Researchers' discoveries yield new treatments for multiple myeloma
When astrophysicist Joseph Schwarz, Ph.D., was diagnosed with multiple myeloma in 1984, he may have been tempted to pin his hopes on stardust.
The disease, in which the bone marrow fails to produce enough red and white blood cells and platelets, has no known cure. The standard treatment, chemotherapy, can quell the disease for a few years, but a relapse is almost inevitable.
Schwarz, who was in his late 30s at the time of his diagnosis, recalls his dissatisfaction with this prospect, his frustration at the lack of new therapies for the condition, and his excitement when he heard about a novel treatment being tested at Dana-Farber Cancer Institute by Kenneth Anderson, M.D.
"I'd been to one of the top myeloma experts in the country, who told me there was nothing new for this disease," says Schwarz, who is currently working at the European Southern Observatory in Munich, Germany. "But a doctor in Boston told me about a patient who had received a novel kind of bone marrow transplant at Dana-Farber. She had an aggressive form of myeloma, and nine months after the transplant, had no detectable signs of disease."
In a short time, Schwarz had signed up for the treatment, a clinical trial in which a portion of his bone marrow would be harvested and cleansed of cells that were crowding out normal blood-making cells. After he received high doses of chemotherapy to destroy his remaining marrow, the purified marrow was reinjected into his body, rebuilding his blood supply and immune system.
The transplant didn't cure Schwarz, but it did give the disease, in Schwarz's words, a "knock on the head." In the following years, he would have several relapses, be treated with interferon, undergo two stem cell transplants in six months, take the drug thalidomide and steroids, try a novel therapy developed by Anderson involving "monoclonal antibodies," and receive yet another transplant, this time with his sister's bone marrow.
That Schwarz is alive and productive today is testimony to his perseverence and luck - and the concern and resourcefulness of his doctors. Though he has been treated by physicians in both the United States and Europe, a constant in his care has been Anderson, who directs the Jerome Lipper Multiple Myeloma Center and Kraft Family Blood Donor Center at Dana-Farber. Whether serving as Schwarz's personal physician, a consultant to his physicians in Europe, or as a combination scientist/clinician/friend, Anderson has been an indispensible ally in Schwarz's long struggle with the disease.
"I'm lucky to be alive, in as good shape as I'm in, and to have had good doctors," reflects Schwarz. "Ken certainly leads that list. He's had new treatments to try, and he's always been perfectly straight with me; he doesn't condescend. Whatever questions I've had, and I've had a lot and asked some of them twice, he's always ready to answer. He's an incredibly warm, smart person."
Schwarz is unusual in the length of time he's survived with multiple myeloma, but he's not unusual in his reasons for seeking treatment at Dana-Farber, or in his assessment of Anderson. The Institute's reputation as a place where novel treatments for myeloma are being developed and tested in patients reaches literally around the world.
"Patients come here because we're able to offer novel treatments that hold great promise in myeloma," Anderson says. "Our work begins in the laboratory, where we're exploring the mechanisms that enable myeloma cells to grow and survive in the bone marrow. Our goal is to translate those findings into new therapies that can be tested in patients in clinical trials."
Deadly Statistics
The disease to which Anderson has devoted his professional life is a rare, but almost invariably fatal, form of cancer. Though it accounts for just 1 percent of all cancers and 2 percent of cancer-related deaths, multiple myeloma is the second most common type of blood cancer, accounting for 11,000 deaths annually in the United States. It is the fourth fastest-growing cancer in terms of mortality and is among the top 10 causes of death among African-Americans.
The causes of the disease are unknown, but exposure to radiation or pesticides is thought to increase risk. The average age of myeloma patients is 60.
The hallmark of the disease is a buildup of plasma cells in the bone marrow. Plasma cells produce infection-fighting antibodies and are an important part of the body's natural arsenal against disease. But when they become too abundant in the bone marrow, plasma cells take the place of tissue that produces red and white blood cells and the platelets needed for clotting. The result is fatigue, an increased susceptibility to infection, and bleeding.
Over the past 20 years, Anderson and his team have pioneered critical advances against the disease, leading not only to improved treatments, but also to a deeper understanding of how myeloma occurs at the basic level of cells and genes.
Some highlights of their investigations include:
- 1981 - Dana-Farber scientists published studies showing how myeloma cells differ from normal bone marrow cells, a project Anderson describes as "identifying the enemy";
- 1984 - Researchers used surface markings to "fingerprint" how myeloma cells differ from lymphoma and leukemia cells;
- 1986 - Investigators applied their discovery of myeloma cells' fingerprints to develop a new treatment for the disease - a bone marrow transplant in which harvested marrow is purged of myeloma cells before being returned to patients' bodies;
- 1998 - Researchers introduced therapies that use the body's immune system as a weapon against myeloma and made new inroads in their understanding of the signaling pathways inside myeloma cells;
- 1999 - The Institute opened the Daryl Elizabeth Layzer Infusion Center, where myeloma patients can participate in clinical trials;
- 2000 - DFCI opened the Jerome Lipper Multiple Myeloma Center, where basic research into the disease is conducted.
United Against Myeloma
To visit the Lipper Center is to witness a revolution in the way myeloma is studied and treated. The center — named after Jerome Lipper, a prominent lawyer and Dana-Farber patient who died of multiple myeloma in 1991 — is a group of laboratories in the Louis B. Mayer Building. There, some 14 scientists and postdoctoral fellows from countries as widely dispersed as the United States, India, Japan, Austria, Germany, Taiwan, and Singapore probe the inner workings of myeloma cells in hopes of developing new therapies. The researchers are so diverse that Anderson lightheartedly refers to them as the "United Nations against myeloma."
