ORLANDO -Thalidomide (Thalomid) added to intensive front-line therapy for multiple myeloma proved superior to intensive therapy alone in a randomized trial led by Bart Barlogie, MD, PhD, director, University of Arkansas Myeloma Institute for Research & Therapy, Little Rock, and lead investigator of the trial. He reported the findings at the American Society of Clinical Oncology 41st Annual Meeting (abstract 6502). The researchers also found that cytogenetic abnormalities were strongly associated with response and survival. Thalidomide(Drug information on thalidomide) benefited only patients without the abnormalities. The phase III trial randomized 668 newly diagnosed patients to receive Total Therapy 2, which involves several rounds of stem cell transplants and chemotherapy, with or without thalidomide, given from the beginning of treatment and continued until recurrence.
After 5 years, complete remissions had occurred in about 65% of patients taking thalidomide vs 40% of those not taking the drug (P < .001). Event-free survival was 58% for the thalidomide group, compared with 45% for the controls (P = .01). No difference has yet been seen between the two groups in overall survival, Dr. Barlogie said.
More patients receiving thalidomide experienced deep vein thrombosis, 34% vs 16% of controls, but this was controlled with heparin(Drug information on heparin). The thalidomide patients also had more nerve discomfort (12% vs 4%) and motor nerve problems (21% vs 13%).An Unexplained Finding
In one unexplained finding, post-relapse survival has been shorter for those on thalidomide. The reasons are unknown, but Jayesh Mehta, MD, director of the Hematopoietic Stem Cell Transplant Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, speculated that thalidomide could have an unfavorable effect on the biology of the disease. In his discussion of the trial at ASCO, he noted that the drug may create resistance to itself and to other salvage therapies, shortening post-relapse survival time.
Dr. Barlogie said that gene expression profiles of patients at baseline and relapse are currently being examined and may shed light on this issue.
The close association between cytogenetic abnormalities and outcomes is a key finding, Dr. Barlogie said. In multivariate regression analysis, three abnormalities-metaphase cytogenetic abnormalities, amplified 1q21, and deletion 13q14-were all independently associated with poor prognosis. "With these three variables, one could actually account for approximately 40% of all outcome variability . . . so with a simple bone marrow test looking at cytogenetics, you can capture outcomes of patients best in my view," he said.
To overcome the poor prognosis associated with cytogenetic abnormalities, the investigators have moved on to a trial of Total Therapy 3, which adds bortezomib(Drug information on bortezomib) (Velcade) to the Total Therapy 2 regimen. Another study presented at ASCO (abstract 6501, see page 19) suggested that bortezomib did indeed appear to overcome the poor prognosis associated with one of the common abnormalities in multiple myeloma, the partial or complete deletion of chromosome 13.
Total Therapy 3 has enrolled more than 170 of a planned 300 patients. "Early results suggest we are moving in the right direction," Dr. Barlogie said.