Results of a Multi-Center Randomized Phase II Trial of Thalidomide and Prednisone Maintenance Therapy for Multiple Myeloma Following Autologous Stem Cell Transplant.

Multiple myeloma (MM) patients benefit from high dose chemotherapy, however relapse is inevitable and novel means of maintaining remission are required. Although oral thalidomide is an attractive agent for maintenance studies no careful dose finding studies have been performed in this setting. Given uncertainties about the long-term tolerability and the appropriate therapeutically active dose of thalidomide in this situation, we completed a prospective multi-center, randomized phase II trial to assess the tolerability of combined thalidomide and prednisone maintenance in MM and to select a preferred dose of thalidomide to eventually test in the phase III setting. Enrolment was from July 2000 to September 2001. Eligibility required administration of melphalan 200mg/m² with blood stem cell support within one year of treatment onset and initiation of maintenance within 60–100 days post stem cell infusion. All patients received prednisone 50mg p.o. on alternate days and thalidomide at a starting dose of 200mg escalating to a target dose of either 200mg or 400mg p.o. daily. The primary endpoint was the incidence of dropout or dose reduction due to treatment toxicity within 6 months. Because of an excess of treatment - related toxicity, entry to the 400 mg dose arm was closed after completing the first stage of the projected sample size. Sixty Seven patients were enrolled. Median follow-up is 36.8 months. The primary endpoint was reached by 31% of patients on the thalidomide 200mg arm and 64% of patients on the thalidomide 400mg arm. Allowing for dose reduction, 76% of patients assigned to thalidomide 200mg and 41% of patients assigned to thalidomide 400mg remained on any maintenance therapy 18 months after registration. The median cumulative dose of thalidomide received is 83.5g (range 16–1626g) on the 200mg arm, while it is 76.9g (range 66–3520g) on the thalidomide 400mg arm. Thus, patients on the higher thalidomide starting dose cumulatively received less drug overall as a consequence of toxicity. Eighty eight percent of all patients dose reduced thalidomide and 72% of all patients dose reduced prednisone within 2 years of beginning maintenance. Using EBMT response criteria 15% of patients at study entry had attained a complete or near complete remission post-transplantation. During follow up, the best response achieved was upgraded in 53% of evaluable patients with 38% assessed as achieving a complete or near complete remission one year after study entry. Median time from start of therapy to registration was 9.9 months. Progression free survival from time of registration post transplant was 32.3 months (42.2 months PFS from beginning of therapy). Seventeen of the 67 patients have died by August 2004; one year survival was 91%.Only the thalidomide 200mg arm of this trial met our definition of a tolerable maintenance therapy defined as no dose reductions or discontinuation due to toxicity in at least 65% of patients for a minimum of 6 months. A randomized Phase III trial is now testing this maintenance regimen versus placebo.