Mass spectrometry-based proteomics and metabolomics in multiple myeloma: a systematic review of prognostic biomarkers and minimal residual disease monitoring

Introduction: Current multiple myeloma (MM) risk stratification, anchored on the Revised International Staging System (R-ISS), provides a static snapshot of disease but fails to capture its dynamic biological evolution, functional tumor-microenvironment crosstalk, and real-time treatment response. Mass spectrometry (MS)-based proteomic and metabolomic profiling has emerged as a high-sensitivity tool for both novel biomarker discovery and minimal residual disease (MRD) monitoring. This systematic review evaluates the independent prognostic value and clinical utility of quantitative MS-based proteomics and metabolomics compared to standard-of-care risk models and traditional disease monitoring techniques. Methods: Following PRISMA 2020 guidelines, a systematic search of PubMed, Embase, and Web of Science was conducted. Inclusion required quantitative MS-based proteomics or metabolomics in MM cohorts with outcomes compared to ISS/R-ISS or traditional MRD detection methods. Data analysis was performed with a focus on overall survival (OS), progression-free survival (PFS), hazard ratios (HR), and MRD sensitivity thresholds. Results: From 1,077 records, 19 studies met the inclusion criteria. Eleven discovery-focused studies identified specific MS-derived signatures, such as microenvironmental proteins (e.g., MTA2, CD44) and dysregulated lipid metabolites (e.g., acylcarnitines, LysoPE) that were consistently associated with PFS and OS. Crucially, MS-based biomarkers retained independent prognostic significance in multivariate models adjusted for R-ISS. Furthermore, 8 studies tackling blood-based MS-MRD detection demonstrated up to 1,000-fold higher sensitivity than traditional immunofixation electrophoresis, identified biochemical relapse 2-11 months earlier, and achieved high concordance with bone marrow-based assays (NGS/NGF). Conclusion: In conclusion, quantitative MS profiling provides a high-resolution molecular lens that significantly refines MM risk stratification beyond static staging. By enabling non-invasive, longitudinal MRD monitoring with superior lead times, MS integration facilitates a shift from reactive to proactive intervention. Standardization of bioinformatics pipelines and MS methodologies is now the final barrier to implementing MS-guided treatment adjustments in routine clinical practice.