The prognostic impact of achieving and in particular maintaining MRD negativity in multiple myeloma is now established, therefore identifying among MRD-negative patients the ones at higher risk of losing MRD negativity is of importance. We analyzed predictors of unsustained MRD-negativity in patients enrolled in the FORTE trial (NCT02203643). MRD was performed by multiparameter flow-cytometry (sensitivity of 10-5) at premaintenance and every 6 months thereafter. The cumulative incidence (CI) of MRD resurgence and/or progression was analyzed in MRD-negative patients. 306/474 (65%) MRD-negative patients were analyzed. After a median follow-up of 50.4 months from MRD-negativity, 185/306 (60%) patients were still MRD-negative and progression-free, 118 (39%) lost their MRD-negative status and 3 patients (1%) died without progression. Amp1q vs. normal (4-years CI 63% vs 34), ≥2 concomitant high-risk cytogenetic abnormalities vs. 0 (4-years CI 59% vs 33%), Circulating tumor cells at baseline (high vs. low 4-years CI 62% vs. 32%) and time-to-reach MRD negativity post-consolidation vs. pre-consolidation (4-years CI 46% vs 35%) were associated with a higher risk of unsustained MRD-negativity in a multivariate Fine-Grey model. During the first 2 years of maintenance, patients receiving carfilzomib-lenalidomide vs. lenalidomide alone had a lower risk of unsustained MRD-negativity (4-years CI 20% vs 33%). CT# NCT02203643