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Abstract Introduction: The Dutch cooperative group HOVON started a randomised phase III study in elderly patients with multiple myeloma (MM) in September 2002 comparing the standard Melphalan and Prednisone (MP) treatment with the combination Melphalan, Prednison and Thalidomide (MPT) (HOVON 49 study). Patients with previous untreated multiple myeloma > 65 years of age with a stage IB or higher were candidates for this trial. Melphalan was given in a dose of 0.25 mg/kg and prednisone 1 mg/kg for 5 days every 4 weeks. Thalidomide was given daily in a dose of 200 mg.. A maximum of 8 cycles was planned. In case of ongoing improvement of response further therapy was allowed till a plateau phase was reached. When a good response and a plateau phase was reached the patients on MPT received maintenance therapy with Thalidomide 50 mg/day until disease progression. Responses were assessed using the IMWG criteria. The primary endpoint was Event Free Survival (EFS). Progression Free Survival (PFS), Overall Survival (OS) and Response Rate (RR) were secondary endpoints. The study was powered for 420 patients. However accrual decreased significantly after the publications of 2 other trials comparing MP with MPT. Therefor the HOVON monitoring board decided to stop the trial when 344 patients had been included. Results: 344 patients from 59 centers were registered. 11 patients were not eligible and 3 patients were excluded for lack of signed informed consent or insufficient data at the time of evaluation. The 333 remaining patients, had been randomized to MP (n=168)and MPT (n=165. The arms were well matched for age, sex, stage of the disease, performance status and type of M-protein. The best response on protocol with MPT was 66% (CR 2%, VGPR 28% and PR 36%) as compared to 47% with MP (CR 2%, VGPR 8% and PR 37%), respectively (p<0.001). RR after three cycles of MPT was 52% as compared with only 32% with MP. That the quality of the responses seen in the Thalidomide treated group was better, is clear from the PFS after CR or PR; median 14 months vs 10 months (p<0.0002). At two years the PFS after CR/PR was 32% vs 12% for MPT vs MP respectively. There was a significant difference for the primary endpoint EFS in favour of the MPT arm; 13 versus 9 months (p< 0.001). Also the PFS was clearly in favour of MPT (p<0.02; median 10 months versus 13 months). The PFS after 2 years was 33% versus 19%.). For patients in CR vs PR the median PFS was 14 and 10 months respectively (p<0.0002). The median OS was 37 months vs 30 months (p=0.16). Toxicity: Grade 2,3 and 4 toxicity of any type was seen in 60% of the patients in the MP arm and in 88% of the MPT patients. This difference was mainly due to grade 2 and grade 3 neurotoxicity. No differences between the two arms were seen for other toxicities. Death during protocol treatment was 31% in the MP arm and 39% in de MPT arm. After three cycles only 36% of the patients used the full Thalidomide dose and after 6 cycles this was only 28%. Only one third of the patients received cycle 3 of Melphalan as planned according the protocol Conclusions: In this randomised phase III study the addition of Thalidomide to MP resulted in a significant better RR. The quality of the responses (number of VGPR and PFS after CR/PR) and time to response were in favour of MPT. EFS and PFS were significantly better in MPT treated patients. Thalidomide added significantly to the toxicity (mainly neurotoxicity) of the treatment. We were unable to confirm the positive effect with Thalidomide as part of front-line therapy on OS perhaps probably because a substantial number of the MP patients received Thalidomide as the second line therapy. Moreover the study might be underpowered due to premature stopping of the inclusion.
Wijermans et al. (Sun,) studied this question.