8009 Background: Immunomodulatory (IMiD) agents are effective therapies for multiple myeloma (MM), with Lenalidomide (Len) having fewer side effects than Thalidomide (Thal), enabling long-term treatment. The optimum IMiD induction and maintenance regimen are unknown. We therefore compared triplet induction regimens of Len vs Thal and examined the role of maintenance Len vs observation, enabling us to explore the interaction of Len induction with Len maintenance. Methods: Myeloma XI is a multicenter, randomized controlled trial for newly diagnosed MM, with pathways for transplant eligible (TE) and non-eligible patients. For TE patients the induction question compared Len or Thal plus cyclophosphamide and dexamethasone (CRD vs CTD) continued for a minimum of 4 cycles and to max. response. For patients with a suboptimal response there was a subsequent randomization to a proteasome inhibitor containing triplet or no further therapy prior to ASCT. A maintenance randomization at 3 months post ASCT compared Len till disease progression vs observation. 2042 TE patients underwent the induction randomization (CRD 1021, CTD 1021). After a median follow up of 36.3 months, 965 PFS and 415 OS primary endpoint events had occurred. Secondary endpoints included response and toxicity. Results: In TE patients, CRD induction was associated with deeper responses than CTD: ≥VGPR CRD 60% vs CTD 53%. This was associated with a significantly improved median PFS (HR 0.85, 95%CI 0.75, 0.96, CRD 35.9 months vs CTD 32.9, p=0.0116) and 3 year OS: 82.9% vs 77.0% (HR 0.77, 95%CI 0.63, 0.93, p=0.0072). Maintenance therapy with Len was associated with a significantly longer median PFS compared to observation (HR 0.47, 95%CI 0.38, 0.60) across all subgroups including patients with high-risk disease. Exploratory analysis across the TE pathway suggested that CRD induction with Len maintenance was optimum: 60 month PFS CRD-R 50.2%, CTD-R 39.1%, CRD-obs 18.5%, CTD-obs 23.4%. Conclusions: CRD was associated with deeper responses than CTD, and with a PFS and OS benefit. The best outcomes were associated with Len induction plus Len maintenance. Our findings support continuing Len therapy through induction until disease progression. Clinical trial information: NCT01554852.