Early results from a major, international Phase III clinical trial decisively show that recurrent multiple myeloma is more effectively treated with the drug bortezomib (trade name: Velcade TM) than with dexamethasone, a drug that for decades has been the standard therapy for relapsed disease, researchers at Dana-Farber Cancer Institute
The findings, which will be presented at the annual meeting of the American Society of Clinical Oncology (Sunday, June 6, 2 p.m. Room 283) were sufficiently striking that the trial was stopped early so that patients who had been randomly assigned to receive dexamethasone could switch to bortezomib.
The study, which involved 669 patients in 92 treatment centers around the world, was the first head-to-head comparison of bortezomib and dexamethasone in a Phase III trial of patients who had relapsed after treatment for multiple myeloma. (Phase III trials test new treatments against standard ones to determine which is safer and more effective.)
"This trial represents the largest, most broad-based assessment to date of bortezomib and dexamethasone in this group of patients," says the study's lead author, Paul Richardson, MD, of Dana-Farber. "The finding that bortezomib significantly lengthened the time to disease progression and improved survival when compared with dexamethasone, with a similar level of safety, is important confirmatory evidence of bortezomib's effectiveness for patients with relapsed multiple myeloma."
Multiple myeloma is a currently incurable cancer of the bone marrow that causes a plunge in the production of vital red and white blood cells. Although relatively rare, it is the second most common type of blood cancer and accounts for 11,000 deaths annually in the United States. It is the fourth fastest-growing cancer in terms of mortality and is among the top 10 causes of death among African Americans.
In the new study, researchers randomly assigned 669 relapsed myeloma patients to receive a six-month course of either bortezomib or dexamethasone, then tracked them to determine when – and if – the disease began to progress. For patients receiving dexamethasone, the average time to progression was 3.6 months; for those receiving bortezomib, the average time was 5.7 months. Overall survival was also higher among the bortezomib patients, 13 of whom died during the trial period, compared to 24 of those receiving dexamethasone. A somewhat lower rate of serious infections was found in the bortezomib patients.
"For the patients receiving bortezomib, the average 5.7-month period before progression of the disease represents a 58 percent increase over that achieved by the dexamethasone-treated group," Richardson commented. "This points to a significant improvement in efficacy, which prompted the trial's Data Monitoring Committee to halt the trial early so all patients participating in the study could receive bortezomib."
Manufactured by Millennium Pharmaceuticals of Cambridge, Mass., Velcade is the first of a class of substances known as proteasome inhibitors to reach the clinical trial stage. Preclinical studies by researchers at Dana-Farber demonstrated that the drug – which acts on intracellular structures called proteasomes, which control the degradation of key proteins controlling myeloma cells – prevented tumor cells from proliferating, and was active even against those that were resistant to other known therapies. Later experiments found that the drug killed myeloma cells in mice without causing serious harm to normal tissue.
The latest study follows a series of Phase I studies and a pivotal, large, multicenter Phase II trial led by Richardson and the team at Dana-Farber. That trial, which involved 202 patients with relapsed and treatment-resistant myeloma, showed bortezomib to be highly active and to have manageable side effects, leading to its rapid approval by the Food and Drug Administration last year. Ongoing studies will now focus on the rate and duration of response to bortezomib, safety, and survival earlier in the disease process, and in combination with other drugs.