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

<b>Background/Objectives:</b> 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 <i>m</i>/<i>z</i> reference library to discriminate drug from disease and assess concordance with IFE. <b>Methods:</b> 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 <i>m</i>/<i>z</i> panel and correlation with SPEP/IFE results. <b>Results:</b> 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 <i>m</i>/<i>z</i> library enabled attribution of interference to linvoseltamab (<i>n</i> = 9), daratumumab (<i>n</i> = 6), and teclistamab (<i>n</i> = 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. <b>Conclusions:</b> MS (EXENT^®)-based characterization of t-mAbs improves response monitoring accuracy in multiple myeloma and supports integration of MS into routine laboratory practice.