Carfilzomib is a second-generation proteasome inhibitor approved for the treatment of multiple myeloma (MM). It seems to determine cardiovascular toxicity, primarily arterial hypertension. No predictive factors for cardiovascular adverse events (CVAEs) are known in patients affected by multiple myeloma treated with carfilzomib. We evaluated the role of cardiovascular organ damage parameters to predict CVAEs in MM patients taking carfilzomib. Seventy patients affected by MM were prospectively enrolled. A comprehensive cardiovascular evaluation was performed before carfilzomib therapy; they underwent a transthoracic echocardiogram and the assessment of carotid-femoral pulse wave velocity. All the patients were followed up (FU) to determine the incidence of CVAEs. The mean age was 60.3 ± 8.2, and 51% were male. The median FU was 9.3 (4.3; 20.4) months. A proportion of 33% experienced CVAEs, 91% of them had uncontrolled hypertension, 4.5% acute coronary syndrome, and 4.5% cardiac arrhythmias. Subjects with CVAEs after carfilzomib treatment had significantly higher blood pressure values, left ventricular mass (98 ± 23 vs. 85 ± 17 g/m2, p = 0.01), and pulse wave velocity (8.5 ± 1.7 vs. 7.5 ± 1.6 m/s, p = 0.02) at baseline evaluation compared to the others. Furthermore, baseline uncontrolled blood pressure, left ventricular hypertrophy, and pulse wave velocity ≥ 9 m/s were able to identify patients at higher risk of developing CVAEs during FU. These preliminary findings indicate that blood pressure control, left ventricular mass, and pulse wave velocity may predict CVAEs in MM patients treated with carfilzomib.

The introduction of carfilzomib in the treatment of relapsing and refractory multiple myeloma has allowed a significant increase in survival. The most frequent adverse effect of Carfilzomib treatment is arterial hypertension, even though the exact physiopathological mechanism are still unclear. MM patients, on the other hand, often present significant cardiovascular risk factors and comorbidities. Uncontrolled hypertension is frequently the cause of cardiovascular complications. It has been estimated that up to 50% of subjects in the general population are unaware of their hypertensive condition and only half of those who are aware of this risk factor present good control of blood pressure. Although the management of arterial hypertension is clearly important in reducing the risk of cardiovascular events, and is well described by the current guidelines, no clear indications are provided on how to approach and treat specifically MM patients undergoing treatment with proteasome inhibitors. The aim of our work is to summarize a practical approach to the stratification of cardiovascular risk of hypertensive in patients who are candidates for or actively treated with carfilzomib for refractory multiple myeloma (MMR). MM patients eligible for carfilzomib treatment should preliminary undergo a careful cardiovascular risk stratification. Perspective studies will help to better identify the specific risk factors that should be considered and treated in these patients.

Background: Carfilzomib improves the prognosis of multiple myeloma (MM) patients but significantly increases cardiovascular toxicity. The timing and effect of Carfilzomib therapy on the left ventricular function is still under investigation. We sought to assess the echocardiographic systo-diastolic changes, including global longitudinal strain (GLS), in patients treated with Carfilzomib and to identify predictors of increased risk of cardiovascular adverse events (CVAEs) during therapy.Methods: Eighty-eight patients with MM performed a baseline cardiovascular evaluation comprehensive of transthoracic echocardiogram (TTE) before the start of Carfilzomib therapy and after 6 months. All patients were clinically followed up to early identify the occurrence of CVAEs during the whole therapy duration.Results: After Carfilzomib treatment, mean GLS slightly decreased (−22.2% ± 2.6 vs. −21.3% ± 2.5; p < 0.001). Fifty-eight percent of patients experienced CVAEs during therapy: 71% of them had uncontrolled hypertension, and 29% had major CVAEs or CV events not related to arterial hypertension. GLS variation during therapy was not related to an increased risk of CVAEs; however, patients with baseline GLS ≥ −21% and/or left ventricular ejection fraction (LVEF) ≤ 60% had a greater risk of major CVAEs (OR = 6.2, p = 0.004; OR = 3.7, p = 0.04, respectively). Carfilzomib led to a higher risk of diastolic dysfunction (5.6 vs. 13.4%, p = 0.04) and to a rise in E/e′ ratio (8.9 ± 2.7 vs. 9.7 ± 3.7; p = 0.006).Conclusion: Carfilzomib leads to early LV function impairment early demonstrated by GLS changes and diastolic dysfunction. Baseline echocardiographic parameters, especially GLS and LVEF, might improve cardiovascular risk stratification before treatment.

