Background: Immune checkpoint blockade (ICB) have improved survival for many pts with MM, offering durable responses in up to 35% of pts, but many have short-lived or no response ( > 40%). A potential immune escape mechanism is the subversion of cellular epigenetic machinery to impact multiple aspects of the immune response such as suppression of Cancer Testis Antigen (CTA), which can be reversed in preclinical models by DNA hypomethylating agents (HMA), thereby increasing cancer cell immunogenicity. HMAs can also increase T cell infiltration and T cell-mediated tumor killing, and they achieve synergy with CBI in preclinical models. This suggests that epigenetic therapy with CBI is a rational combination to target MM. We hypothesize that CC-486 (an oral HMA) + PEMBRO will be tolerated at biologically relevant doses and enhance response to PEMBRO in pts with MM who are PD-1 naïve and reverse resistance to (ICB) in pts refractory/resistant to PD-1. Methods: This study (NCT02816021) evaluated the safety and efficacy of CC-486 (300 mg PO QD on days 1-14/21 day cycle) + PEMBRO (200mg IV Q 21 days) defined by Objective Response Rate (ORR) by RECIST 1.1 in pts with MM. PD-1 naïve pts were assigned to Arm A and pts with progression on prior PD-1 therapy to Arm B. Unlimited prior systemic therapies were allowed on Arm B. Continuous monitoring for toxicity and futility was performed and assumes an ORR of > 35% (Arm A) and > 15% (Arm B) at 95% power. Tumor biopsies at baseline and post treatment were mandated. Results: 22pts, 11 in each arm, have been treated. The most common AEs were nausea, vomiting, diarrhea, fatigue, and anemia. The most common gr 3/4 toxicities were neutropenia (3), diarrhea (2), dehydration (2), and rectal hemorrhage (1). 5 of 9 evaluable pts in Arm A achieved a PR (55% ORR); 0 of 9 evaluable pts in Arm B pts have responded. Conclusions: Although this regimen was tolerated in both arms, Arm B met futility stopping rules and was closed. The initial response rate in Aim A (55%) is promising, and accrual to this Arm continues. Analyses of longitudinally collected tumor biopsies are underway to interrogate the effects of HMA on the immune response to both arms. Clinical trial information: NCT02816021