Lenalidomide, Ixazomib, and Rituximab as Front-Line Therapy for High Risk Indolent B-Cell Lymphoma

Primary: To determine the maximum tolerated dose and toxicity of the combination of oral ixazomib and lenalidomide plus rituximab in patients with previously untreated low-grade B cell lymphoma having high tumor burden by GELF criteria or FLIPI 3-5 Secondary: * To determine overall response rate in an expanded cohort at the MTD for follicular lymphoma and for non-follicular low-grade B cell lymphoma * Duration of response, time to progression, progression free survival, time to treatment failure and overall survival * Create tissue microarray from paraffin embedded tissue for future studies. * Assessment of baseline lymphocyte subsets as prognostic markers. Overview of Study Design: This study combines three classes of agents that have non-overlapping mechanisms of action and toxicity profiles, with each pair having demonstrated clinical evidence of benefit without unexpected toxicity. We use the lenalidomide-rituximab backbone, feasible and active in lymphoma, and add a novel oral proteasome inhibitor to potentially enhance efficacy, minimize toxicity and limit patient visits for treatment. Patients with previously untreated low-grade B cell lymphoma having high tumor burden by GELF criteria or FLIPI 3-5 will be treated with the combination of oral ixazomib + lenalidomide + rituximab. The primary objective is to determine the maximum tolerated dose and toxicity of this regimen. The study will use a standard 3 + 3 design for determination of MTD during cycle 1. There will be three dose levels for escalation, followed by two expansion cohorts of 12 patients each at the MTD, one cohort with follicular lymphoma and one cohort with non-follicular low-grade lymphoma (SLL, marginal zone, lymphoplasmacytic).