B-cells (p=0.045). Conclusion: We showed for the first time how treatment with anti-BCMA bsAb induces greater depletion of mature B cells and normal PC as well as of neutrophils compared to anti-GPRC5D bsAb. These immune dynamics may explain the higher incidence of infections with anti-BCMA bsAb. These data, which can be collected simultaneously to MRD assessment, may potentially help in treatment individualization of RRMM patients to reduce the risk of severe infections.