Population Pharmacokinetic and Exposure-Response Analyses for Daratumumab in Combination Therapies for Patients with Multiple Myeloma Who Have Received 1 or More Prior Lines of Therapy
Authors: Xu X. Steven , Liao Sam , Dimopoulos Meletios A , Sonneveld Pieter , Ho P. Joy , Belch Andrew , Leiba Merav , Capra Marcelo , Gomez David , Medvedova Eva , Iida Shinsuke , Min Chang-Ki , Qi Ming , Schecter Jordan , Khokhar Nushmia Z. , Yan Xiaoyu , Zhang Liping , Clemens Pamela L. 
Published: October 2019

Abstract
Introduction: Daratumumab (DARA) is a first-in-class human CD38 IgG1κ monoclonal antibody that has demonstrated activity as monotherapy and in combination with standard of care regimens for multiple myeloma (MM). Population pharmacokinetics (PPK) analyses were conducted to describe the PK characteristics of DARA following its administration in combination therapies, to evaluate the influence of covariates on its disposition in patients with MM who had received ≥1 prior therapy, and to compare its PK in combination therapies with that of monotherapy. Exposure-efficacy/safety analyses were performed to investigate the relationship between DARA exposure and selected efficacy and safety endpoints.
Methods: The PPK analysis primarily included data from two phase 3 studies in which DARA was combined with background regimens: MMY3003 (POLLUX; lenalidomide [R]/dexamethasone [d]) and MMY3004 (CASTOR; bortezomib [V]/d). Data from two phase 1/2 studies (GEN503 [Rd] and MMY1001 [pomalidomide/d; Vd; V-thalidomide-d; V-melphalan-d]) were also used. Most patients included in the analysis (684 of 694) received 16 mg/kg DARA intravenously. A PPK model based on previous monotherapy studies was used to fit the concentration-time data from combination studies. Subgroup analyses were conducted to evaluate the influence of patient and disease characteristics on exposure to DARA. Based on data from MMY3003 and MMY3004, the exposure-efficacy analyses investigated the relationship between maximal trough concentrations (Cpre-infusion,max) and progression-free survival (PFS), duration of response (DOR), and overall response rate (ORR), while the exposure-safety relationship was explored for infusion-related reactions (IRRs), thrombocytopenia, anemia, neutropenia, lymphopenia, and infections.
Results: Exposure to DARA was similar between the monotherapy and combination therapies. Based on combination therapy data, the effects of the intrinsic and extrinsic factors (age, sex, race, renal and hepatic impairment, baseline albumin, type of MM, region, type of combination therapy, ECOG, refractory status, and number of prior lines of therapy) were similar to or smaller than those in the monotherapy studies. Consistent with the monotherapy studies, none of the investigated intrinsic and extrinsic factors had clinically important effects on the exposure to DARA as all the covariate effects were within 25%. Although the clearance and volume of distribution of DARA increased with increasing body weight, the exposure to DARA was relatively consistent across the range of body weights after administration on a mg/kg-basis. Despite the decreasing concentration of DARA over time due to less frequent dosing, the current dosing schedule was adequate to produce concentration levels that maintained target saturation during the Q4W dosing period in the dosing schedules for MMY3003 (QW for 8 weeks, Q2W for 16 weeks, and Q4W, thereafter) and MMY3004 (QW for 9 weeks, Q3W for 15 weeks, and Q4W, thereafter).
The exposure-efficacy analyses on the data from combination therapies suggest that maximum clinical benefit to PFS, DOR, and ORR was attained for the majority of the patients with an acceptable safety profile at the recommended dose of 16 mg/kg. No apparent relationships between drug exposure and IRRs, thrombocytopenia, anemia, neutropenia, and lymphopenia were identified within the studied concentration range. Although the overall rate of infection (any grade) appeared to increase with drug exposure, this trend was not observed for grade ≥3 infections. These findings were consistent with results from the monotherapy studies.
Conclusion: The PK of DARA was similar between monotherapy and combination studies. No clinically relevant demographic or clinical characteristics were identified. Therefore, no dose adjustment based on these factors is recommended. Population PK and exposure-response analyses for combination therapies support the recommended body weight-based 16 mg/kg dose and the dosing schedules for the MMY3003 and MMY3004 studies.

Disclosures
Xu: Janssen: Employment, Equity Ownership. Liao:Pharmax: Employment; Janssen Research & Development: Consultancy; Johnson & Johnson: Equity Ownership. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Amgen, Celgene, Janssen, Karyopharm, Takeda: Consultancy, Honoraria; Amgen, Celgene, Janssen, Karyopharm: Research Funding. Ho:Janssen, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Belch:Amgen, Celgene, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Capra:Janssen: Speakers Bureau. Gomez:Janssen, Bristol Myers Squibb, Celgene, Amgen: Consultancy. Medvedova:Oregon Health & Science University: Employment. Iida:Janssen Pharmaceuticals, Takeda Pharmaceuticals Co, Celgene, Bristol-Myers Squibb, Ono Pharmaceuticals Co: Honoraria; Janssen Pharmaceuticals, Takeda Pharmaceuticals Co, Celgene, Bristol-Myers Squibb, Chugai Pharmaceuticals, Kyowa Hakko Kirin Co, Eli Lilli Japan, Novartis Pharma, Sanofi, Bayer Yakuhin, Toyama Chemical Co, Teijin Pharma, Astellas Pharma: Research Funding. Qi:Janssen: Employment. Schecter:Janssen: Employment, Equity Ownership. Khokhar:Janssen: Employment. Yan:Janssen: Employment; Johnson & Johnson: Equity Ownership. Zhang:Janssen: Employment, Equity Ownership. Clemens:Johnson & Johnson: Equity Ownership; Janssen: Employment.