Background sustained MRD negativity is emerging as a surrogate biomarker of patients (pts)’ outcome in clinical trials. We implemented this tool in our clinical practice and we analyzed outcome according to sustained MRD negativity in MM pts treated with autologous stem cell transplantation (ASCT) at our Institution. Methods We retrospectively analyzed the outcome of 77 newly diagnosed MM pts (median age 61 years) diagnosed between January 2015 to December 2019 in ≥ VGPR after ASCT. Bone marrow samples were collected for MRD by 8-color FCM (Sn 10-5) at day +100 after ASCT, before maintenance. Sustained 1 year MRD negativity was also evaluated and the prognostic impact of MRD status on PFS and OS was analyzed. Results out of 77 pts, 28 (36%) were ISS stage 3 and 18 (23%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 51, VRD 5, Dara-VRD 5, KRD 14, KCD 2. Single ASCT with MEL200 conditioning was performed in 49 pts (64%), whereas 28 pts (36%) received double ASCT. Subsequent maintenance was performed with lenalidomide (70), daratumumab-lenalidomide (5), carfilzomib-lenalidomide (2). Response rates were VGPR 26%, CR 61% and sCR 13%. MRD before maintenance was positive in 20 pts (26%) and negative in 57 (74%). Sustained MRD negativity lasting ≥ 1 year was documented in 49 pts (64%), whereas early loss of MRD negative status was observed in 8 (10%) of cases. After a median follow up of 40.2 months, PFS was significantly longer in pts with sustained MRD negativity (≥1 year) compared to MRD positive patients before maintenance: median NR vs 41.4 months, p 0.0002, HR 0.17 (0.044-0.65). The worst PFS (24.7 months) was observed in pts with early loss of MRD negativity (<1 year) and was significantly inferior if compared both to pts with sustained MRD negativity (p<0.0001, HR 0.06; 0.01-0.54) and to MRD positive pts before maintenance (p 0.03, HR 0.35; 0.11-0.16), with significantly different outcome of the three subgroups (p<0.0001). Different OS trend was also observed among the three subgroups: NR in sustained MRD negative pts, 58.5 months in MRD positive pts and 35.3 months in pts with early loss of MRD negativity (p<0.0001), although OS difference between sustained MRD negativity (≥ 1 year) and MRD positive pts was not statistically significant on a direct comparison (p 0.054). The worst OS observed in pts with early loss of MRD negativity (<1 year) was significantly inferior if compared both to pts with sustained MRD negativity (p<0.0001, HR 0.05; 0.003-0.80) and to MRD positive pts before maintenance (p 0.020, HR 0.21; 0.035-1.26). Conclusion we confirm the predictive value of MRD assessment after ASCT and therefore the importance of achieving sustained MRD negativity regardless of different treatment strategies. Moreover, the detection of early loss of MRD negativity can help the physician to identify pts with particularly poor prognosis sustained MRD negativity is emerging as a surrogate biomarker of patients (pts)’ outcome in clinical trials. We implemented this tool in our clinical practice and we analyzed outcome according to sustained MRD negativity in MM pts treated with autologous stem cell transplantation (ASCT) at our Institution. We retrospectively analyzed the outcome of 77 newly diagnosed MM pts (median age 61 years) diagnosed between January 2015 to December 2019 in ≥ VGPR after ASCT. Bone marrow samples were collected for MRD by 8-color FCM (Sn 10-5) at day +100 after ASCT, before maintenance. Sustained 1 year MRD negativity was also evaluated and the prognostic impact of MRD status on PFS and OS was analyzed. out of 77 pts, 28 (36%) were ISS stage 3 and 18 (23%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 51, VRD 5, Dara-VRD 5, KRD 14, KCD 2. Single ASCT with MEL200 conditioning was performed in 49 pts (64%), whereas 28 pts (36%) received double ASCT. Subsequent maintenance was performed with lenalidomide (70), daratumumab-lenalidomide (5), carfilzomib-lenalidomide (2). Response rates were VGPR 26%, CR 61% and sCR 13%. MRD before maintenance was positive in 20 pts (26%) and negative in 57 (74%). Sustained MRD negativity lasting ≥ 1 year was documented in 49 pts (64%), whereas early loss of MRD negative status was observed in 8 (10%) of cases. After a median follow up of 40.2 months, PFS was significantly longer in pts with sustained MRD negativity (≥1 year) compared to MRD positive patients before maintenance: median NR vs 41.4 months, p 0.0002, HR 0.17 (0.044-0.65). The worst PFS (24.7 months) was observed in pts with early loss of MRD negativity (<1 year) and was significantly inferior if compared both to pts with sustained MRD negativity (p<0.0001, HR 0.06; 0.01-0.54) and to MRD positive pts before maintenance (p 0.03, HR 0.35; 0.11-0.16), with significantly different outcome of the three subgroups (p<0.0001). Different OS trend was also observed among the three subgroups: NR in sustained MRD negative pts, 58.5 months in MRD positive pts and 35.3 months in pts with early loss of MRD negativity (p<0.0001), although OS difference between sustained MRD negativity (≥ 1 year) and MRD positive pts was not statistically significant on a direct comparison (p 0.054). The worst OS observed in pts with early loss of MRD negativity (<1 year) was significantly inferior if compared both to pts with sustained MRD negativity (p<0.0001, HR 0.05; 0.003-0.80) and to MRD positive pts before maintenance (p 0.020, HR 0.21; 0.035-1.26). we confirm the predictive value of MRD assessment after ASCT and therefore the importance of achieving sustained MRD negativity regardless of different treatment strategies. Moreover, the detection of early loss of MRD negativity can help the physician to identify pts with particularly poor prognosis