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    MRD and Biomarkers

    Category: MRD and Biomarkers

    Peripheral Blood Clonotypic Mass Spectrometry-Based MRD Stratification Identifies Patients at Increased Risk of Progression After Quadruplet Therapy in NDMM

    (PA-187) Peripheral Blood Clonotypic Mass Spectrometry-based MRD Stratification Identifies Patients at Increased Risk of Progression After Quadruplet Therapy in NDMM

    Thursday, September 18, 2025
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    Introduction: In newly diagnosed multiple myeloma (NDMM), many patients achieve complete or stringent complete response (CR/sCR) following quadruplet induction. Measurable residual disease (MRD) testing helps to further stratify outcomes but traditionally requires painful bone marrow (BM) sampling, highlighting the need for sensitive, minimally invasive biomarkers of MRD. M-inSight mass spectrometry allows non-invasive, longitudinal detection of clonotypic monoclonal proteins in peripheral blood (PB). Unlike binary tests, M-inSight provides continuous quantitative readouts, but clinically validated thresholds remain undefined.

    Methods: We analyzed patients in CR/sCR from two prospective trials (EloKRD and DaraKRD without transplant). Eligibility for this post-hoc analysis required samples with M-protein concentrations sufficient for clonotypic peptide tracking. The lowest clonotypic protein concentration across all timepoints was used to define each patient’s best MRD response. Receiver operating characteristic (ROC) curve analysis using 48-month progression status identified an optimal threshold by Youden’s index, which was used to classify patients as MRD-negative or positive. Survival was analyzed using Kaplan-Meier and Cox models. BM MRD was assessed via next-generation sequencing (NGS) at 10-5 sensitivity, and patients were further categorized as “double-negative” (negative by both methods) or “positive” (positive by one or both).

    Results:

    Among 64 CR/sCR patients, 33 were included in the M-inSight analysis. Baseline characteristics, PFS, and OS did not differ between included and excluded patients.



    ROC analysis identified a cutoff with strong prognostic value (AUC = 0.77; sensitivity 75%; specificity 76%). Patients above this threshold had significantly shorter PFS (p = 0.002; HR = 8.76; 95% CI: 1.7–45.1).



    Addition of BM MRD further refined risk stratification. Patients not achieving double-negativity (M-inSight PB positive or BM MRD-positive) had worse outcomes (HR = 8.12; 95% CI: 0.94–70.2; p = 0.057; C-index = 0.713). Although not statistically significant, the survival curves were clearly separated (log-rank p = 0.02), potentially indicating meaningful clinical differentiation in this small cohort.


    Agreement between PB M-inSight and BM NGS MRD at 10-5 was low (Cohen’s kappa = 0.043; p = 0.82), suggesting potential complementarity, though further investigation is warranted.

    Conclusions:

    A ROC-derived M-inSight threshold identifies patients in CR/sCR with increased risk of progression after quadruplet therapy. Integration with BM MRD enhances stratification, supporting the role of PB clonotypic mass spectrometry as a non-invasive, clinically meaningful tool in MRD-guided monitoring.