Multiple Myeloma

Disease Background

Multiple myeloma is a cancer of the plasma cells, a type of infection-fighting white blood cells that produce immunoglobins, also known as antibodies. Multiple myeloma occurs when the body begins to overproduce abnormal plasma cells. These abnormal cells can grow to form multiple tumors in the bone marrow. When the cells appear in a number of sites, the condition is called multiple myeloma. There is no cure yet for multiple myeloma using conventional therapy, although lengthy remissions have been achieved with newer experimental therapies. Before the era of chemotherapy, the median survival for people diagnosed with multiple myeloma was less than one year. Now, people often live three to four years, and some patients survive five to 10 years after diagnosis.

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The American Cancer Society (ACS) estimates that 16,570 Americans will be diagnosed with multiple myeloma in 2005 and more than 11,300 men and women will die from the disease. Age is the most significant risk factor for multiple myeloma. Only 1 percent of diagnosed cases occur in people under age 40, and the average age at diagnosis is 68. African-Americans are twice as likely to be diagnosed with the disease as European-Americans. Some studies have suggested that petroleum industry workers may run an increased risk of developing the disease.

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Our Research

Overview of Hutchinson Center Research

Hutchinson Center researchers are pursuing a number of clinical trials aimed at improving survival of multiple myeloma patients. The treatment approaches include bone-marrow and stem-cell transplantation and immunotherapies. Other approaches include new drugs that increase the potential for immune suppression before and after transplant, reduce graft-vs.-host disease (GVHD) and produce better growth of new cells.

In a promising new approach called a tandem transplant, center researchers are evaluating a standard autologous (self-donor) transplant followed after recovery with a mini-transplant, or nonmyeloablative allogeneic (donor) transplant. Mini-transplants involve low-dose radiation that doesn't destroy the marrow combined with a tissue-matched stem-cell transplant. In a Hutchinson Center-led multi-center clinical trial of this technique, 85 percent of the 41 patients who underwent the tandem procedure were still alive after one year. This compares to an average of 40 percent of patients who survive that long after a classic high-dose allogeneic (donor) transplant.

Other therapy approaches include immunotherapies that involve transplanting stem cells that have been stimulated to actively destroy remaining cancer cells as well as targeted radiation using radiolabeled antibodies that bind to cancer cells and concentrate radiation at the tumor sites. Drugs under evaluation include thalidomide and dexamethasone for curative therapies and bisphosphonates to relieve pain for those who are incurable.

Center researchers are also looking into environmental and occupational hazards that may lead to development of multiple myeloma. They are also seeking to identify genetic or protein markers in the blood to make possible much earlier detection and diagnosis of myeloma.

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Using the immune system to improve stem cell transplant outcomes

A new treatment developed at Hutchinson Center offers new hope for patients with lymphoma, multiple myeloma and a number of other cancers. The procedure combines a high-dose stem-cell transplant using the patient's own stem cells, followed by a nonmyeloablative transplant, also known as a mini-transplant, using stem cells from a matched sibling. This approach appears to increase survival and reduce toxicity compared to conventional transplants.

Dr. David Maloney, lead researcher, explains that success relies on the cancer-fighting properties of the sibling-donated stem cells. The process has also been successfully used for the treatment of leukemia and renal-cell cancer.

Harnessing the immense power of the body's own immune system to combat lymphomas and myeloma and other cancers has long been the goal of Maloney's laboratory team. A core area of his research is the development of monoclonal antibodies. These immune system components are engineered to recognize and bind to specific proteins on the surface of cancer cells. Such antibodies can be designed to attack cancer cells by themselves or they can be used to deliver cancer-killing doses of chemotherapy or radiation.

In addition, the team is investigating a variety of treatment regimens based on nonmyeloablative transplants, in which the patient undergoes low-dose therapy that does not ablate, or wipe out, the bone marrow, as in a conventional stem-cell or bone-marrow transplant. Ultimately the patient experiences both substantially reduced side effects and a more vigorous graft-vs.-tumor (GVT) effect to extend remissions. GVT is when the donor marrow recognizes the tumor cells and destroys them.

In support of these therapeutic strategies the Maloney laboratory is seeking a better understanding of how the immune system reconstructs itself after stem-cell transplantation to improve the efficiency and effectiveness of stem-cell transplantation for lymphomas, myelomas and other blood-based cancers.

