Background: Long term overall survival (OS) follow-up data in pts with MM treated on clinical trials is limited. TT approach uses all MM-active drugs upfront to target drug-resistant subclones during initial treatment to prevent later relapse. We report the longest follow up of MM trials (TT1 (NCT00580372), TT2 (NCT00083551), TT3a (NCT00081939) and TT3b (NCT00572169)) reported to date with RSRs to assess for curability. Methods: Pts treated on TT1, TT2, TT3a and TT3b were followed at the University of Arkansas for Medical Sciences after completion of therapy including multi-agent chemotherapy, high dose melphalan followed by tandem autologous stem cell transplantation (ASCT) and fixed duration maintenance therapy with introduction of thalidomide (thal) (TT2+thal vs TT2-thal), bortezomib (TT3a) and lenalidomide (TT3b). Expected survival rate was defined as probability of a population surviving from yr to yr. RSR was defined as ratio between observed survival of trials to expected survival in population adjusting for age and sex based on enrollment year. Data cut-off was October 10, 2022. Results: 1379 pts were enrolled (TT1:231, TT2:668, TT3a:303, TT3b:177) with median follow up duration of 16.6 years (yrs) (TT1:25 yrs, TT2:18.4 yrs, TT3a:16.2 yrs, TT3b:14.2 yrs). 10-yr PFS increased from 8.8% (TT1) to 15.5% (TT2-thal) to 25.1% (TT2+thal) to 32.9% (TT3a) to 42.4% (TT3b). Median OS improved over time (TT1:5.8 yrs, TT2:10.4 yrs, TT3a:11.9 yrs, TT3b:10.1 yrs). 15-yrs OS improved from 24.2% in TT1, 33% in TT2, 40% in TT3a and 37% in TT3b. 20-yr OS is 24.4% for pts treated on TT2 protocol. Outcomes were better for standard risk disease defined by low-risk gene expression profiling (GEP) with 20-yrs OS of 30% in TT2 and 15-yrs OS of 45% in TT3a. RSRs approach 1 at 10-15 yrs for TT1, but this occurs earlier, at 5-10 yrs, for TT2+Thal, TT3a and TT3b [Table]. No difference in RSR between TT3a and TT3b was noted. Relative excess risk (RER) showed an estimated 23%, 44% and 54% lower excess mortality when comparing TT2 (+ thal), TT2 (-thal) and TT3a with TT1, respectively. Conclusions: In the longest follow up duration of any MM clinical trial, a subset of MM pts are cured as evidenced by RSRs approaching 1. Approximately one third of pts treated on TT2 protocol and one-half pts treated on TT3a are alive at 20 year and 15 yrs from initial diagnosis, respectively. Incorporation of immunomodulatory drugs and proteasome inhibitors along with tandem ASCT resulted in cumulative improvement of OS as evidenced by lower RER of mortality. Clinical trial information: NCT00580372, NCT00083551, NCT00081939, NCT00572169.