October 30, 2002
Early studies show promise for multiple myeloma treatment
Kenneth Anderson, MD
Normally hard-to-impress scientists are using phrases like "remarkable" and "more effective than anything I've seen before" to describe a new medication being tested in patients with advanced multiple myeloma, an incurable cancer of the bone marrow.
The medication, called PS-341, has been extensively studied in Dana-Farber laboratories and has achieved dramatic successes — including many remissions — in early studies with very ill myeloma patients. Those studies have now progressed to an advanced, Phase III clinical trial involving 600 patients at 66 hospitals around the world. It will test the new drug against existing therapies.
"The Phase III study, which is being led by Dana-Farber researchers, will give us a definitive picture of PS-341's effectiveness," says senior investigator Kenneth Anderson, MD, director of the Jerome Lipper Multiple Myeloma Center at DFCI. "If it proves to be as potent as early studies indicate it to be, we'll have a major new weapon in the arsenal against this disease."
PS-341, developed by Millenium Pharmaceuticals and formerly known as LDP-341, first attracted researchers' attention as a tool for studying proteosomes, small chambers of cells that dispose of unneeded proteins. Its journey from the laboratory, where it was found to act against cancer cells, to tests in animals, to clinical studies in patients is "an outstanding example of translational research," says Paul Richardson, MD, of Hematologic Oncology, lead investigator of the clinical trials. Translational research teams basic scientists with clinical researchers to generate new forms of treatment.
Paul Richardson, MD
Each step of PS-341's evolution into a promising myeloma drug was led by researchers at Dana-Farber. Teru Hideshima, MD, PhD, and his colleagues in Hematologic Oncology performed much of the initial work linking the drug to the death of cancer cells. In laboratory samples of cells, Hideshima's group showed that PS-341 prevents myeloma cells from proliferating, even those which are resistant to all known therapies.
When Richard LeBlanc, MD, tested the compound in mice, he found it killed myeloma cells without seeming to harm normal tissue.
"I haven't seen any other agent that is so effective against myeloma cells," Hideshima remarks. His colleagues Constantine and Nicholas Mitsiades, both MDs, have recently begun to identify PS-341's mechanism of action and how best to use it with other drugs.
From lab to clinic
The DFCI investigators, who also include Robert Schlossman, MD, Deborah Doss, RN, Mary McKenney, NP, Kathy Kelley, RN, and others have carried PS-341 research into the clinic. They took part in a Phase II clinical trial involving 202 myeloma patients at 10 medical centers across the country. All the patients had advanced myeloma and had relapsed after several previous treatments — as many as 13, in some cases. (Phase II trials are primarily concerned with the effectiveness of a potential drug.)
The results of the trial, which have not yet been published in a scientific journal but were announced at last year's meeting of the American Society of Hematology (ASH), were attention-grabbing. Of the first cohort (or group) of 78 patients, 70 percent had their condition stabilize or improve, an outcome that Richardson, who led the study, calls "very promising." Some patients achieved complete remissions, and half showed a measurable benefit from the medication in this preliminary analysis. Researchers will update the findings at the ASH meeting later this year in Philadelphia.
While many unknowns remain — including how long the improvements will persist — the results are so encouraging that Anderson, Richardson, and their team have embarked on a large, multicenter, Phase III clinical trial of the drug. The trial, which began this year, is expected to be completed in early 2003.
"The pre-clinical work at Dana-Farber put PS-341 on the map for treating multiple myeloma," Richardson says. "The early results in clinical trials have borne out what we saw in the laboratory, suggesting that PS-341 can become an important treatment for a disease that affects nearly 15,000 new patients a year in the U.S."
(Inside the Institute, Oct. 29, 2002)
