The Transformative Role of Mass Spectrometry in Diagnosing and Monitoring Monoclonal Gammopathies and Plasma Cell Disorders

Abstract Background Mass spectrometry (MS) is emerging as a transformative diagnostic tool for plasma cell disorders, including multiple myeloma, Waldenström macroglobulinemia, and light chain amyloidosis. Traditional diagnostic methods such as serum protein electrophoresis, immunofixation electrophoresis, and serum free light chain assays, though effective, have limitations in sensitivity and specificity. These techniques may miss small monoclonal proteins or be affected by therapeutic antibody interference. Content Recent advances focus on top-down MS techniques, particularly matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and monoclonal immunoglobulin rapid accurate mass measurement (miRAMM). These methods analyze intact monoclonal proteins to enhance detection sensitivity and specificity. MALDI-TOF offers a streamlined workflow suitable for clinical laboratories, while miRAMM provides highly precise mass measurements, albeit requiring more sophisticated instrumentation. MS has demonstrated superior capabilities in detecting monoclonal proteins, including the ability to distinguish them from therapeutic antibodies. Additionally, MS enables structural characterization of monoclonal proteins, such as glycosylation patterns linked to amyloidosis. Notably, emerging evidence indicates that MS may match or surpass the sensitivity of molecular techniques. These include next-generation sequencing and next-generation flow cytometry, which are commonly applied to bone marrow biopsy for minimal residual disease detection, providing a less invasive alternative for disease monitoring. Summary MS, particularly MALDI-TOF and miRAMM, represents a promising advancement in the diagnosis and monitoring of plasma cell disorders. Its high sensitivity, efficiency, and noninvasive nature support its potential to complement or replace existing diagnostic methods, improving patient care and clinical outcomes as the technology continues to evolve.