Paul Richardson, MD
When the targeted drug bortezomib stops working in patients with advanced multiple myeloma, the patients survive only an average of five months longer. But a phase 2 clinical trial has shown that pairing bortezomib with an experimental drug, panobinostat, may be a promising new treatment for such patients, Dana-Farber Cancer Institute researchers say.
"This study demonstrated encouraging response rates with manageable toxicity in these patients with very advanced disease," says Paul Richardson, MD, of Dana-Farber. "We think this is a remarkably effective combination strategy given the heavily pre-treated nature of our patients in this study," adds Richardson, who led the study and is presenting the results (abstract 814) on Monday, Dec. 12, at 4:30 p.m. PST in Ballroom 20D at the annual meeting of the American Society of Hematology.
The results came from the PANORAMA 2 clinical trial of panobinostat combined with bortezomib (Velcade) and dexamethasone in relapsed multiple myeloma patients whose disease became resistant to bortezomib.
Panobinostat is a histone deacetylase (HDAC) inhibitor, a type of drug that blocks key processes involved in gene expression and protein degradation. Panobinostat clogs up a protein disposal mechanism in myeloma cells so that harmful byproducts accumulate and eventually cause programmed cell death.
Abnormal cells in multiple myeloma accumulate in the blood, bones and other organs, causing them to malfunction. The effectiveness of a multiple myeloma drug can be evaluated by the magnitude of its effect on the amount of disease present in the body, typically assessed by measuring serum monoclonal protein.
The PANORAMA 2 trial included 53 patients with relapsed multiple myeloma who had undergone multiple rounds of prior treatment and, in more than half, also stem cell transplant. The researchers reported on 44 patients receiving the panobinostat-bortezomib-dexamethasone combination.
Results showed that in the first phase of the treatment, 9 of the patients had at least a partial response of their disease, and 2 of the 9 saw their myeloma almost disappear, a so-called near complete response. Another 7 patients experienced minimal response, which is also associated with clinical benefit.
Eight patients have advanced to a second phase of treatment, and 6 of them are still on treatment as much as 8 months later, says Dr Richardson.
Side effects included fatigue, diarrhea, low platelet counts, nausea and anemia, but Richardson says that these problems have proven manageable with supportive care and dose-reduction.
Richardson is first author of the report on the multicenter clinical trial, and Robert Schlossman, MD, also of Dana-Farber, is senior author. Other authors are from the H. Lee Moffitt Cancer Center in Tampa, Fla.; M.D. Anderson Cancer Center in Houston; Stanford University School of Medicine; Emory University School of Medicine in Atlanta; Duke University Medical Center; and Novartis Pharmaceuticals Corp.
Preclinical work for this project was led by Teru Hideshima, MD, PhD, James Bradner, MD, and Kenneth Anderson, MD, all from Dana-Farber.
Funding for the work was provided by Novartis.