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Minimal residual disease (MRD) negativity is a well-established prognostic marker in multiple myeloma (MM), yet the clinical relevance of MRD response timing and duration remains unclear, particularly in real-world settings. We retrospectively analyzed 1048 newly diagnosed MM patients from the National Longitudinal Cohort of Hematological Diseases in China (NICHE) between 2012 and 2023, with a total of 5406 MRD assessments. A longer time to best MRD response (> 6 months) was significantly associated with improved progression-free and overall survival, especially among those with persistent MRD positivity but stable low-level disease burden. Early responders were more likely to exhibit high tumor burden and high-risk cytogenetic abnormalities. Notably, a prolonged MRD duration (≥ 36 months) predicted favorable outcomes regardless of MRD negativity status. Integrating response timing and duration identified a "Late + Durable" MRD pattern consistently associated with the best prognosis, even in patients with persistent MRD positivity, high-risk cytogenetics, or without ASCT. These findings highlight the prognostic significance of longitudinal MRD monitoring beyond single-timepoint assessments. A slow but durable MRD response may overcome adverse biological features and support individualized risk stratification, therapeutic decisions, and long-term disease monitoring in MM.