Clinical Research Directory

Inclusion Criteria: * Histological confirmation of relapsed/refractory CD20 positive diffuse large B-cell lymphoma * Ann Arbor stage I to stage IV DLBCL at the time of relapsed/refractory disease to be eligible * Measurable or assessable disease is required; measurable tumor size (at least one node measuring 2.25 cm\^2 in bidimensional measurement) per computed tomography (CT) scan, other radiological study, and/or physical exam * Patients must have received at least 1 prior rituximab-based immunochemotherapy (e.g., R-CHOP, R-EPOCH, etc.) * \>= 2 weeks since major surgery * Patients must not have any significant toxicity associated with prior surgery, radiation therapy, chemotherapy, or immunotherapy, per principal investigator (PI) discretion * Life expectancy \>= 3 months * Karnofsky score (KS) \>= 50 * Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =\< 3.5 times the upper limit of normal within 14 days prior to starting therapy * Absolute neutrophil count (ANC) \>= 1.0 x 10\^9/L within 14 days prior to starting therapy\* * Hemoglobin \>= 8 g/dL (80 g/L) within 14 days prior to randomization (subjects may be receiving red blood cell \[RBC\] transfusions in accordance with institutional guidelines)\* * Platelet count \>= 50 x 10\^9/L (\>= 20 x 10\^9/L if lymphoma involvement in the pretreatment bone marrow is found) within 14 days prior to starting therapy\* * \*Note: If patient has cytopenias due to bone marrow involvement, these requirements are not applicable * Serum creatinine of =\< 1.5 mg/dL; if creatinine \> 1.5 mg/dL creatinine clearance must be \> 60 mL/min within 7 days prior to treatment either measured or calculated using a standard Cockcroft and Gault formula * Written informed consent in accordance with federal, local, and institutional guidelines * Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately * Male subjects must agree to practice contraception * No known hypersensitivity to murine products * Patients must have normal baseline cardiac function based upon echocardiogram or gated blood pool scan (multigated acquisition scan \[MUGA\]) with an ejection fraction \>= 50% * Patients who test positive for hepatitis C (HepC) antibodies (Ab) are eligible provided all of the following criteria are met: bilirubin =\< 2 x upper limit of normal; ALT/AST =\< 3 x upper limit of normal; and clinical evaluation to rule out cirrhosis * Specific guidelines will be followed regarding inclusion of relapsed/refractory DLBCL based on hepatitis B serological testing as follows: * Hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (HBcAb) negative, hepatitis B surface antibody (HBsAb) positive patients are eligible * Patients who test positive for HBsAg are ineligible (regardless of other hepatitis B serologies) * Patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status) should have a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) testing done and protocol eligibility determined as follows: * If HBV DNA is positive, the subject will be excluded from the study * If HBV DNA is negative, the subject may be included but must undergo at least every 2 months HBV DNA polymerase chain reaction (PCR) testing from the start of treatment throughout the duration the treatment course Exclusion Criteria: * Patients with non-Hodgkin lymphoma (NHL) other than DLBCL; including "transformed" DLBCL * Known to be seropositive for human immunodeficiency virus (HIV); an HIV test is not required for entry on this protocol, but is required if the patient is perceived to be at risk * Positive serology for HBV defined as a positive test for HBsAg; in addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HepB DNA test will be performed and if positive the subject will be excluded * Patients with symptomatic brain involvement * Peripheral neuropathy of grade 2 or greater severity as defined by the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0; patients with grade 2 or higher (NCI-Common Toxicity Criteria \[CTC\]) neuropathy * Myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemia * Uncontrolled intercurrent illness including, but not limited to, active infection, poorly controlled hypertension, diabetes mellitus or other serious medical or psychiatric conditions that could interfere with adherence to or completion of this study * Pregnant or breastfeeding * Patient has received other investigational drugs within 4 weeks before enrollment * Chemotherapy within 3 weeks of the first scheduled study treatment * Less than 2-years disease free from another primary malignancy (other than squamous or basal cell carcinoma of the skin, "in-situ" carcinoma of the cervix or breast, superficial bladder carcinoma, or previously treated localized prostate cancer with normal prostate-specific antigen \[PSA\] levels); patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy, are considered by their physician to be at less than 30% risk of relapse and at least 2 years have lapsed * Major surgery, other than diagnostic surgery, within 2 weeks * Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib) * Medical condition requiring chronic use of high dose systemic corticosteroids (i.e., doses of prednisone higher than 10 mg/day or equivalent) * Prior high-dose chemotherapy (HDC)-ASCT * Active central nervous system (CNS) disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma; a lumbar puncture demonstrating DLBCL at the time of registration to this study is not exclusion for study enrollment