8594 Background: The benefit of initiating lenalidomide plus dexamethasone at first relapsed was evaluated in this subset analysis from phase III studies in patients with relapsed or refractory multiple myeloma (MM). Methods: Patients from the randomized, multicenter clinical trials MM-009 and MM-010 who had received at least 1 prior treatment and were not resistant to dexamethasone were treated with lenalidomide (25 mg daily for 21 days of every 28 day cycle) plus dexamethasone (40 mg on days 1–4, 9–12, and 17–20 every 28 days for 4 months, then 40 mg on days 1–4 every cycle thereafter until disease progression or intolerance), or dexamethasone (same dose and schedule) plus placebo. Baseline characteristics such as age, sex, ECOG score, and baseline β2-microglobulin levels between the 2 patient groups were similar, however, median time from diagnosis and prior therapy were statistically different. Results: Multivariate analysis showed that more prior therapies is associated with shorter time-to-progression (TTP). Patients who received 1 prior therapy demonstrated a significant improvement in outcomes such as TTP, progression-free survival (PFS), overall response rate (ORR), complete response/very good partial response rate (CR/VGPR), median duration of treatment and overall survival (OS) after first relapse compared with those who received ≥ 2 prior therapies ( Table ). Toxicity, rate of dose reduction, or treatment discontinuation in the cohort with 1 prior therapy did not increase, despite longer treatment. Conclusions: When used at first relapse compared with salvage therapy, lenalidomide plus dexamethasone treatment resulted in significantly prolonged TTP, PFS, and OS, and an improved quality of response. Lenalidomide plus dexamethasone should be considered at an early stage of therapy for patients with MM. [Table: see text] [Table: see text]