MRD2STOP is a pragmatic trial evaluating maintenance therapy cessation guided by measurable residual disease (MRD) negativity in multiple myeloma (MM). Eligible patients had previous MRD < 10, received ≥1 year of maintenance, and were prospectively confirmed to have undetectable disease by positron emission tomography, bone marrow (BM) flow cytometry (limit of detection [LoD] 10), and BM clonoSEQ (LoD 10). BM aspirates enriched for CD138 cells were analyzed by clonoSEQ to achieve MRD 10 sensitivity. We evaluated the incidence of disease resurgence and progression-free survival (PFS), stratified by 10 status. Forty-seven patients discontinued maintenance after a median of 36 months. Baseline MRD ≥ 10 was observed in 19% (9/47). The median follow-up post-discontinuation was 30 months. Disease resurgence (MRD 10 ≥ ) occurred in 11 patients, including 5 disease progressions. One patient died from a second cancer. The estimated 3-year cumulative incidence of disease resurgence was 20% for patients with baseline MRD < 10 compared to 75% for MRD ≥ 10 (HR 7.8, 95% CI 2.2-27.6, p = 0.001). Baseline MRD ≥ 10 was associated with inferior PFS compared to MRD < 10 (HR 10.1, 95% CI 1.6-62.3; 3-year PFS 49% vs 92%). Maintenance discontinuation in patients with MM and MRD < 10 led to low rates of disease resurgence. MRD < 10 may be a superior cessation threshold, requiring further validation.