Thalidomide-Induced Peropheral Neuropathy in Newly Diagnosed and Pre-Treated Multiple Myeloma Patients.

Thalidomide is remarkably active in advanced relapsed and refractory multiple myeloma (MM), so that its use has been recently proposed either in newly diagnosed patients or as maintenance treatment after conventional or high-dose therapy. This latter therapeutic approach has risen the concern of side effects occurring after long-term therapy with this drug. In order to investigate this issue we analyzed the outcome of 74 patients who have been treated with thalidomide + dexamethasone for longer than 8 months at our Institution. Thirty-four patients (18M, 16F, median age = 55 years) had newly diagnosed symptomatic MM and were treated with four monthly courses of thalidomide 200mg/day + dexamethasone 40 mg on days 1 to 4 (even cycles), or on days 1 to 4, 9 to 12 and 17 to 20 (odd cycles), followed by cyclophosphamide 7g/m2 + G-CSF, peripheral blood stem cell (PBSC) collection, and double autologous PBSC transplant. Thalidomide + dexamethasone was administered throughout the whole treatment program. Forty patients (27M, 13F, median age = 61 years) were treated with thalidomide 200mg/day +dexamehasone 40mg on days 1–4 every four weeks as salvage therapy for relapsed (n = 14) or progressive (n=26) MM. Neurotoxicity was the most troublesome and frequent toxic effect that was observed after > 8 months treatment, the incidence averaging 74% in newly diagnosed patients and 75% in pretreated ones. Symptoms included paresthesias, tremor and dizziness; serial electromyographic studies revealed a symmetrical, mainly sensory peripheral neuropathy, with minor motor involvement. The severity of neuropathy, graded according the NCI-CTC 2.0 scoring system, varied greatly in the two groups of patients, as pretreated patients showed grade 2 and 3 toxicity in 32.5% and 27.5% of the cases, respectively, while the majority of newly diagnosed patients complained about grade 1 toxicity (57%), and none of them experienced grade 3 toxicity. In both groups thalidomide neurotoxicity was not related to sex, M protein isotype, and thalidomide daily dose. In pretreated patients, a significant correlation between grade 2 + 3 neurotoxicty and longer disease duration was found, thus suggesting that subclinical MM-related neurotoxicity could favour drug-induced toxic effects. These results suggest that long-term thalidomide therapy in MM may be hampered by the remarkable neurotoxicity of the drug, and that a neurological evaluation should be mandatory prior to thalidomide treatment, in order to identify patients at risk of developing a periperal neuropathy.