Oral drug combination proven as effective as standard chemotherapy

For newly diagnosed multiple myeloma; Previously scorned thalidomide gives new option for patients with difficult-to-treat cancer

A recent study conducted at The University of Texas M. D. Anderson Cancer Center shows that patients with multiple myeloma, a cancer of the bone marrow, were more likely to achieve remission when treated with a combination of drugs that included thalidomide, a medicine that had previously been shelved for causing birth defects.

Donna Weber, M.D., assistant professor of medicine, Raymond Alexanian, M.D., professor of medicine, and their colleagues at M. D. Anderson report in the January 1, 2003 issue of the Journal of Clinical Oncology that 72 percent of 40 newly diagnosed patients with multiple myeloma who received a combination of thalidomide and the steroid dexamethasone achieved remission rapidly, usually within one month of treatment. Among these patients, 16 percent achieved complete remission. The results were superior to a second set of patients in a parallel study treated with thalidomide alone. In these patients, about one-third (10 of 28 patients), achieved partial remission and none achieved complete remission.

“We found that even in patients with resistant disease where each of the two drugs didn’t work alone, they were effective when taken together, which very rarely happens,” says Weber, who was the principal investigator on both studies. “There was true synergy in terms of the anti-myeloma effect.”

Researchers aren’t sure how thalidomide works to reduce the bone marrow tumors associated with multiple myeloma, but it may stop cancer cells from creating the network of blood vessels that provides oxygen and nutrients. As a result, the tumors starve to death. Since thalidomide is known to cause birth defects, women of child-bearing age who take the medicine must use strict methods of birth control. The results were as good as that achieved with intravenous combination chemotherapy, but without the side effects of nausea, vomiting and hair loss as well as low blood counts, the risk of infection and the need for a central venous catheter. An added benefit, says Weber, is that thalidomide-dexamethasone are taken orally, while previous chemotherapy has been given intravenously.

“This combination therapy achieved the highest frequency of response observed against myeloma for an oral regimen,” says Alexanian. “This program appears to represent the new treatment of choice for patients as an initial program of therapy, provided side effects can be addressed and prevented.”

The researchers noted that about 15 percent of patients treated with the thalidomide-dexamethasone combination developed blood clots in their legs or lungs. Subsequent studies showed that anti-coagulants prevent blood clots and could eliminate this side effect, Weber says.

The M. D. Anderson results were nearly identical to those found by researchers at the Mayo Clinic. In fact, says Weber, the two studies, which were conducted during the same time frame from 1999 to 2001, provide strong evidence of thalidomide’s benefit for patients with multiple myeloma when combined with the intermittent high-dose dexamethasone. Previous studies had already shown that thalidomide could be safely and effectively used to treat patients with multiple myeloma who had failed to achieve remission after prior chemotherapy treatments.

The goal of treating patients with multiple myeloma is to reduce the number and size of bone marrow tumors as quickly as possible so that normal stem cells can be collected for use as an autologous bone marrow transplant, a transplant of a patient’s own stem cells to repopulate the bone marrow after intensive treatment. For patients with multiple myeloma, the sequence of primary therapy followed by intensive treatment has become a standard of care for the majority of patients, in order to achieve the highest frequency of complete remission.

The American Cancer Society estimates that about 14,600 new cases of multiple myeloma will be diagnosed during 2002 and 10,800 people will die from the disease in the United States. The average survival time after diagnosis has been only three-and-a-half years, but new programs now under study are likely to improve this figure. Results from the M. D. Anderson study and others have spawned laboratory research into the mechanism of action of thalidomide, says Alexanian. These studies have led to the production of promising new drug candidates that are in the same chemical family as thalidomide and may produce even better results with less toxicity.

“We’ve waited a long time for an effective, convenient program with few side effects that would make an impact on the initial phase of treatment for multiple myeloma and that time has come,” says Alexanian.