By Faith Reidenbach

“It’s smart‚” Lee Grayson says ruefully‚ describing the myeloma he’s been fighting for eight years. “It’s an immune system cell‚ and it’s wonderfully designed to help protect your body. So now you have this cell that’s turning on you‚ but because it’s so wonderfully designed it’s hard to get rid of the darned thing.”

Grayson‚ a professional musician from Huntington Station‚ New York‚ says he has learned that no matter what drug is sent forth to eradicate them‚ myeloma (usually called multiple myeloma) cancer cells come back. Though lengthy remissions are possible‚ multiple myeloma is considered one of the more difficult cancers to treat‚ because myeloma cells can eventually develop resistance to chemotherapy.

Over the last few years‚ major progress has been made in understanding the biology of multiple myeloma. New drugs work differently from standard chemotherapy. In addition to killing myeloma cells directly‚ they change the cells’ home—bone marrow—in ways that keep myeloma cells from developing in the first place. New approaches include Thalomid® (thalidomide)‚ immunomodulatory drugs‚ and proteasome inhibitors‚ but to understand these drugs‚ it’s important to understand the disease.

Cancer of Bone Marrow Cells
Multiple myeloma is a cancer of the plasma cells in the bone marrow‚ the soft‚ spongy tissue that fills the center of most bones. Plasma cells are part of the immune system‚ and‚ under normal circumstances‚ they produce a variety of antibodies that help the body fight off infection and disease.

As in most cancers‚ uncontrolled reproduction of cells is a hallmark of multiple myeloma. Usually plasma cell tumors grow at multiple sites within the bone marrow and throughout the body; thus‚ the disease is called “multiple myeloma.”

The excess plasma cells indirectly result in reduced numbers of red blood cells‚ resulting in anemia. Anemia then causes symptoms such as fatigue and shortness of breath on exertion. Increased susceptibility to infections may occur because of an inability to form normal antibodies. Excess protein created by the cancer cells may accumulate in the urine‚ overloading the kidney and leading to kidney malfunction or failure. When protein accumulates in the blood it causes hyperviscosity (abnormal thickness) with symptoms such as weakness or exhaustion‚ confusion‚ headache‚ blurry vision‚ and bleeding from the gums or nose.

The excess cells produce substances that leach calcium out of bones. This can result in hypercalcemia (excess calcium in the bloodstream)‚ with symptoms of nausea‚ confusion‚ frequent urination‚ and constipation. Hypercalcemia is the result of some of the most debilitating consequences of multiple myeloma: osteolytic lesions (holes in bones)‚ bone pain‚ fractures‚ and collapse of vertebrae in the spine.

Myeloma patient Helen McDowell‚ 68‚ says that the compression fractures of her vertebrae are causing “havoc.”

“I have multiple compression fractures of my vertebrae‚” says the Brooklyn‚ New York resident‚ ”and as a result I’ve lost about five inches in height. If I didn’t have these compression fractures‚ I would be independent and more mobile.“ Virtually all patients with multiple myeloma receive a bisphosphonate‚ a drug that fights bone loss.

Room for Improvement
There have been many attempts to improve on the standard chemotherapy combination of the drug Alkeran® (melphalan) plus the steroid prednisone. Only about 50-60% of patients respond to this treatment‚ even when other drugs are added.

In the early ’80s‚ doctors started trying to increase the dosage of another of the more successful regimens: Oncovin® (vincristine ) and Adriamycin® (doxorubicin ) plus high doses of the steroid dexamethasone. This combination‚ abbreviated VAD‚ yields a better response rate than the standard Alkeran and prednisone‚ and it increases duration of survival‚ on average‚ although not by much. Also‚ 30–40% of patients respond to high–dose steroids alone‚ according to Brian Durie‚ MD‚ director‚ Myeloma Program‚ Salick Health Care‚ Inc.‚ Cedars–Sinai Comprehensive Cancer Center in Los Angeles‚ California.

Bone Marrow Transplant
An even higher chemotherapy dose became possible in the 1990s once doctors started following chemotherapy with autologous stem cell transplantation. Stem cells from the patient’s bone marrow‚ which can develop into red blood cells‚ white blood cells‚ or platelets as needed‚ are stimulated with drugs to move into the bloodstream where they can be collected prior to high–dose chemotherapy. After the chemotherapy‚ the stem cells are reinfused to rescue the bone marrow. About 50% of patients achieve complete remission after this procedure‚ which frequently translates into excellent quality of life‚ according to Dr. Durie. He adds that about 50% of patients who go into remission stay in remission longer than 18 months‚ and about 25% stay in remission for at least four years. “The ongoing negative is the constant threat of relapse.”