The focus of their research is worlds removed from traditional chemotherapy. The aim of chemo and radiation therapy — for more than 25 years the standard treatments for multiple myeloma — is to home in on myeloma cells and destroy them. The regimen can extend patients' lives by an average of three or four years, and high doses of chemo can lengthen the time when patients are free of active myeloma, but it doesn't prolong their overall survival.
"The limitations of conventional therapy make clear the need for new approaches," Anderson says. "At Dana-Farber, we've taken a broad perspective that includes, but isn't limited to, myeloma cells themselves."
Although research at the Lipper Center includes dozens of individual studies, the work is moving along four main tracks: investigations of the genetic abnormalities of myeloma cells; studies of the circuitry that enables myeloma cells to grow and resist chemotherapy; efforts to unleash the power of the immune system against myeloma; and explorations of the way myeloma cells interact with their environment in the bone marrow.
Some of the most exciting projects are in the final category. "We know that chemotherapy works by targeting and destroying myeloma cells," Anderson says. "The aim of our current research is to understand the relationship between myeloma cells and their 'microenvironment,' the bone marrow cells among which they live. Ultimately, we want to develop and test therapies that make the bone marrow inhospitable to myeloma cells — that, in effect, evict myeloma cells from the neighborhood."
One agent that seems able to do that has a familiar, if notorious, name: thalidomide. The drug, which caused thousands of birth defects in the 1950s and '60s when taken during pregnancy, has a potent effect against some cancers (see page 8). At the Lipper Center, investigators have sought to discover how thalidomide achieves its anti-myeloma effect. "We found that thalidomide works in several ways," says Faith E. Davies, M.D., a postdoctoral fellow at the Lipper Center. "It not only acts on myeloma cells themselves, killing them or causing them to become dormant, but it also acts on their environment, reducing the cells' ability to stay in the marrow."
The Power of Immunity
Part of the reason patients succumb to multiple myeloma is because their immune systems — which normally detect and kill diseased cells — lose their ability to determine that myeloma cells are diseased. At the Lipper and Layzer Infusion centers, investigators are collaborating with researchers throughout Dana-Farber on ways to overcome this problem. Their advances have led to new treatments now being tested in patients.
One of the treatments involves a procedure called "adoptive immunotherapy" — a way of adding to the immunological punch of traditional bone marrow transplants. Doctors including Edwin Alyea, M.D., Jerome Ritz, M.D., and Robert Soiffer, M.D., first perform a bone marrow or stem cell transplant from a compatible donor. The transplant regenerates patients' blood and immune systems and reinvigorates their bodies' ability to fight myeloma. To further strengthen that response, doctors then give patients an infusion of donor lymphocytes — cells that reinforce the immune system. This is the treatment Joseph Schwarz received most recently.
Clinical trials are also under way to test novel kinds of vaccines against myeloma. One trial, being conducted by John Gribben, M.D., of Dana-Farber's Department of Adult Oncology, seeks to "decamouflage" myeloma cells so they can be detected and attacked by the immune system.
Researchers have found that if a protein called CD40 on the surface of myeloma cells is activated, the cells become "visible" — and vulnerable — to the immune system. In the technique being tested by Gribben and his colleagues, these visible myeloma cells are used in a vaccine. The goal is to trigger an immune response against myeloma cells throughout the marrow.
Another approach to a vaccine is being tested by David Avigan, M.D., Donald Kufe, M.D., and Jianlin Gong, M.D., of Adult Oncology. As in the CD40 technique, doctors remove some of patients' diseased marrow, but in this case, they fuse the myeloma cells to dendritic cells, whose job is to alert the rest of the immune system to the presence of foreign or diseased cells. The fused cells are used as a vaccine, potentially sparking a powerful immune attack on myeloma cells everywhere in the body.
The Human Touch
Crucial as such cutting-edge treatments are in attracting myeloma patients to Dana-Farber, it is the quality of care they receive at the Institute that engages their loyalty.
Nancy Orazem, who has been treated at the Institute since 1990, remarks that "the focus of everyone - from physicians and nurses to housekeeping staff — is on the well-being of the patient. Everyone has been so supportive: there's a real sense that they care about your health, that they want you to get better. It's the most caring, upbeat environment imaginable for patients with this condition."
She reserves special praise for Anderson, who, she says, has managed to balance being "truthful and non-alarmist" during 10 years of ups and downs with the disease. "He always gives hope," she notes. "Even now, when things are going really well with my condition, he tells me what he and his colleagues are working on in the lab. These are treatments that I don't need yet, but it's comforting to know they're there.
"He's full of human kindness," she continues. "He's a rare combination of someone who's a marvelous scientist as well as a wonderful caregiver and human being."
Her comments are echoed by Kathy Giusti, who directs the Multiple Myeloma Research Foundation in Connecticut and whose myeloma is in the "smoldering" stage before becoming an active disease.
"For people with cancer, it's crucial to identify a physician who's a leader in treating their specific type of disease," she says. "For multiple myeloma, it's Ken Anderson. Anything that offers potential for a cure or for extending my life is being tested at Dana-Farber. There's no one I'd trust more than Dr. Anderson, no one who's better educated about this disease or more committed to taking care of me."
Source: Paths of Progress, Winter/Spring 2001
