Minimal residual disease (MRD) status in multiple myeloma (MM) is an important prognostic biomarker. Personalized blood-based targeted mass spectrometry (MS-MRD) detecting M-proteins was shown to provide a sensitive and minimally invasive alternative to MRD assessment in bone marrow. However, MS-MRD still comprises manual steps that hamper upscaling of sample size. Here, we introduce a proof-of-concept for a novel workflow using dia-PASEF technology and automated data processing.Using automated data processing of PASEF DDA and dia-PASEF measurements, we developed a workflow that identified unique targets from MM patient sera and personalized protein sequence databases. We generated patient-specific libraries linked to dia-PASEF methods and subsequently quantitated and reported M-protein concentrations in follow-up samples from MM patients. Assay performance of prm-PASEF and dia-PASEF workflows were compared and we tested mixing patient intake sera for multiplexed target identification and selection.