Background: Lenalidomide, an immunomodulator with antineoplastic and antiproliferative effects, showed clinically significant improved activity over investigator choice (IC) in relapsed/refractory (R/R) MCL. This preplanned MCL-002 analysis evaluated efficacy across patient subgroups receiving lenalidomide vs IC. Methods: Patients received lenalidomide (25 mg/day PO on days 1-21/28 days) or single-agent IC therapy (chlorambucil, cytarabine, fludarabine, gemcitabine, or rituximab). The primary endpoint was progression-free survival (PFS); prespecified exploratory analyses of PFS by subgroups were conducted. Results: 254 patients with R/R MCL (median 2 prior therapies) were randomized 2:1 to lenalidomide (n = 170) or IC (n = 84). Patients receiving lenalidomide showed a significant improvement in median PFS vs IC (8.7 vs 5.2 months; HR = 0.61, P= 0.004). Subgroup analysis of PFS by central review demonstrated statistically significant reductions in the risk of progression or death in favor of lenalidomide vs IC across most baseline demographic and disease characteristics including: age ≥ 65 years, females, any stage at diagnosis, ECOG PS 0-1, both high or low tumor burden, Ki-67 < 10%, normal/elevated LDH , WBC counts < 10x10⁹/L, no bulky disease, high MIPI score, negative bone marrow, and normal renal function. The only subgroups without risk reduction were WBC ≥ 15x10⁹/L and positive bone marrow (both statistically insignificant), partly explained by low patient numbers in the IC arm. Risk reduction in the remaining categories was insignificant. Overall, factors associated with significantly better PFS by univariate Cox regression analysis, beside treatment group (HR = 0.619; P= 0.004), were non-elevated LDH, WBC < 10x10⁹/L, low+intermediate MIPI, low tumor burden, and Ki-67 ≤ 30%. Highly significant in the multivariate analysis were treatment group (HR = 0.384) and Ki-67 ≤ 30% (HR = 0.344). Conclusions: Multivariate and subgroup analyses of the primary study endpoint PFS favored lenalidomide over IC therapy in providing consistent clinical benefit in patients with R/R MCL irrespective of baseline demographics or disease characteristics. Clinical trial information: NCT00875667