Phase II Study of Daratumumab in Combination with Azacitidine and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients Previously Treated with Daratumumab: Darazadex

Background: Daratumumab, a human anti-CD38 monoclonal antibody, is approved in many countries for use as monotherapy in relapsed/refractory multiple myeloma (RRMM), and in combination with standard-of-care regimens in RRMM. The phase 2 DARAZADEX study will evaluate the efficacy and safety of daratumumab plus azacitidine and dexamethasone in RRMM patients previously treated with daratumumab. Pre-clinical data from our laboratory has demonstrated that azacitidine induces a 1.2 - 2.4 increase in CD38 median fluorescent intensity (MFI) in a dose-dependent manner across four different MM cell lines. (Figure 1A) Using an immortalized transgenic natural killer (NK) cell line to mediate lysis, we observed a significant increase in antibody-dependent cell-mediated cytotoxicity (ADCC) in the azacitidine-treated MM cells as opposed to control. Importantly, this increase in ADCC correlated with CD38 MFI upregulation. (Figure 1B). Based on this data we hypothesize that azacitidine, by upregulating the expression of CD38, can potentially increase the ADCC and efficacy of daratumumab on multiple myeloma cells and help reverse daratumumab resistance. Methods: In this single-arm, 2-stage, phase II study, approximately 23 RRMM patients in the United States will be treated with combination of daratumumab, azacitidine, and dexamethasone. Eligible patients must have progressed on ≥2 lines of prior therapy, including an immunomodulatory drug (IMiD) and proteasome inhibitor, and have previously been treated with daratumumab with most recent daratumumab treatment being at least 6 months prior to enrollment to allow for CD38 normalization. Patients who were previously primary refractory to daratumumab will be excluded from the study. Patients will receive azacitidine at the standard 75 mg/m2 dose 5 days consecutively every 4 weeks starting day -7 to day -3 of Cycle 1 and then Day 22-26 of Cycle 1-3, and subsequently Day 1-5 of Cycle 5 and thereafter until disease progression or intolerance, with dose modifications for toxicities. Daratumumab will be administered intravenously at the standard dose of 16 mg/kg, with first dose administered on day 1. Daratumumab will be dosed in standard fashion: weekly for 8 doses (induction phase), every two weeks for 8 doses (consolidation phase), and then every 4 weeks thereafter (maintenance phase). Daratumumab will be switched to the subcutaneous formulation at a later timepoint. There will be no dose modifications for daratumumab. Dexamethason