Cardiotoxicity in Patients with Multiple Myeloma Treated with Tandem Autologous Hematopoetic Stem Cell Transplantation.
Authors: Zver Samo , Kozelj Mirta , Mlakar Uros 
Published: October 2019

Abstract
BACKGROUND. Tandem autologous hemopoetic stem cell transplantation (HSCT) was recognised as effective treatment modality in patients with multiple myeloma (MM). During the treatment period patients are treated with high doses of cyclophosphamide followed twice with high doses of melphalan. There are scant data, if any, regarding potential cardiotoxic side effects of this treatment modality. METHODS. We included 30 patients with newly diagnosed multiple myeloma. After they were treated with three cycles of chemotherapy, they received high doses of cyclophosphamide 4 mg/m2 (cycle CY), followed by two autologous tandem HSCT, where patients received melphalan 200 mg/m2 (cycle MEL I and cycle MEL II). During each fifteen-day treatment period blood was routinely controlled for biochemical parameters troponin I (TnI), brain natriiuretic peptide (BNP) and endothelin-1 (ET-1) at six time points. All patients underwent conventional and tissue Doppler echocardiographic examination before treatment with cyclophosphamide (Eho 0), before cycle MEL I (Eho 1), before cycle MEL II (Eho 2) and three months after completion of the therapy (Eho 3). RESULTS. None of the patients developed clinical signs of heart insufficiency. Highest TnI values in all three cycles of chemotherapy were observed on the eighth, eleventh and fifteenth day of treatment. But all TnI values in patients were lower than 0.04 μg/L. During all three cycles we noticed a significant increase in BNP values compared with the basal values and values on day one after treatment with cyclophosphamide and melphalan (CY: P = 0.0001, MEL I: P = 0.001, MEL II: P= 0.001). In cycle CY this was also the highest BNP value (0.517 ± 0.391 μg/L). The maximum BNP values in cycles MEL I and MEL II were noticed on day four after chemotherapy (MEL I 0.376 ± 0.418 μg/L; MEL II 0.363 ± 0.379 μg/L). The highest ET-1 values in all three cycles were noticed on day one after chemotherapy (CY 1.146 ± 1.313 ng/L; MEL I 1.054 ± 2.242 ng/L; MEL II 0.618 ± 0.539 ng/L). We observed a significant increase in ET-1 values compared with the basal values only in cycle MEL II (P = 0.003). Concerning the parameters of diastolic left ventricular function, the duration of wave a in Doppler pulmonary vein flow signal significantly increased compared with it’s basal value (Eho 0/Eho 1: P = 0.008, Eho 0/Eho 3; P = 0.026). The ratio A/a in flow velocities significantly decreased with cycles of chemotherapy (Eho 0/Eho 1: P = 0.002, Eho 0/Eho 3: P < 0.0001). Early diastolic tissue Doppler velocities (Em) decreased significantly within individual cycles of chemotherapy (P = 0.006). After the treatment a significant increase in mitral regurgitation was observed (Eho 0/Eho 3; P = 0.003). Pericardial effusion was observed in six patients (20.6%). CONCLUSIONS. Treatment of MM patients with autologous tandem HSCT is cardiotoxic. Patients did not develop clinical signs of overt heart failure and normal TnI values excluded myocardial necrosis. On the other hand, increased plasma BNP and ET-1 levels confirm transient neurohormonal activation of heart failure, likely in combination with toxic endothelial damage. Doppler echocardiography studies prove worsening of the left ventricular diastolic function and appearance of functional mitral regurgitation. The age of the patients has no influence on the clinical, laboratory and echocardiography parameters of cardiotoxicity.