Bortezomib

Abstract

Thrombotic microangiopathy: case report A 70-year-old woman developed thrombotic microangiopathy (TMA) during treatment with bortezomib for multiple myeloma. The woman with a history of hypertension, depression and breast cancer, was diagnosed with stage 3 IgG kappa multiple myeloma in 2017. She was initiated on treatment with the VMP regimen consisting of SC bortezomib 1.3 mg/m2 given on days 1, 4, 8, and 11 of a 21 day cycle, along with melphalan and prednisone. One day after the third dose of bortezomib in the first cycle, she was admitted at another hospital with decreased visual acuity and weakness. Examinations at admission showed papilloedema, flame shaped retinal haemorrhage and severe hypertension. Blood tests showed anaemia, thrombocytopenia and normal creatinine. Her coagulation tests results were normal. Acute infarct on the right caudate head, hyperintensity of subcortical white matter in the bilateral anterior and upper frontal region were seen on a hear MRI. The presence of intracranial hypertension was excluded. The woman received blood and platelet transfusions. Her BP stablilised visual acuity improved. She was discharged. Her chemotherapy was continued. She received 4 cycles of the VMP therapy and one week after the fourth cycle, she was admitted again with acute onset dyspnea and hypertensive pulmonary oedema. Bilateral pleural effusion and pericardial effusion with absent pulmonary embolism were seen on chest CT-angiography. She did not show signs of myocardial necrosis and the markers were negative. Her kidney function remained unchanged; she also did not show thrombocytopenia or exacerbation of the anaemia. After 6 days, she was discharged. However, one month later, she was admitted again with hypertensive pulmonary oedema. The episodes were thought to be related to acute cardiac insufficiency. She was discharged and continued on bortezomib-containing chemotherapy. After 6 cycles of the VMP regimen, she was admitted for the third time, with hypertensive pulmonary oedema and cardiac insufficiency. She also exhibited Coombs-negative haemolytic anaemia, worsening kidney function and thrombocytopenia. She received RBC transfusions. Her renal ultrasound showed normal kidneys without obstruction. During hospitalisation, her renal function deteriorated and her serum creatinine reached 4.5 mg/dL. Further testing revealed increased IgG and free Kappa light chain levels. Her kidney failure was attributed to progression of multiple myeloma. Her bortezomib was suspected to be associated with her episodes of cardiac decompensation. Her treatment was thus changed to cyclophosphamide and prednisolone. However, her renal function deteriorated further with anuria and she was initiated on haemodialysis. She was transferred to the author’s hospital, where she showed persistent haemolytic anaemia and thrombocytopenia with frequent RBC transfusions. She did not show significant decrease in the ADAMTS13 activity and inhibiting autoantibodies of ADAMTS13 were not seen. A renal biopsy revealed both TMA and kappa cast nephropathy. Her kidney sample showed ischaemic 8 glomeruli and areas of mesangiolysis with focal double contours. Additionally, thrombi were seen in three afferent arterioles. Some glomeruli presented thrombus in capillaries and some arterioles presented intimal mucoid oedema. The distal tubules showed casts with inflammatory reaction. Immunofluorescence was positive for kappa light chain and negative for lambda. Electron microscopy showed preservation artifacts and glomerular basement membrane wrinkling, focal endothelial cell injury, fibrin thrombus, podocyte foot process effacement and expanded subendothelial space. Based on the results, a diagnosis of kappa light chain cast nephropathy and bortezomib-associated TMA was established. Additionally, her previous visual abnormalities and MRI findings were suggestive of an episode of reversible posterior leukoencephalopathy syndrome (RPLS), associated with TMA. Her episodes of acute heart failure were also attributed to TMA, whereas, the progressive renal failure was attributed to her multiple myeloma. She was treated with additional RBC transfusions and her platelet transfusions were held. She continued dialysis and was transferred to another institution for multiple myeloma therapy with daratumumab.