Funding Acknowledgements Type of funding sources: None. Background Cardiovascular adverse events (CVAEs) are closely related to Carfilzomib (CFZ) therapy in multiple myeloma (MM), but validated management protocols are lacking. Moreover, the incidence, nature and risk factors for each type of CVAEs are incompletely characterized. Purpose To assess if the European Myeloma Network Guidelines (EMN) protocol is effective on cardiovascular risk assessment before CFZ starting. A prediction model for estimating the probability of CVAEs was developed and validated. Major and hypertensive-related CVAEs were investigated. Methods A perspective study on 116 MM patients scheduled for CFZ therapy was conducted from 2015 to 2020. Before CFZ starting, a baseline evaluation, according to the EMN protocol, was performed; during the follow-up, the incidence of CVAEs was detected. The potential risk factors for CVAEs were identified and a risk score was developed. Results The rate of all-grade CVAEs was 44.8% (24.1% CTCAE≥3): 14.7% experienced major CVEAs (41.2% arrhythmias, 23.5% acute ischemic cardiopathy as most represented) and 30.2% hypertensive-related CVAEs. At baseline, five independent predictors for all-CVAEs were identified: office systolic blood pressure (p = 0.003), 24-hours blood pressure variability (p = 0.004), left ventricular mass (p = 0.015), pulse wave velocity (p = 0.002) and global longitudinal strain (p = 0.033). The resulting CVAEs risk score allows to define the low- and high-risk groups, obtaining a sensibility of 94% in predicting CVAEs (AUC 0.76). Conclusions The comprehensive evaluation of EMN Guidelines is effective in CVAEs prediction. The use of CVAEs risk score will identify the higher risk patients, targeting appropriate follow-ups and organizing effective risk mitigation strategies. Instrumental determinants with CVAEs Parameters No CVAEs N = 64 [N (%)] CVAEs N = 52[N (%)] P value LV mass/BSA 85.30 ± 19.72 95.14 ± 21.75 0.013 LV hypertrophy [> = 95 g/m2 F > = 115 g/m2 M] 8 (12.7) 16 (30.8) 0.018 LV dilation 5 (9.3) 4 (8.9) 0.949 LV EF % 63.03 ± 6.56 61.96 ± 7.13 0.414 GLS % -22.37 ± 2.56 -21.3 ± 2.46 0.029 LV Diastolic dysfunction 1 (1.6) 0(0) 0.362 PWV 7.41 ± 1.63 8.55 ± 1.855 0.002 PWV ³ 8.75 m/s 10 (17.5) 24 (54.2) 0.000 SBP Systolic Blood Pressure; ABPM Ambulatory Blood Pressure Monitoring; BPV Blood Pressure Variability; BSA Body Surface Area; SD Standard Deviation; EF Ejection Fraction; GLS Global Longitudinal Strain; LV Left Ventricle; PWV Pulse Wave Velocity Abstract Figure. CVAEs risk score

Funding Acknowledgements Type of funding sources: None. Background Carfilzomib improves the prognosis of multiple myeloma (MM) patients, but significantly increases cardiovascular toxicity. The timing and effect of carfilzomib therapy on left ventricular function is still under investigation. Purpose We sought to assess the echocardiographic systo-diastolic changes, including global longitudinal strain (GLS), in patients treated with carfilzomib and to identify predictors of increased risk of cardiovascular adverse events (CVAEs) during therapy. Methods 88 patients with MM performed a baseline cardiovascular evaluation comprehensive of transthoracic echocardiogram (TTE) before the start of Carfilzomib therapy and after about 6 months. All patients were clinically followed-up to early identify the occurrence of CVAEs for the whole therapy duration. Results After Carfilzomib treatment, mean GLS slightly decreased (-22.2% ± 2.6 vs -21.3% ± 2.5; p < 0.001). 58% of patients experienced CVAEs during therapy: 71% of them had uncontrolled hypertension, 29% had major CVAEs or CV events not related to arterial hypertension. GLS variation during therapy was not related to an increased risk of CVAEs; however, patients with baseline GLS ≥ -21% and/or left ventricular ejection fraction (LVEF) ≤ 60% had an increased risk of major CVAEs (OR = 6.2, p = 0.004;  OR = 3.7, p = 0.04, respectively). Carfilzomib led to an increased risk of diastolic dysfunction (5.6% vs 13.4% p = 0.04) and to a rise in E/e’ (8.9 ± 2.7 vs 9.7 ± 3.7; p = 0.006). Conclusions Carfilzomib leads to early LV function impairment early demonstrated by GLS changes and diastolic dysfunction. Baseline echocardiographic parameters, especially GLS and LVEF, might improve cardiovascular risk stratification before treatment.