Split First Dose Administration of Intravenous Daratumumab for the Treatment of Multiple Myeloma (MM): Clinical and Population Pharmacokinetic Analyses

MMY1001 is a phase 1b, open-label, nonrandomized, multicenter study evaluating the safety, tolerability, and dosing regimen of daratumumab in combination with established treatment regimens for patients with newly diagnosed MM or relapsed/refractory MM. Eligible patients were ≥ 18 years of age with measurable documented MM and an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. The split first dose administration for daratumumab was investigated in the D-KRd and D-Kd cohorts of MMY1001. Patients with newly diagnosed MM were enrolled in the D-KRd cohort irrespective of transplant eligibility. Patients in the D-Kd cohort had relapsed/refractory MM with one to three prior lines of therapy including bortezomib and an immunomodulatory agent. Daratumumab 16 mg/kg IV was administered to D-KRd and D-Kd cohorts weekly for Cycles 1 and 2, every 2 weeks for Cycles 3–6, and every 4 weeks for the remaining cycles. In the D-Kd arm of MMY1001, ten patients received the first daratumumab dose as a single infusion [16 mg/kg (1000 ml) on Day 1 Cycle 1] and 75 patients received a split first dose [8 mg/kg (500 ml) on Days 1–2 Cycle 1]. In the D-KRd arm, all patients received a split first dose of daratumumab.

Pharmacokinetic data from the D-Kd and D-KRd cohorts (n = 107) were used for PK analysis. Serum samples were collected pre- and postinfusion of daratumumab on Day 1 of Cycle 1 through Cycle 4 and then 3 and 9 weeks posttreatment for all patients in the D-Kd and D-KRd cohorts. Serum samples were also collected pre- and postinfusion on Cycle 1 Day 2 for patients receiving the split first dose in the D-Kd and D-KRd cohorts. An enzyme-linked immunosorbent assay (ELISA) validated in 2009 by Bio Analytical Research Corporation (BARC) Global Central Laboratory (Ghent, Belgium) was used to determine serum daratumumab concentrations in previous studies. In 2014, the BARC ELISA PK method was transferred to Janssen Research & Development, LLC (Spring House, PA, USA), and successfully cross-validated for reproducibility at two separate laboratories. The transferred ELISA PK method was used by Janssen Research & Development, LLC, to determine daratumumab concentrations in human serum in subsequent analyses of daratumumab studies. In general, the ELISA method was validated according to the European Medicines Agency, the US Food and Drug Administration, bioanalytical method validation guidance, and industry white papers (EMEA/CHMP/EWP 2011, Guidance for Industry 2018) [20, 21]. The lowest quantifiable concentration of daratumumab in a sample was 0.2 µg/ml, and the upper limit of quantification was 145.8 µg/l at a 1:40 dilution. The inter-assay variability across the standard curve range was < 10%.

Serum daratumumab concentrations were summarized using descriptive statistics and presented as arithmetic mean, standard deviation, and coefficient of variation. PK values are summarized by nominal time and presented as arithmetic mean, standard deviation (SD), and coefficient of variation.

The population PK analysis used nonlinear mixed-effects modeling and simulation to compare the PK profile of the daratumumab split first dose regimen (8 mg/kg on Cycle 1 Day 1 and Cycle 1 Day 2) with approved or recommended single first dose regimens (16 mg/kg on Cycle 1 Day 1) using individual PK parameters of patients with MM from seven clinical studies of daratumumab, including daratumumab monotherapy studies [GEN501 (NCT00574288) and SIRIUS (NCT01985126); n = 223]; D-Rd treatment studies [GEN503 (NCT01615029) and POLLUX (NCT02076009); n = 326]; D-Vd treatment studies [CASTOR (NCT02136134) and MMY1001 (NCT01998971); n = 246]; D-VMP treatment studies [MMY1001 and ALCYONE (NCT02195479); n = 352]; MMY1001 D-Pd treatment arm (n = 99), and MMY1001 D-Kd and D-KRd treatment arms (n = 107), all of which have been described in detail previously and are briefly summarized in Online Resource 1 [10‐16, 22‐24].

The individual PK parameters for D-Kd and D-KRd were generated using a newly developed, nonlinear, mixed-effects population PK model in the current report. Serum concentration-time data were used for nonlinear mixed-effects modeling using NONMEM (ICON plc, version 7 or higher). The population PK model included a two-compartment structure with parallel linear and Michaelis-Menten nonlinear eliminations [25], where linear clearance represents the nonspecific clearance for IgG, and the Michaelis-Menten elimination represents the saturable target-mediated clearance. The interpatient variability in structural parameters was modeled with an exponential term to ensure positive values of individual parameters, and an additive model was used to model residual variability. The final covariate model included body weight, albumin, type of myeloma, and sex as significant yet non–clinically relevant covariates. PK parameter estimates for individual patients treated with other regimens were obtained from previously developed population PK models [18, 19, 25]. Simulations were performed to predict the PK profiles for all patients who had participated in previous daratumumab studies and to compare the difference in PK between the split- and single-first dose of daratumumab among those patients. Therefore, we mimicked a cross-over design, so each patient was assumed to receive both split- and single-first dose approaches in a sequential manner. The cross-over design removes the influence of between-patient variability and enables a better comparison of PK for both dosing approaches. The empirical Bayesian estimates of PK parameters for each patient were used for simulations. Simulations were conducted for individual treatments or indications with dosing schedules for daratumumab monotherapy, D-Rd, D-Pd, D-Kd, and D-KRd that consisted of daratumumab 16 mg/kg given once weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter. For D-Vd, the dosing schedule consisted of daratumumab 16 mg/kg given every week for 9 weeks, every 3 weeks for 15 weeks, and every 4 weeks thereafter. The D-VMP dosing schedule consisted of daratumumab 16 mg/kg given every week for 6 weeks, every 3 weeks for 48 weeks, and every 4 weeks thereafter.

