The radical treatment of paraprotein disorders affecting the kidney.

Multiple myeloma is the classic disorder in which paraproteinaemia causes renal dysfunction. It is a malignant disease of plasma cells characterized by bone pain, anaemia, immunosuppression and renal impairment. Renal failure is present at the time of diagnosis in 20–30% of patients with myeloma, and is due mainly to the nephrotoxic effects of the abnormal immunoglobulin light chains [1], but may be exacerbated by hypercalcaemia, dehydration and drugs [2]. Conventional cytotoxic treatment for myeloma includes melphalan (with or without prednisolone) [3] or combination chemotherapy using regimens such as VAD (vincristine, adriamycin and dexamethasone) [4]. Randomized trials show combination chemotherapy to be superior to melphalan in terms of response rate, but equivalent in terms of life expectancy [4]. Chemotherapy results may be improved further by dose intensification with autologous bone marrow stem cell support. In a landmark study from the Intergroupe Français Myélome (IFM), patients under the age of 65 years (with normal renal function) were randomized between conventional chemotherapy and autologous bone marrow transplantation (ABMT) [5]. Patients in the ABMT arm were shown to have superior event-free and overall survival rates at 5 years of 28 and 52%, respectively, compared with 10 and 12% in the conventional treatment arm. Conventional chemotherapy followed by high-dose therapy (HDT) has now become the standard treatment in newly diagnosed myeloma patients. Peripheral blood stem cells (PBSCs) have succeeded bone marrow as the stem cell of choice, largely because of their more rapid engraftment kinetics [6]. Subsequently, the IFM have demonstrated that conditioning with melphalan 200mg/m is at least as effective as the combination of melphalan 140mg/m with total body irradiation used in their original study [6]. Recent data support the use of tandem high-dose procedures [7,8]. Initially, most centres offering this treatment excluded patients with renal failure. However, a number of reports described cases with renal failure in which a relatively successful outcome was achieved with HDT [9–11]. The main question about treating myeloma patients with renal failure with HDT is whether the toxicity of the treatment is increased, thereby risking the potential survival advantage. The Spanish ASCT registry reported the outcome after transplantation in 14 myeloma patients with renal failure. The treatment-related mortality (TRM) in this group was 29% compared with 3.4% in 552 patients with normal renal function at the time of transplantation [12]. Lower TRM rates have been reported by other groups, e.g. the Arkansas group reported the outcome in a series of 81 myeloma patients with renal failure at the time of HDT. This included 38 dialysisdependent patients [13]. Because patients treated with 200mg/m of melphalan suffered significant toxicity, subsequently patients received 140mg/m. If HDT was well tolerated, patients proceeded to a second transplant procedure. Patients receiving the higher melphalan dose, particularly those on dialysis, suffered the effects of increased toxicity, i.e. mucositis, pulmonary complications, atrial dysrhythmias and neurological side effects. The authors suggested that melphalan metabolism may be affected by the hypoalbuminaemia present in renal failure, since the drug is normally bound to albumin. Previous reports suggested that high-dose melphalan was metabolized adequately, even in patients on dialysis [14,15], but the Arkansas experience emphasizes the advice that melphalan dosage should be limited in renal failure. TRM was Correspondence and offprint requests to: Dr A. J. Peniket, Department of Haematology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. Email: [email protected]