This multicenter, open-label, randomized phase 2 study assessed the efficacy and safety of pomalidomide (POM) with/without low-dose dexamethasone (LoDEX) in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior therapies (including lenalidomide [LEN] and bortezomib [BORT]) and had progressed within 60 days of their last therapy were randomized to POM (4 mg/day on days 1-21 of each 28-day cycle) with/without LoDEX (40 mg/week). The primary end point was progression-free survival (PFS). In total, 221 patients (median 5 priortherapies, range1-13) received POM+LoDEX (n = 113) or POM (n = 108). With a median follow-up of 14.2 months, median PFS was 4.2 and 2.7 months (hazard ratio = 0.68, P = .003), overall response rates (ORRs) were 33% and 18% (P = .013), median response duration was 8.3 and 10.7 months, and median overall survival (OS) was 16.5 and 13.6 months, respectively. Refractoriness to LEN, or resistance to both LEN and BORT, did not affect outcomes with POM+LoDEX (median PFS 3.8 months for both; ORRs 30% and 31%; and median OS 16 and 13.4 months). Grade 3-4 neutropenia occurred in 41% (POM+LoDEX) and 48% (POM); no grade 3-4 peripheral neuropathy was reported. POM+LoDEX was effective and generally well tolerated and provides an important new treatment option for RRMM patients who have received multiple prior therapies. This trial was registered at www.clinicaltrials.gov as #NCT00833833.