The individual protocols and amendments for each study included in this report were reviewed and approved by affiliated local independent ethics committees or internal review boards (see Online Resource 2 for a list of committees for MMY1001). Studies were conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with Good Clinical Practices and applicable regulatory requirements. All patients provided written consent prior to any study-specific procedures.

The PK-evaluable population was composed of 107 patients in the D-Kd (n = 85) and D-KRd (n = 22) cohorts of MMY1001. A total of 97 patients received a split first dose of daratumumab 8 mg/kg on Cycle 1 Day 1 and Cycle 1 Day 2 (D-Kd, n = 75; D-KRd, n = 22). An additional ten patients in the D-Kd cohort received the standard single first dose regimen of daratumumab 16 mg/kg on Cycle 1 Day 1. Patient demographics and baseline disease characteristics are summarized in Table 1. Briefly, the majority of patients in both treatment cohorts had an ECOG score  < 2 (D-Kd, 91.8%; D-KRd, 95.5%). Patients with relapsed/refractory MM in the D-Kd cohort were numerically older (median: 66 years of age) than patients with newly diagnosed MM in the D-KRd cohort (median: 60 years of age). However, the impact of the difference in age between the populations was minimal since the relative difference in PK from the split- and single-first dose regimens were compared and the PK parameters from each patient were used for simulations of both the single-first and split-dose regimens.

In MMY1001, measured daratumumab Cycle 1 Day 1 postinfusion median (range) concentrations after the first half (8 mg/kg) of a split first dose [D-Kd, 151.5 (82.5–345.0) µg/ml; D-KRd, 177.8 (121.9–215.7) µg/ml; combined, 156.7 (82.5–345.0) µg/ml] were lower than the concentrations after a 16-mg/kg single first dose [D-Kd, 319 (237.5–394.7) µg/ml; Table 2]. Following administration of the second half (8 mg/kg) of a split first dose on Cycle 1 Day 2, postinfusion median (range) daratumumab concentrations were similar between patients who received a split first dose [D-Kd, 254.9 (125.8–435.5) µg/ml; D-KRd, 277.2 (164.0–341.8) µg/ml; combined, 256.8 (125.8–435.5) µg/ml] and those who received a single first dose (Table 2; Fig. 1). At the end of weekly dosing, median (range) Cycle 3 Day 1 preinfusion daratumumab concentrations (C_troughs) were similar between patients who received a split first dose [D-Kd, 663.9 (57.7–1110.7) µg/ml; D-KRd, 575.1 (237.9–825.5) µg/ml; combined, 639.2 (57.7–1110.7) µg/ml] and those who received a single first dose [D-Kd, 463.2 (355.9–792.9) µg/ml; Table 2].

Serum concentrations at the end of infusion on Days 1 and 2 of Cycle 1 and maximum serum C_trough (at the end of weekly dosing) were compared between the split first dose regimens and the single first dose regimens from the MMY1001 D-Kd and D-KRd cohorts with other single first dose daratumumab combination studies, MMY1001, GEN503, POLLUX, CASTOR, and ALCYONE (Online Resource 3). Similar concentrations were observed after administration of the first total dose of 16 mg/kg per patient across monotherapy and combination therapies, indicating that the regimen has no meaningful impact on the concentration of daratumumab after Cycle 1 Day 1. The maximum C_trough at the end of weekly dosing was also similar (< 10% difference in maximum C_trough) across studies, regardless of the split or single first dose and dosing regimen.

A prediction-corrected visual predictive check of the final population PK model was performed to compare the simulation and observed daratumumab concentrations over time (Online Resource 4). The visual predictive check plot showed good agreement between the simulated concentrations and the individual observed concentrations (Online Resource 4). The estimated inter-patient variability adequately captured the observed variability.

Simulation of daratumumab PK following the split first dose and single first dose regimens was conducted using individual PK parameters of patients with MM from seven clinical studies of daratumumab. Regimens included daratumumab monotherapy, D-Rd, D-Vd, D-Pd, D-VMP, D-Kd, and D-KRd. The split first dose and single first dose regimens were virtually identical with respect to their overall PK profiles (Fig. 2a, Online Resource 5). Simulated PK profiles of the split first dose and single first dose regimens varied only during the first day of treatment (Cycle 1 Day 1) when the dosing regimens were different (8 mg/kg versus 16 mg/kg; Fig. 2b). Differences in simulated PK profiles were minimal following the second split dose on Cycle 1 Day 2. The difference in concentrations between the split-dose and single-infusion regimens was reduced to < 1% for the majority of patients by Week 4 (Fig. 3).

The final model of the monotherapy studies was used to fit data for daratumumab serum concentration versus time. The model-based covariate analysis identified body weight, baseline albumin level, and type of myeloma (IgG versus non-IgG) as statistically significant covariates on linear clearance, whereas body weight and sex were identified as statistically significant covariates on the volume of distribution in the central compartment. Parameter estimates of the final covariate model are shown in Online Resource 6. The estimated linear clearance and volume of distribution parameters were very close to the estimates from previous studies. The condition number of the final model was 27.80, indicating the final covariate model was appropriately parameterized.