Multiple Myeloma, STEPS Program, Thalidomide


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Letter to Oncologist About Thalidomide and STEPS program

The Dominion Group
Marketing Research and Consulting, Inc.

November 25, 1998

Lonnie Harper, MD
500 Lilly Road
Olympia WA 98506

Dear Dr. Harper:

Thank you for agreeing to participate in our research project regarding the treatment of multiple myeloma and the role of thalidomide. Your telephone interview has been scheduled for 12:00 PM on Tuesday December 1, 1998. A member of our staff will be calling you at that time for the interview.

During the interview we will be discussing the thalidomide product profile, STEPS program, and the package insert that you will find enclosed. Please read these enclosed documents before your scheduled interview. We look forward to speaking with you.

Thank you for your participation in this study.

If for any reason you are unable to participate, please call me.

Sincerely,

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Thalidomide - An Investigational Agent For The Treatment of End Stage Multiple Myeloma

Background

Recently, the FDA approved THALOMID (thalidomide) as a treatment for the cutaneous manifestations of erythema nodosum leprosum, a serious inflammatory condition that occurs in patients with Hansen's disease (leprosy). Thalidomide is an immunomodulatory agent with spectrum of activity that is not fully characterized. In vitro studies and preliminary clinical trials suggest that the immunologic effects of the drug are related to suppression of excessive TNF-a production and down-modulation of selected cell surface adhesion molecules. These factors are involved in numerous physiologic processes, including angiogenesis and apoptosis. As a result. thalidomide is undergoing further study to determine its clinical utility as an antineoplastic agent.

Phase II Investigation Of -THALIDOMIDE In Multiple Myeloma

Currently, a pilot Phase II clinical trial is ongoing to evaluate the efficacy and safety of thalidomide in the treatment of advanced multiple myeloma. Bone marrow biopsies of patients with this disease reveal the presence of abundant neovascularity, suggesting that an immunomodulatory treatment strategy involving inhibition of apoptosis, angiogenesis and resulting neovascularity would be of benefit.

To-date, 90 end-stage multiple myeloma patients have been enrolled in the study, all of whom relapsed after high-dose therapy and transplantation and had documented disease progression over the preceding two months. Patients receive thalidomide orally as monotherapy at a dose of 200 mg administered at bedtime, with dose increases in 200 mg increments every two weeks (based on response). for a maximum daily dose of 800mg.

Twenty-six patients receiving treatment for a minimum of 4 weeks (median 2.5 months, range 1 - 6 months) have been evaluated. The primary clinical endpoint assessed was the proportion of patients experiencing a greater than 20%, 50%, or 75% decline in the serum or urine monoclonal paraprotein after at least one month of therapy. Among patients with urine and serum paraprotein, response was judged on the basis of the paraprotein showing the smaller decline. Patients with a decline in serum paraprotein, but not in the urine (n=2), were considered treatment failures.

The following observations have been made:

Decline in paraprotein

Declines of >20% and >50% in paraprotein levels were observed in 58% and 42% of all patients, respectively, and in 67% and 50% of the 18 patients treated for at least 2 months. Four patients experienced a >75% paraprotein decline. Of these 4 patients, 3 experienced a reduction of paraprotein to trace quantities. Three patients attained near complete remission on thalidomide; one of these patients had relapsed after an allograft. (See Table 1.)

Table I

Responses to thalidomide by time on therapy. Maximum % response is based upon the lower of the serum or urine paraprotein decline. The patient with non-secretory disease did not respond The near-CR group is a subset of the > 75 % group. y )
Time on therapN Overall response >20% to 50% >50% to 75% >75% (Near CR
31-60 days 8 3 (37%) 1 2 - -
>60 days 18 12 (67%) 3 5 4 (3)
Total 26 15 (58%) 4 (15%) 7 (27%) 4 (15%) (12%)

Reduction in marrow plasmacytosis

Follow-up bone marrow evaluation in 3 of the 4 patients experiencing >75% decline in paraprotein showed resolution of marrow plasmacytosis and trace paraprotein level with immunofixation-positivity for monoclonal paraprotein (near-CR); the fourth patient had stable marrow plasmacytosis. Among the 7 patients with >50-75% decline in the paraprotein, 5 patients underwent repeat marrow evaluation revealing normalization of marrow in 2 patients, at least 50% reduction in marrow plasmacytosis in 2 patients, and stable plasmacytosis in 1 patient. Three of the 4 patients with >20-50% decline in the paraprotein underwent repeat marrow evaluation; 1 patient had a 50% reduction in plasmacytosis whereas the other 2 patients had increased plasmacytosis.

