Background: CFZ is an epoxomicin derivative with ability to irreversibly inhibit proteosomes, with clinical activity. It has been shown in preclinical and early clinical studies to have activity in myeloma. We performed a phase II study evaluating the efficacy of this drug in RRMM. Methods: First cycle CFZ was given at 20mg/m2 IV day 1,2, then 27mg/m2 IV days 8,9,15,16 every 28 days; 4mg of dexamethasone (DEX) was given with each CFZ dose. In the absence of PR, CFZ dose was escalated to 36 mg/m2 IV and DEX increased to 20mg. Other drugs were added with subsequent cycles. Cox regression modeling was employed for OS/EFS. Results: 74 patients with RRMM were enrolled. Baseline characteristics included age >=65yr in 34%, ISS stage >=II was seen in 76% of patients, cytogenetic abnormalities (CA) in 71%, and GEP-defined high risk in 58% of patients. 73 patients had prior autologous stem cell transplant. 61 patients (82%) had at least 2 transplants. 67 patients had received regimens containing bortezomib, thalidomide, lenalidomide, melphalan and steroids. At least 1 cycle of treatment was administered to all 74 patients enrolled, 62% patients receiving >1 cycle of treatment and only 16% received >5 cycles. 54/74 patients discontinued therapy primarily due to progression, death or toxicity. 15/74 (20%) patients achieved nCR/CR, 53% had stable disease. EFS benefit was observed in patients receiving > 3 cycles on univariate (HR= 0.16, p=0.001) and multivariate (HR=0.04, p=0.006) analyses after adjusting for GEP defined risk status. Most common toxicities (grades 1-5) were: hyperglycemia (96%), thrombocytopenia (96%), anemia (95%), hypoalbuminemia (92%), leucopenia (89%), hypokalemia (86%), hypophosphatemia (82%) and fatigue (76%). Overall and event free survival at 6 months were 53% and 21%, respectively. Conclusions: In this far advanced patient population, CFZ seemed to have single agent activity, especially in combination with other agents an improvement in disease was seen in about half the patients.