Bispecific antibodies teclistamab and talquetamab are emerging as promising immunotherapeutic approaches for multiple myeloma (MM), according to recent findings from phase 1 clinical trials MajesTEC-1 and MonumenTAL-1. These antibodies, which redirect T-cell responses to tumor surface antigens, have shown significant reductions in soluble B-cell maturation antigen (sBCMA) levels in patients with relapsed/refractory MM (RRMM). The studies suggest that sBCMA could serve as a potential marker for treatment response and tumor burden.
Mechanism of Action and Clinical Studies
Teclistamab (JNJ-64007957) and talquetamab (JNJ-64407564) are CD3-bispecific antibodies that recruit CD3+ T cells to BCMA+ and GPRC5D+ MM cells, respectively. The phase 1 studies, MajesTEC-1 (NCT03145181) for teclistamab and MonumenTAL-1 (NCT03399799) for talquetamab, evaluated sBCMA levels in patients with RRMM. Patient responses were determined by the International Myeloma Working Group response criteria.
Impact on sBCMA Levels and Treatment Response
In the studies, most patients responding to teclistamab (88%) or talquetamab (98%) experienced a reduction in sBCMA levels from baseline to cycle 3, day 1 (C3D1). The degree of sBCMA reduction correlated with the depth of response. Patients achieving a complete response (CR) or stringent complete response (sCR) with teclistamab showed median sBCMA reductions of -92.8% and -94.5%, respectively. Similarly, patients achieving a very good partial response (VGPR) or partial response (PR) with talquetamab had median sBCMA reductions of -92.3% and -89.7%, respectively. Conversely, a significant proportion of non-responders to both treatments showed increased sBCMA levels from baseline to C3D1.
sBCMA as a Potential Marker for Tumor Burden
Combined data from both studies revealed a correlation between baseline sBCMA levels and the percentage of bone marrow plasma cells (BMPCs). Patients with extramedullary plasmacytomas and low BMPC levels (<10%) tended to have high sBCMA levels (≥400 ng/mL). These findings suggest that sBCMA might serve as a comprehensive marker for tumor burden in MM.
sBCMA and Cytogenetic Risk
Baseline sBCMA levels were similar in patients with high-risk and standard-risk cytogenetics in both studies. Teclistamab and talquetamab modulated sBCMA levels in both cytogenetic risk groups by C3D1, with no statistically significant differences observed between the groups.
Pharmacokinetic Analysis
Population pharmacokinetic (PK) analysis indicated that baseline sBCMA was not a significant covariate affecting teclistamab exposure. Teclistamab also demonstrated a higher binding affinity to full-length BCMA compared to sBCMA, suggesting that high sBCMA levels are unlikely to diminish the clinical activity of teclistamab.
Implications for Clinical Practice
These findings suggest that sBCMA might be a useful surrogate marker of response irrespective of the target. The ongoing phase 3 trials, including MajesTEC-7, MagnetisMM-5, and MonumenTAL-5, are evaluating these agents in earlier relapse and maintenance settings, which could change how myeloma is treated. Bispecific antibodies are specifically meant for the community setting, and clinicians will need to learn how to administer them safely as their use grows across cancer types.