Another approach has been the allogeneic bone marrow transplant (allografting)‚ in which a normal donor’s stem cells are used instead of the patient’s. The obvious advantage of donor cells is that they don’t contain tumor cells that can lead to relapse. Unfortunately‚ the results of conventional allografting are generally poor. Remission occurs in only a minority of multiple myeloma patients‚ and the death rate from the transplant itself is estimated to be 10-30%.

This is partly due to the toxicity of the technique‚ according to Jayesh Mehta‚ MD‚ director of Hematopoietic Stem Cell Transplantation Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago‚ Illinois. Before conventional allografting‚ very high doses of chemotherapy (and/or radiation) are used to kill myeloma cells‚ a process known as cytoreduction. This preparation also suppresses the immune system‚ so the “invading” donor cells won’t be fought off.

Today‚ minitransplants‚ also called miniallografts‚ offer an advanced treatment that is less costly and more tolerable than conventional allogeneic transplants. Before the mini was available‚ patients received high–dose chemotherapy. In contrast‚ in the mini they receive lower-dose chemotherapy‚ which suppresses the immune system enough that the donor cells are accepted‚ but then it’s up to the donor cells to recognize and destroy the tumor cells in the patient. That’s called a graft-versus-myeloma effect.

A number of centers are trying minitransplants‚ but so far there hasn’t been a controlled study‚ says Dr. Mehta. Meanwhile‚ he and his colleagues have had promising results with “microallografting” (giving a low dose of Alkeran followed by four small infusions of donor stem cells over 112 days).

“It is not the very first treatment we offer‚” Dr. Mehta emphasizes. “All patients always get some chemotherapy to bring their disease under control. But if a patient has newly diagnosed disease which is high risk in terms of likelihood of a very short remission duration‚ then we would consider it very early.”

Dr. Mehta says patients usually stay in the hospital for a shorter time for a miniallograft than the approximate six weeks after a conventional allograft. But they are still at risk for complications such as graft-versus–host disease‚ in which the donor cells attack the patient's immune system‚ so patients need medication and weekly blood tests.

The urgently needed new era in multiple myeloma treatment began in 1998‚ when for the first time in three decades a single drug‚ thalidomide‚ was reported to have independent activity against the disease. But the story of thalidomide goes back much further.

A Tragic Past‚ A Promising Future
Thalidomide was first marketed in West Germany in 1957 as an over-the–counter sleep aid. Its sedative effects were subsequently found to reduce morning sickness in pregnant women‚ and it was prescribed for that purpose and others in 46 countries. However‚ concern over neurological side effects kept it off the market in the United States.

In the late ’50s‚ physicians began noticing what was eventually termed an “epidemic” of unusual birth defects‚ especially malformations in which babies’ arms and legs were greatly reduced in length or absent altogether. When enough evidence had accumulated to link these defects to thalidomide use during pregnancy‚ the drug was removed from world markets in 1961 and 1962.

Decades later Bart Barlogie‚ MD‚ PhD‚ director‚ Myeloma Transplantation Research Center‚ Arkansas Cancer Research Center‚ Little Rock‚ Arkansas‚ pioneered the use of thalidomide for multiple myeloma.

“It all came about through the tragic experience of a young cardiologist in Manhattan‚” Dr. Barlogie says. The cardiologist‚ who was 35‚ had very aggressive disease that had recurred despite numerous treatments‚ including three stem cell transplants. His wife was relentlessly searching to find something else to try.

Eventually‚ she heard about Judah Folkman‚ MD‚ of Harvard Medical School in Boston‚ Massachusetts‚ who was conducting laboratory experiments with endostatin‚ a naturally occurring protein that blocks angiogenesis‚ the growth of new blood vessels that feed a tumor.

The patient’s wife asked Dr. Barlogie to call Dr. Folkman‚ but Dr. Folkman said endostatin was not available as a drug. Dr. Barlogie asked if there was something else that might have antiangiogenic properties. The answer: thalidomide.

