Background: In the relapsed/refractory (R/R) setting for indolent non-Hodgkin lymphoma (iNHL), duration of response (DOR) to and types of prior therapy are important factors in predicting outcomes to subsequent therapy. Lenalidomide plus rituximab (R²) has shown promising efficacy and tolerability in multiple NHL studies. This report explores the association between prior number of therapies and response to R². Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, global study of R/R NHL patients, including follicular lymphoma (FL) grade 1-3a and marginal zone lymphoma (MZL). Patients receive 12 cycles of R² (lenalidomide 20 mg/d, d1-21/28 + standard rituximab). Patients with stable disease or better are then randomized 1:1 to maintenance with R² vs rituximab alone. This analysis focuses on the initial period before randomization (12 cycles R²) for patients with <2 (<2L) vs ≥2 lines (≥2L) of prior systemic anti-lymphoma therapies. Results: As of May 1, 2017, 232 patients with FL gr1-3a (n = 186) and MZL (n = 46) were enrolled for the initial treatment period. Overall, median age was 66 years (range 35-91) and 89% were stage III/IV. Patients received a median of 2 prior systemic treatments (31% ≥3) and 97% received prior rituximab-containing regimens. Analyzed subgroups included 43% <2L (n = 99) and 57% ≥2L (n = 133) with generally similar baseline characteristics. In efficacy-evaluable patients, the overall response rates (70% and 66%) and complete response (51% and 36%) were similar in <2L and ≥2L patients. Median time to response was 2.8 months (range, 2-12) for both groups. For <2L and ≥2L groups, 1-year rates for PFS were 68% and 70%, and DOR were 77% and 81%, respectively. The most common grade ≥3 treatment-emergent adverse events for <2L and ≥2L patients, respectively, were neutropenia (29%; 37%), thrombocytopenia (10%; 6%), and leukopenia (4%; 7%). Conclusions: R² therapy showed favorable activity and tolerable safety profiles in patients who had R/R FL and MZL, regardless of the number of prior anti-lymphoma therapies. Enrollment in MAGNIFY is ongoing. Clinical trial information: NCT01996865