Daratumumab for Relapsed/Refractory Primary Effusion Lymphoma, Plasmablastic Lymphoma, and Multicentric Castleman Disease

Background * Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma caused by the Kaposi sarcoma herpesvirus (KSHV) with clinicopathologic and molecular profiles distinct from other HIV-related lymphomas. * Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma frequently caused by Epstein-Barr virus (EBV) with frequent extranodal presentations involving the bones and gastrointestinal tract. * Immunophenotypically, PEL and PBL are post-germinal center B cell neoplasms expressing surface markers consistent with plasmacytic differentiation, such as CD45, CD38, CD138, MUM-1, and IRF4, similar to that of multiple myeloma (MM). * Outcomes for PEL and PBL treated with front-line combination chemotherapy are inferior to those of other HIV-associated lymphomas, and second-line cytotoxic chemotherapy is often ineffective, and profound immunosuppression often prevents this approach. * In the second-line setting, chemotherapy-sparing treatments that do not contribute to further immune suppression may be more effective. In addition, patients with PEL often have concurrent KS, which can be severely exacerbated by immune suppression and contributes to mortality in PEL. * Kaposi sarcoma herpesvirus-associated multicentric Castleman disease (KSHV-MCD) is a rare lymphoproliferative disorder that develops predominantly in people with HIV with inflammatory symptoms associated with high levels of interleukin-6 (IL-6), KSHV-encoded viral IL-6 (vIL-6), and other cytokines. * The pathologic hallmark of KSHV-MCD is the presence of KSHV-infected Lambda-restricted plasmablasts in the mantle zones of lymph nodes which stain brightly for CD45 and CD38 and negative for CD20. * KSHV-MCD is generally treated with the anti-CD20 monoclonal antibody, rituximab, with the goal to rapidly improve symptoms and eliminate reservoirs of KSHV-infected plasmablasts. * Concurrent Kaposi sarcoma is often exacerbated by or develops during rituximab therapy and contributes to morbidity in KSHV-MCD. * Daratumumab is a human monoclonal antibody that binds to a unique region on CD38 and induces killing of CD38-expressing cells via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. * Daratumumab also depletes immunosuppressive non-plasma cells that express CD38 thereby reducing local immunosuppression and stimulating an increase in T-helper cells, cytotoxic T cells, T-cell functional response, and T-cell receptor (TCR) clonality in the tumor microenvironment. Objective -To evaluate the partial response (PR) plus complete response (CR) rate (further referred to as the overall response rate \[ORR\]) of daratumumab SC in participants with relapsed/refractory PEL or PBL and/or symptomatic KSHV-MCD or who are ineligible for front-line chemotherapy Eligibility * Age \>=18 years * Participants with pathologically confirmed relapsed and/or refractory PEL, including extracavitary variant and KSHV-associated large cell lymphoma, PBL, or ineligible for front line chemotherapy * Participants with PEL or PBL must have: * Measurable or assessable disease * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-3 * Received first-line curative-intent therapy for PEL or PBL, unless such therapy is contraindicated * Participants with KSHV-MCD must have: * ECOG PS 0-2 or 3 if secondary to PEL or PBL/MCD * At least one clinical symptom and at least one laboratory abnormality attributable to KSHV-MCD Design * This is a Phase 2 study to evaluate the response rate of daratumumab SC in participants with relapsed/refractory PEL or PBL, and/or symptomatic KSHV-MCD. * The study will accrue up to 12 evaluable participants with PEL or PBL and up to 12 evaluable participants with KSHV-MCD. * For participants with relapsed/refractory PEL or PBL, daratumumab SC will be administered subcutaneously (SC) as 1800 mg/30,000 units weekly for a total of 8 weeks followed by every 2 weeks for a total of 16 weeks followed by every 4 weeks for up to 96 weeks in the absence of off-treatment criteria. Participants who are deriving benefit from therapy and exhibit disease worsening without meeting the criteria for progression may resume therapy every two weeks for up to 96 weeks. * Participants with relapsed/refractory PEL or PBL who are benefiting from treatment but show progression in effusions or CSF may continue therapy for up to an additional 3 months. * For participants with symptomatic KSHV-MCD, daratumumab SC will be administered SC as 1800 mg/30,000 units weekly for 8 weeks. If response assessment indicates progressive or stable disease, daratumumab SC will be given every 2 weeks for up to 24 weeks (6 months).