Use of thalidomide in patients with myeloma and renal failure may be associated with unexplained hyperkalaemia

Thalidomide is being increasingly used in the treatment of myeloma. Response rates of up to 31% have been reported using thalidomide in refractory myeloma (Barlogie et al, 2001). Higher response rates have been reported when used in combination with dexamethasone (Cavenagh & Oakervee, 2003), and its use in combination with chemotherapy is under further investigation. Renal failure is a common complication of myeloma and is associated with a poor prognosis. There is little information on the safety of thalidomide in this setting. We report on the use of thalidomide in eight patients with significant renal failure, of whom six developed severe unexplained hyperkalaemia, a hitherto unreported side-effect of thalidomide therapy. Table I shows the patient characteristics of the eight patients. Six were dialysis dependent. Patients 1–4 developed unexplained resistant hyperkalaemia that was temporally associated with the introduction of thalidomide, without further deterioration in renal function. No other cause of hyperkalaemia could be identified, and in three patients the hyperkalaemia was fatal. Patients 5 and 6 had stable urea and electrolytes during thalidomide treatment until they developed an intercurrent illness. In patient 5, this was a massive venous thromboembolism and, in patient 6, it was septic shock from a line infection. Both patients then developed hyperkalaemia that was out of proportion to their renal failure, and thalidomide was thought to be a contributory factor. Patient 5 recovered following cessation of thalidomide and dialysis but in patient 6 the hyperkalaemia proved resistant to all measures and the patient died. Patients 7 and 8 both received treatment with thalidomide and remained normokalaemic. There were no obvious clinical differences between those patients who developed hyperkalaemia and those who did not (Table I). The side-effects of thalidomide are well recognized, and include peripheral neuropathy, sedation, constipation, hypothyroidism, skin rashes and venous thrombosis (Cavenagh & Oakervee, 2003). Hyperkalaemia has not previously been reported. The pharmacokinetic properties of thalidomide in humans are not well characterized and the effects of renal or hepatic dysfunction on the clearance of thalidomide are unknown. Singhal et al (1999) showed a greater than 50% increase in baseline serum creatinine in 8/84 patients treated with thalidomide, but this was ascribed to disease progression. The mechanism behind this apparent thalidomide-induced hyperkalaemia is unclear. Alexanian and Weber (2000) noted rapid responses in refractory myeloma patients treated with thalidomide, consistent with direct cytotoxic effects on tumour cells. It is possible, therefore, that hyperkalaemia results from a type of tumour lysis effect. Cany et al (2002) reported that a patient with relapsed myeloma developed renal failure with hyperphosphoraemia and hyperuricaemia within 1 week of starting thalidomide and attributed this to tumour lysis syndrome. However, in our series of patients, hyperkalaemia was not associated with deterioration of renal function, nor has it been observed in patients with normal renal function. Alternatively, hyperkalaemia may develop by an unknown mechanism when thalidomide is used in the presence of other metabolic challenges. Dexamethasone was used in conjunction with thalidomide in six of the eight patients reported here and it is possible that it was this combination that was responsible. However, two patients on thalidomide alone developed hyperkalaemia, and the two patients who were unaffected were receiving the combination. From our small series of patients, we conclude that thalidomide remains a useful agent for patients with relapsed and refractory disease and is effective in patients with renal failure. Although we can not definitively prove that thalidomide was responsible for the hyperkalaemia observed in these patients, we recommend caution when thalidomide is used in patients with moderate to severe renal failure (creatinine greater than 300 µmol/l) or on dialysis. We suggest commencement at low doses of 100 mg/d with twice weekly monitoring of K+ levels for the first 2 weeks and then weekly thereafter, with close monitoring at times of intercurrent illness.