Thalidomide Improves Survival for Older Multiple Myeloma Patients

LILLE, France, Oct. 5 -- Older treatment-naïve stages II or III multiple myeloma patients have a survival advantage when thalidomide (Thalomid) is added to standard therapy, researchers found in a randomized trial.
Overall survival at 51.5 months with the combination of thalidomide, melphalan (Alkeran), and prednisone was 41% (18.4 months) longer than with melphalan and prednisone alone--and 31% (13.3 months) longer than with melphalan-based stem cell infusion therapy.
These findings provided a third large randomized trial to the published evidence for a survival benefit from adding thalidomide to the therapy mix, reported Thierry Facon, M.D., of Hôpital Claude Huriez at the Centre Hospitalier Universitaire here, and colleagues, in the Oct. 6 issue of The Lancet.
A thalidomide-based combination should be the new standard of care for multiple myeloma in older treatment-naïve patients, the researchers said.
In an accompanying editorial, Antonio Palumbo, M.D., and Mario Boccadoro, M.D., both of the Università di Torino in Italy, agreed.
"After 50 years of unsuccessful attempts to find new and more effective treatment approaches suitable for most patients," they wrote, "we now have extensive evidence to support the introduction of melphalan and prednisone plus thalidomide as the standard of care for elderly patients with multiple myeloma."
Dr. Facon's Intergroupe Francophone du Myélome group study included 447 newly diagnosed multiple myeloma patients ages 65 to 75. They were randomized to 12 six-week cycles of 0.25 mg/kg of melphalan and 2 mg/kg of prednisone given orally for four days per cycle, the same regimen plus thalidomide given daily at a dose not exceeding 400 mg per day continuously during the 12 cycles, or autologous stem cell transplantation with two 100 mg/m² doses of melphalan.
After an average 51.5 months of follow-up, median overall survival was significantly better in the thalidomide group than with melphalan and prednisone alone (51.6 versus 33.2 months, hazard ratio 0.59, P=0.0006) or with stem cell transplantation (51.6 versus 38.3 months, HR 0.69, P=0.027).
After adjustment for prognostic factors, the thalidomide combination remained best at prolonging overall survival (HR 0.49 versus the standard regimen, P=0.0002, and HR 0.56 versus stem cell transplant, P=0.006).
For progression-free survival, the thalidomide group again came out ahead of melphalan and prednisone alone (HR 0.51, P<0.0001) and stem cell transplantation (HR 0.59, P=0.0002). Progression-free survival did not vary with the thalidomide dose (P=0.22 for initial, P=0.75 for maximum, and P=0.92 for average dose).
The stem cell group was similar to the melphalan and prednisone group for both overall survival (HR 0.86, P=0.32) and progression-free survival (HR 0.87, P=0.25).
Complete, partial, and "very good" partial responses were all significantly more common with the thalidomide combination and stem cell transplantation compared with the melphalan and prednisone group.
Toxicity was higher when thalidomide was added to melphalan and prednisone but lower than with stem cell transplantation.
Grade 3 or 4 neutropenia was significantly more common than expected in the thalidomide group compared with melphalan and prednisone alone (48% versus 26%, P<0.0001), particularly "since thalidomide is not regarded as a myelosuppressive drug." However, severe infections were not more common with thalidomide (13% versus 9%, P=0.32).
Thromboembolism "remains a concern," the researchers said. The rate was significantly higher with thalidomide than with melphalan and prednisone alone (12% versus 4%, P=0.008) but similar to that with stem cell transplantation (8%, P=0.31).
Peripheral neuropathy and grade 3 or 4 somnolence and constipation were also a concern with thalidomide, but the toxic effects of the combination regimen were "counterbalanced" by a low rate of toxic and early deaths (2% versus 9% and 14% in the other groups), the researchers said.
"Although the toxic effects we observed with melphalan and prednisone plus thalidomide were acceptable," they wrote, "efforts should be made to reduce neurotoxicity, somnolence, and constipation through use of a lower thalidomide dose (100 mg or 200 mg per day) along with a shorter treatment duration, and to prevent thromboembolism with adequate prophylaxis."
Although "a new standard of care has been defined" with thalidomide for multiple myeloma, Drs. Palumbo and Boccadoro said, "the optimum dose of thalidomide, the number of cycles, and the need for maintenance therapy with single-agent thalidomide still need to be investigated."
Laphal, and later, Pharmion, supplied free thalidomide for the study. The study was sponsored by the Centre Hospitalier et Universitaire de Lille and supported by a research grant from the French Ministry of Health and by the Swiss Group for Clinical Cancer Research.
Dr. Facon and two coauthors reported receiving scientific advisory board and lecture fees from Pharmion, Janssen Cilag, and Celgene. Drs. Palumbo and Boccadoro reported receiving scientific advisory board and lecture fees from Pharmion and Celgene. Primary source: The LancetSource reference: Facon T, et al "Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): A randomized trial" Lancet 2007; 370:1209-18. Additional source: The LancetSource reference: Palumbo A, Boccadoro M "A new standard of care for elderly patients with myeloma" Lancet 2007; 370:1191-2.