Background: Lenalidomide (L) is an immunomodulatory drug with both anti-inflammatory and antiangiogenic properties. Preclinical studies demonstrate that the immunological function of tumor-infiltrating lymphocytes is impaired in patients with follicular lymphoma (FL) and that treatment with L can repair this dysfunction (Ramsay, Blood, 2009). In phase 2 investigations of frontline L + rituximab (R), in patients with indolent NHL, overall response rate (ORR) reached 90% and complete response/complete response unconfirmed (CR/CRu) was 64% (Fowler, ASH, 2012); a second study in patients with FL achieved 93% ORR and 72% CR (Martin, ICML, 2013). In patients with recurrent FL, treatment with L+R yielded higher response rates (73% ORR, 36% CR) compared with L alone (51% ORR, 13% CR; Leonard, ASCO 2012 oral presentation). Together, these preclinical and phase 2 data provide a rationale for further investigation of L+R in indolent NHL. Methods: This phase 3, multicenter, double-blind, randomized study (AUGMENT) is designed to evaluate the efficacy and safety of L+R versus placebo (P)+R in patients with relapsed/refractory indolent lymphoma. Eligible patients must have grade 1, 2, or 3a FL or marginal zone lymphoma; have received previous systemic therapy; be refractory to or have relapsed after their last treatment; be R-sensitive if prior R therapy was administered; have ≥1 measurable lesion; and have adequate bone marrow, liver, and renal function (moderate renal impairment acceptable). Approximately 350 patients will be randomized 1:1 to one of two study arms (experimental or control). During each 28-day cycle, patients enrolled in the experimental group will receive L (20 mg/day; days 1 to 21 up to 12 cycles) + R (375 mg/m²; days 1, 8, 15, 22 of cycle 1 and day 1 of cycles 2 to 5). Patients in the control group will receive P+R (375 mg/m²) in the same schedule. The primary endpoint is progression-free survival. Key secondary endpoints include rate of durable CR, overall survival, ORR, safety, and time to next anti-lymphoma treatment. This trial is currently enrolling patients. Clinical trial information: NCT01938001.