The goal of this multi-center Phase II study is to add bortezomib to the highly active regimen of bendamustine and rituximab. In this study, bortezomib will be administered on a weekly schedule (Days 1, 8, 15) and will be added to bendamustine/rituximab given in 4-week cycles. This combination uses the standard bendamustine dosing schedule, and is more convenient than the 5-week regimen of these 3 drugs currently being studied.

Inclusion Criteria:

1. Histologically-confirmed indolent lymphoma by the World Health Organization (WHO) classification. The biopsy must fulfill one of the following criteria:

   • Follicular lymphoma, grade 1 or 2
   • Marginal zone lymphoma
   • Small lymphocytic lymphoma (circulating lymphocyte count must be <5,000)
   • Lymphoplasmacytic lymphoma

2. At least one of the following criteria must be met:

   • Presence of any symptoms related to lymphoma. These can include classic B-symptoms (fever [>38°C] of unclear etiology, night sweats, weight loss of greater than 10% within the prior 6 months) or other lymphoma-related symptoms (fatigue, pain, etc.).
   • Large tumor mass (bulky disease) characterized by lymphomas with a diameter of more than 3 cm in three or more regions or by a lymphoma with a diameter >7 cm in one region
   • Presence of lymphoma-related complications, including narrowing of ureters or bile ducts, tumor-related compression of a vital organ, lymphoma-induced pain, cytopenias related to lymphoma/leukemia, splenomegaly, pleural effusions, or ascites
   • Hyperviscosity syndrome due to monoclonal gammopathy

3. The lymph node biopsy or other lymphoma pathology specimen has CD20+ B-cells.

4. Ann-Arbor Stage 2 (non-contiguous), 3, or 4 disease.

5. No previous systemic treatment for lymphoma. Patients may have had a single course of radiation therapy to a limited field (i.e., not exceeding two adjacent lymph node regions).

6. The patient has bidimensionally measurable disease with at least 1 lesion measuring ≥2.0 cm in a single dimension, and the field was not previously radiated.

7. An Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.

8. Adequate hematologic function ≤7 days prior to start of study treatment:

   • Hemoglobin ≥10.0 g/dl
   • Absolute neutrophil count (ANC) ≥1000/µL
   • Platelet count ≥75,000/µL. If low counts are attributable to bone marrow infiltration or hypersplenism due to lymphoma, ANC must be ≥750/µL and platelets ≥50,000/µL.

9. Calculated or measured creatinine clearance ≥30 mL/min ≤7 days of study enrollment (using Cockcroft-Gault method).

10. Adequate hepatic function (≤2.5 x upper limit of normal [ULN] for alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase and total bilirubin within normal limits).

11. Patients must be ≥18 years of age.

12. Women of childbearing potential must agree to use a medically acceptable method of birth control (e.g., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and for 12 months after their last dose of rituximab. Men must use an acceptable method/form of contraception for the duration of treatment and for 3 months after the end of treatment.

13. Patients must be able to understand the investigational nature of this study and give written informed consent prior to study entry.

Exclusion Criteria:

1. The patient has chronic lymphocytic leukemia.
2. The patient has transformed lymphoma.
3. History of, or clinically apparent, central nervous system (CNS) lymphoma or leptomeningeal lymphoma.
4. The patient has received corticosteroids for treatment of lymphoma. Chronic, low-dose corticosteroids (e.g., prednisone ≤20 mg/day) are allowed for treatment uses other than lymphoma or complications of lymphoma.
5. Peripheral neuropathy ≥ CTCAE v3.0 grade 2, ≤14 days of study enrollment.
6. Myocardial infarction ≤6 months prior to study enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, ECG abnormalities at screening must be documented as not medically relevant.
7. History of solid organ transplantation, or post-transplant lymphoproliferative disorder.
8. Patients with known history of hepatitis B or hepatitis C infection. Hepatitis B surface antigen must be tested.
9. The patient has known human immunodeficiency virus (HIV) infection.
10. Active, clinically serious infection > grade 2. Patients may be eligible upon resolution of the infection.
11. Female patient is pregnant or breast-feeding. Confirmation that female patients of childbearing potential are not pregnant must be established by a negative serum pregnancy test ≤7 days prior to the start of treatment.
12. Known hypersensitivity to bendamustine, bortezomib, boron, mannitol, or rituximab.
13. Concomitant active malignancy requiring therapy.
14. Diagnosis or treatment for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
15. Treatment with other investigational agents ≤14 days prior to study enrollment.
16. Any other disease(s), psychiatric condition, metabolic dysfunction, or findings from a physical examination or clinical laboratory test result that would cause reasonable suspicion of a disease or condition, that contraindicates the use of study drugs, that may increase the risk associated with study participation, that may affect the interpretation of the results, or that would make the patient inappropriate for this study.