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Problems in the management of myeloma.

While there can be no doubt that the middle-aged patient who presents with the classical form of myeloma uncomplicated by renal failure needs prompt and effective specific chemotherapy, there are undoubtedly some patients with paraproteinaemia that give rise to difficulty. The problem of benign monoclonal gammopathy, or, as it is more appropriately called 'monoclonal gammopathy of undetermined significance' (MGUS)', is now a wellrecognized entity. The presence of little clinical disability, a low level of paraprotein, the absence of lytic lesions in the bones and of Bence Jones protein in the urine, clearly indicate a 'benign' course and no treatment is required. However, some patients with a small quantity of paraprotein do have up to three small lesions in the bone, and may also be anaemic with haemoglobin of under 10 g/dl. These patients, with indolent myeloma2 or smouldering myeloma,3 appear to have stabilized with a low level of paraprotein. Although they generally show progress to overt myeloma in 3 to 5 years, it is considered unwise to start active specific therapy before that time. Their progress can be monitored by regular estimation of paraprotein and bone radiology. Two clinical complications that may present special problems, either at presentation or subsequently during the course of the disease, are hypercalcaemia and renal failure. Approximately 30% of cases are hypercalcaemic at presentation.4'5 It is now recognized that bone damage and liberation of calcium into the extracellular fluid is not confined to the lytic lesions in the bone, but is a generalized process in which the activity of osteoclasts and osteoblasts is no longer controlled in a complementary fashion, but becomes uncoupled.6 Thus the removal of bone by the osteoclasts is not followed, as in the normal condition, by attraction ofosteoblasts with laying down ofbone and remodelling. Specific factors are now known to act on the 'uncoupled osteoclast', resulting in its increased activity. Tumour necrosis factor ,B and interleukin-l form part of a complex group of cytokines which are components of an osteoclast-activating factor (OAF). Knowledge of these factors has allowed a more rational approach to therapy. Agents are now available which can prevent the activity of these cytokines.7'8 A frequent problem in the management of the elderly patient with hypercalcaemia is that they may often have concurrent heart disease. One of the most important methods of reducing serum calcium is by giving large volumes (3-6 litres) of normal saline, but this may readily precipitate heart failure in these patients from fluid overload, particularly if they are also given the customary 30-100 mg ofprednisolone.9 The fall in calcium may be delayed for hours or even weeks, during which time the patient may go into intractable heart failure despite loop diuretics such as frusemide. Calcitonin may help, but its effect is usually transient: mithromycin is effective, but produces thrombocytopenia, delaying specific therapy, and oral phosphate may work but produces unpleasant gastrointestinal disturbance with diarrhoea. Faced with this dilemma, the use of biphosphonates, etidronate or clodronate, may be helpful. Etidronate'0 should be given as an infusion over 3 hours to avoid renal damage. This effectively relieves bone pain and will reduce serum calcium when given daily for 3 days. Its prolonged use may inhibit recalcification of bone, but as reconstruction of the bony skeleton does usually start once specific chemotherapy has been instituted, this difficulty may be more theoretical than real. It does appear that clodronate, by contrast, actively encourages the deposition of calcium in bones, but further evidence for this is needed." Renal failure is often associated with hypercalcaemia, but may be an independent complication. The blood urea and creatinine is raised in more than 50% of patients presenting with myeloma,9 and this has a bad effect on prognosis. A problem may be faced with determining how agressive management should be in elderly patients who present with the features of renal failure. Some of them may be dehydrated, and treatment of hypovolaemia, associated hypercalcaemia and infection may result in restoration of renal function to normal. Thus specific intervention may be justified after a few days when the urea and creatinine levels have returned to normal. In the younger patient,