Understanding the Dose Regimen for Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma (MM) after Prior Proteasome Inhibitors (PIs) and Immunomodulatory Drugs (IMiDs): A Quantitative Pharmacologic Perspective
Authors: Xu Xu Steven , Yan Xiaoyu , Puchalski Thomas , Lonial Sagar , Lokhorst Henk M. , Voorhees Peter M. , Liu Kevin , Khan Imran , Jansson Richard , Ahmadi Tahamtan , Perez Ruixo Juan Jose , Zhou Honghui , Clemens Pamela L 
Published: October 2019

Abstract
Introduction: Daratumumab is a first-in-class human anti-CD38 immunoglobulin G1 (IgG1) monoclonal antibody in clinical development for multiple myeloma (MM). Nonlinear concentration- and time-dependent pharmacokinetics was observed due to target-mediated drug disposition. Identification of an optimal dose regimen was complicated by the interactions between daratumumab pharmacokinetics and pharmacodynamics of the target (CD38) and a clinical dosing schedule with decreasing dose frequency over time. The objective of this analysis was to understand and justify the recommended dose and dosing schedule for daratumumab in MM patients from a quantitative pharmacologic perspective.
Methods: Analyzed data were from a phase 1/2, 2-part study beginning with dose-escalation followed by a single-arm multiple cohort phase (GEN501, NCT00574288) and a phase 2 study that evaluated the efficacy and safety of daratumumab monotherapy (MMY2002, NCT01985126). Doses ranged from 0.01 to 24 mg/kg and dose schedules varied by cohort in these studies. We explored the exposure-response relationship for the efficacy and safety endpoints. Simulations were conducted based on a previously developed population pharmacokinetic model to understand the association between target saturation and daratumumab exposure.
Results:
There was a maximum effect (Emax) relationship between daratumumab exposure (ie, maximal trough concentration) and overall response rate (ORR), and between daratumumab and target saturation. The concentration associated with 90% maximal effect on ORR (ECORR90) was 274 µg/mL which is similar to the concentration providing 99% model-predicted target saturation (ECTAR99, 236 µg/mL). The 16 mg/kg dose was the lowest tested dose at which the majority (approximately 80%) of subjects achieved serum concentrations above ECORR90 and ECTAR99 thresholds after weekly administration (weekly for 8 weeks). Since the total clearance of daratumumab decreased over time, the intensive weekly dosing at the beginning of treatment was intended to overcome the high initial clearance and rapidly establish the efficacious concentration. Thereafter, every 2-week followed by every 4-week 16 mg/kg dosing intervals appeared to be adequate to saturate the target and maintain the total clearance close to the non-specific linear clearance. Although the concentration of daratumumab tended to decrease following every 2-week and every 4-week dosing intervals until reaching steady state, the reduction in concentration over time observed in the studies was not associated with either shorter duration of response or higher risk of disease progression. This result corroborates the clinical analysis which indicated the rate of subjects experiencing disease progression was consistent in the every 2-week and every 4-week dosing periods.
The exposure-safety analysis demonstrated no apparent relationship between the drug exposure and infusion-related reactions, thrombocytopenia, anemia, neutropenia, or lymphopenia. Although the overall event rate of infection increased numerically with drug exposure, this trend was not observed for infections of Grade 3 or higher. The clinical data suggested that the safety profile of the 16 mg/kg dose was consistent with the total population, and there was no increasing trend noted in the overall incidence of treatment-emergent adverse events across increasing dose groups. Treatment with 16 mg/kg daratumumab weekly for 8 weeks, then every 2 weeks for 16 weeks, then every 4 weeks thereafter until progression resulted in high ORRs of 29% in Study MMY2002 and 36% in Study GEN501.
Conclusion: Our analysis demonstrated that the recommended dose regimen is appropriate in the relapsed or refractory MM patient population. Lowering the dose would likely result in reduced efficacy, whereas increasing the dose may not improve the benefit-risk profile. In addition, the dosing schedule rapidly establishes efficacious concentrations during the initial, intense, weekly dosing period and maintains target saturation thereafter; thus reducing the risk of disease progression at the later, less frequent, dosing periods (i.e., every 2 weeks and every 4 weeks).

Disclosures
Xu: Janssen: Employment. Yan:Janssen: Employment. Puchalski:Janssen: Employment. Lonial:Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Lokhorst:Amgen: Honoraria; Janssen: Honoraria, Research Funding; Genmab: Honoraria, Research Funding. Voorhees:Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Janssen, Celgene, GlaxoSmithKline,Onyx Pharmaceuticals and Oncopeptides: Consultancy, Research Funding; Millennium/Takeda and Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Liu:Janssen: Employment. Khan:Janssen: Employment. Jansson:Janssen: Employment. Ahmadi:Janssen: Employment. Perez Ruixo:Janssen: Employment. Zhou:Janssen: Employment. Clemens:Janssen: Employment.