Background: Nivolumab (nivo) and combination ipilimumab (ipi) + nivo are highly active in pts with unresectable and stage IV MM. Nivo is also safe and effective adjuvant treatment for MM pts with resected stage III disease. Preclinical studies demonstrate that neo ICB may be more effective than adjuvant treatment, but the safety and efficacy of neo ICB in pts is unknown. We designed a randomized trial to assess the safety and activity of neo nivo +/- ipi ICB in pts with high-risk, resectable MM. Methods: We conducted a non-comparative randomized phase II study for pts with resectable, clinically detectable stage III or oligometastatic stage IV MM. Pts were randomized to receive neo nivo 3mg/kg IV every 2 weeks for up to 4 doses (Arm A) or neo ipi 3mg/kg + nivo 1mg/kg IV every 3 weeks for up to 3 doses (Arm B) prior to surgery, then nivo 3mg/kg IV every 2 weeks for 13 doses (Arms A and B) after surgery (NCT02519322). Planned total accrual was 40 pts (1:1 randomization) with stratification by stage and PD-L1 status. The primary endpoint was pathologic complete response (pCR) rate. Results: The trial was closed after 23 pts were enrolled (12 to Arm A, 11 to Arm B). Neo nivo achieved 25% pCR and 25% radiographic response rate (RR), but 17% were unable to undergo surgery due to rapid disease progression during neo therapy. All pts on neo ipi + nivo underwent surgery, and the pCR and RR rates were 45% and 73%, respectively. Grade 3 treatment related adverse events occurred in 8% of pts on Arm A and 73% on Arm B. Conclusions: Neo treatment with nivo +/- ipi can produce pCR in high-risk resectable MM. While neo nivo was well tolerated, RRs were lower than observed in stage IV pts and some pts experienced rapid progression that precluded surgery. Neo ipi + nivo achieved higher RRs but with high toxicity. This data provides a foundation for further optimization and testing of neo ICB. Clinical trial information: NCT02519322