Tracking MRD in multiple myeloma: Soluble BCMA reflects flow cytometry changes

Abstract Background: Soluble B-cell maturation antigen (sBCMA) is increasingly recognized as a quantitative biomarker of tumor burden and disease activity in multiple myeloma (MM). However, its cross-sectional correlation with measurable residual disease (MRD) by 8-color multiparameter flow cytometry (MFC) and the concordance of their longitudinal trajectories remain undefined. In this retrospective, single-center study we assess for the first time both the strength of association and the parallel kinetics of sBCMA and MFC-MRD, with the goal of validating a minimally invasive surrogate for MRD monitoring. Methods: From January 2013 to July 2025, we retrospectively identified multiple myeloma patients at Kameda Medical Center who achieved VGPR or better (IMWG criteria) at least three months after therapy; their −40 °C–stored serum was assayed for sBCMA by ELISA (R&D Systems, MN) and MRD assessed by eight-color MFC (sensitivity 1 × 10-5) on bone marrow aspirates collected within one week. We excluded patients who died or ended follow-up before VGPR confirmation, those without MFC-based MRD data, and specimens obtained during BCMA-targeted bispecific antibody therapy or at time points without immunoparesis (any uninvolved immunoglobulin below its lower limit of normal). MRD values were log₁₀-transformed and stratified by the integer part of the log (for example, 1.5×10-3 classified as MRD −3 log group), with values below 10-5 considered negative. Changes in sBCMA and MRD levels were categorized into three patterns: Increasing, Declining, and Stable. The Increasing pattern was defined by a ≥100% increase in sBCMA, a ≥50% increase from a baseline sBCMA ≥30 ng/mL, or a ≥1-log increase in MRD. The Declining pattren was defined by a ≥25% decrease in sBCMA or a ≥1-log decrease in MRD. Observations not meeting either criterion were classified as the Stable pattern. The 30 ng/mL threshold was derived from our previous report (EHA 2025 Annual Congress, #PF766, M. Toho). Correlations between sBCMA levels and MRD groups were analyzed using the Kruskal–Wallis test. All statistical analyses were performed in R version 4.4.2. Results: Of 328 MM patients who achieved at least VGPR, 117 were excluded from analysis, leaving 211 patients included. In total, 668 bone marrow specimens were analyzed for MRD and the corresponding 668 serum specimens were measured for sBCMA. sBCMA levels declined significantly as MRD burden decreased. Median sBCMA concentrations were 54.76 ng/mL in the MRD −2 log group, 21.55 ng/mL in the MRD −3 log group, 15.82 ng/mL in the MRD −4 log group, 12.91 ng/mL in the MRD −5 log group, and 10.96 ng/mL in the MRD-negative group. All pairwise comparisons were statistically significant (p < 0.05), except for the comparison between the MRD −5 log group and the MRD-negative group (p = 0.4). To assess whether changes in sBCMA paralleled changes in MFC-MRD over time, we analyzed 118 patients who maintained VGPR or better at two consecutive bone marrow evaluations (median interval, 377 days; IQR, 295.5–524.3 days). Trajectories of sBCMA levels were classified as Increasing (n = 14), Stable (n = 69), or Declining (n = 35), while MRD trajectories were classified in the same way: Increasing (n = 14), Stable (n = 76), and Declining (n = 27). Among patients with the sBCMA Increasing pattern, 85.7 % (12/14) also fell into the MRD Increasing pattern and 14.3 % (2/14) into the MRD Stable pattern (i.e., all originally MRD-positive). In the sBCMA Stable pattern, 76.8% (53/69) were MRD Stable, 21.7% (15/69) were MRD Declining, and 1.4% (1/69) were MRD Increasing (i.e., an increase from MRD-negative to the MRD −5 log group). Of those in the sBCMA Declining pattern, 62.9% (22/35) were MRD Stable, 34.3% (12/35) were MRD Declining, and 2.9% (1/35) were MRD Increasing (i.e., an increase from MRD-negative to the MRD −4 log group). Finally, of the 41 patients who were MRD-negative at both time points, none were sBCMA Increasing, 39 (95%) were Stable, and 2 (5%) were sBCMA Declining. Conclusion: sBCMA levels correlate strongly with MFC-MRD depth and reflect its longitudinally kinetics. Monitoring sBCMA offers a minimally invasive, cost-effective surrogate for MRD dynamics, potentially enabling earlier detection of relapse or treatment resistance. Prospective, multicenter studies are warranted to validate these findings, define actionable sBCMA thresholds, and integrate monitoring into routine clinical decision-making.