MAGNIFY: Phase IIIb Randomized Study of Lenalidomide Plus Rituximab (R²) Followed By Lenalidomide Vs. Rituximab Maintenance in Subjects with Relapsed/Refractory Follicular, Marginal Zone, or Mantle Cell Lymphoma

Background:Lenalidomide is an immunomodulatory agent with direct and immune-mediated mechanisms of action, as well as clinical activity in NHL. Recent studies in frontline and relapsed/refractory NHL show high activity for lenalidomide plus rituximab (R²), supporting further study of this combination.

Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of subjects with grades 1-3b FL (including transformed lymphoma [TL]), MZL, or MCL who received >=1 prior therapy and had stage I-IV, measurable disease (>1.5 cm). Subjects received 12 cycles of R² induction, consisting of oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle (d1-21/28) plus intravenous rituximab 375 mg/m², days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles). Subjects with stable disease (SD) or better after induction were then were randomized 1:1 to R² vs. rituximab maintenance. Stratification to the 2 maintenance arms was based on histology (FL grade 1-3b and TL vs. MZL vs. MCL), number of prior lines of antilymphoma therapy (<=2 vs. >2), and age (<65 vs. >=65 years).Maintenance R² consisted of lenalidomide 10 mg/day, d1-21/28, cycles 13-30 plus rituximab 375 mg/m², day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (Arm A). Rituximab maintenance alone was on the same schedule (Arm B). Subjects receiving R² maintenance after 18 cycles are eligible to continue maintenance lenalidomide monotherapy 10 mg/day, d1-21/28 (optional per subject and/or investigator discretion) until disease progression as tolerated. The primary endpoint isprogression-free survival (PFS) comparing maintenance arms using a two-sided test with alpha=0.05 and HR=0.67. Secondary endpoints include safety, overall survival, and response rates. Efficacy is evaluated per modified 1999 IWG criteria and safety per NCI CTCAE version 4.03.

Results: As of Jan 11, 2016, 135 subjects have been enrolled, including 91 (67%) with FL, 24 (18%) with MZL, 19 (14%) with MCL, and 1 (1%) with TL. At the time of enrollment, subjects had a median age of 66 years (range, 41-91); 81% had stage III/IV disease. Subjects had received a median of 2 prior therapies (range, 1-10), with 36% refractory to rituximab (defined as SD/PD to or PR/CR for <6 months with prior rituximab). The most common prior regimens were rituximab (41%), BR (25%), R-CHP (14%), R-CHOP (11%), and R-CVP (7%). At data cut-off, 45 (33%) subjects discontinued treatment before the maintenance period. Primary reasons for discontinuation of lenalidomide and/or rituximab, respectively, were due to AEs in 16 (12%) and 14 (10%) subjects, PD in 15 (11%) subjects for either treatment, withdrawal by subject in 6 (4%) and 7 (5%) respectively, and death 3 (2%) in either treatment. In the safety population (n=124), treatment-emergent adverse events (AE) during induction that led to dose reduction/interruption of lenalidomide or rituximab occurred in 55% or 24% of subjects, respectively, mainly due to neutropenia for lenalidomide and infusion-related symptoms for rituximab. The most common grade 3/4 AEs during induction were 27% neutropenia, 9% leukopenia, 6% thrombocytopenia, and 5% fatigue. 11 subjects have died (5 due to PD, 3 AEs, 3 other). At a median duration of 23.1 weeks (range, 0.1-51.1) of induction, 90 subjects were evaluable for response. Best responses to induction were 56 (62%) subjects with ORR, 8 (9%) CR, 12 (13%) CRu, 36 (40%) PR, and 22 (24%) SD. Responses with R² treatment were observed in all histologies (Table 1). At data cut-off, 19 subjects have completed induction and 18 have proceeded to maintenance (n=7 R², n=11 rituximab alone). Continued study and follow-up are ongoing to enroll more subjects in the induction and maintenance arms.

Conclusions: R² induction therapy shows favorable activity and a tolerable safety profile in subjects with advanced-stage, relapsed/refractory FL, MZL, MCL, and TL. Continued study is ongoing to determine the effect of R² vs. rituximab maintenance following 1 year of R² induction.

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