Phase I/II Carfilzomib Plus Lenalidomide and Rituximab in the Treatment of Relapsed/Refractory Mantle Cell Lymphoma

Inclusion Criteria:

1. Patients must have previously treated relapsed and/or refractory MCL, follicular lymphoma grade 1-3, marginal zone lymphoma, or non-germinal center B-cell diffuse large B-cell lymphoma with 1 - 4 prior lines of therapy. (prior anthracycline, rituximab or stem cell transplant (auto or allo) are acceptable).
2. Understand and voluntarily sign an institutional review board (IRB)-approved informed consent form.
3. Age \>/= 18 years at the time of signing the informed consent.
4. Patients must have bi-dimensional measurable disease (bone marrow only involvement is acceptable).
5. Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
6. Serum bilirubin \<1.5 mg/dl and Cr Clearance \>/= 60 mL/min, platelet count \>75,000/mm\^3 and absolute neutrophil count (ANC) \> 1,000/mm\^3, aspartate aminotransferase (AST)/ serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/ serum glutamic pyruvic transaminase (SGPT) \< 3 x upper limit of normal or \< 5 x upper limit of normal if hepatic metastases are present.
7. Disease free of prior malignancies of equal to or greater than 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated, with a life expectancy \> 3 years.
8. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as required by RevAssist) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. See Appendix E: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.
9. Patients must be willing to receive transfusions of blood products.
10. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation \[patients intolerant to acetylsalicylic acid (ASA) may use warfarin or low molecular weight heparin\].
11. Patients may have received prior Ibrutinib, lenalidomide, rituximab, and/or bortezomib either alone or in combination.
12. All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.

Exclusion Criteria:

1. Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled congestive heart failure, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, COPD, LVEF less than 40, renal failure, active infection, active hemorrhage, laboratory abnormality, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form. Patients with history of cardiac arrhythmias should have cardiac evaluation and clearance.
2. Pregnant or lactating females.
3. Use of any standard/experimental anti-lymphoma drug therapy, including steroids, within 3 weeks of initiation of the study or use of any experimental non-drug therapy (e.g., donor leukocyte/mononuclear cell infusions) within 56 days of initiation of the study drug treatment. Prior allogeneic stem cell transplant (SCT) within 16 weeks or autologous SCT within 8 weeks of initiation of therapy.
4. Known hypersensitivity to thalidomide, lenalidomide or rituximab; including the development of erythema nodosum if characterized by a desquamating rash while taking thalidomide.
5. Known HIV infection. Patients with active hepatitis B infection (not including patients with prior hepatitis B vaccination; or positive serum Hepatitis B antibody). Known hepatitis C infection is allowed as long as there is no active disease and is cleared by GI consultation.
6. All patients with history of central nervous system lymphoma.
7. Patients with peripheral blood involvement with white blood count (WBC) \> 20,000 or those considered to be at high risk for tumor lysis syndrome (TLS) by high tumor burden are EXCLUDED for the Phase I component of the study.
8. Significant neuropathy (Grades 3 - 4, or Grade 2 with pain) within 14 days prior to enrollment
9. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
10. Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis to ascites requiring paracentesis.
11. Patients with active pulmonary embolism or deep vein thrombosis (diagnosed within 30 days of study enrollment).
12. Patients with severe bradycardia (heart rate \<40 bpm, hypotension, light-headedness, syncope).
13. Patients with NYHA Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities, including but not limited to atrial fibrillation, AV block, QT prolongation, sick sinus syndrome, ventricular tachycardia, as these patients may be at greater risk for cardiac complications, per carfilzomib labeling.