New Drugs Offer Hope in Treatment of Blood Cancer

MILWAUKEE _ A better understanding of plasma cells and how they act inside bone marrow has enabled scientists to improve dramatically treatment of patients with the blood cancer multiple myeloma.

In the past decade, they’ve tweaked old drugs and created new ones to either slow or stabilize tumor growth. As a result, patients now live longer and doctors have become increasingly hopeful that the often fatal and incurable disease soon will be treated more like a chronic condition.

“It’s like night and day,” said Mitchell Smith, director of the lymphoma service at Fox Chase Cancer Center in Philadelphia, who’s been treating patients with multiple myeloma for almost 20 years.

“When I started practicing, you’d tell patients they’d have problems with bone fractures and bone pain and chemotherapy side effects,” he said. “Then you’d say, `You need a stem cell transplant and even with that, the disease will stay away awhile before coming back, and there won’t be much more that we can offer you.’”

But the recent approval of three drugs for multiple myeloma treatment _ thalidomide, lenalidomide and bortezomib _ and the testing of several others in clinical trials have changed the outlook for most patients, Smith said. He is also a member of a committee that develops the multiple myeloma clinical practice guidelines set by the National Comprehensive Cancer Network.

Multiple myeloma is a cancer characterized by an excessive number of abnormal plasma cells in the bone marrow. Plasma cells play a major role in the immune system because they produce antibodies to fight infections and disease. When they grow out of control, plasma cells can form a tumor, usually in the bone marrow. This means that the bone marrow may not be able to make enough red blood cells, platelets or normal white blood cells. As a result, patients can become anemic, more susceptible to infections and bleeding, and develop bone damage. In rare cases, the disease can lead to organ damage, particularly in the kidneys.

The American Cancer Society estimates that there will be about 19,900 new cases and 10,790 deaths from multiple myeloma in 2007. The disease is more common in men and African-Americans.

For years, multiple myeloma was treated with chemotherapy in combination with hematopoietic stem cell transplantation, which uses the cells found in adult bone marrow. But now, patients typically receive some form of initial therapy such as the steroid dexamethasone in combination with thalidomide or lenalidomide, as well as treatment for bone disease and other complications.

“It’s a very exciting time because we have lots of drugs (that) basically change the bone marrow environment and make it hard for cancer cells to live there,” said Parameswaran Hari, an assistant professor of medicine at the Medical College of Wisconsin and a myeloma specialist at Froedtert Hospital.

In May 2003, Velcade, or bortezomib, became the first new treatment in more than a decade. It slows the progression of the disease in patients who have relapsed after two prior treatments and who have shown resistance to their last treatment. The Food and Drug Administration approved the drug in less than four months.

Three years later, the agency approved Revlimid, or lenalidomide, to delay cancer progression in patients who had failed previous therapy. The drug works similar to the cancer drug thalidomide, which caused thousands of birth defects in the 1960s, but it has fewer side effects. Thalidomide was also approved in 2006 for use in combination with the dexamethasone for initial treatment in patients diagnosed with multiple myeloma.

Patients taking either lenalidomide or thalidomide must comply with a carefully monitored program developed by the FDA.

The expanded choices are a boon for patients, but they also make it difficult for doctors to determine where to start treatment because there are now so many right choices, said Natalie Callander, an associate professor of medicine and an oncologist at the University of Wisconsin Carbone Cancer Center in Madison.

“For the last 15 years, stem cell transplants have been the standard treatment,” she said. “But with these new therapies, some people are wondering: Should we just skip the transplant step?”

Thalidomide originally was used as a sleeping pill and to treat morning sickness during pregnancy, but was later found to be beneficial in multiple myeloma patients. Although researchers are unsure exactly why the drug works, they believe it targets the myeloma cells and surrounding cells to inhibit the growth of new blood vessels that feed the tumor cell and alters the production of chemical messengers called cytokines that help the cells grow and survive. The drug may also help to boost the immune system.

However, it has problematic side effects, including severe peripheral neuropathy, or nerve damage, and deep-vein thrombosis.

Bortezomib, which is now approved for initial treatment use, is a proteasome inhibitor that targets a process critical for cell growth. Though normal cells can recover from proteasome inhibition, cancer cells die when their proteasomes are inhibited. Bortezomib also is believed to inhibit the growth and survival of myeloma cells by preventing the cells from sticking inside the bone marrow.

Clinical trials are now looking at other ways to attack the cancer, such as combination therapy using bortezomib, use of genetically engineered proteins called monoclonal antibodies to deliver treatment to the tumors and inhibition of substances released during the immune response that help stimulate tumor cell growth.

“Any one of these drugs by itself is not going to be the answer,” Hari said. “It will likely take a combination of all effective strategies.”

Although multiple myeloma responds to therapy, it is not curable and often recurs.

According to the National Cancer Institute, the median survival was about seven months before the introduction of chemotherapy in the 1960s. However, the chemotherapy has expanded that median to 24 to 30 months with a 10-year survival rate of 3 percent.

Earlier this month, researchers reported that using lenalidomide and dexamethasone prolonged median survival by nine months, to 29.6 months compared with 20.2 in patients not taking the combination. In addition, the combination produced a response in 61 percent of patients taking the drug, compared with only 20 percent in those not taking it.

Common side effects included fatigue, insomnia, diarrhea, constipation and muscle cramps. However, patients also reported more infections and blood clots, though these symptoms usually were eliminated by adjusting the lenalidomide dose, or administering antibiotics or anticoagulants.

The clinical trial was conducted at 44 centers in the United States and Canada.

Last year, another study found that though thalidomide treatment failed to prolong overall survival, patients taking the drug had a significantly higher rate of complete response and five-year event-free survival compared with the control patients. A complete response means no evidence of the disease is found using sensitive molecular techniques.

The study involved more than 600 patients newly diagnosed with multiple myeloma who received two cycles of chemotherapy along with hematopoietic stem cell transplantation.

Bortezomib has also been shown to increase overall survival in patients taking the drug.

Pam Vanasten went to her family doctor in July 2006 believing she had a pulled muscle. However, an X-ray found a two-inch hole in her femur and she was diagnosed with multiple myeloma.

“At that moment, I really didn’t know what it was, but I looked at my doc and asked, `Do you think I can beat it,’” she said. “And he said, `You know what? I think you can.’”

Vanasten discussed her treatment options with oncologist Callander before deciding to take thalidomide once a day and then have a stem cell transplant.

Two months after she began her treatment, she added bortezomib to her regimen.

Vanasten, 41, had her stem cell transplant in February. She says she’s back to her busy lifestyle, which includes coaching basketball, shuttling three kids to their extracurricular activities and maintaining the salon she owns.

Part of her motivation throughout the ordeal came from her 9-year-old son, who constantly told her to “suck it up” _ a phrase she often uses with her kids.

“That was awesome to hear,” she said. “I thought, `Yeah, suck it up and move on.’”

Now she says that she lives every day to its fullest and that she tries to only think of the future.

“I am really lucky because not everyone gets this chance,” she said.

___

(c) 2007, Milwaukee Journal Sentinel.

Visit JSOnline, the Journal Sentinel’s World Wide Web site, at http://www.jsonline.com/

Distributed by McClatchy-Tribune Information Services.

For reprints, email tmsreprints@permissionsgroup.com, call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.