Background: B-cell maturation antigen (BCMA, CD269) is a single transmembrane protein that is selectively expressed in the B-cell lineage and is a validated target for multiple myeloma. BCMA exists as both surface protein and as a free soluble form (sBCMA). γ-secretase activity at the transmembrane domain leads to a shed BCMA protein fragment of approximately 6 kilodalton that can exist as free circulating sBCMA in blood. Teclistamab and talquetamab are CD3 bispecific antibodies that have been developed to recruit CD3⁺ T-cells to BCMA⁺ or GPRC5D⁺ multiple myeloma (MM) cells, respectively. The objective of this work was to evaluate sBCMA in relapsed and/or refractory MM patients in response to treatment with teclistamab or talquetamab. Methods: Serum samples from relapsed and/or refractory MM patients in teclistamab and talquetamab phase 1 studies (64007957MMY1001 and 64407564MMY1001) were collected (at various timepoints between baseline and cycle 4 or end of treatment) and analyzed for sBCMA by an electrochemiluminescence ligand binding assay. Soluble BCMA data were quantitatively analyzed in reference to patient’s tumor burden and response, as well as pharmacokinetic data. Results: Teclistamab and talquetamab modulated levels of sBCMA in patients with high ( ≥ 50%) and low ( < 50%) frequency of tumor plasma cells (TPCs), as well as in high and low risk cytogenetic groups. In cycle 3, majority of the responders had reduction in sBCMA [88% (50 out of 57) for teclistamab and 98% (49 out of 50) for talquetamab] compared to baseline. On the contrary, non-responders (progressive disease, stable disease, or minimal response) seemed to show an increase in sBCMA [80% (33 out of 41) for teclistamab and 49% (24 out of 49) for talquetamab] from baseline. Patients with deep responses tend to have higher magnitude of sBCMA reduction compared to others. Based on few patients who responded to teclistamab or talquetamab and then relapsed, sBCMA seemed to have an initial reduction followed by an increase in the levels. Soluble BCMA corelated with % bone marrow TPCs. Majority of patients with plasmacytoma (limited data) seemed to have high sBCMA; suggesting 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 was not acting as a sink for teclistamab. Conclusions: Teclistamab and talquetamab induced changes in levels of sBCMA that correlated with clinical activity, further supporting clinical development of these bispecific antibodies. Lastly, the results support that sBCMA is a potential surrogate marker of myeloma tumor burden, and as a valuable marker for response in MM patients. Clinical trial information: NCT03145181 and NCT03399799