contributed to data acquisition, interpretation, and analysis; T.P. increases in CD8+:CD4+ and CD8+:Treg ratios, and increased memory T cells while decreasing na?ve T cells. The majority of patients exhibited these broad T-cell changes, although patients with a partial response or better showed greater maximum effector and helper T-cell increases, elevated antiviral and alloreactive functional responses, and significantly greater increases in T-cell clonality as measured by T-cell receptor (TCR) sequencing. Increased TCR clonality positively correlated with increased CD8+ PB T-cell counts. Depletion of CD38+ immunosuppressive cells, which is usually associated with an increase in T-helper cells, cytotoxic T cells, T-cell functional response, and TCR clonality, represents possible additional mechanisms of action for daratumumab and deserves further exploration. Introduction Proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) have improved outcomes in patients with multiple myeloma (MM).1-3 Despite these advances, prognosis for patients with relapsed MM remains poor, particularly for those who have relapsed after PI and IMiD treatment.4 New therapies with novel mechanisms of action are needed for resistant patient populations. Myeloma is usually associated with immune dysfunction,5 including immune evasion through the expression of immune checkpoint ligands on plasma cells,6 elevated adenosine receptor and adenosine activity,7,8 and immune suppression through myeloid-derived suppressor cells (MDSCs) and regulatory T cell (Treg) activity.9-11 CD38 is ubiquitously expressed on MM cells,12,13 but is also present on other immune cells, including MDSCs and regulatory B cells Epiberberine (Bregs).14,15 These CD38-positive (CD38+) immunosuppressive Epiberberine cell populations are associated with decreased immune function and disease progression. Thus, the role of CD38 in myeloma and Epiberberine immune cell biology may be important for the treatment of disease. Daratumumab is usually a human immunoglobulin G1 (IgG1) monoclonal antibody that targets CD38, inducing tumor cell death through multiple mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP).16,17 Daratumumab has shown promising Epiberberine antimyeloma activity in 2 clinical studies (GEN501 and SIRIUS) in patients with relapsed and refractory MM, resulting in remarkable response rates that include stringent complete responses (sCRs) and prolonged clinical responses in heavily pretreated patients.18,19 Based on these data, daratumumab was approved by the US Food and Drug Administration for patients with MM who have received 3 prior lines of therapy, including a PI and an IMiD agent, or who are double refractory to a PI and an IMiD.20 The observation that CD38 is expressed on various immune cells prompted an evaluation of the potential immunomodulatory effects of daratumumab monotherapy in patients with relapsed or relapsed and refractory MM. The impact of daratumumab on CD38+ immunosuppressive populations, T-cell proliferation and activation, and T-cell receptor (TCR) clonality was evaluated. Methods Clinical study design Immune profiling and assessments of functional activity were performed in samples from patients with relapsed or refractory MM treated with daratumumab 16-mg/kg monotherapy and who were enrolled in 2 concurrent clinical studies (ClinicalTrials.gov Identifiers: #”type”:”clinical-trial”,”attrs”:”text”:”NCT00574288″,”term_id”:”NCT00574288″NCT00574288 [GEN501] and #”type”:”clinical-trial”,”attrs”:”text”:”NCT01985126″,”term_id”:”NCT01985126″NCT01985126 [SIRIUS]) that have been described in detail elsewhere.18,19 Briefly, in the GEN501 study, a phase 1/2 dose-escalation and dose-expansion study, patients had documented MM and had Epiberberine relapsed from or were refractory to 2 prior therapies.18 In SIRIUS, a phase 2 study, patients had received 3 prior therapies, including a PI or an IMiD, Mouse monoclonal to PTH1R or were refractory to both classes of agents.19 Patients enrolled in these studies also received low to intermediate doses of corticosteroids to manage infusion-related reactions before and after daratumumab dosing. Best overall clinical responses were decided using the International Myeloma Working Group consensus recommendation for MM treatment response criteria.21 Patients were grouped into responders (ie, patients with best overall responses of partial response [PR], very good PR [VGPR], complete response [CR], or stringent CR [sCR]) and nonresponders (ie, patients with a best response of minimal response [MR], stable disease [SD], or progressive disease [PD]). The investigators and sponsors were responsible for the study design and statistical analysis plan. The investigators and their research teams collected the data. Janssen Research & Development and Genmab compiled the data for summation.