About 35 percent of 193 relapsed patients treated in the multi-center phase 2 clinical trial responded positively to the compound, researchers found, including seven whose myeloma protein became undetectable and 12 whose telltale protein could be found only with a special test called immunofixation. Overall, side effects were manageable.
A report on the encouraging findings appears in the June 26 issue of the New England Journal of Medicine.
Authors include Drs. Paul G. Richardson, instructor in medicine at Harvard University Medical School, Kenneth C. Anderson, professor of medicine at Harvard and director of the Dana-Farber Cancer Institute's multiple myeloma center, and Robert Z. Orlowski, assistant professor of medicine at the University of North Carolina at Chapel Hill School of Medicine.
Dr. Beverly S. Mitchell, professor and chief of hematology/oncology at UNC, wrote a separate accompanying commentary. Mitchell and Orlowski are members of UNC's Lineberger Comprehensive Cancer Center.
Multiple myeloma, a cancer of plasma cells, is the second most common cancer arising from blood-related tissue, Orlowski said. The American Cancer Society estimates that 13,600 new U.S. residents will be diagnosed this year with the disease, the 10th leading cause of cancer death in women and a cancer seen more commonly among blacks.
"Patients typically experience fatigue, bony pain and anemia and sometimes suffer bone and kidney damage as well," he said. "While therapies are available for multiple myeloma, most patients cannot be cured of the disease. Furthermore, myeloma tends to become resistant to treatment and less and less responsive to the few available chemotherapies, with briefer periods of remission. New drugs are badly needed so that patients will have additional treatment options."
Bortezomib, formerly known as PS-341, has shown special promise in the treatment of myeloma, Orlowski said.
"This drug inhibits an important protease, or enzyme, that is present in all cells but is especially interesting because studies performed in part in our laboratory showed that cancer cells are much more sensitive to its effects than are normal cells," he said. "A phase 1 clinical study we performed, along with investigators at Memorial Sloan Kettering, showed that the drug could be given safely."
Several myeloma patients benefitted significantly from the treatment, including one whose disease went into remission.
"As a result of those findings and also encouraging laboratory studies by
Dr. Anderson at Dana-Farber, a group of investigators led by Drs. Richardson and Anderson performed a larger clinical study," Orlowski said. "In the new research, patients were treated with bortezomib, and the results confirmed significant clinical benefits from therapy, including some patients who had complete responses."
The results led to recent Food and Drug Administration approval. A phase 3 clinical trial is now under way comparing bortezomib's efficacy with a standard myeloma treatment.
"Studies are also looking at using it in patients with myeloma who have not received other therapy before since these patients may have disease that is more sensitive to this drug," Orlowski said "Combination studies with other chemotherapies are examining whether there might be even better activity if bortezomib is added to other drugs for myeloma. The drug already offers a new, active option for patients with advanced myeloma, and the studies we're doing will help to determine its best role."
UNC's Mitchell wrote that now is an exciting time for anti-cancer drug treatment.
"The identification of promising molecular targets has led to the development of many exciting new drugs for which an anti-tumor mechanism of action has been clearly delineated," she wrote. "Given the recent major advances in our understanding of the biology of cancer cells, one might surmise that an era of truly rational therapeutics has arrived. Nevertheless, we continue to find new therapeutic agents that target unforeseen molecular pathways."
The new report "brings to the fore a relatively new and unexpected target," a large protein complex called the 26S proteasome, which is found in high amounts in both the cytoplasm and nucleus of all eukaryotic cells, Mitchell said. Among the complex's several key jobs is to break down selected proteins as a central part of cell metabolism.
"At first glance, the features of the proteasome would scarcely make it a plausible target for highly selective cancer therapy," she wrote. Nonetheless, it "would appear that the sensitization of tumor cells to cytotoxic drugs through inhibition of the proteasome will continue to generate enthusiasm for numerous clinical applications."
By David Williamson
UNC News Services
Millennium Pharmaceuticals of Cambridge, Mass., supported the research. Medical scientists from 12 other U.S. cancer centers, including those at Northwestern University, the Mayo Clinic and Massachusetts General Hospital, and Millennium Pharmaceuticals also participated in the study.
Note: Orlowski and Mitchell can be reached at 919-966-9762 and 966-5720, respectively, and
Richardson and Anderson at 617-632-2127.
Lineberger Cancer Center Contact: Dianne Shaw, 919-966-5905
News Services Contact: David Williamson, 919-962-8596
Journal
New England Journal of Medicine