Background: MRD assessment is a known surrogate marker for survival in multiple myeloma (MM). However, some patients with non-detectable MRD, do relapse, and some MRD-positive patients with an extensive follow-up, do not relapse. Clonal diversity is defined as the number of unique Immunoglobulin (H, K, or L) sequences in each sample. Here, we present a single institution experience assessing MRD by NGS of Ig genes and the long-term impact of depth of response as well as clonal diversity on the clinical outcome of a large population of MM patients. Methods: 482 MM patients at University of California, San Francisco (UCSF) diagnosed from 2008 to 2020. Of them, 304 were newly diagnosed and 178 in ≥ 2nd line. MRD was assessed in patients achieving VGPR or better by IMWG criteria. MRD assessment was performed by NGS (Adaptive Biotechnologies, Seattle, WA). PFS curves were plotted by the Kaplan-Meier method, and the log-rank test was used to estimate statistical significance. Results: 1098 MRD samples were analyzed. MRD was available at 3 time points for 118 patients. Median follow-up was 26m. Overall, 181 of 482 patients (38%) achieved MRD- ( < 10^-6) on one or more samples. Clonal diversity was available in 87 of those patients. In the newly diagnosed group, 84 of 120 (39%), achieved MRD- at the level of 10^-6 at least once. These patients had a prolonged PFS versus patients who were persistently MRD+ at different levels (p > 0.0001). Notably, patients achieving a MRD < 10^-5 have longer OS than those with MRD > 10^-5 (p = 0.009). Of the 178 patients who received therapy for relapsed disease, 64 achieved MRD- at 10^-6 (36%) and PFS was also prolonged versus patients who remained MRD+ (44 m v NR, p = 0.03). Then, we analyzed the effect of repeated MRD monitoring on PFS. Three categories were defined: (A) patients with ≥3 MRD- samples, (B) patients with continuously declining detectable clones, and (C) patients with a stable number of clones. Groups A and B had a more prolonged PFS than group C (NR vs NR vs 38m, p < 0.0001). Finally, we analyzed clonal diversity at the moment of maximum response: patients MRD+ who have not relapsed have higher clonal diversity than MRD+ patients who relapsed. Moreover, patients who were MRD- who have not relapsed have higher clonal diversity than patients who were MRD- who did relapse. This was also observed independently for the 3 receptors analyzed (IgH p = 0.026; IgK p = 0.036 and IgL p = 0.036). Patients with more than 66000 IgH unique sequences at the moment of maximum response had a prolonged PFS (p = 00.5). Conclusions: MRD assessment in a real-world setting has the same predictive power as that seen in clinical trials even on OS. MRD dynamics can accurately predict disease evolution and drive clinical decision-making. Clonal Diversity could complement MRD assessment in the prediction of the outcome in MM.