Thrombotic microangiopathy after treatment with bortezomib and dexamethasone in a patient with multiple myeloma

Abstract

Bortezomib (Bz) is extensively used for treating patients with multiple myeloma. There has been an accumulation of information on its efficacy and safety. Thrombotic disorders after treatment with Bz are rare, except for complication caused by tumor lysis syndrome. Here, we report a rare case of thrombotic microangiopathy (TMA) after treatment with Bz and dexamethasone (Dexa) in a patient with multiple myeloma. A 54-year-old Japanese man with refractory IgAjtypemultiple myeloma was treated with Bz (1.3 mg/m, days 1, 4, 8, and 11 in 21-day cycles) and Dexa (20 mg/body, days 1, 2, 4, 5, 8, 9, 11, and 12) in November 2007. He had received high-dose melphalan with autologous peripheral blood stem cell transplantation in May 2005 and allogeneic bone marrow transplantation after a reduced-intensity conditioning regimen [fludarabine, busulfan, and 4 Gy of total body irradiation (TBI)] in November 2006. He had dry skin and bronchiolitis obliterans organizing pneumonia (BOOP) caused by chronic graft-versus-host disease (GVHD), and he was treated with oral tacrorimus (1.2 mg/ day) and prednisolone (10 mg/day) and showed improvement. He had not had TMA, thrombotic thrombocytoprnic purpura (TTP), hemolytic uremic syndrome (HUS) or veno-occlusive-disease (VOD). The patient complained of chest pain and dyspnea on the fifth day in the first course of treatment with Bz and Dexa. His oxygen saturation (SpO2) was 88% in room air. Computed tomography of the chest showed ground glass opacities throughout the bilateral upper and middle lobes (Fig. 1). He suffered from severe interstitial pneumonia (IP). Since we thought that Bz was the cause of his pneumonia, we administered methylpredonisolone at 1,000 mg/ body intravenously for 3 days and stopped the treatment with Bz and Dexa. His pneumonia improved rapidly and did not recur despite steroid tapering off. Three days after the onset of IP (first course, day 8), he had scattered petechiae and suggillation. His consciousness was clear and vital signs were normal. Results of laboratory tests are shown in Tables 1 and 2. Anemia and thrombocytopenia had progressed, and aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and indirect bilirubin were elevated and haptoglobin was decreased. Coombs test results were negative. Erythrocyte fragmentation ratio was 12.7% (Fig. 2). These data suggested microangiopathic hemolytic anemia. Decreased fibrinogen and extended prothrombin time observed by coagulation tests appeared 2 days before this event. Activity of ADAMTS-13 was slightly low (Table 2) and an inhibitor of ADAMTS-13 was not detected. Cytomegalovirus antigens were not detected, and beta-D-glucan, candida antigens and aspergillus antigens were normal. Bacterial cultures in sputa, stools, and urine were negative. We thought he suffered from TMA and administered fresh frozen plasma (240 ml/day) and haptoglobin (2,000 U/day). His symptoms improved gradually. Within 20 days, his laboratory data returned to the levels before treatment with Bz and Dexa. TMA is thought to be caused by endothelial damage derived from high-dose chemotherapy, TBI, GVHD, immunosuppressive agents and opportunistic infections in R. Morita (&) S. Hashino S. Shirai N. Fujita M. Onozawa K. Kahata T. Kondo M. Asaka Department of Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan e-mail: r-mori@f3.dion.ne.jp