We conducted a phase 1/2 trial combining lenalidomide (R) with adriamycin (A) and dexamethasone (D) for relapsed and relapsed-refractory myeloma to determine tolerability and efficacy of this novel regimen, RAD, delivered for six 28-day cycles. A total of 69 intensively pretreated patients with a median age of 65 years (range, 46-77 years) were enrolled. Using pegfilgrastim (G), the maximum tolerated dose (MTD) was formally not reached at the highest dose level (R, 25 mg on days 1-21; A, 9 mg/m(2) intravenously on days 1-4; and D, 40 mg on days 1-4 and 17-20; dose level 5+G), which was then used to determine efficacy. Grades 3/4 neutropenia and thrombocytopenia were seen in 48% and 38% of patients, respectively. Thromboembolic events occurred in 4.5% and severe infections in 10.5% of patients. On an intent-to treat analysis, overall response rate (ORR) was 73% for the whole study and 77% including 74% complete response (CR) plus very good partial response (VGPR) for dose level 5+G. Response rates and progression-free survival did not differ between relapsed and relapsed-refractory patients. Deletion of chromosome 17p and elevated beta(2)-microglobulin were associated with significantly inferior response and shortened time to progression. In conclusion, RAD induces substantial and durable remission with an acceptable toxicity profile in patients with relapsed and relapsed-refractory myeloma. This trial was registered at www.ClinicalTrials.gov as no. NCT00306813.