Mass Spectrometry Profiling of Therapeutic Antibodies in Multiple Myeloma: m/z Features and Concordance with Immunofixation Electrophoresis

Background/Objectives: Therapeutic monoclonal antibodies, including bispecifics (t-mAbs), can interfere with serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE), mimicking residual M-protein. We evaluated a mass spectrometry (MS; EXENT®)-based workflow supported by an m/z reference library to discriminate drug from disease and assess concordance with IFE. Methods: Fifty-eight serum samples from 29 multiple myeloma patients were analyzed at baseline and after 3 months. Targeted enrichment of t-mAbs followed by MS enabled detection of peaks annotated through matching to a theoretical m/z panel and correlation with SPEP/IFE results. Results: Comparison of IFE versus MS showed 11/29 (38%) double positives, 15/29 (52%) double negatives, and 3/29 (10%) IFE−/MS+; no IFE+/MS− cases were observed. Using MS as a reference, IFE exhibited 78.6% sensitivity and 100% specificity. The m/z library enabled attribution of interference to linvoseltamab (n = 9), daratumumab (n = 6), and teclistamab (n = 3); in 16 patients treated with other bispecifics, no drug-related peaks were detected after 3 months. Longitudinal analysis discriminated therapeutic from endogenous immunoglobulins, identified baseline M-protein, and prevented false residual signals. Conclusions: MS (EXENT®)-based characterization of t-mAbs improves response monitoring accuracy in multiple myeloma and supports integration of MS into routine laboratory practice.