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)

Tomas Jelinek,David Zihala，Bruno Paiva,Roman Hajek

Blood（2024）

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Abstract

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.

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【要点】：该研究探讨了抗BCMA和抗GPRC5D双特异性抗体治疗复发难治性多发性骨髓瘤（RRMM）患者时，感染率差异的免疫机制，发现抗BCMA抗体治疗导致成熟B细胞和正常浆细胞更显著地减少，可能是感染率更高的原因。

【方法】：研究采用多中心设计，纳入75名接受抗BCMA（teclistamab、elranatamab）或抗GPRC5D（talquetamab）单药或联合抗CD38单抗及/或IMiD治疗的RRMM患者，使用下一代流式细胞术在基线和最小残留病（MRD）评估时对骨髓免疫进行剖析。

【实验】：在基线和MRD评估时，对比了两组患者的B细胞前体、成熟B细胞、正常及克隆性浆细胞、T细胞和自然杀伤细胞、中性粒细胞及单核细胞的百分比变化。发现抗BCMA组与抗GPRC5D组相比，成熟B细胞和正常浆细胞显著减少，且中性粒细胞也显著降低。使用CTCAE 5.0评估感染及其分级。结果显示，抗BCMA组感染频率显著高于抗GPRC5D组（82% vs. 53%），但III级以上感染发生率相当（27% vs. 31%）。