In autumn 1997‚ Dr. Barlogie obtained permission from the U.S. Food and Drug Administration (FDA) to prescribe thalidomide. Sadly‚ the cardiologist died in March 1998‚ but Dr. Barlogie decided to try thalidomide in another patient with advanced disease.

“Four to six weeks later he had a normal blood count‚ and he almost had a complete remission‚” Dr. Barlogie recalls.

Dr. Barlogie quickly wrote a formal protocol that was moved through the FDA in a matter of weeks. At the same time‚ Celgene Corporation of Warren‚ New Jersey‚ was petitioning the FDA for approval to market thalidomide for treatment of a complication of leprosy. It won approval in July 1998‚ and in October 1998 the company won orphan drug status for thalidomide for treatment of multiple myeloma.

In the November 1999 issue of The New England Journal of Medicine‚ Dr. Barlogie and colleagues reported early results on 84 patients with treatment–resistant multiple myeloma who had taken thalidomide for up to 15 months. Almost a third of the patients had at least partial remission of their disease and two had complete remission. This demonstrated that thalidomide could‚ in some cases‚ overcome the resistance that myeloma cells develop to conventional therapies. The most common side effects were constipation‚ weakness or fatigue‚ and daytime sleepiness.

As of March 2002‚ Dr. Barlogie and his colleagues in Arkansas have treated a total of 169 patients‚ and the longest follow up is 3.5 years. Dr. Barlogie says that of the entire group‚ 40% are alive and 20% are disease free. Prospective thalidomide users are required by the company to participate in an educational program about birth defects and pledge to use adequate birth control while taking the drug.

“For me [the sedative effect] was great‚” says Grayson‚ who had such severe bone pain and weakness before he started taking thalidomide that he was sleeping sitting up. “I know some people on it were having a little difficulty getting started the next day‚ but for me it was: Take a few pills at night‚ have a nice sleep‚ wake up in the morning.” On a dosage of 400 mg a day‚ later reduced to 300 mg a day‚ over a few months he went into “a complete‚ true remission.” He was able to resume playing tennis and even took tap dancing lessons.

There is evidence that thalidomide can have a greater impact when used as the initial treatment for multiple myeloma. The first such report came in August 2001 in the journal Leukemia‚ where a Mayo Clinic team described using thalidomide to treat 16 patients with early–stage multiple myeloma (also known as smoldering or indolent disease). Over several months‚ two of the patients showed worsening disease‚ but six had a 50% or greater reduction in protein levels‚ and five others had a minor (25–49%) reduction.

Dr. Barlogie says the questions now are about how best to use thalidomide‚ when‚ at what dose‚ and with what other drugs‚ if any.

“In some cases thalidomide is being combined up front [soon after diagnosis] with chemotherapy or dexamethasone‚” says Dr. Durie. “The response rate approximately doubles when you combine it with something else as an upfront approach.” He adds that thalidomide and dexamethasone‚ sometimes in combination with other drugs‚ can be used to get a patient into remission before an autologous stem cell transplant.

It isn’t yet known‚ Dr. Durie explains‚ whether it’s better to stay on a low-maintenance dose of thalidomide‚ or stop it and consider restarting if the myeloma comes back. “But the traditional approach is that you just keep taking it at a dose that is not causing too much neuropathy.”

Polyneuropathy (nerve disturbance or damage in the hands and/or feet) is the most common side effect of long-term thalidomide use. “At first it was just what I called a slight nuisance‚” Grayson says. “Eventually it went from a kind of a tingliness to a numbness. Then the numbness started moving up my leg over time.”

After two years of use‚ thalidomide quit working for Grayson. The neuropathy‚ he says‚ hasn’t cleared up since he has been off thalidomide.

“It’s almost as if I’m wearing these tight‚ heavy boots. I have to be a little careful about my walking. I?m a little unsteady. But again‚ I’ve been able to play tennis. I’m getting around just fine.”

BLT-D
Morton Coleman‚ MD‚ FACP‚ head of the Center for Lymphoma and Myeloma and professor of medicine at Weill Medical College of Cornell University in New York‚ and other physicians are experimenting with a drug cocktail known as BLT–D: Biaxin® (an antibiotic‚ generic name clarithromycin)‚ low–dose thalidomide‚ and dexamethasone. “Biaxin by itself is not very active in multiple myeloma‚” Dr. Coleman explains. He says he believes that Biaxin’s primary effect is altering how steroids are used by the body so that they stay longer or work more effectively‚ adding that it may also alter the metabolism of thalidomide.

