Serum samples from multiple myeloma (MM) patients are collected regularly for conventional tests to quantify the M-protein longitudinally. However, the limited sensitivity of conventional tests makes quantification of minimal residual disease (MRD) difficult. MRD can be quantified with highly sensitive molecular techniques on bone marrow, but bone marrow procedures are invasive and cannot be performed regularly. In this study, we introduce highly sensitive targeted mass spectrometry (MS-MRD) to quantify M-protein from patient serum. Therefore, we can follow each patient’s course of disease and dynamically measure MRD.