Background: Despite the introduction of several novel agents over the past decade, patients with HRMM continue to have relatively poor outcomes. In a first-in-human study, we previously showed the feasibility of using CB-NK cells up to a dose of 1 x 10⁸ cells/kg in MM patients undergoing high-dose melphalan (200 mg/m²; Mel200) plus lenalidomide and ASCT (NCT01729091). Lenalidomide enhances NK cell function and antibody-mediated cell toxicity against tumor targets. Our preclinical data showed that ex vivo expanded NK cells demonstrated higher elotuzumab-mediated cytotoxicity against myeloma targets than non-expanded cells, and the addition of elotuzumab to lenalidomide augmented the CB-NK cell ADCC against MM1.S myeloma targets. Hence, we aimed from this expansion part of the phase 2 clinical trial to determine the efficacy of CB-NK cells combined with elotuzumab/lenalidomide for HRMM undergoing ASCT. Methods: Patients with HRMM, ages 18-75 years, were eligible. HRMM defined as: disease relapse within 18 months of ASCT; fluorescence in situ hybridization (FISH) showing t(4:14), t(14:16), t(14:20), deletion (del) 17/17p or gain (amp) 1q; del(13) by conventional cytogenetic analysis; high-risk signatures as determined by the GEP-70 or EMC-92 gene expression profiles. With day 0 defined as day of stem cell infusion, treatment consisted of IV elotuzumab 10 mg/kg (days -15 and -8), oral lenalidomide 10 mg (days -8 to -2 prior to ASCT), Mel200 on day -7, and CB-NK cells on day -5. The primary endpoints were best response rate (≥VGPR) and minimal residual disease (MRD) at 3 months after ASCT, as defined per the IMWG criteria. MRD was tested by using 8-color multiparametric flow cytometry validated to a sensitivity level of 0.001% (1 cell in 100,000). Results: Thirty patients, with a median age of 63 (range, 40-72) years, were enrolled between 03/2018 and 01/2021. 97% had R-ISS stages 2/3, 40% had ≥2 high-risk genetic abnormalities, and 23% had del TP53. Most (80%) received induction therapy with bortezomib or carfilzomib + lenalidomide + dexamethasone, 1 patient had prior ASCT, and 4 received >1 prior line of therapy. Before ASCT, 73% had VGPR or better (40% in CR/sCR) and 40% had negative MRD. At 3 months after transplant, 97% achieved ≥VGPR (76%, CR/sCR) and 75% had negative MRD. At median follow-up of 26 (range, 12-44) months, only 4 patients progressed (3 had positive MRD after ASCT). The 2-year PFS and OS rates were 83% and 97%, respectively. No unexpected serious adverse effects attributable to NK cells were noted. Conclusions: CB-derived expanded NK cells plus elotuzumab/lenalidomide combined with Mel200 and ASCT results in excellent and durable hematologic and MRD responses in HRMM patients. Furthermore, PFS and OS rates compare favorably to published outcomes for HRMM patients. Clinical trial information: NCT01729091.