Bortezomib-associated tumor lysis syndrome in multiple myeloma

Tumor lysis syndrome (TLS) is characterised by a combination of metabolic disturbances resulting from the rapid release of neoplastic intracellular contents [1]. It is an oncological emergency occurring either due to administration of cytotoxics in the treatment of malignancy or due to the progression of aggressive disease. It has been reported in patients with a variety of diagnoses [2,3], but most commonly occurs in the treatment of high-grade lymphoproliferative disorders, in which the disease is extremely chemosensitive and there is fast cell turnover. In contrast to these disorders, the proliferative rate of plasma cells in multiple myeloma is slow, and a relatively small proportion of the cells are in S phase at any one time [4]; TLS is consequently rare in this disease. Bortezomib (VELCADE) is a reversible inhibitor of the 26S proteosome – an important intracellular protease enzyme responsible for appropriate degradation of intracellular proteins involved in both cell growth and proliferation and the regulation of apoptosis. The inhibition of this enzyme results in the accumulation of excess proteins leading to cell cycle arrest and eventual apoptosis. The use of bortezomib in the treatment of relapsed multiple myeloma is increasing and due to its various modes of action on myeloma cells it has been infrequently associated with TLS in these patients [5,6]. We present here a case history of bortezomibinduced TLS in multiple myeloma and subsequent literature review. A 74-year-old lady presented with a pathological fracture of her right humerus following a fall in January 2006. Routine blood tests revealed Hb 5.4 g/dL, Calcium 3.17 mmol/L and creatinine 182 mmol/L. Subsequent investigation showed an IgGk paraprotein of 68 g/L with immuneparesis. Urine was Bence Jones positive (0.13 g/L) and bone marrow aspirate and trephine had 80% plasma cell infiltration. Skeletal survey showed multiple lytic lesions and soft tissue mass at the sacrum – presumed plasmacytoma. She was treated with melphalan (9 mg/m) and prednisolone (60 mg/m) within a clinical trial and initially responded with a drop in her paraprotein to 33 g/L after three courses of chemotherapy. This later rose to 40 g/L and plateau’d there after eight courses of treatment. She became progressively pancytopenic necessitating withdrawal of chemotherapy; however, despite this her cytopenias worsened, accompanied by a rise in her paraprotein to 61 g/L. Bone marrow assessment undertaken at this time showed no change in her plasma cell burden, with 80% plasma cell infiltrate. She was commenced on second line treatment with thalidomide and weekly dexamethasone. The dose of thalidomide was titrated up to 200 mg/day over a 3month period with poor response. The best achieved response was a drop in paraprotein to 57 g/L. She commenced bortezomib (1.3 mg/m) in March 2008, and tolerated the initial three doses of cycle 1 with no problems aside from diarrhoea post the third dose. At presentation for her fourth dose of bortezomib it was found that her creatinine had risen from 128 mmol/L to 358 mmol/L with a urea 30.8 mmol/L, potassium of 5.3 mmol/L and sodium of 119 mmol/L. Phosphate was 4.11 mmol/L and calcium was 2.04 mmol/L. Uric acid rose to 1338 mmol/L and LDH was markedly elevated at 22520 IU/L.