Soluble B-Cell Maturation Antigen As a Disease Biomarker in Relapsed or Refractory Multiple Myeloma (RRMM): Evaluation from Elranatamab (ELRA) Magnetismm Studies

BACKGROUND B-cell maturation antigen (BCMA) is primarily expressed on the cell membranes of terminally differentiated B cells and malignant or normal plasma cells. BCMA is a validated target for the treatment of multiple myeloma (MM). The γ-secretase enzyme cleaves the extracellular domain and releases soluble BCMA (sBCMA) in the circulation. sBCMA is elevated in patients with (pts) MM vs healthy subjects. Response to treatment in MM is routinely measured by serum and urine M-protein and free light chain (FLC). sBCMA could serve as a useful biomarker for disease response enabling a more rapid disease assessment given its faster turnover compared to serum FLC and/or M-protein (half-life of sBCMA, FLC, and M-protein is ~1, 2.75, and 11.9 days, respectively). This work a) evaluated the correlation of baseline sBCMA in plasma with key disease biomarkers and subgroups, and b) investigated the correlation of changes from baseline sBCMA with responses over time. METHODS Data from 4 studies in RRMM were pooled for the evaluation of baseline correlation with key disease biomarkers. These studies were the first-in-human MagnetisMM-1 (NCT03269136) study, the Japan Phase 1 MagnetisMM-2 (NCT04798586) study, MagnetisMM-3 (NCT04649359) study, and a Phase 1/2 MagnetisMM-9 (NCT05014412) study. Data from MagnetisMM-3 Cohort A only was used to investigate the correlation of changes from baseline sBCMA with responses over time. Two assays were used to measure sBCMA levels in plasma: 1) an electrochemiluminescent (ECL) ligand binding assay for measuring free (ie, drug unbound) sBCMA, and 2) an immunoaffinity LC-MS/MS assay for measuring total sBCMA (ie, free sBCMA in addition to drug bound and sBCMA bound to APRIL or BAFF). Plasma samples were collected at baseline and at various timepoints on treatment. Key disease biomarkers included disease stage a: derived International Staging System (ISS), b) Revised-ISS (R-ISS) based on investigator assessment, and c) Derived R-ISS, tumor burden (high vs intermediate/low) which is derived as High: plasma cell in bone marrow (PCBM) ≥80%, or serum M-spike ≥ 5 g/dL, or FLC ≥5000 mg/L; Low: PCBM 50%, or serum M-spike 3 g/dL, or FLC 3000 mg/L; Intermediate: neither High nor Low. Other factors included β-2 microglobulin, cytogenetics, and presence of extramedullary disease (EMD). Statistical comparisons were conducted using t-test and one-way ANOVA. Statistical significance was defined as P 0.01. Correlations between post baseline changes in sBCMA levels and responses were explored graphically. RESULTS Baseline sBCMA was higher in participants with ISS or R-ISS 3 2 1 P 0.001. Similarly, pts with high tumor burden had higher baseline sBCMA vs those with intermediate or low tumor burden. A moderate correlation was observed between baseline sBCMA and β-2 microglobulin. Participants with BMPC ≥50% had higher baseline sBCMA than those with 50%. A trend for association was observed in pts with EMD ( P=0.047). There was no statistically significant difference in baseline sBCMA levels between participants with high vs standard risk cytogenetics ( P=0.29). Results from the two assays for the baseline correlation were generally comparable. In MagnetisMM-3, free sBCMA declined in the majority of responding participants within 2 to 3 cycles. Concentrations of sBCMA in non-responding participants remained largely unchanged or increased in some patients. 92.5% (86/93) of responding participants (who also had free sBCMA measured) experienced at least 50% reduction from their baseline free sBCMA level vs 17.9% (12/67) in non-responding participants by Cycle 2 Day 1 (C2D1). An increase (or lack of decline) from baseline levels was observed in 90% of non-responders. Participants with deeper responses had higher magnitude of free sBCMA reduction by C2D1. Total sBCMA concentrations increased in non-responders and declined in responders, however, the decline was observed at later timepoints (eg, C6) as total sBCMA levels are affected by ELRA half-life. CONCLUSIONS Results from MagnetisMM studies showed that sBCMA is a potential disease biomarker of myeloma disease stage and disease burden. ELRA induced deep and rapid declines in free sBCMA levels. These declines correlated with clinical activity in patients with RRMM, which is demonstrated by ≥50% reduction in free sBCMA levels in 90% of responders, and an increase from baseline (or lack of decline) in 90% of non-responders.