UAMS Scientists Encouraged by Myeloma Clinical Trials with Treatment Driven by Tumor Genetics

By Jon Parham

The UAMS Myeloma Institute for Research and Therapy began the two trials in 2008 using a tool developed by UAMS researchers for identifying aggressive and less aggressive forms of multiple myeloma, a cancer of plasma cells, a type of white blood cell present in the bone marrow.

The clinical trials are tailored for patients with low-risk myeloma (Total Therapy 4) or high-risk disease (Total Therapy 5). They are among 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.

This personalized approach to treatment is based on genetic analysis completed within 96 hours of a new patient’s arrival at the Myeloma Institute.

“For the low-risk group of patients, cure is now the expectation through treatment and support from our clinical care team,’” said Bart Barlogie, M.D., Ph.D., director of the Myeloma Institute. “At the same time, for high-risk patients, our research allows us to combat multiple myeloma at the cellular level.”

Elias Anaissie, M.D., a professor of medicine in the UAMS College of Medicine and director of supportive care at the Myeloma Institute, is the principal investigator for Total Therapy 4, the trial for low-risk multiple myeloma patients.

Frits van Rhee, M.D., Ph.D., professor of medicine in the UAMS College of Medicine and director of clinical research at the Myeloma Institute, is the principal investigator for Total Therapy 5, the trial for high-risk multiple myeloma patients.

Of 95 patients enrolled in Total Therapy 4, starting in July 2008, 90 are alive. All 12 patients enrolled in Total Therapy 5, which began in October 2008, are still alive.

Less than a decade ago, only a third of patients with multiple myeloma could expect to live more than five years after being diagnosed. A patient diagnosed today with low-risk multiple myeloma can expect to survive more than 10 years.

The latest trials build on the success of earlier applications of the Total Therapy approach. Twenty-one percent of the 231 patients enrolled in UAMS’ initial multiple myeloma clinical trial, known as Total Therapy 1, are still alive beyond 10 years, with some alive at 19 years. About 55 percent of those enrolled in Total Therapy 2, started in 1998, are still alive. Of almost 480 patients enrolled in Total Therapy 3, initiated in 2003, 78% are alive.

The latest trials, Total Therapy 4 and 5, evolved from results of Total Therapy 3, showing 83 percent of those with low-risk multiple myeloma still alive after four years, including 85 percent in complete remission with no signs of multiple myeloma.

Low-risk patients on Total Therapy 4 are given a different version of standard Total Therapy 3 designed to limit side effects. Total Therapy 5 for high-risk patients is aimed at sustaining effective tumor control by giving a series of lower doses of an eight-drug combination with short intervals between the treatments.

“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., professor of medicine in the UAMS College of Medicine and 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 hypothesized 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.

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 9,000 patients from every state in the United States and more than 50 foreign countries.