August 26, 2008

UAMS Begins Landmark Myeloma Clinical Trials with Treatment Driven by Tumor Genetics

LITTLE ROCK – Armed with a method for identifying patients with a more aggressive or less aggressive form of multiple myeloma based on tumor cell gene activity, University of Arkansas for Medical Sciences (UAMS) researchers are beginning clinical trials with treatment plans for this cancer of the bone marrow tailored for each group.

The UAMS Myeloma Institute for Research and Therapy is starting two clinical trials with treatment plans that identify patients as having low-risk myeloma (Total Therapy 4) or a high-risk form of the disease (Total Therapy 5). They are believed to be the first clinical trials for multiple myeloma or any other cancer to involve risk-specific treatment plans based on the genetic makeup of the tumor.


The new trials come as 25 percent of the 231 patients enrolled in UAMS’ initial multiple myeloma clinical trial, known as Total Therapy 1, are still alive beyond 10 years all the way out to 18 years. Almost 60 percent of those enrolled in a 1998 clinical trial, Total Therapy 2, are still alive. With Total Therapy 3, initiated in 2003, 85 percent of almost 480 patients enrolled are currently alive.

“With these new clinical trials, combined with the 19 years of patient data, we believe we can quit saying ‘myeloma is incurable,’” said Bart Barlogie, M.D., Ph.D., director of the Myeloma Institute.


With the new trials, some low-risk patients will be given a different version of standard Total Therapy 3 intended to limit side effects. Total Therapy 5 for high-risk patients aims at more effective tumor control by stressing short intervals between treatment cycles (“dose-dense”), however at relaxed dose intensity.


These clinical trials evolved from results of the Total Therapy 3 program at the Myeloma Institute showing 85 percent of those with low-risk multiple myeloma still alive after four years, 90 percent of whom continue in complete remission with no signs of multiple myeloma.


“With the availability of new treatment approaches and drugs, most patients do remarkably well with current therapies for multiple myeloma, but we know that others do not,” said John Shaughnessy, Ph.D., director of the Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics at the Myeloma Institute. “Until recently the means of predicting the difference in outcome was rudimentary and not very accurate. Without the ability to accurately identify high- and low-risk disease, past treatments were given according to a ‘one size fits all’ approach.


“It has been a goal of modern cancer therapy to identify risk and modify treatment accordingly,” he said.

Scientists led by Shaughnessy at the Myeloma Institute, a part of the UAMS Winthrop P. Rockefeller Cancer Institute, hypothesized nearly 10 years ago that genetic analysis of multiple myeloma cells at time of diagnosis might be sensitive enough to predict a patient’s ultimate response to therapy.


The human genome consists of approximately 20,000 genes and the information in them is determined in large part by the precise, coordinated timing of gene activation and inactivation – much like switches being turned on or off. Cancers are caused by DNA mutations that lead to alterations in gene activity. Using tools designed to analyze how large numbers of genes interact, researchers can precisely measure the activity of all genes in a given sample and identify the gene patterns related to the cancer.


Researchers determined gene patterns in multiple myeloma cells from more than 1,000 patients. After nearly eight years of follow up on about 800 patients receiving uniform treatment, the scientists were able to show that patterns of just 70 of the 20,000 genes tested could predict low- and high-risk myeloma. These findings set the stage for the current genomics-based, risk-adapted clinical trials.


“We firmly believe that the molecular-based, risk-adapted treatment algorithms pioneered here in Arkansas will eventually become a standard of care across many areas of medicine,” Shaughnessy said.


UAMS treats more than 2,250 patients with multiple myeloma annually at the Myeloma Institute – more myeloma patients than are treated at any other facility in the country. Between 1995 and 2001 the five-year survival rate reported by the National Cancer Institute for newly diagnosed multiple myeloma patients was 34 percent. Five-year survival rates at the institute are now more than 65 percent. UAMS has achieved a median survival rate of seven years.


Elias Anaissie, M.D., a professor of medicine in the UAMS College of Medicine, is the principal investigator together with Barlogie for the trial involving low-risk multiple myeloma patients, using the treatment program called Total Therapy 4.


Mauricio Pineda-Roman, M.D., and Yazan Alsayed, M.D., assistant professors of medicine in the UAMS College of Medicine, are the principal investigators for the trial involving high-risk multiple myeloma patients, using the treatment program called Total Therapy 5.


The Myeloma Institute for Research and Therapy was the first institute in the world devoted to research and clinical care related to multiple myeloma and related disorders. Founded in 1989 by Barlogie, the UAMS multiple myeloma program has seen more than 8,000 patients from every state in the United States and more than 40 foreign countries.