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Stem-cell transplantation pioneer develops new radiotherapy for multiple myeloma

It was clear from the beginning that stem-cell transplants were easier than bone-marrow transplants on the donor, but it wasn't known whether the patient fared better with a bone-marrow or stem-cell transplant.

In a study published in the New England Journal of Medicine, Dr. William Bensinger and colleagues showed that stem-cell transplants are better for some patients than bone-marrow transplants. The five-year study showed that patients with advanced blood cancers might experience fewer complications, speedier recovery and improved relapse and survival rates when treated with stem-cell transplants as compared to traditional bone-marrow transplants.

In the late 1980s, it was Bensinger's research that led to the development of Hutchinson Center's procedure for extracting from circulating, or peripheral, blood the stem cells that produce all the cells of the blood and immune systems. The procedure, called apheresis, is similar to an extended blood donation. The donor sits in a chair with a tube in each arm, the machine collects the stem cells in a few hours while returning the rest of the blood cells to the donor. The donor needs no anesthesia and is able to return home the same day. That contrasts with the overnight operating room procedure to extract the lifesaving bone marrow, in which the donor under anesthesia undergoes hundreds of large-bore needle punctures of the pelvic bone.

Bensinger's development of Hutchinson Center's peripheral stem-cell procedure not only made stem-cell transplantation possible, it sped up research on stem cells, allowing researchers to better understand the migration and growth of these cells critical to saving patients treated with high-dose chemotherapy and radiation.

Bensinger's team is also seeking to use a radioactive isotope (166-Holmium) coupled to a bone-seeking compound that is taken up almost exclusively by bone with very little impact to the lungs, liver, kidneys and intestines. The approach is ideally suited to treating patients with cancer originating from the bone marrow, such as multiple myeloma. In an early clinical trial, 45 percent of the 25 patients treated achieved complete remissions of their myeloma. The results are so encouraging that a randomized phase III study is under way to compare the treatment with standard therapy.

If successful, this strategy could be extended to other diseases such as prostate cancer and is currently being studied in Ewing's sarcoma and breast cancer. The treatment may also serve as a platform for mini-transplants, which use less intensive conditioning prior to allogeneic (donor) stem-cell transplantation.

See also the Multiple Myeloma Research & Treatment Web site.

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Harnessing the immune system to prevent relapse after transplantation

Cancer relapse remains a major obstacle to cure after stem-cell transplantation for a variety of cancers, from lymphoma and melanoma to ovarian and advanced prostate cancer.

The high relapse rates seen after autologous transplantation, in which a patient receives stem cells that have been harvested from his own body, is likely due to the fact that the patient's immune system has been suppressed by the treatment, which makes it less likely that residual cancer cells will be eliminated by an immune response.

The research of Dr. Leona Holmberg and colleagues focuses on developing ways to strengthen the immune system after autologous transplantation to prevent cancer from recurring.

For example, in a series of clinical trials patients have received stem cells that have been grown in interleukin-2 (IL2), a growth factor that stimulates production of activated T cells and other immune-system fighters that eliminate abnormal cells from the body.

In an effort to maximize immune responsiveness of transplanted cells, Holmberg and colleagues are also treating breast-cancer patients whose stem cells have been fortified with IL2 in combination with a white-blood-cell growth factor called granulocyte macrophage colony stimulating factor. Another immune-based regimen, for patients with non-Hodgkin's lymphoma, combines IL2 with a drug called Rituxan.

Holmberg and colleagues also are investigating tumor-specific vaccines to maintain a primed immune system after transplantation. By combining immunotherapy drugs with standard high-dose autologous transplantation regimens, Holmberg and colleagues aim to reduce the relapse rate and improve survival in patients who undergo autologous transplantation for a variety of cancers.

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Relevant Articles

• Multiple Myeloma: Turning a Once-Deadly Disease into a Manageable Disease — Forum will detail latest treatments to combat this cancer of the elderly
  
  
• Fred Hutchinson Research Center Awarded $7 Million Grant To Lead Cancer Research Initiative — Investigation Is Part of The Leukemia & Lymphoma Society's $52 Million Global Research Program that Seeks to Find Cures for Blood Cancers
  
  
• High-dose chemo, mini-transplants offer hope for incurable myeloma
  
  
• Mini-transplants for those over 50: Success! — Storb/McSweeney study says outpatient treatment combination of low radiation, potent drugs works for older patients
  
  

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