Influence of Disease and Patient Characteristics on Daratumumab Exposure and Clinical Outcomes in Relapsed or Refractory Multiple Myeloma

• Type of Material: Article
• Authors: Xiaoyu Yan, Janssen Research & Development, LLC; Pamela L. Clemens, Janssen Research & Development, LLC; Thomas Puchalski, Janssen Research & Development, LLC; Sagar Lonial, Emory University; Henk Lokhorst, Vrije Universiteit Amsterdam; Peter M. Voorhees, Carolinas HealthCare System; Saad Usmani, Carolinas HealthCare System; Paul G. Richardson, Harvard Medical School; Torben Plesner, Vejle Hospital and University of Southern Denmark; Kevin Liu, Janssen Research & Development, LLC; Robert Z. Orlowski, University of Texas MD Anderson Cancer Center; Nedjad Losic, Genmab AS; Richard Jansson, Janssen Research & Development, LLC; Tahamtan Ahmadi, Janssen Research & Development, LLC; Kristen Lantz, Janssen Research & Development, LLC; Juan Jose Perez Ruixo, Janssen Research & Development, LLC; Honghui Zhou, Janssen Research & Development, LLC; Xu Steven Xu, Janssen Research & Development, LLC
• Language: English
• Date: 2018-04-01
• Publisher: Adis
• Publication Version: Final Published Version
• Copyright Statement: © 2017, The Author(s).
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s40262-017-0598-1
• Title of Journal or Parent Work: Clinical Pharmacokinetics
• ISSN: 0312-5963
• Volume: 57
• Issue: 4
• Start Page: 529
• End Page: 538
• Grant/Funding Information: Medical writing and editorial support were provided by Erica S. Chevalier-Larsen, PhD, of MedErgy and funded by Janssen Global Services, LLC.; The clinical studies were supported by research funding from Janssen Research & Development and Genmab, and the analyses presented here were supported by research funding from Janssen Research & Development.
• Keywords: THERAPEUTIC MONOCLONAL-ANTIBODIES; Science & Technology; MECHANISMS; DEXAMETHASONE; RECEPTOR; Pharmacology & Pharmacy; MONOTHERAPY; Life Sciences & Biomedicine; PHARMACOKINETICS; CD38
• Research Categories: Health Sciences, Oncology

Abstract

Objective: The aim of this study was to understand the influence of disease and patient characteristics on exposure to daratumumab, an immunoglobulin Gκ (IgGκ) monoclonal antibody, and clinical outcomes in relapsed or refractory multiple myeloma (MM). Patients and Methods: Baseline myeloma type, albumin levels, renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group (ECOG) status, refractory status, and number of prior therapies were evaluated using data from two clinical studies—GEN501 (N = 104) and SIRIUS (N = 124). Results: Daratumumab clearance was approximately 110% higher in IgG myeloma patients than non-IgG myeloma patients, leading to significantly lower exposure in IgG myeloma patients based on maximum trough serum concentrations (p  <  0.0001). However, the overall response rate was similar for IgG and non-IgG myeloma patients (odds ratio 1.08, 95% confidence interval 0.54–2.17, p = 0.82). For a given exposure, the drug effect was significantly higher (approximately two times) in IgG versus non-IgG patients (p = 0.03). The influence of other patient and disease characteristics on daratumumab exposure was minimal and no significant effect on efficacy was observed (p ≥ 0.1). The incidences of infections and overall grade 3 or higher adverse events in subpopulations were generally consistent with that of the overall population. Conclusion: Due to competition with the MM-produced IgG M-protein for neonatal Fc receptor protection from clearance, IgG-based monoclonal antibodies in general may have significantly higher clearance and lower concentrations in IgG MM patients compared with non-IgG MM patients. Careful evaluation of the impact of exposure and patient and disease characteristics on safety and efficacy is warranted for all IgG-based monoclonal antibodies used in MM.