A Multicenter, Open-Label Feasibility Study of Daratumumab With Dose-Adjusted EPOCH in Newly Diagnosed Plasmablastic Lymphoma With or Without HIV

• Participants must have histologically and immunophenotypically (via at least a core or ideally, incisional or excisional biopsy) documented plasmablastic lymphoma.

• Stage II-IV disease (Ann Arbor staging criteria) or stage I disease with elevated lactate dehydrogenase (LDH) or bulky tumor (\> 7.5 cm).

• Known HIV status. At most 7 HIV negative patients will be allowed on the study. Once 7 HIV negative patients have been enrolled, future enrollment will allow only HIV positive patients. Participants may be HIV positive, with documentation of HIV infection by means of any one of the following:

‣ Documentation of HIV diagnosis in the medical record by a licensed health care provider;

⁃ Documentation of receipt of highly active antiretroviral therapy (HAART) (at least three different medications) by a licensed health care provider (documentation may be a record of an HAART prescription in the participant?s medical record, a written prescription in the name of the participant for HAART, or pill bottles for HAART with a label showing the participant?s name);

⁃ HIV-1 ribonucleic acid (RNA) detection by a licensed HIV-1 RNA assay demonstrating \>1000 RNA copies/mL;

⁃ Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 Western blot confirmation or HIV rapid multispot antibody differentiation assay.

∙ NOTE: A ?licensed? assay refers to a U.S. Food and Drug Administration (FDA)-approved assay, which is required for all Investigational New Drug (IND) studies.

⁃ Participants without HIV infection must have evidence of a negative result using any licensed HIV screening antibody assay and/or HIV antibody/antigen combination assay.

• Participants must have measurable disease (unless marrow-only disease is present), defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter) as \>= 15 mm (\>= 1.5cm) by computed tomography (CT) or positron emission tomography (PET) scan or evaluable by bone marrow.

• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 50%).

• Absolute neutrophil count \>= 1,000 cells/mcL unless decreased due to bone marrow involvement.

• Platelets \>= 75,000 cells/mcL unless decreased due to bone marrow involvement.

• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (\< 3.0 x ULN for patients with Gilbert syndrome). If, however, the elevated bilirubin is felt to be secondary to antiretroviral therapy, the total bilirubin must be =\< 3.5 mg/dL, provided that the direct bilirubin is normal and the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 3 x the upper limit of normal.

• AST (serum glutamic oxaloacetic transaminase \[SGOT\])/ALT (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN (=\< 5 x ULN is acceptable if liver metastases are present).

• Creatinine =\< 1.5 x institutional ULN OR glomerular filtration rate (GFR) \>= 45 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal, as calculated by the Cockcroft-Gault formula.

• Adequate cardiac function defined as an ejection fraction on echocardiogram (ECHO) or multigated acquisition scan (MUGA) that is at or above 45%.

• CD4 count \>= 100 cell/mL for HIV-positive participants.

• If HIV-positive, participant must not have a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past year.

• If HIV-positive, participant should have concurrent treatment with effective highly active antiretroviral therapy (HAART) or agree to start HAART.

• The effects of daratumumab on the developing human fetus are unknown. For this reason and because another monoclonal antibody (mAb), rituximab, crosses the placenta and other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, the duration of study participation, and 90 days after completion of therapy. 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. Men with female partners treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 90 days after completion of daratumumab administration.

• Ability to understand and the willingness to sign a written informed consent document.