Impact of sustained MRD negativity for up to 5 years on long-term outcome of transplant-eligible newly diagnosed multiple myeloma patients enrolled in the randomized phase 2 FORTE trial.

7504 Background: Novel combinations induce high rates of minimal residual disease (MRD) negativity (neg) in multiple myeloma (MM) patients (pts). However, the optimal duration of MRD negative status to predict long term outcomes remains a matter of debate. We analyzed the impact of different sustained (sust) MRD neg cut-offs on progression free survival (PFS) and overall survival (OS) in transplant eligible Newly Diagnosed MM pts treated in the randomized phase 2 FORTE trial (NCT02203643). Methods: We included all pts enrolled in the trial who were randomized to maintenance. MRD was assessed in the bone marrow in pts with ≥very good partial response by multiparameter flow cytometry (sensitivity of 10 -5 ) at premaintenance and every 6 months thereafter. SustMRD neg was defined as consecutive MRD-negative evaluations for at least 1, 2, 3, 4 or 5 years without intercurrent MRD-positive results. The primary aim of the analysis was the impact of different SustMRD neg durations on PFS. A subgroup analysis according to a modified Consensus Genomic Staging (mCGS as described in Avet-Loiseau et al JCO 2025 without the use of molecular data), and the presence of an MGUS-like profile at diagnosis (Burgos et al JCO 2023) was performed. Results: 356 pts were randomized to maintenance according to study protocol. After a median follow-up of 85 months from maintenance randomization, 77% of pts have > 1 MRD negative evaluation. The rate of at least 1, 2, 3, 4, 5-years sustMRD neg was 53%, 42%, 36%, 28% and 20% respectively. Compared to MRD positive patients (n=83), MRD neg lasting <1 year (HR 0.72; 95% CI 0.47-1.09), 1 year (HR 0.40; 95% CI 0.22-0.72), 2 years (HR 0.36; 95% CI 0.19-0.66), 3 years (HR 0.17; 95% CI 0.07-0.40), 4 years (HR 0.15; 95% CI 0.06-0.35) and 5 years (HR 0.06; 95% CI 0.03-0.15) significantly and progressively improved pts’ PFS. In pts with ≥ 3-years sustMRD neg vs < 3-year sustMRD, 7-years PFS rates were 84.7% vs 35.4% (HR 0.16, 95% CI 0.10-0.27) and 7-years OS rates were 97% vs 69% (HR 0.08, 95% CI 0.02-0.27). Stratifying patients according to mCGS and 3-years sustMRD neg, 7-years PFS rates were 84% for mCGS standard risk with ≥ 3-y sustMRD, 83% for mCGS high risk and ≥ 3-y sustMRD, 43% for mCGS standard risk with < 3-y sustMRD, 23% for mCGS high risk with < 3-y sustMRD. Among patients with < 3-years sustMRD neg, the presence of an MGUS-like profile predicted a significantly better PFS and OS compared to non MGUS-like pts (7-years PFS 67% vs 33%, HR 0.37 95% CI 0.17-0.85; 7-years OS 93% vs 66%, HR 0.15 95% CI 0.02-1.08). Conclusions: SustMRD neg for more than 3 years significantly improved PFS and OS of NDMM pts, with pts with at least 5-year SustMRD neg having a 7-year PFS of 91%. Reaching > 3-y sustMRD neg is mandatory in high-risk pts to achieve long term remissions, while MGUS-like pts may have good outcomes despite the absence of 3-y sustMRD neg. Clinical trial information: NCT02203643 .