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June 2000 Volume 3, Issue 9:
Thalidomide in The Treatment Of Multiple Myeloma
By S. Vincent Rajkumar, MD, Mayo Clinic
Second in a series of articles intended to provide readers with perspectives from different centers treating myeloma patients with thalidomide. This article reflects the experience at Mayo Clinic in Rochester, Minnesota.
Thalidomide was first marketed in 1956 as a sleeping pill. Other sleeping pills available at the time were not very safe because patients could die from an overdose. Thalidomide became popular since it produced a very calm sleep and it was impossible to die from an accidental overdose. Beginning in 1958, it was marketed in over 40 countries. Due to FDA concerns about nerve damage, the drug was not approved at that time in the United States. Thalidomide was subsequently found to be effective in the treatment of morning sickness associated with pregnancy. Thousands of women took the pill for this purpose. Unfortunately, it was not realized that the drug could cause severe malformations of the arms, legs, and other organs in the unborn child. This devastating side effect occurred mainly in women who took the drug in the early portion of their pregnancy, between 27 and 40 days. This was not recognized until 1961, and by then it was too late. Almost 10,000 children had been born around the world with severe malformations. The drug was taken off the market worldwide by 1962.

Despite its tragic past, thalidomide has re-entered the medical field due its remarkable beneficial effects in a variety of diseases. By the mid 1960s it became clear that the drug was effective in severe cases of leprosy, due to its effects on the immune system. In the last ten years, thalidomide has been studied and found to be useful in the treatment of certain patients with AIDS, and some who have skin reactions following donor bone marrow transplants.

One of thalidomide's main effects is that it decreases the blood supply to cancers. It is now known that almost all cancers, including myeloma, need a blood supply to grow. Cancers have the ability to initiate the formation of blood vessels through a process called "angiogenesis". When this blood supply is prevented, cancers will stop growing and die due to lack of oxygen and other nutrients. Treatments aimed at decreasing the blood supply to cancers ("anti-angiogenic therapy"), rather than directly attacking the cancer cells is currently one of the most active areas of research. Studies done at the Mayo Clinic and elsewhere have shown that blood supply is important for myeloma cells. Myeloma patients who have increased blood vessels in their bone marrow (the bone marrow is the site where myeloma cancer cells are made), do not live as long as patients in whom the blood supply is not well developed. Therefore myeloma appears to be an ideal target for treatments that attack blood vessels.

Based on the theory that thalidomide can interrupt the blood supply to myeloma cancer cells, Dr. Barlogie and other researchers at the University of Arkansas studied 84 patients with advanced myeloma. Their study showed that roughly one-third of patients with advanced myeloma responded well to thalidomide therapy, with reduction in their myeloma protein levels and bone marrow myeloma cells. The patients also had improvement in their blood counts and symptoms. Patients who had failed stem cell transplantation showed responses to treatment with thalidomide. Further, the drug was taken as a pill by mouth, and did not have some of the side effects of chemotherapy. This represents an important advance in the treatment of myeloma, and has brought hope to many patients.

The findings of the Arkansas researchers have now been confirmed by similar studies at the Mayo Clinic,

M. D. Anderson Cancer Center, and several other institutions. It is now clear that a quarter to a third of patients with advanced myeloma have a good response to treatment with thalidomide. Although one of the main reasons to study thalidomide in myeloma was its ability to reduce the blood supply to cancer cells, it may have other effects as well. Thalidomide has important effects on the immune system that allow the body to better fight the cancer. Thalidomide may also act on proteins that are important for the growth of myeloma cells. We are currently doing studies to determine how thalidomide works in myeloma.

The usual starting dose of thalidomide in myeloma is 200 mg/day (four capsules). The dose is then gradually increased, depending on side effects. The usual maximum dose is 800 mg/day (16 capsules), but most patients average a dose of 400 mg/day because of side effects. Studies are ongoing to see if doses less than 200 mg/day may provide the same benefits without the undesirable side effects.

Regulations are in place in the United States for prescribing thalidomide, due to the danger if a pregnant woman took the medication. To ensure absolute safety, all patients, prescribing physicians, and dispensing pharmacists are required to participate in the System for Thalidomide Education and Prescribing Safety (STEPS) program. Under this program, women in the childbearing age group must undergo pregnancy testing before starting therapy, and every 2-4 weeks during treatment. Patients must abstain from sexual intercourse, or use two highly effective contraceptive methods, during treatment. Males who have not had a vasectomy must abstain from sexual intercourse or use a condom while on treatment. All patients must continue these measures for at least one month following the last dose of the medication. Women should not breast-feed when taking thalidomide. All patients sign a consent that explains the risks and precautions prior to starting therapy.

The most common side effects of thalidomide are sleepiness, fatigue, constipation, and a skin rash. As a result, many patients cannot tolerate doses greater than 400 mg/day; occasionally only 100 mg/day is possible. Laxatives are usually prescribed routinely to prevent constipation, which can be severe. If a skin rash occurs, the drug should be discontinued, and restarted at a lower dose after the rash clears. If the rash is severe, the drug should be stopped and not used again. A less common but important side effect of thalidomide is nerve damage. This usually occurs when the drug is taken for a longer period. It is important to monitor symptoms of numbness and tingling in the feet and hands, so that the medication may be stopped before serious complications occur.

It is clear that thalidomide is a good treatment option for patients with myeloma who have failed other chemotherapy regimens or bone marrow transplantation. However, several questions still remain regarding thalidomide therapy in myeloma. What is the best dose? When is the best time to start thalidomide therapy? Should it be given alone or combined with other medications? How long should the treatment be given? Can we reduce the dose to minimize side effects once the disease is under control? What are the long-term risks of taking thalidomide at high doses? These questions are the focus of ongoing studies.

As a result of the encouraging results seen with thalidomide in myeloma patients who have failed multiple other chemotherapy programs, we are now looking at earlier treatment with thalidomide. At the Mayo Clinic, there are currently studies looking at the effect of thalidomide in patients with newly diagnosed myeloma who have not yet developed bone destruction or symptoms. These patients have "smoldering" or "indolent" myeloma, and the goal of treatment is to delay the need for future chemotherapy. For newly diagnosed patients who have symptoms or bone damage, we are combining thalidomide with dexamethasone. Researchers at other institutions are studying the effectiveness of thalidomide combined with other chemotherapy treatments for myeloma. Studies with thalidomide are ongoing in several other cancers as well. There is also research ongoing to find treatments that would have the beneficial effect of thalidomide without its side effects, especially with regard to birth defects.

Clearly, the results with thalidomide represent an important advance in the battle against myeloma. Further research in this area provides hope for the discovery of other effective agents in myeloma. The goal remains a cure for myeloma. s

Read more about thalidomide therapy

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