P-006: sBCMA has utility for early response monitoring in the blood and is correlated with forimtamig pharmacodynamic activity, clinical response and MRD

Introduction: Forimtamig is a GPRC5DxCD3 T-cell engaging bispecific antibody that induces T-cell directed Multiple Myeloma (MM) cell killing and has shown promising clinical activity in a Phase I study in patients (pts) with relapsed refractory MM (NCT04557150; Carlo-Stella et al. ASH 2022). Soluble B-cell maturation antigen (sBCMA) was demonstrated to correlate with tumor burden, is a potential prognostic marker and, having shorter half-life compared to other peripheral MM disease markers, is a promising early response predictor in MM (Nakamura et al. EHA 2022, Girgis et al. Blood Adv. 2023). Here, we investigate sBCMA as a blood-based surrogate marker of clinical response and disease monitoring for forimtamig treatment.

Methods: Plasma samples were collected in the NCT04557150 dose-escalation study. sBCMA and cytokines were quantified with Protein ELLA System. Peripheral blood immune cells were monitored with flow cytometry and minimal residual disease (MRD) was measured by next generation sequencing. Pts were grouped by age, prior therapy, refractory status, ISS score, cytogenetic risk (high risk: del(17p), t(4;14), t(14;16)) and objective response (responder [≥PR] or non-responder [< PR]). All pts provided informed consent. Updated data will be presented.

Results: At cut-off (January 25, 2023), 109/120 pts were biomarker evaluable. Baseline sBCMA levels did not significantly differ between pt groups defined by age, refractory status, ISS score, number of prior therapy lines, prior anti-CD38 or anti-BCMA therapy. Pts with high-risk cytogenetics (n=30) tend to have higher baseline levels of sBCMA than standard risk pts (n=16); median: 619.5 ng/mL vs 271.0 ng/mL, p=0.0439. Patients with baseline sBCMA concentrations below median had a higher ORR (above and below median ORR of 55.6% and 80.0%, respectively). A drop in sBCMA levels was detected as early as C1D8 (median=-22.4%) reaching a median of -88.8% by C2D1 in responding pts, whereas sBCMA concentrations increased in non-responding pts (median of 6.7% and 5.1% at C1D8 and C2D1, respectively). Pts with an early drop of sBCMA showed higher likelihood of strong T-cell margination (86% vs. 15%), increase in T-cell proliferation (76% vs. 28%) and modest increase in inflammatory cytokine release compared to those pts without an early drop of sBCMA. ≥50% decrease in sBCMA levels at C2D1 was associated with higher rate of MRD negativity at the same time point: 10-5 MRD neg reported for 13 out of 32 pts (40.6%). All pts not reaching the 50% sBCMA threshold level at C2D1 were MRD positive (n=9).

Conclusions: sBCMA is a blood-based biomarker that is easily applicable, cost effective, and has potential prognostic value. For the first time, our data indicates a correlation of sBMCA decrease with T-cell activation and MRD negativity. Based on the results of our study, sBCMA may be used as a patient-centric and dynamic surrogate biomarker of response complementary to MRD in the future.