TED GRIGGS

Every year, a few thousand people from around the world visit Little Rock with no plans to see the Old Statehouse or the William J. Clinton Presidential Center and Park. The attraction that draws these visitors is far more powerful: life…or the hope for more of it.

The visitors have cancer, multiple myeloma to be precise.

The median survival rate for these patients in the United States is around two and a half to three years. At the University of Arkansas for Medical Sciences Myeloma Institute for Research and Therapy, the median survival rate is six to seven years and getting higher all the time.

Those kinds of results have drawn attention from the national media, including the Wall Street Journal and the New Yorker. But John D. Shaughnessy Jr., PhD, director of Basic Research and director of the Lambert Laboratory of Myeloma Genetics, said other publications are far more important to bringing patients to the institute.

“We get a lot of patients from outside Arkansas, and that typically results not so much from the lay press, but from the fact that we tend to publish in peer-reviewed journals on the order of 30 manuscripts a year that referring physicians across the globe also read,” Shaughnessy said. “They read the articles and we realize we’re pushing the envelope here and making great progress that they then apply in their clinics.”

The envelope pushing began in 1989. Founded by Dr. Bart Barlogie, the institute has treated more than 7,400 patients from the United States and 40 other countries since then. Last year, the institute performed its 7,000th bone marrow transplant.

Shaughnessy said there are several keys to the institute’s success. One is that the University of Arkansas was ripe for developing and establishing a world-class program.

Barlogie, the institute’s director, and Epstein convinced the school’s administration to provide the resources for the program. In turn, the university allowed the program to grow and supported it.

“This doesn’t happen on the left and right coasts as readily as it does in the center of the country where they’re trying to get name recognition and establish some center of excellence that will bring prestige to the university,” Shaughnessy said.

The institute’s treatment success also rests on the backbone provided by the tandem transplant strategy or regimen, Shaughessy said.

With a tandem transplant, the patient receives two sequential courses of high-dose chemotherapy, each followed by a stem cell transplant.

The institute’s frontline treatment now includes high-dose therapy with Melphalan, a chemotherapy drug that eliminates the myeloma cells from bone marrow, Shaughnessy said. Because Melphalan also kills the stem cells and other cells needed for normal immune cell functions, doctors at the institute first harvest healthy stem cells from the patient’s bone marrow. After the chemo, the patients are given back the stem cells, which repopulate the bone marrow and re-establish normal blood cell production.

“The philosophy was copied from acute childhood leukemia … where aggressive treatment preceded the cure,” said Joshua Epstein, D.Sc., professor of medicine at the institute. “Until we got very aggressive treatment, there was no cure. The thought was more is better.”

So the institute used and uses a mixture of drugs to treat the disease because tumors can easily develop a resistance to a single drug, Epstein said.

“The idea was if the cell was resistant to one, it would be killed by another,” Epstein said.

In the past five to seven years, the institute has added new drugs to the tandem-transplant backbone, including thalidomide, Shaughnessy said. The institute pioneered the use of the drug in myeloma treatment; a study of that therapy in patients who had relapsed was published in the New England Journal of Medicine.

The institute’s treatment also includes proteasome inhibitors (Bortezomib or Velcade), Shaugnessy said.

Proteasomes help regulate the growth of cells. In multiple myeloma, plasma cells reproduce uncontrollably.

Each one of the frontline protocols the institute has developed — the institute is now on Total Therapy III — has built on the success of the former, Shaughnessy said.

“What we’re seeing are dramatic improvements in the overall survival of patients with this therapy,” he said.

The median survival rate of patients with low-risk myeloma is three years nationally, Shaughnessy said. At the institute, the median survival of low risk patients enrolled on the Total Therapy II protocol has not been reached with over 70% of patients alive 8 years after starting therapy.

There are a number of other factors in the institute’s treatment results, including translating scientific discoveries into practical applications.
Although much of the institute’s research has been adopted by other treatment centers, most cannot offer the kind of supportive care that the institute does, Shaughnessy said. Patients reap the benefit of doctors who are experts in treating the immunocompromised.

Epstein said the huge numbers of patients the institute treats and that experience provides a tremendous advantage.

“We anticipate what might happen, what’s going to happen with the patients, rather than responding to things that happen,” Epstein said. “If you can anticipate all the bad things that can happen, you can prevent most of them.”
Meanwhile, the institute’s researchers are working hard to figure out why bad things happen in myeloma. Part of that involves looking at risk stratification and disease classification.

By studying genes within myeloma patients’ tumor cells, researchers discovered that myeloma is not one disease, Shaughnessy said. It’s probably seven to eight distinct entities, each with a unique mechanism of development. So while the tumors might all look identical under a microscope the molecular mechanisms that drive the development of the tumor are different for each subtype that we have discovered.

This means that sometime in the future, possibly within the next 10-20 years, or even sooner, treatments could be based on the particular molecular mechanisms that cause the cancer’s development.

Shaughnessy said researchers also know that the course myeloma follows varies widely.

A certain percentage of patients die within a year while others survive 10 years even though both receive the same treatment, he said.

At present, clinicians and scientists do not have an adequate way to identify high-risk patients, around 15 percent of the total myeloma population.

But that appears to be changing. Last year, researchers at the institute found a gene signature that could identify the high-risk form of the disease.

“Now what we’re trying to understand is how this occurs, why it occurs, what are the genes that are important and can we modify this?” Shaughnessy said.

Researchers have also discovered that patients who originally present with a
low-risk signature can many times relapse into a high-risk form of the disease, he said. When they do they have a poor post-relapse survival rate.

Researchers are also investigating a factor secreted by myeloma cells that causes bone destruction, Shaughessy said. It’s possible that this molecule may play a major role in how the disease progresses, infiltrating the bone marrow and usurping its normal function for the myeloma cell’s advantage.

Phase I clinical trials, or safety trials, are now underway for a treatment that will target that specific mechanism, he said.

Epstein said that one thing many people don’t realize is that myeloma, like many cancers, is a disease of the elderly.

“The median case for diagnosis is between 60 and 70,” he said. “To add 10 years to that is very significant.”

Many of the institute’s patients that died were not killed by the disease but by the other things that people die from normally, such as car accidents, heart disease and stroke, he said.



March 2008