The marked synergy of thalidomide and dexamethasone in advanced and refractory multiple myeloma (MM) provided the basis for a phase 2 clinical study aimed at investigating the efficacy and toxicity of this combination as first-line therapy for patients less than 65 years old with newly diagnosed disease. Both thalidomide and dexamethasone were administered for 4 months in an attempt to reduce tumor cell mass before collection of peripheral blood stem cells (PBSC) and subsequent double autologous transplantation. Thalidomide was given at the fixed dose of 200 mg/day; dexamethasone was administered at the dose of 40 mg/day on days 1-4, 9-12 and 17- 20 in odd cycles and 40 mg/day on days 1-4 in even cycles, repeated monthly. Seventy-one patients with symptomatic MM were evaluated for response and toxicity. On an intent-to-treat basis, the overall response (>or= partial remission) rate was 66%, including 17% of patients who attained a complete remission or a very good partial remission. In addition to common toxicity of thalidomide, deep-vein thrombosis was a troublesome adverse event (16%). Nine patients (13%) required thalidomide discontinuation because of toxicity, including 3 patients who died during the study treatment. Fifty-nine patients proceeded to PBSC mobilization and yielded a median number of 7.1x10(6) CD 34(+ ) cells/kg. The combination of thalidomide and dexamethasone is an effective and relatively well tolerated induction regimen for previously untreated patients with MM. This combination may provide an oral alternative to vincristine-doxorubicin-dexamethasone in preparation for autologous stem cell transplantation.