“Almost everyone responds‚ usually within six weeks‚” Dr. Coleman asserts. Myeloma patient Richard Dennison calls BLT–D “a good mixture of drugs that seems to work for many‚ many people‚” including him. But after two years he is starting to have to take more medication in order to control his protein level. Also‚ he adds that the patient gets the side effects both of the thalidomide and the dexamethasone.

Building a Better Thalidomide
Grayson says he focused on thalidomide’s ability to starve the tumor instead of poisoning it‚ as conventional chemotherapy does —an approach that sets it apart from previous myeloma drugs. Another is that it blocks certain chemicals in bone marrow that promote the development of myeloma cells.

Celgene‚ the manufacturer of thalidomide‚ is developing a group of thalidomide derivatives that seem to be more effective and better tolerated than the parent drug. The company calls them “immunomodulatory drugs”or IMiDs™.

“The IMiDs are 1‚000 to 5‚000 times more potent than thalidomide‚”according to Ken Anderson‚ MD‚ Director of the Multiple Myeloma Center at Harvard University in Boston‚ Massachusetts. They also seem to be able to overcome resistance to other multiple myeloma treatments‚ he says‚ even thalidomide. Plus‚ they do not appear to cause birth defects or the other side effects of thalidomide.

In particular‚ Dr. Barlogie says the IMiD drugs over time do not seem to have the neuropathy effect that is seen with thalidomide in patients who take the drug for very long periods of time and at a certain dose. Both Dr. Anderson and Dr. Barlogie are conducting patient trials of Revlimid™‚ one of the drugs in the IMiD category.

A Precisely Targeted Drug
Another group of new drugs takes aim at just one part of a myeloma cell: the proteasome.

Proteasomes‚ present in every cell in the body including cancer cells‚ are responsible for promoting cell division and preventing the death of the cell. New drugs called proteasome inhibitors interfere with this regulatory function‚ so that cancer cells stop dividing and eventually die. Fortunately‚ healthy cells seem to be able to recover from the effects of these drugs.

Dr. Anderson‚ along with scientists at Millennium Pharmaceuticals‚ conducted some of the preliminary studies of MLN341‚ which later became the first proteasome inhibitor to be tested in patients. MLN341‚ formerly known as PS–341 and LDP–341‚ is being developed by Millennium. Dr. Anderson comments that‚ like thalidomide and the IMiDs‚ MLN341 “kills the myeloma cell directly and also acts to inhibit the production of factors in the bone marrow that are necessary for the myeloma cell to grow and survive and resist treatments.”

In laboratory studies‚ MLN341 was able to induce the death of myeloma cells that were resistant to Alkeran‚ Adriamycin‚ and dexa-methasone. Similarly‚ early patient trials show that proteasome inhibitors can overcome resistance to standard cancer treatments.

With respect to multiple myeloma‚ David Schenkein‚ MD‚ of Millennium Pharmaceuticals has preliminary data from an ongoing trial of 200 patients with treatment–resistant multiple myeloma. Of 78 patients analyzed so far‚ 40% had at least a 50% reduction in protein levels‚ including 20% who had greater than a 90% reduction. Some patients have entered into complete remission. Moreover‚ MLN341 completely halted progression of the disease in an additional 30% of patients. Overall‚ 77% of these patients were either stable or improved.

“MLN341 at this point appears to have very promising activity in patients with advanced multiple myeloma who have few treatment options left to them‚” Dr. Schenkein said. “Additionally‚ MLN341 suggests that proteasome inhibitors‚ when used alone or in combination with other chemotherapeutic treatments‚ may offer a novel strategy for the treatment of solid cancer. We’re working as quickly as we can to bring these agents to the patients who need them.”

There have been only a few trials of MLN341‚ and only one of the patients interviewed for this article‚ Dennison‚ has tried it. “It didn’t work but I felt it was something I needed to try‚” he reports. “For some people it’s worked great.
“When I look back I don’t have any regrets for trying these drugs‚” he says of the seven years since his diagnosis. “I could say an autologous transplant might have been better. But there is no absolute way to go in this disease. Patients have to really decide for themselves what they think is best.”