Related Experiment Video
Updated: Nov 20, 2025
Evaluation of Cardiac Contractility Modulation Therapy in 2D Human Stem Cell-Derived Cardiomyocytes
Published on: December 16, 2022
Evaluation of Cardiac Repolarization in the Randomized Phase 2 Study of Intermediate- or High-Risk Smoldering
Ajai Chari1, Markus Munder2, Katja Weisel3,4
1Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA. ajai.chari@mountsinai.org.
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.
Insights
Daratumumab, a CD38-targeting antibody for multiple myeloma, showed a clinically insignificant effect on QTc prolongation in a cardiac safety substudy. This finding supports its use without major cardiac concerns.
Area of Science:
- Cardiology
- Oncology
- Pharmacology
Background:
- Daratumumab targets CD38, expressed on immune cells and cardiomyocytes, raising potential cardiac safety concerns.
- Multiple myeloma treatment with CD38 inhibitors necessitates evaluation of cardiac function.
- The CENTAURUS study assessed daratumumab's efficacy in smoldering multiple myeloma.
Purpose of the Study:
- To investigate the effect of daratumumab monotherapy on QTc interval prolongation.
- To evaluate other electrocardiogram (ECG) parameters during daratumumab treatment.
- To perform concentration-QTc effect modeling for daratumumab.
Main Methods:
- A QTc substudy of the phase 2 CENTAURUS trial.
- Inclusion of patients with intermediate- or high-risk smoldering multiple myeloma.
- Exclusion of patients with pre-existing QTc prolongation or conduction abnormalities.
- Collection of triplicate ECGs at multiple time points.
- Primary analysis using time-matched baseline ECGs.
- Pharmacokinetic-pharmacodynamic (PK/PD) and outlier analyses were performed.
Main Results:
- Daratumumab caused a small, clinically insignificant increase in QTcF (maximum mean increase of 9.1 ms).
- PK/PD modeling predicted a maximum QTcF increase of 8.5 ms.
- A small increase in heart rate (5-12 bpm) was observed, with unclear significance.
- No patients experienced significant QTcF prolongation (>500 ms or >60 ms change from baseline) or abnormal U waves.
Conclusions:
- Daratumumab monotherapy demonstrated a small, clinically insignificant effect on QTc prolongation.
- ECG interval analysis and concentration-QTc modeling support the cardiac safety profile of daratumumab.
- These findings suggest daratumumab can be used in multiple myeloma patients with careful cardiac monitoring.
