Maintenance Treatment with Thalidomide after Autologous Transplantation for Myeloma: Final Analysis of a Prospective Randomized Study of the “Intergroupe Francophone du Myelome”.

High dose therapy (HDT) supported with autologous stem cell transplantation has been introduced in the management of myeloma. However, after a single or a double transplantation, almost all patients ultimately relapse. New strategies are required to control the residual disease after HDT. The “Intergroupe Françophone du Myélome” (IFM) initiated a trial designed to evaluate the impact of maintenance treatment with Thalidomide on the duration of response after HDT.

From April 2000 to October 2003, 1017 myeloma patients at diagnosis under the age of 65 years were enrolled in the IFM 99 protocol. 780 of them, without or with only one adverse prognostic factor (beta-2 microglobuline ≥ 3 mg/l or deletion of chromosome 13), were enrolled in the IFM 99 02 protocol. They received the following treatment: 1) 3–4 cycles of the VAD regimen; 2) a first autologous transplant prepared with Melphalan 140 mg/m2; 3) a second autologous transplant prepared with Melphalan 200 mg/m2. Patients without progressive disease 2 months after the second transplant were randomized to receive: no maintenance treatment (arm A), maintenance treatment with Pamidronate (arm B) or maintenance treatment with Thalidomide and Pamidronate (arm C). As of June 2005, 593 patients (76%) have been randomized: 197 in arm A, 195 in arm B and 201 in arm C. Clinical characteristics of each group were similar. The median follow-up from diagnosis was 3 years (1 to 6 y). Thalidomide was found to improve the Event-free-survival (EFS). Indeed, the 4-year post-diagnosis probability of EFS was 39% (95% CI= 29–51) in arm A, 37% (95% CI= 26–48) in arm B, and 50% (95% CI= 37–60) in arm C (p<0.02). We compared EFS according to the treatment groups in different subgroups of patients (beta-2-microglobulin ≤ 2.5 mg/l, beta-2-microglobulin > 2.5 mg/l, deletion of chromosome 13, and no deletion of chromosome 13). Thalidomide was found to improve the 4-year EFS of patients without deletion of chromosome 13 (39% in arm A, 38% in arm B, 52% in arm C, p<0.01) and of patients with a beta-2-microglobulin > 2.5 mg/l at diagnosis (28% in arm A, 21% in arm B, 57% in arm C, p<0.001). On the opposite, patients with a deletion of chromosome 13 or with a beta-2-microglobulin ≤ 2.5 mg/l at diagnosis did not benefit significantly from Thalidomide (p=0.5 and p=0.9, respectively).

The 4-year overall survival was similar in the 3 treatment groups: 86% in arm A, 78% in arm B, and 86% in arm C (NS). Among the 593 randomized patients, 3 factors were found to be associated with a longer EFS in the multivariate analysis: low beta-2-microglobulin at diagnosis (p<0.03), treatment arm (p<0.02), and deletion of chromosome 13 (p<0.03). In conclusion, the final analysis of the IFM9902 trial demonstrates that Thalidomide improves the duration of response after high dose therapy among patients with myeloma, especially those who have a beta-2-microglobulin >2.5 mg/l without deletion of chromosome 13.