Background Minimal residual disease (MRD) is an important prognostic factor for evaluating a deeper treatment response in patients with multiple myeloma (MM). We evaluated the clinical utility of next-generation flow (NGF)-based MRD assessment in a heterogeneous MM patient population. Methods Patients with suspected morphological remission after or during MM treatment were prospectively enrolled. In total, 108 bone marrow samples from 90 patients were analyzed using NGF-based MRD assessment according to the EuroFlow protocol, and progression-free survival (PFS) was evaluated according to the International Myeloma Working Group response status, cytogenetic risk, and MRD status. Results The overall MRD-positive rate was 31.5% (34/108 samples), and MRD-positive patients showed a lower PFS than MRD-negative patients ( P =0.005). MRD-positive patients showed inferior PFS than MRD-negative in patients with stringent complete remission (sCR)/complete remission ( P =0.014) and high-risk cytogenetic abnormalities ( P =0.016). MRD was assessed twice in 18 patients with a median interval of 12 months. Sustained MRD negativity was only observed in patients with sustained sCR, and their PFS was superior to that of patients who were not MRD-negative ( P =0.035). Conclusions Clinical application of NGF-based MRD assessment can provide valuable information for predicting disease progression in patients with MM in remission, including those with high-risk cytogenetic abnormalities.