The value of quantitative immunoprecipitation mass spectrometry (QIP-MS) to identify the M-protein is being investigated in patients with monoclonal gammopathies but no data are yet available in high-risk smoldering myeloma (HRsMM). We have, therefore, investigated QIP-MS to monitor peripheral residual disease (PRD) in 62 HRsMM patients enrolled in the GEM-CESAR trial. After 24 cycles of maintenance, detecting the M-protein by MS or clonal plasma cells by next-generation flow cytometry (NGF) identified cases with a significantly shorter median progression-free survival (mPFS) (MS: not reached vs. 1.4 years, P=0.001; NGF: not reached vs. 2 years, P=0.0002) but reaching complete response (CR) + stringent CR (sCR) did not discriminate between patients with different outcome. With NGF as a reference, the combined results of NGF and MS showed a high negative predictive value (NPV) of MS: 81% overall and 73% at treatment completion. When sequential results were considered, sustained negativity by MS or NGF was associated with a very favorable outcome with an mPFS not yet reached versus 1.66 years and 2.18 years in cases never attaining PRD or minimal residual disease (MRD) negativity, respectively. We can, thus, conclude that: 1) the standard response categories of the International Myeloma Working Group do not seem to be useful for monitoring treatment in HRsMM patients; 2) MS could be used as a valuable, non-invasive, clinical tool with the capacity of guiding timely bone marrow evaluations (based on its high NPV with NGF as a reference); and 3) similarly to NGF, sequential results of MS are able to identify a subgroup of HRsMM patients with long-term disease control. This study was registered at www.clinicaltrials.gov (clinicaltrials.gov identifier: 02415413).