Background: MM often presents at an advanced stage with a median survival of ~1 year. Treatments are limited; none clearly improve survival in second-line. In 40–60% of MM patients (pts) BRCA1 associated protein 1 (BAP1) is inactive and linked to a dependency on EZH2 (enhancer of zeste-homolog 2). EZH2 regulates gene expression to prevent differentiation of stem and progenitor cells, and aberrant EZH2 activity is implicated as an oncogenic driver. Tazemetostat, a potent, selective, oral EZH2 inhibitor demonstrated clinical activity in other malignancies; here we report preliminary data in inactive BAP1 MM. Methods: This is a phase 2, multicenter, open-label, single-arm study of tazemetostat (800 mg po BID) in pts with measurable R/R MM. PK and safety were assessed in a cohort of 13 pts. Efficacy was assessed via a 2-stage Green Dahlberg design in 61 pts with inactive BAP1 with a primary endpoint of 12-week disease control rate [DCR; CR or PR + SD]. Response was evaluated every 6 weeks with modified RECIST and/or RECIST 1.1. Secondary endpoints included ORR, PFS, OS, safety, population PK and response biomarkers (RNAseq, immunomodulation, exploratory prognostic indices). Results: Enrollment is complete (N = 74). Disease characteristics were typical of MM with the exception of a bias towards epithelioid histology (88%) that has a higher incidence of BAP1 inactivation. All pts had ≥1 prior systemic therapy. No pts discontinued due to AEs; however, 5 pts had dose reductions due to AEs. Fatigue (32%), decreased appetite (28%), dyspnea (28%), and nausea (27%) were the most frequently reported AEs of any grade regardless of attribution. In the efficacy portion of the study, the Stage 2 DCR criterion of ≥35% was surpassed, with 31 pts (51%) achieving disease control at 12 weeks and 15 pts (25%) sustained disease control at 24 weeks, 5 of whom are ongoing. Two of 61 patients had a confirmed partial response. Conclusions: Tazemetostat monotherapy shows promising antitumor activity, including confirmed responses and long-term disease control, with favorable safety/tolerability in pts with MM. These results support further evaluation of tazemetostat in pts with MM. Clinical trial information: NCT02860286