Background: The advent of novel therapies has significantly improved outcomes in MM, yet most patients will eventually relapse. Patients progressing on CD38-targeting monoclonal antibodies, proteasome inhibitors (PIs) and IMiDs have dismal outcome. While treatment modalities based on novel mechanisms have shown promising results, the current study explores the use of high dose chemotherapy followed by autologous stem cell transplantation (ASCT) in these heavily pretreated MM patients. Methods: We investigated the outcome of 57 patients who received salvage ASCT after MM progression on Daratumumab. All patients had also been exposed to at least two PIs and two IMiDs. We assessed overall response using IMWG criteria, minimal residual disease (MRD) using 8 color flow cytometry with a sensitivity of 10^-5, progression free (PFS) and overall survival (OS). Results: Median age of the patient cohort was 62 years (39-75) and all patients had been exposed to Daratumumab, Thalidomide, Revlimid and Velcade. 93% (53/57), 91% (52/57) and 32% (18/57) of the patients had also received Carfilzomib, Pomalidomide and Ixazomib respectively. Pre-ASCT conditioning regimen included high dose melphalan in 23% (13/57), melphalan in combination with VDT-PACE (Velcade, Dexamethasone, Thalidomide, Cisplatin, Adriamycin, Cytoxan and Etoposide) in 30% (17/57) and BEAM (BCNU, Etoposide, Ara-C and Melphalan) in 47% (27/57). Post-ASCT response was assessed in 90% (51/57) within 100 days of ASCT. Overall response rate was 81% (46/57) with a CR in 39% (22/57), a VGPR in 23% (13/57) and a PR in 19% (11/57). Stable disease was seen in 3.5% (2/57) and progressive disease in 5% (3/53) patients. MRD negativity was attained in 44% (25/57) patients, all of whom had at least a VGPR. After response assessment, patients were started on maintenance treatment with combinations of either previously used agents (pomalidomide [20/57], carfilzomib [11/57] and CD38 moAbs [16/57]) or agents with no or little prior exposure (cytoxan [11/57], selinexor [4/57] or venetoclax [3/57]). The median PFS for the entire patient cohort was 8.5 months with a median OS of 19.6 months. For patients with ≥ VGPR, median PFS and OS improved to 11 months and 24.9 months respectively. Achievement of MRD negativity in ≥ VGPR did not improve outcome, median PFS = 11 and median OS = 20 months. 17% (10/57) of patients were still alive at 36months post salvage ASCT. Conclusions: High dose chemotherapy followed by ASCT achieves substantial responses in 81% of patients with 17.5 % still alive at 3 years. The results suggest a role for salvage ASCT in selected heavily pre-treated patients, albeit there remains an obvious clinical need for novel therapies. While the achievement of ≥ VGPR improved outcome, achievement of MRD negativity had no further impact on survival in our study, although that may be due to the relative small number of patients and the major overlap between ≥VGPR and MRD negativity.