Studies Advance Myeloma Treatment

One finds two transplants are better than one

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HealthDay Reporter

WEDNESDAY, Dec. 24, 2003 (HealthDayNews) -- Two studies provide new hope for people suffering from myeloma.

The first study found myeloma patients who received two transplants of their own stem cells after chemotherapy doubled their rates of overall survival and relapse-free survival compared with patients who had only one transplant.

The second study identified a gene that governs the process of bone destruction, which is a hallmark of myeloma. This gene, DKK1, is now a potential target for new drug therapies.

Both findings appear in the Dec. 25 issue of the New England Journal of Medicine.

Myeloma is cancer of the plasma cells, a type of white blood cell found primarily in the bone marrow. It is the second most common cancer of the blood after lymphoma, making it more common than leukemia. About half of the 15,000 people who are diagnosed with myeloma each year are under the age of 60.

Initial therapy usually consists of steroids and chemotherapy followed by one stem cell transplant, using the patient's own cells. "We're pretty comfortable that we know how to do the initial therapy," says Dr. Edward A. Stadtmauer, author of an accompanying editorial and director of the Bone Marrow and Stem Cell Transplant Program at the University of Pennsylvania in Philadelphia.

Several previous studies have shown no benefit to a second transplantation. The current study, conducted by researchers in France, was larger, lasted longer and did, in fact, find a benefit.

About 400 previously untreated patients all received chemotherapy and then were randomly assigned to receive either a single stem cell transplantation or a double transplantation.

Among the single-transplant recipients, the probability of surviving with no relapse for seven years after being diagnosed was 10 percent. Among the double-transplant group, that number was 20 percent. The overall seven-year survival rate in the single transplant group was 21 percent vs. 42 percent in the double group.

The double therapy seemed to work best in those who did not have a good response to the first transplantation.

Still, this double-fisted approach is not a cure. "Even with the double transplant approach, seven years later 80 percent have still had progression so there's a lot more to be done," Stadtmauer says.

"This is just one approach to pound away further at minimal disease [when the person is in remission] after a transplant. There are other things that we've done, too," Stadtmauer adds.

Lois Kozel, a 51-year-old accounting assistant in Doylestown, Pa., and one of Stadtmauer's patients, had one stem cell transplantation and then participated in a clinical trial. This involved having some of her own immune cells removed before the transplant, having them activated and then reinserted into her body after the transplant. "They don't call it a cure," Kozel says. However, Stadtmauer told her the remission could last 97 years. Kozel might also be a candidate for a second stem-cell transplantation if her myeloma starts to progress.

Meanwhile, Arkansas researchers have identified a gene, DKK1, which is produced by the tumor cells and is responsible for the bone disintegration associated with myeloma. Those same researchers have already started looking for a compound that will counteract the effect of the gene's hyperactivation.

"I think everybody in the community would agree that this is compelling evidence that this molecule is playing a key role in [myeloma-related bone destruction]," says study author John D. Shaughnessy Jr., an associate professor of medicine at the University of Arkansas for Medical Sciences' College of Medicine. "Knowing the molecule that causes the pathology means that we can develop drugs to disable this molecule."

Shaughnessy and his colleagues looked at the gene expression level of 10,000 genes in plasma cells from the bone marrow of patients who had recently been diagnosed with multiple myeloma and who also had bone destruction. These were compared with plasma cells from people recently diagnosed with multiple myeloma but without bone destruction. Four out of 10,000 genes were different. DKK1 was one of them.

The gene, which was first discovered in frogs, produces a molecule that prevents another molecule from binding to the cell surface.

What is still unclear is how the gene gets turned on in myeloma cells. "What we think is happening is that the tumor cell early on actually commandeers and usurps the bone marrow into making factors that turn the gene on," Shaughnessy explains. "The tumor cell enslaves these cells and gets them to make a factor to turn DKK1 on." Eventually, it results in the melting away of the bones.

"By preventing this, we're not only going to prevent bone loss but we're going to prevent tumor from growing," he adds.

The team is looking at both monoclonal antibodies -- bioengineered drugs that seek out a specific target -- to neutralize the molecule and molecules that would soak up the DKK1 like a sponge. "Pre-clinical studies ought to be finished in the next year to two years and then it all depends on the FDA [U.S. Food and Drug Administration]," Shaughnessy says.

More information

For more on multiple myeloma, visit the Leukemia & Lymphoma Society or the International Myeloma Foundation.

SOURCES: John D. Shaughnessy Jr., Ph.D., associate professor, medicine, College of Medicine, University of Arkansas for Medical Sciences, and member, Myeloma Institute for Research and Therapy, Little Rock; Edward A. Stadtmauer, M.D., director, Bone Marrow and Stem Cell Transplant Program, University of Pennsylvania, hematologist-oncologist, Abramson Cancer Center, University of Pennsylvania, and associate professor, medicine, University of Pennsylvania School of Medicine, Philadelphia; Lois Kozel, Doylestown, Pa.; Dec. 25, 2003, New England Journal of Medicine

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