Current Evidence for Integrating Mass Spectrometry into Clinical M-Protein Assessment in Plasma Cell Dyscrasias.

BACKGROUND: Accurate detection of M-proteins is essential for diagnosing and monitoring plasma cell dyscrasias. With the advent of highly effective therapies, conventional assays lack sensitivity for low-level M-protein detection and specificity to distinguish M-proteins from therapeutic monoclonal antibodies. Novel mass spectrometry (MS)-based assays may address these limitations. CONTENT: This review outlines the clinical utility of MS-based M-protein detection using intact light chain approaches (MALDI-TOF and LC-high-resolution MS) and clonotypic peptide-based methods across multiple myeloma (MM), amyloid light chain (AL) amyloidosis, and other diagnostically challenging entities. A structured literature search was performed (in PubMed/MEDLINE, Embase, and Web of Science), including studies published through April 2026. Studies were selected using predefined criteria, critically appraised for methodological quality, and narratively synthesized.Across retrospective studies in MM, intact light chain MALDI-TOF MS negativity at treatment milestones was generally associated with improved progression-free survival. Prognostic performance of intact light chain MALDI-TOF MS varied across time points, likely reflecting M-protein elimination kinetics. Compared with intact light chain MALDI-TOF MS, assays measuring bone marrow residual disease often provided superior or complementary prognostic information. Higher-sensitivity (high-resolution/clonotypic) MS approaches may further improve prognostic stratification, although available data were derived from small cohorts. In AL amyloidosis, MS-based assays detected residual disease beyond complete response criteria, although evidence for prognostic relevance remains preliminary. SUMMARY: MS-based M-protein detection represents a clinically meaningful advancement in plasma cell dyscrasias. Prospective studies with standardized work flows and direct comparison to bone marrow assays and functional imaging are required before full integration into updated response criteria.