P-001: Modulation of soluble B-cell maturation antigen levels in patients with relapsed and/or refractory multiple myeloma after treatment with teclistamab and talquetamab

Abstract

<h3>Background</h3> B-cell maturation antigen (BCMA, CD269), a single transmembrane protein, can be shed as a soluble 6 kilodalton protein fragment (sBCMA) upon cleavage at the transmembrane domain by γ-secretase. Given its selective expression in the B-cell lineage, BCMA is a validated target for multiple myeloma. Teclistamab and talquetamab are CD3 bispecific antibodies developed to recruit CD3+ T cells to BCMA+ or G protein-coupled receptor family C group 5 member D (GPRC5D)+ multiple myeloma (MM) cells, respectively. Levels of sBCMA after teclistamab or talquetamab treatment were evaluated in patients with relapsed and/or refractory MM (RRMM). <h3>Methods</h3> Serum samples from patients with RRMM in teclistamab and talquetamab phase 1 studies (64007957MMY1001 and 64407564MMY1001, respectively) were collected at various timepoints between baseline and cycle 4 or end of treatment and analyzed for sBCMA by an electrochemiluminescence ligand binding assay. Quantitative analyses of sBCMA data were conducted with reference to a patient's tumor burden and response, and to pharmacokinetic data. <h3>Results</h3> Teclistamab and talquetamab modulated levels of sBCMA in patients with high (≥50%) and low (<50%) frequency of tumor plasma cells (TPCs) and in high and low risk cytogenetic groups. In cycle 3, a majority of the responders showed sBCMA reductions (teclistamab: 88% [50/57]; talquetamab: 98% [49/50]) compared with baseline. In contrast, non-responders (progressive disease/ stable disease/ minimal response) showed an increase in sBCMA (teclistamab: 80% [33/41]; talquetamab: 49% [24/49]) compared with baseline. A higher magnitude of sBCMA reductions was noted in patients with deep responses. In a few patients who initially responded to teclistamab or talquetamab and then relapsed, sBCMA levels trended toward an initial reduction followed by an increase. Levels of sBCMA correlated with % bone marrow TPCs. A majority of patients with plasmacytoma (based on limited data) appeared to have high sBCMA levels, suggesting that sBCMA could be a comprehensive marker for tumor burden. Teclistamab preliminary population pharmacokinetic analysis showed that sBCMA did not appear to impact teclistamab exposure, suggesting that sBCMA does not act as a sink for teclistamab. <h3>Conclusions</h3> Changes in the levels of sBCMA upon treatment with teclistamab and talquetamab correlated with clinical activity, supporting further clinical development. The findings support BCMA as a potential surrogate marker of myeloma tumor burden and as a valuable marker for response in patients with MM.