Background: Despite high response rates to MCL induction therapy, relapse is common. Stem cell transplant (SCT) is often utilized, though not curative in most patients (pts), and many are not candidates due to age or comorbidities. Thalidomide and bortezomib have demonstrated activity in MCL. In a phase II trial of rituximab+thalidomide, including thalidomide maintenance, in relapsed/refractory MCL pts, overall/complete response rate (ORR/CR) was 81/31%; median progression free survival (PFS) was 20.4 months; 3-year overall survival (OS) was 75%. In a phase II bortezomib trial with 141 evaluable MCL pts, ORR/CR was 33/8%, with median remission duration (MRD) 9.2 months (mos), and median time to progression (TTP) 6.2 mos. Grade (gr) 3/4 toxicities were peripheral neuropathy (13%), fatigue (12%), and thrombocytopenia (11%). Bortezomib+lenalidomide has been studied in relapsed/refractory myeloma pts, with 61% achieving >minimal response, with MRD of 10.8 mos and acceptable tolerability. Methods: Eligibility criteria: histologically-documented MCL (CD5+, CD23-, cyclin D1+); measurable disease; prior therapy with >1 regimen, including autologous, but not allogeneic, SCT; age ≥18 yrs; no prior radioimmunotherapy; no ≥gr 3 peripheral neuropathy; performance status 0-2. Treatment: Induction: bortezomib 1.3 mg/m² IV, d1,4,8,11; lenalidomide 20 mg/day PO, d1-14; 21d cycle, 8 cycles. Maintenance (for responders): bortezomib 1.3 mg/m² IV, d1,8; lenalidomide 15 mg/day PO, d1-14; 21d cycle, till disease progression. Primary endpoint is ORR/CR; secondary endpoints are TTP, disease-free and OS, and correlation of changes in NK/T-cells and plasma cytokines with response. The protocol was modified in 9/09 with separate dose reductions by agent (e.g., myelosuppression-lenalidomide; neuropathy-bortezomib). Accrual: Accrual goal is 54 (49 evaluable) pts. The study was activated in 11/07; a planned interim analysis occurred after 19 patients, with >10 responses required to continue the trial. As of 1/11/11, 48 pts are accrued, with completion anticipated for 6/2011.