Multiple myeloma (MM) is a systemic malignancy of monoclonal plasma cells that accounts for 10% of hematologic cancers. With development of highly effective therapies for MM, minimal residual disease assessment (MRD) has emerged an important end point for management decisions. Currently, serological assays lack the sensitivity for MRD assessment, and invasive bone marrow sampling with flow cytometry or molecular methods has emerged as the gold standard. We report a sensitive and robust targeted mass spectrometry proteomics method to detect MRD in serum, without the need of invasive, sequential bone marrow aspirates. The method detects immunoglobulin (Ig) derived clonotypic tryptic peptides predicted by sequencing the clonal plasma cell Ig genes. A heavy isotope labeled Ig internal standard is added to patient serum at a known concentration, the Ig is enriched in a light chain type specific manner, proteins are digested and analyzed by targeted mass spectrometry. Peptides from the constant regions of the lambda or kappa light chains, Ig heavy chains, and clonotypic peptides unique to the patient monoclonal immunoglobulins are targeted. This technique is highly sensitive and specific for the patient specific monoclonal immunoglobulins, even in samples negative by multi-parametric flow cytometry. Our method can accurately and precisely detect monoclonal protein in serum of patients treated for myeloma and has broad implications for management of hematologic patients.