Multiple myeloma - linalidomide

Multiple myeloma is characterised by an overproduction of malignant plasma cells in the bone marrow. Plasma cells are white blood cells that produce immunoglobulins to fight infection and disease, but the cells in multiple myeloma patients make a form of immunoglobulin called paraprotein or M protein, which has no beneficial effect in the body.

These malignant cells also replace normal plasma cells and other white blood cells that are critical in the normal functioning of the immune system. The malignant cells can also attach themselves to other tissues in the body and grow tumours.

While the cause of the disease remains unknown, potential treatments are being investigated. Among these is Celgene's linalidomide, previously referred to as CC 5103, a derivative of the notorious immunomodulatory drug thalidomide, which inhibits the overproduction of tumour necrosis factor alpha.

Linalidomide is more potent than its parent compound, and is also non-neurotoxic. It was shown in in vitro studies to induce apoptosis or arrest growth even in resistant multiple myeloma cell lines, decrease binding of the cells to bone marrow stromal cells, and stimulate host natural killer cell immunity. It also inhibits tumour growth and decreases angiogenesis.

A Phase I dose escalation clinical trial was carried out in 27 patients with relapsed, or refractory relapsed, multiple myeloma, who had received previous treatment including autologous stem cell transplantation and thalidomide.1

They were given 5, 10, 25 and 50 mg/day. It was well tolerated up to the 25mg dose, and no significant somnolence, constipation or neuropathy were seen. Seventeen of the 24 evaluable patients gained benefit from the treatment.

In a randomised, double-blind placebo-controlled Phase III trial, 354 patients were given linalidomide plus dexamethasone or dexamethasone alone.2 More than half of the evaluable patients (51.3%) given the combination exhibited a clinical response, compared with 22.9% of those given dexamethasone alone.

Similar drug regimens were given to 351 heavily pretreated relapsed or refractory multiple myeloma patients in a second randomised, double-blind placebo-controlled Phase III trial.3 Again, better results were seen with the combination, with 47.5% responding in comparison with 18.4% of those given dexamethasone alone.

In both of these Phase III trials, patients given the combination had a higher incidence of side effects than those given dexamethasone alone. These included anaemia, thrombocytopenia, neutropoenia, fatigue, neuropathy and constipation. They were also more likely to develop deep vein thrombosis or pulmonary embolism.