We performed a phase 1/2 trial to determine the maximum tolerated dose (MTD) of pomalidomide and to explore its efficacy when combined with cyclophosphamide-prednisone in relapsed/refractory myeloma patients. Pomalidomide was given at 1 to 2.5 mg/d, cyclophosphamide at 50 mg every other day, prednisone at 50 mg every other day, for 6 28-day cycles, followed by pomalidomide-prednisone maintenance therapy. Thromboprophylaxis was recommended. Sixty-nine patients were enrolled, 55 received the MTD (2.5 mg/d) and were evaluated. Best responses included complete response in 3 patients (5%), very good partial response in 10 (18%), partial response in 15 (27%), minimal response in 11 (20%), stable disease in 15 (27%), and progressive disease in 1 (3%), for an overall response rate of 51%. The median time-to-response was 1.83 months. After a median follow-up of 14.8 months, median progression-free survival was 10.4 months and 1-year overall survival was 69%. At the MTD, grade 3 to 4 toxicities included anemia (9%), thrombocytopenia (11%), neutropenia (42%), neurologic events (7%), dermatologic events (7%), and thromboembolism (2%). Grade 3 to 5 infections occurred in 5 patients (9%). Five patients (9%) discontinued treatment for toxicity. New grade 3 to 4 adverse events were low during maintenance. Pomalidomide-cyclophosphamide-prednisone is safe and effective in relapsed/refractory myeloma patients. This trial was registered at www.clinicaltrials.gov as #NCT01166113.