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 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. 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
Dr. Barlogie said that gene expression profiles of patients
at baseline and relapse are currently being examined and may shed light on this
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 (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
Total Therapy 3 has enrolled more than 170 of a planned 300
patients. "Early results suggest we are moving in the right direction," Dr.