Of the 11 non-responders (including a patient with non-secretory disease), 6 underwent repeat marrow examination, which showed stable plasmacytosis in 2 patients and increased tumor cell infiltration in 4 patients. Thus, 8 of 12 patients with >20% decrease in paraprotein had reduction in marrow plasmacytosis compared with 0 of 5 patients (excluding the patient with non-secretory disease) with no decrease in the paraprotein (P = 0.02, Fisher's exact test)

Time to response

Among responding patients, decline in paraprotein was evident within 1 to 8.5 weeks (median 3) of treatment. Of the 12 responding patients who were treated for at least 60 days, decline in paraprotein was obvious before day 60 in all, although the degree of response increased with further therapy. The 3 near-CRs became apparent at days 68, 90 and 124 of therapy, respectively. (See Table 1.)

Current status

Two of the 26 patients have died; one of probable sepsis while the paraprotein was declining and another of progressive myeloma. Eight of the remaining 24 patients discontinued thalidomide after 34-98 days of therapy (median 60) because of lack of response (n=2) or progressive disease (n=6). Sixteen patients are still receiving the drug at 51+ to 171+ days (median 82+). Fourteen of the 16 responding patients have a continued decline in paraprotein. Limited progression has been seen in one patient (decline over the first 4 weeks from a paraprotein of 2.5 g/dL to 0.9 g/dL. and subsequently an increase to 1.6 g/dL by day 71), and another died while the disease was responding (vide supra).

Adverse effects

Side effects included drowsiness, (n=16, 62%), constipation (n=10, 38%), and peripheral neuropathy (n=7, 27%), none of which necessitated discontinuation of thalidomide. Clinically significant granulocytopenia (<1 x 109 /L) occurred in one patient who was maintained on thalidomide with G-CSF support.

In addition to the adverse effects experienced in this patient population. thalidomide is known to be a powerful teratogen. If thalidomide is ingested during pregnancy, it causes severe birth defects and possible death of the fetus. The drug should never be prescribed for women who are pregnant or women who are not using effective birth control.

Other Areas Of Investigation

In addition to multiple myeloma, thalidomide is being evaluated in a number of other malignant diseases to determine its anti-tumor properties. Alone or in combination with standard chemotherapy, the efficacy and safety of this agent are being studied in the treatment of Kaposi's sarcoma, cancers of the breast and prostate, recurrent and untreated malignant gliomas, various vascular malignancies, and has been used with some success in chronic graft vs host disease. It is also being studied for the treatment of cancer cachexia based on controlled clinical trials that have demonstrated the drug's ability to reverse the wasting syndrome associated with HIV.

Product Availability

THALOMID (TM) (thalidomide) is available as 50 mg capsules in blister packages containing 14 capsules. The drug can not be repackaged. The average wholesale price is $7.50/capsule.

Because THALOMID (TM) (thalidomide) is a known teratogen. the drug is made available through an FDA-mandated restricted distribution program. Celgene Corporation, the manufacturer of the drug, has developed the System for Thalidomide Education and Prescribing Safety (S. T. E. P. S. (TM)) to help prevent fetal exposure to this agent. Only prescribers who are registered in the S. T. E. P. S. (TM) program may prescribe THALIDOMID (TM) (thalidomide). In addition, patients must be advised of, agree to, and comply with the requirements of the S. T. E. P. S. (TM) program which include mandatory contraceptive measures and completion of mandatory, confidential surveys.

4135 / October 30, 1998

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Major Components of the STEPS Program

Project 4135; 10/30/98

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