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Spring 2000 Volume 3, Issue 8:
Thalidomide For Multiple Myeloma
By Raymond Alexanian, MD
There is clearly optimism that thalidomide can find a place in myeloma management. The IMF will publish a series of articles to provide readers with a perspective from different centers treating myeloma patients with thalidomide. This first in a se
Prior to 1958, when melphalan was found to be effective against myeloma by Russian physicians, treatment for this disease was supportive and the median survival was approximately one year. During the past 40 years, many effective treatments have been developed, such as combinations of melphalan and prednisone, VAD, high-dose dexamethasone alone, and very intensive therapy supported by autologous stem cell transplantation. The frequency of complete remission among all patients has increased from the 5% range with standard treatments to the 30% range with added intensive treatment. While the median survival for all patients has increased to approximately 3 years, approximately 20% of currently referred patients are expected to live longer than 10 years. Excluding transplant-related deaths that still occur in approximately 5% of treated patients; the median survival for patients with complete remission is approximately 10 years. Thus, the occurrence of complete remission represents the single most important early goal of therapy.

As prognosis was becoming more clear, a surprising and dramatic event occurred with the discovery by Dr. Barlogie and his group at the University of Arkansas Medical Center that thalidomide was effective in controlling many cases of myeloma that had become resistant to multiple prior therapies, including intensive treatments supported by autologous stem cell transplant. This drug had been banned more than 35 years ago because of severe birth defects that had occurred in Europe and Canada. The fortuitous combination of clinical circumspection and bureaucratic delay that blocked approval in this country represents a complicated story in itself. Nevertheless, thalidomide was reapproved approximately 3 years ago for use in patients with leprosy and other rare skin disorders. When the wife of a patient with progressive and resistant myeloma insisted on a trial with this drug because of its potential in blocking blood flow to tumors (anti-angiogenesis), Dr. Barlogie began clinical studies that showed approximately one-fourth of patients with previously resistant or relapsing disease achieved meaningful remission of respectable duration. An additional 1.5% of patients showed less myeloma reduction. Virtually the same conclusions were reached in follow up trials at the M.D. Anderson Cancer Center in Texas and elsewhere.

Thalidomide is a drug that is taken by mouth each evening, appears to be unpredictably absorbed by the bowel, and has rarely caused serious toxicity. Virtually all severe side effects appear to be associated with higher doses (>400 mg). Thus, treatment usually begins at 200 mg each evening, with incremental increases at weekly intervals to tolerance. The average dose that has been acceptable to most patients has been in the 150-400 mg range, but some older subjects cannot tolerate doses as low as 100 mg. The most common side effects have been constipation, fatigue and tremors, dry skin and rash, and neuropathy that may cause numbness of hands or feet. For our patients, constipation is usually prevented by high fiber diet, stool softener twice daily and laxative as needed. Morning drowsiness and fatigue may be relieved by modest caffeine intake when medically sound and dry skin is relieved with a moisturizer. When side effects occur despite these measures, interruption of treatment for several days followed by resumption of a lower dose has usually been acceptable. Other less common side effects include dry mouth, reduced white blood count, and ankle swelling. Uncommon instances of clots in leg veins or changes in heart rhythm may be coincidental.

Thalidomide is an important drug for the treatment of myeloma, especially when the disease has become resistant to standard treatments. We have observed that a combination with repeated dexamethasone is even more effective and marked benefit has been observed, even after resistance of myeloma to prior separate trials of dexamethasone and thalidomide given alone. Combinations of thalidomide with other drugs are also under study. The effect in maintaining disease stability for a long duration or in controlling newly diagnosed disease or for a long period is not clear.

The mechanism of action in reducing myeloma and in causing most side effects remains unknown. While an antiangiogenetic role has been postulated, some responses in our patients have been so rapid as to suggest a direct antitumor effect. Whether an immunologic role exists for controlling myeloma is not clear, especially when one considers the diverse effects of thalidomide on the immune system. Clarification of these questions may reveal new mechanisms of tumor control, and perhaps lead to new drugs that are even more effective and less toxic.

All patients with myeloma should be considered for treatment with thalidomide at some time in their disease course. Because of the special approvals and consents now required for prescribing and dispensing this agent, some physicians may not yet be in a position to prescribe thalidomide. These difficulties should be overcome with time as more data on the efficacy and safety of this drug are demonstrated.

One can only speculate on how thalidomide might prolong the survival of individual patients. With current treatment approximately 40% of patients with resistant or relapsing myeloma achieve disease control or stabilization for varying periods. Not clear is whether those in partial remission from other drugs may remain stable for a longer duration with thalidomide maintenance, or whether partial remission might even be converted to complete remission in some patients. How effective the drug might be in newly diagnosed patients and for how long is also unknown, since such early remissions may preserve sensitivity to later established agents, and thereby improve survival by delaying the need for standard chemotherapy. All of the foregoing requires clarification, best accomplished by treatment programs at myeloma centers with structured programs that address the questions.

Thus, thalidomide is a new active agent for multiple myeloma with a potential for benefit on a scale similar to that of other landmark treatments for myeloma such as melphalan, VAD, high-dose dexamethasone, or an intensive program supported by autologous stem cells. Despite the rejection of this drug many years ago for its tragic toxicity, we now welcome the very clear activity against multiple myeloma.

Thalidomide Information On The Web

The Friday Symposium at the 1999 annual meeting of the American Society of Hematology focused on the use of thalidomide. More than 800 hematologists attended the Thalidomide: An Emerging Role in the Treatment of Myeloma symposium. Key presentations by Drs. Raymond Alexanian, Kenneth Anderson, Bart Barlogie, and David Stirling can now be accessed at your convenience. Visit www.cancereducation.com and click on Professional Center.

Thalidomide Financial Assistance

Celgene Corporation is offering financial assistance information to multiple myeloma patients. The following patient information will be asked of you when you call:

  • Patient name, address, telephone number, date of birth, social security number;
  • Physician’s name, address, telephone number;
  • Diagnosis;
  • Name of insurance plan(s), policy number(s), address(es), telephone number(s)

For information, please contact the Celgene Patient Financial Assistance Program at (888) 423-5426.

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