By Cathy Dunn

Ask Alma Barnett what drug treatments she has received to combat multiple myeloma and she readily recites the whole list. She knows them all by heart.

Since her diagnosis in 1996, she says she has taken prednisone, melphalan, Aredia® (pamidronate), Zometa® (zoledronic acid), Decadron® (dexamethasone), Velcade® (bortezomib), VAD (Oncovin® [vincristine], Adriamycin® [doxorubicin] and Decadron), Cytoxan® (cyclophosphamide) and Myleran® (busulfan) preparatory to a stem cell transplant. “Now I’m in a clinical trial taking MAC (melphalan, Trisenox® [arsenic trioxide] and vitamin C),” says the 67-year-old retired teacher and amateur photographer. “Every drug kept the disease at bay for a while. When each therapy’s effectiveness fades, there’s another treatment to try.”

Myeloma, a malignant proliferation of plasma cells that attacks and destroys bone, can result in bone pain, bone fractures, renal failure, anemia and increased susceptibility to infection (see illustration). Because the disease is so insidious, it is also one of the more difficult cancers to treat, says James R. Berenson, MD, medical and scientific director of the Institute for Myeloma & Bone Cancer Research in Los Angeles.

“Unlike more curable cancers such as childhood leukemia—which is characterized by rapid tumor growth—myeloma may take years to develop. These slow-growing cancers are often more resistant to treatment,” Dr. Berenson remarks. “To further complicate matters, myeloma is not just one cancer; it is a varied group of cell abnormalities leading to different clinical characteristics and responses to therapy, so treatment is often very complex.”

About 15,000 Americans are diagnosed with the disease annually and the average survival is approximately five years, making early diagnosis and treatment essential to improve survival odds. Only about 10 percent of those diagnosed have the slow-growing or “indolent” form of the disease, which progresses slowly over many years.

Myriad new drugs in clinical and pre-clinical stages are being developed to fight myeloma. Among the most notable are proteasome inhibitors, immunomodulatory (IMiD) drugs and arsenic compounds.

Proteasome Inhibitors Take the Lead

Velcade® (bortezomib), the first treatment in more than a decade to be approved for patients with multiple myeloma, passed the strict regulatory hurdles of the Food and Drug Administration (FDA) in May 2003, an unprecedented four months after the drug’s submission.

The FDA approval came with positive results from a clinical trial involving 202 patients with relapsed or refractory multiple myeloma. Treatment with Velcade resulted in 28 percent of patients having partial or complete responses—an encouraging result in a disease with few effective treatment options. Also, disease stabilization was achieved in an additional 18 percent of patients.

Initially the drug was developed as a treatment for muscle-wasting conditions that would prevent the destruction of proteins needed for cell growth. Research showing Velcade could selectively stop the growth of cancer cells led to its use in myeloma treatment.

“Velcade blocks the activity of the proteasome, an enzyme molecule crucial to the normal functioning of all cells,” says Dr. Berenson. “This essential cell element has long been known as a cellular garbage disposal, destroying damaged proteins.”

Many of the processes that rely on proteasome function also can contribute to the growth and survival of cancer cells (see illustration). By disrupting normal cellular processes, Velcade promotes apoptosis (cell death) in cancer cells (see illustration). Because the drug’s ability to inhibit the proteasome is reversible, normal cells can recover from its effects, while cancer cells are more likely to die.

“Many of Velcade’s cancer-destroying effects may be due to its ability to block a key survival protein known as nuclear factor kB (NF-kB),” says Dr. Berenson. “NF-kB is found within the cell and acts as a transcription factor, turning on genes that cause production of proteins that stimulate growth and prevent death of tumor cells.”

Proteasomes are so essential to cellular function that many thought they would cause unacceptable damage to healthy cells as a cancer treatment. But clinical trials by researchers including Kenneth D. Anderson, MD, director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, showed it could act against cells of multiple myeloma and other blood cancers without disabling side effects.

Final results of the phase III APEX trial comparing Velcade and Decadron were presented at the 2004 meeting of the American Society of Hematology. The multicenter trial, which included 669 patients, is the largest randomized study to achieve a survival benefit in relapsed multiple myeloma. Specifically, during the first year, there was an estimated 41 percent reduction in the risk of death in patients receiving Velcade compared to those receiving Decadron. In addition, a 78 percent improvement in time to disease progression was seen in patients taking Velcade.

The drug’s most common side effects include a decline in platelets, which are required for blood clotting, and peripheral neuropathy. Neuropathy, the most troublesome, can usually be relieved by reducing the dosage or changing the dosing schedule, says Dr. Anderson. Velcade also can be given to patients with renal failure, even to those on dialysis, he adds.

“It’s the first drug of its class,” says Dr. Anderson, “and we hope more potent, second-line derivatives will be developed. Combining Velcade and Decadron is showing early promise. And we plan to test the drug with other conventional and novel therapies, as well as use it to treat patients with myeloma earlier in their disease course.

“We’re particularly excited about using Velcade as a first-line therapy,” he adds. “Although it is still too soon to fully evaluate the data, a majority of the patients in a phase II trial with Velcade as first-line therapy either showed disease stabilization or improvement.”

Barnett says Velcade kept her disease under control for about a year. During that time, she had some nausea but otherwise felt fine.

“I’m very active and I kept up with my schedule without any trouble,” she says. “But when Velcade showed signs of no longer controlling my disease, I was ready to try the next treatment.”

Dr. Berenson remarks, “Velcade is becoming more and more significant as a treatment option and, in combination with Doxil or melphalan, seems to have even more anti-myeloma activity. As a result, it is being used in previously untreated patients. It is truly a promising therapy for patients with this disease.”

