Pharmacokinetics and Exposure-Response Analyses of Daratumumab in Combination Therapy Regimens for Patients with Multiple Myeloma

IntroductionDaratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes.MethodsFour clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis. Using various dosing schedules, the majority of patients (684/694) received daratumumab at a dose of 16mg/kg. In GEN503, daratumumab was administered at a dose of 2mg/kg (n=3), 4mg/kg (n=3), 8mg/kg (n=4), and 16mg/kg (n=34). A total of 650 patients in EQUULEUS (n=128), POLLUX (n=282), and CASTOR (n=240) received daratumumab 16mg/kg. The exposure-efficacy and exposure-safety relationships examined progression-free survival (PFS) and selected adverse events (infusion-related reactions; thrombocytopenia, anemia, neutropenia, lymphopenia, and infections), respectively.ResultsPharmacokinetic profiles of daratumumab were similar between monotherapy and combination therapy. Covariate analysis identified no clinically important effects on daratumumab exposure, and no dose adjustments were recommended on the basis of these factors. Maximal clinical benefit on PFS was achieved for the majority of patients (approximately 75%) at the 16mg/kg dose. No apparent relationship was observed between daratumumab exposure and selected adverse events.ConclusionThese data support the recommended 16mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies.FundingJanssen Research & Development.