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Validation and Exploratory Refinement of the HFA-ICOS Score for Cardiovascular Risk in Proteasome Inhibitor-Treated
Eduardo Pons-Fuster1, Alejandro Riquelme-Perez2, Vyacheslav Shumbar2
1Clinical Pharmacy and Therapeutics Research Group, Virgen de la Arrixaca University Clinical Hospital, Biomedical Research Institute of Murcia Pascual Parrilla (IMIB), 30120 Murcia, Spain.
Insights
Proteasome inhibitors for multiple myeloma increase cardiovascular risks. A refined risk score using NT-proBNP and carfilzomib exposure shows improved prediction of cardiotoxicity in these patients.
Area of Science:
- Cardio-Oncology
- Hematology
- Cardiovascular Medicine
Background:
- Proteasome inhibitors (PIs) are crucial for multiple myeloma (MM) treatment.
- PIs are associated with significant cardiovascular adverse events (CVAEs).
- The HFA-ICOS risk score's utility in MM patients is uncertain.
Purpose of the Study:
- To externally validate and refine the HFA-ICOS risk score for predicting CVAEs in MM patients treated with PIs.
- To identify novel predictors of cardiotoxicity in this population.
Main Methods:
- Retrospective analysis of 98 MM or primary amyloidosis patients treated with PIs (2019-2024).
- External validation and refinement of the HFA-ICOS score.
- Independent predictors of CVAEs were identified using Cox regression.
Main Results:
- CVAEs occurred in 22.5% of patients, primarily heart failure.
- The original HFA-ICOS score had modest predictive accuracy (AUC 0.66) and low sensitivity (50%).
- Carfilzomib exposure and elevated NT-proBNP (>300 pg/mL) before cycle 2 independently predicted CVAEs. A refined dynamic model showed improved discrimination (AUC 0.72) and sensitivity (90.9%).
Conclusions:
- The original HFA-ICOS score has limited prognostic value in PI-treated MM patients.
- A refined dynamic model incorporating carfilzomib, NT-proBNP, and age (≥65) shows promise for improved CVAE risk prediction.
- Further validation in larger cohorts is needed before clinical application of the refined model.
Abstract:
Background: Proteasome inhibitors (PIs) are integral in multiple myeloma (MM) treatment but carry a substantial risk of cardiovascular adverse events (CVAEs). The Heart Failure Association-International Cardio-Oncology Society (HFA-ICOS) risk score was designed to identify patients at risk of cardiotoxicity, but its performance in MM remains uncertain. Methods: We retrospectively evaluated 98 patients with MM or primary amyloidosis treated with PIs between 2019 and 2024 to externally validate and refine this score. Results: CVAEs occurred in 22 patients (22.5%), predominantly heart failure. The original HFA-ICOS model demonstrated modest predictive accuracy (AUC 0.66) and sensitivity (50%), with frequent risk overclassification. Carfilzomib exposure (HR 4.68, 95% CI 1.47-14.90; p = 0.009) and elevated NT-proBNP before cycle 2 (>300 pg/mL; HR 3.13, 95% CI 1.10-8.93; p = 0.033) independently predicted CVAEs. A dynamic model incorporating these parameters and adjusting the age threshold to ≥65 years was associated with improved discrimination (AUC 0.72, p = 0.032), model fit (ΔAIC = -4), and CVAE-free survival stratification (p = 0.026), achieving 90.9% sensitivity. Conclusions: These findings indicate that the original HFA-ICOS score has limited prognostic value in PI-treated MM patients. Incorporating early NT-proBNP monitoring, carfilzomib exposure, and refined age categorization may improve risk prediction and support more personalized cardiovascular surveillance strategies in cardio-oncology. However, this refined dynamic model should be regarded as exploratory and requires validation in larger independent cohorts before it can be considered for clinical application.