Immunomodulatory Drugs (IMiDs) Show Promise

Thalomid® (thalidomide) was introduced to the European public in the 1950s, where it developed a reputation as a popular sleeping pill that was also effective against morning sickness. Although widely distributed elsewhere, it was not approved for use in the United States because of concerns about its effect on the nervous system.

Before long, the drug’s dangerous downside became evident in pregnant women: Those taking thalidomide delivered deformed babies at a startling rate. The drug was taken off the market and shelved for many years. Periodically, it was tested for other uses and became an accepted treatment for leprosy in the 1960s.

“In the past few years, thalidomide has been used to treat multiple myeloma as a salvage therapy and increasingly as a first-line treatment, either alone or in combination with other medications,” says Jayesh Mehta, MD, director of the Hematopoietic Stem Cell Transplantation Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago.

In fact, the FDA recently accepted the supplemental new drug application for thalidomide. Celgene Corporation, the drug’s manufacturer, expects accelerated approval of the drug by the middle of 2005.

Thalidomide’s side effects, particularly constipation, nerve damage and blood clots, can sometimes be severe. Less serious effects include constipation and fatigue.

Richard Dennison, 62, can attest to the downside of thalidomide. He suffers from chronic neuropathy, having completed treatment several years ago.
“Since my diagnosis in 1994, I’ve taken a variety of drugs—including BLTD (a combination of the antibiotic Biaxin with low-dose thalidomide and Decadron) and Velcade. Some of them worked for a while but the disease always came back again,” Dennison says.

“Ultimately, I had two stem cell transplants—an autologous graft, and then an allogeneic graft from my sister—in 2002. Since then, I’ve been in remission.”
Unlike many with the disease, Dennison does not have cancer in his bones. “I was diagnosed early, and I was lucky. I can still lead a fairly active lifestyle.”

Dr. Mehta says doctors are not exactly sure how IMiDs affect cancer cells, but they appear to halt growth or cause the death of multiple myeloma cells, keeping them from adhering to bone marrow stromal cells. “We do know that the drugs reduce blood vessel growth and angiogenesis in the bone marrow of patients with multiple myeloma.”

Two substances produced by bone marrow cells, interleukin-6 and tumor necrosis factor-a, are reduced by thalidomide, further inhibiting cancer cell growth. Immunomodulatory medicines (IMiDs) also enhance T-cell stimulation and proliferation, which triggers natural-killer cells that attack and destroy myeloma cells.

The most effective dose and schedule for thalidomide is still unknown, but researchers are testing lower doses of thalidomide and developing derivatives that maintain effectiveness while diminishing side effects. Revlimid™ (lenalidomide, CC-5013) has already been shown to produce fewer side effects and is showing good results in clinical trials for patients with relapsed multiple myeloma.

In a phase I trial, 71 percent of 24 patients with multiple myeloma that had progressed on other therapies stabilized or responded to Revlimid, which is now in phase III trials. In response to the FDA’s fast-track designation, Brian Gill, director of investor and public relations for the drug’s developer Celgene Corporation, says the company plans to submit a supplemental new drug application for Revlimid in mid-2005 with expected FDA approval by the end of next year.

“Thalidomide and its derivatives have definitely raised the bar for successive generations of treatment,” says Dr. Mehta. “Although there is only limited data about IMiDs in the literature, both preclinical and initial clinical studies are encouraging. There is still much to learn about how these compounds work in combating multiple myeloma. Even so, IMiDs clearly represent an exciting new generation of anti-cancer drugs.”

Investigating Arsenic Compounds

Arsenic has been used for medicinal purposes for more than 2,400 years. Now Trisenox® (arsenic trioxide), FDA-approved to treat a form of leukemia, is making inroads as a successful myeloma therapy.

“Trisenox activates proteins that cause tumor cell death and downregulates Bcl-2, a protein that protects cells from dying,” says Dr. Berenson. “It also inhibits the growth of new blood vessels that feed tumor-supporting cells.

“We’re particularly excited about using Trisenox in combination with other drugs. We’ve discovered that the addition of vitamin C appears to enhance the activity of Trisenox in destroying cancer cells resistant to other treatments,” he adds.

Barnett has been participating in the phase II trial using the MAC combination since November 2003, and she has few complaints.

“Other than being a bit tired and sometimes queasy from the melphalan, I’m doing fine. The treatments don’t keep me from traveling to national parks, taking photographs and visiting with my children and grandchildren. And those are the things that are important to my husband and me.”

Dr. Berenson says Barnett is now in partial remission and doing well on the new therapy.

In clinical trials, patients on Trisenox reported manageable symptoms including low blood counts, fatigue, diarrhea, fluid retention and abdominal pain.

“We’re combining Trisenox with other drugs, including Velcade and Decadron, to further investigate its potential,” says Dr. Berenson.

Finding Other Combinations

Another drug being used successfully in combination is Doxil® (doxorubicin), a drug that prevents cancer cells from growing by attacking and interfering with DNA, the genetic material in a cell.

Doxil, a reformulation of Adriamycin, encloses the drug in a bubble of fat molecules (liposome), which minimizes adverse side effects and allows the drug to be more active in the body for a longer period of time.

“Trials using combinations such as Doxil, vincristine and Decadron with or without thalidomide show high frequency and extent of response. And we are now beginning a trial of Velcade with Revlimid in patients with relapsed refractory disease and anticipate good results,” says Dr. Anderson.

The potential for treating myeloma with novel drug combinations is staggering, says Dr. Berenson. “There’s a smorgasbord of opportunities to be explored.”

“I think it’s very important for people with multiple myeloma to explore all their options,” says Dennison. “A treatment that is right for one person may not work for another. Some might choose stem cell transplants, others more traditional medications or novel therapies. Just keep trying until you find something that works.”