Background: The role of alloHCT and subsequent maintenance for the treatment of high-risk MM has not been fully defined. We evaluated the efficacy of ixazomib maintenance therapy after alloHCT using reduced intensity fludarabine/melphalan/bortezomib (Flu/Mel/Bort)-based conditioning regimen to treat patients with high risk MM. Methods: This phase 2 prospective multicenter trial (NCT#02440464) enrolled adults 70 years or younger, with either high-risk MM defined by cytogenetics or plasma cell leukemia (PCL) or relapse within 24 months after autologous HCT. Conditioning regimen consisted of Flu/Mel/Bort. Patients received HLA-matched donor unmanipulated peripheral blood grafts. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus plus methotrexate. Between days +60 and +120 after allogeneic HCT, patients were randomly assigned (1:1, stratified by number of prior progressions) to receive ixazomib at 3 mg orally on days 1, 8, 15 on a 28-day cycle or matching placebo for 12 cycles. The study aimed to enroll 138 patients with 110 patients achieving randomization for a progression-free survival (PFS) comparison ixazomib maintenance vs. placebo. Results: Fifty-seven patients from 15 centers were enrolled (2015-18), of whom 52 (91.2%) received allogeneic HCT, and 43 (82.7%) proceeded to randomization (21 assigned to ixazomib and 22 to placebo). Enrollment was delayed by a clinical hold after enrollment of 17 patients due to toxicity concerns related to the conditioning regimen. Remaining patients were enrolled after an amendment reduced bort to a single pre-HCT dose. These and other delays in enrollment led to premature study closure. Median age was 56 (range, 35-65) years, and 33 patients (57.9%) had high-risk MM with 9 patients (15.8%) with primary PCL. At 24 mo post alloHCT, PFS and OS among all alloHCT recipients was 52% and 85% respectively with a corresponding transplant-related mortality (TRM) of 11%. At 21 mo post-randomization, ixazomib vs. placebo groups had similar PFS (55.3% vs. 59.1%) and OS (95% vs. 87%, p = 0.17). Cumulative incidences of grade III-IV acute GVHD at 100 days (9.5% vs. 0%) or chronic GVHD at 12 months (69% vs 64%) were similar. Best response, incidence of progression for ixazomib vs. placebo groups were similar while cumulative incidence of transplant-related mortality (TRM) at 21 months was 0.0% and 4.5% (90%CI: 0.5-16.5%), respectively. Conclusions: AlloHCT with reduced intensity fludarabine/melphalan and a single pre-HCT dose of bortezomib is safe and can produce durable disease control in extremely high-risk patients. ixazomib maintenance after alloHCT could not be assessed as intended due to early termination of study, but there was no signal of an impact in outcomes. Clinical trial information: NCT02440464