P-005: Association of baseline soluble BCMA with measures of disease burden and response to linvoseltamab: a comprehensive analysis in patients with relapsed/refractory multiple myeloma (RRMM)

Introduction: B-cell maturation antigen (BCMA) is a receptor expressed in normal and malignant plasma cells, which is cleaved to release the ectodomain, known as soluble BCMA (sBCMA). sBCMA concentrations range from normal to very high in patients with MM, and high concentrations reduce the ability of BCMA-directed therapies to induce cytotoxicity of MM cells in vitro (Frerichs, et al. Clin Cancer Res. 2020). Based on these data and correlations of sBCMA to plasma cell levels and M protein in patients with MM (Ghermezi, et al. Haematologica. 2017), it was hypothesized that high circulating sBCMA may reflect high disease burden and correlate with lower response to plasma cell-targeting T-cell engagers (Girgis, et al. Blood Adv. 2023). Since MM cells vary in their secretion of disease proteins, we evaluated the relationship between sBCMA and M protein, involved free light chains (FLCs), IgA, and bone marrow (BM) plasma cells. We also assessed response to linvoseltamab, a BCMA×CD3 bispecific antibody, in patients with RRMM with high vs low baseline sBCMA.

Methods: A sandwich ELISA was established for human sBCMA, with a sensitivity of 1.56 ng/mL in neat serum. Baseline serum samples were collected from 2 clinical trials in RRMM (NCT03761108 and NCT04083534; N=302 for sBCMA analysis). Baseline levels of M protein, FLC kappa, FLC lambda, and IgA were quantified using standard techniques. Baseline BM plasma cells were quantified using EuroFlow at a central laboratory. Spearman correlations were performed to assess the relationships between sBCMA and disease parameters. To assess correlation between baseline sBCMA and objective response rate (ORR) in patients treated with the recommended Ph 2 dose (RP2D) of linvoseltamab (N=117), an analysis by baseline sBCMA concentrations according to tertiles was performed.

Results: Baseline sBCMA ranged from 17.1–10,200 ng/mL. Median concentrations in our studies were higher than in other reports in RRMM (Girgis, et al. Blood Adv. 2023). Baseline sBCMA was correlated to serum M protein (rho=0.42, P=3.1 e-08), and modestly correlated to involved FLC (rho=0.67, P=6.2 e-08). Correlations to IgA in patients with IgA myeloma at baseline were also modest (rho=0.52, P=1.1 e-05). Correlation of sBCMA to pretreatment BM aspirate plasma cells was weak (rho=0.26, P=00062). Overall ORR was 71% in the cohort of patients treated at the RP2D of linvoseltamab 200 mg. The ORRs according to tertiles of baseline sBCMA were 91.7% (≤210 ng/mL), 70.6% (>210–≤607 ng/mL), and 55.9% (>607–≤4460 ng/mL).

Conclusions: In contrast to previous data indicating that sBCMA is highly correlated with disease burden, our study demonstrates variable correlations to secretory proteins in patients with RRMM. While prior studies suggested that patients with high baseline sBCMA may have a low response to bispecific therapeutics targeting BCMA and GPRC5D, our study shows that a high ORR can be achieved with linvoseltamab 200 mg in patients with RRMM, including in those with high sBCMA concentrations.