Evaluation of Cardiac Repolarization in the Randomized Phase 2 Study of Intermediate- or High-Risk Smoldering Multiple Myeloma Patients Treated with Daratumumab Monotherapy

Abstract

Introduction: Daratumumab is a CD38-targeting monoclonal antibody that has demonstrated clinical benefit for multiple myeloma. Daratumumab inhibition of CD38, which is expressed on immune cell populations and cardiomyocytes, could potentially affect cardiac function. This QTc substudy of the phase 2 CENTAURUS study investigated the potential effect of intravenous daratumumab monotherapy on QTc prolongation and other electrocardiogram (ECG) parameters, including concentration-QTc effect modeling.

Methods: Patients had intermediate- or high-risk smoldering multiple myeloma. Patients with QT interval corrected by Fridericia's formula (QTcF) > 470 ms, QRS interval ≥ 110 ms, or PR interval ≥ 200 ms were excluded. Triplicate ECGs were collected at screening, Dose 1, and Dose 8. Analyses of on-treatment ECGs were conducted with a time-matched baseline (primary analysis). By time-point, pharmacokinetic-pharmacodynamic (PK/PD), and outlier analyses were conducted.

Results: Of 123 patients in CENTAURUS, 31 were enrolled in the QTc substudy. Daratumumab produced a small increase in heart rate (5-12 beats per minute) of unclear significance. There was a small but clinically insignificant effect on QTc, as measured by both time-matched time-point and PK/PD analyses. The primary analysis demonstrated a maximum mean increase in QTcF of 9.1 ms (90% 2-sided upper confidence interval [CI], 14.1 ms). The primary PK/PD analysis predicted a maximum QTcF increase of 8.5 ms (90% 2-sided upper CI, 13.5 ms). No patient had an abnormal U wave, a new QTcF > 500 ms, or > 60 ms change from baseline for QTcF.

Conclusion: Analysis of ECG intervals and concentration-QTc relationships showed a small but clinically insignificant effect of daratumumab.

Trial registration: ClinicalTrials.gov Identifier: NCT02316106.

Keywords: Daratumumab; Monoclonal antibody; Pharmacokinetic-pharmacodynamic analysis; QTc substudy; Smoldering multiple myeloma.

Figures

Fig. 1

CENTAURUS study design [20]. QW once weekly, Q2W every 2 weeks, Q4W every 4 weeks, Q8W every 8 weeks, IV intravenously, PD progressive disease, LPFD last patient first dose, CR complete response. This figure was adapted from Fig. 1a from Landgren et al. (10.1038/s41375-020-0718-z) [20], which is licensed under the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)

Fig. 2

Time-point analyses. Mean change from baseline in a heart rate, b PR interval, c QRS duration, and d QTcF interval. Values are means ± 90% CIs; estimates and CIs are model based. PR interval time from onset of P wave to the start of the QRS complex, QRS duration interval of time between Q wave and S wave, QTcF interval QT interval corrected for heart rate using Fridericia’s formula, CI confidence interval, IV intravenously, bpm beats per minute, C Cycle, D Dose

Fig. 3

Relationship between QTcF change from baseline and serum concentration of daratumumab. Shown is a scatterplot of all QTcF change from baseline and daratumumab serum concentration pairs at each time point. Each of the 31 patients could have up to 4 pairs for each of the time points: Cycle 1 Dose 1 post-infusion, Cycle 1 Dose 8 pre-infusion, Cycle 1 Dose 8 post-infusion, and Cycle 1 Dose 8 1 h post-infusion. The prediction line was based on a mixed-effects regression model using concentration, treatment dose, and least square mean estimates of the time values. QTcF interval QT interval corrected for heart rate using Fridericia’s formula, IV intravenously