Pulmonary Hypertension after Thalidomide Administration in Multiple Myeloma Patients. Pilot Study.

Multiple myeloma (MM) is thrombogenic as a consequence of multiple hemostatic effects and endothelial damage. Thalidomide is effective (anti-inflammatory, immunomodulatory and anti-angiogenic) both in advanced MM and as first-line therapy in combination with dexamethasone or other cytotoxic chemotherapy. It has been associated with an increased risk of thromboembolic pulmonary hypertension (PH). PH in the absence of thromboembolism has been also described in MM patients during thalidomide treatment.

Aim: detection of clinical and subclinical PH in MM patients after thalidomide treatment. 82 patients, 46–82 years (median age 61), 41 females, were studied. They underwent echocardiographic study at baseline, one month thearafter, six months later and whenever symptoms indicating deterioration of cardiac function were appeared. Echocardiographic signs of PH were especially identified: Right atrial and ventricular enlargement, hypokinesia or hypertrophy, systolic flattening of intraventricular septum as a result of the right ventricular pressure overload, pulmonary artery dilatation and septal displacement. Doppler echocardiographic quantitation of systolic arterial PH was obtained by measuring velocity of the tricuspid regurgitant jet using the Bernoulli formula and summing central venous pressure evaluated by inferior vena cava diameter and its alteration during inspiration as it enters right atrium. Clinical and echocardiographic evaluation revealed four patients (4/82, 4.87%) with PH. One patient had clinical signs and symptoms of right heart failure three months after thalidomide administration with progressive deterioration. He was a 59 year- old man with multiple myeloma IgG λ and 85% diffuse bone marrow infiltration. Echocardiogram performed at baseline, revealed mild aortic regurgitation due tocalcification of non coronary cusp, good biventricular function, mild left ventricular hypertrophy, diastolic dysfunction of impaired relaxation, no evidence of PH and no signs of amyloid cardiac infiltration. He had no history of obstructive pulmonary disease and his functional status was Class I (NYHA). The second patient was a 62 years old woman with IgG κ MM. Echocardiogram at baseline identified good biventricular function and left ventricular diastolic dysfunction of impaired relaxation. Echocardiogram six months after thalidomide administration detected mild pulmonary hypertension without clinical symptoms of functional status deterioration. Her medical history was unremarkable except for arterial hypertension. The other two patients (72 and 76 years) had coronary artery disease and developed subclinical PH 1 and 3 months after thalidomide administration. A significant corelation between structural heart disease, age and PH was observed. Nonimaging (plasma D-Dimer,ECG) and imaging (chest roentgenography, lung scanning and chest computed tomography) diagnostic methods excluded deep venous thrombosis and pulmonary embolism. Vascular involvement seems to be a plausible mechanism in the pathophysiology of PH. Pre-existed endothelial dysfunction due to structural cardiac disease enhances the vasoactive substances release (nitric oxide, endothelin) causing increased pulmonary vascular resistance. Thalidomide causes a vasodilator and vasoconstriction impalance which may cause abnormal pulmonary vascular response interfering to a vicious circle perpetuating PH.