Cardiac toxicity of high-dose cyclophosphamide and melphalan in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation

Abstract

Tandem autologous hematopoetic stem cell transplantation (HSCT) is an effective treatment in patients with multiple myeloma (MM). Patients receive high-dose cyclophosphamide (CY) followed by two myeloablative dosages of melphalan (MEL). Cardiotoxicity treatment related data are scanty. In 30 patients with MM chemotherapy was followed by high-dose CY (cycle CY), and two autologous tandem HSCT treatments with MEL (cycles MEL I and MEL II). During each 15-day treatment troponin I (TnI), brain natriuretic peptide (BNP) and endothelin-1 (ET-1) were controlled at six time points. All patients underwent conventional and tissue Doppler echocardiography prior to CY therapy (Eho 0), before cycle MEL I (Eho 1), before cycle MEL II (Eho 2), and 3 months after the completion of therapy (Eho 3). None of the patients developed clinical signs of heart failure. The peak TnI concentrations were noted at days 8, 11, and 15 during all three chemotherapy cycles. During all three cycles there was a significant increase in baseline BNP concentrations and BNP levels measured at day 1 after treatment with CY and MEL (CY: P = 0.0001, MEL I: P = 0.001, MEL II: P = 0.001). The highest BNP concentration occurred during CY treatment (0.517 +/- 0.391 microg/L). During cycles MEL I and MEL II we noted the peak BNP concentrations at day 4 following chemotherapy (MEL I 0.376 +/- 0.418 microg/L; MEL II 0.363 +/- 0.379 microg/L). During all three cycles the highest ET-1 levels occurred at day 1 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). A significant increase in ET-1 concentrations relative to the basal values occurred only in cycle MEL II (P = 0.003). The duration of wave a in the Doppler pulmonary vein flow increased significantly (Eho 0/Eho 1: P = 0.008, Eho 0/Eho 3: P = 0.026). There was a significant decrease in the A/a ratio in flow velocities during chemotherapy (Eho 0/Eho 1: P = 0.002, Eho 0/Eho 3: P < 0.0001). Early diastolic tissue Doppler velocities (Em) decreased significantly during individual cycles of chemotherapy (P = 0.006). A significant post-treatment increase in the incidence of mitral regurgitation was observed (Eho 0/Eho 3: P = 0.003). Treatment of MM patients with tandem autologous HSCT is cardiotoxic. Our patients did not develop clinically overt heart failure or myocardial necrosis. Increased plasma levels of BNP and ET-1 were compatible with transient neurohormonal activation of heart failure. Doppler echocardiography studies revealed worsening of left ventricular diastolic function and occurrence of functional mitral regurgitation.