Soluble B-Cell Maturation Antigen As a Serum Marker of Minimal Residual Disease in Patients with Multiple Myeloma

Introduction: Multiple Myeloma (MM) is an incurable hematologic malignancy which requires close monitoring of disease status for appropriate ongoing management. The absence of detectable minimal/measurable residual disease (MRD) in the bone marrow has been shown to be highly predictive of survival in MM (Mazzotti et al. Blood Adv 2018); however, serial sampling of the bone marrow is not practical as a biomarker for MRD. While serum soluble B-cell maturation antigen (sBCMA) has been noted to correlate with disease activity and to be associated with response or progression of disease (Sanchez et al. Clin Cancer Res 2016; Ghermezi et al. Haematologica 2017), it has not been evaluated extensively as a marker of MRD. In this prospective observational correlative study, we assessed paired peripheral blood and bone marrow specimens in patients with MM post systemic therapy to determine the relationship between serum sBCMA and bone marrow MRD, as well as serum sBCMA and serum standard myeloma markers.

Methods: Adult patients with MM who received standard of care systemic therapy, achieving at least a partial response per International Myeloma Working Group (IMWG) Uniform Response Criteria, and who eventually proceeded to first or salvage autologous hematopoietic stem cell transplantation with melphalan conditioning at our institution between 3/2023 and 6/2024 were included. Patients who received anti-BCMA therapy or investigational agents prior to transplant were excluded. Bone marrow MRD was assessed by standard MRD flow cytometry with a limit of detection (LOD) of 10^-3 and/or Next Generation Sequencing with a LOD of 10^-6 (5 mL and 2 mL bone marrow aspirate samples, respectively). Serum sBCMA was measured by a sandwich enzyme-linked immunosorbent assay (1 mL whole blood samples). Serum standard myeloma markers included immunoglobulins (Ig), immunoglobulin free light chains, monoclonal spike (M-spike), and immunofixation (IFE). The relationship between sBCMA and clinical response status was determined by Pearson correlation. Comparisons between myeloma markers were made by applying the Welch Two Sample t-test.

Results: Twenty-nine patients were included in the study. Their median age was 65 (range, 44-78) years and 22 were male. There were 22 white, 20 non-Hispanic/7 black, all non-Hispanic patients. Fourteen patients were diagnosed with IgG kappa, 2 with IgG lambda, 4 with IgA kappa, 4 with IgA lambda, 3 with kappa light chain (KLC), and 2 with lambda light chain (LLC) MM. Per Durie-Salmon Staging, 9 patients had stage IIA-IIIB MM; per Revised International Staging System, 10 patients had stage I-III MM; and stage was not available for 10 patients. Fourteen patients had received systemic therapy with a triplet regimen containing lenalidomide/bortezomib/dexamethasone, 9 patients a quadruplet regimen with daratumumab-lenalidomide/bortezomib/dexamethasone, 3 patients other triplet regimens, and 3 patients two lines of therapy for disease control; 5 patients had supplemental radiation therapy. Twelve patients had achieved partial response, 12 very good partial response, 3 complete response, and 2 stringent complete response. Post-systemic therapy, the mean (standard deviation) of serum sBCMA was 19.3 (12.2) ng/mL; KLC 2.9 (2.6) mg/dL, LLC 4.2 (4.7) mg/dL, KLC/LLC ratio 2.5 (2.4), IgG 674.6 (250.9) mg/dL, IgA 325.5 (189.4) mg/dL. Higher levels of sBCMA correlated with higher levels of tumor burden by IMWG response category (Pearson coefficient r= 0.4, p= 0.02). Bone marrow overt disease (< 15% malignant plasma cells) was present in 11 patients and MRD in 20 patients, with MRD not available for 2 patients. Nine patients had MRD only and 7 patients had no overt disease or detectable MRD. The mean value of sBCMA was significantly associated with the presence of bone marrow overt disease (p= 0.004) and with MRD only/no overt disease or detectable MRD (p= 0.04). In addition, the mean value of sBCMA was associated with elevated KLC (p< 0.001) and KLC/LLC ratio (p= 0.005), but not elevated LLC (p= 0.3), IgG (p= 0.7) or IgA (p= 0.9), or positive M-spike (p= 0.1) or IFE (p= 0.3).

Conclusions: Serum sBCMA was associated not only with bone marrow overt disease and elevated serum KLC/LLC ratio, but also with bone marrow detectable or below LOD MRD. Further evaluation of sBCMA is warranted to evaluate it as a potential non-invasive biomarker of MRD in patients with MM.