Correspondence

Thalidomide in Multiple Myeloma

N Engl J Med 2000; 342:975-976March 30, 2000

Article

To the Editor:

Singhal et al. (Nov. 18 issue)1 report the results of a phase 2 study of thalidomide for the treatment of multiple myeloma and conclude that the drug can reduce serum and urine levels of paraprotein in some patients with refractory multiple myeloma. We are concerned that the maximal tolerated dose of thalidomide was not clarified in this study.

Thalidomide was started at a dose of 200 mg per day, and the dose was increased by 200 mg every two weeks, until a dose of 800 mg per day was reached. It is surprising that only 55 percent of the patients could tolerate receiving 800 mg per day of thalidomide. Although the authors emphasize that thalidomide had mild toxic effects and that grade 3 or 4 adverse effects were rarely observed, some adverse effects might have developed in 45 percent of the patients. These findings do not support their suggestion that thalidomide is a safe drug.

What is the minimal effective dose of thalidomide in treating multiple myeloma? Because high-dose thalidomide causes some unfavorable effects, as shown in this study, it will be important to determine whether the effect of thalidomide reported by Singhal et al. was dose-dependent.

We would also like to know whether the efficacy of this drug was influenced by the status of the multiple myeloma (i.e., the stage of the disease and the cytogenetic abnormality).

Yukiko Kishi, M.D.
Yasuhiro Oki, M.D.
Utako Machida, M.D.
University of Tokyo, Tokyo 108-8639, Japan

1 References

1. 1

   Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341:1565-1571
   Full Text | Web of Science | Medline

Author/Editor Response

Dr. Barlogie replies:

To the Editor: Kishi et al. correctly point out that our phase 2 study of thalidomide for the treatment of multiple myeloma was not designed to investigate dose intensity. The dose-escalation design we used permitted individual patients to receive their maximal tolerated dose, which we considered important in patients who had already received a substantial amount of chemotherapy. Patients who did not tolerate dose escalation beyond 400 mg probably would have had clinically significant toxic reactions at the 600-mg and 800-mg doses. Pharmacokinetic studies are needed to elucidate the reasons for the heterogeneity of toxic effects and responses at a given dose level that we observed. Furthermore, as suggested in the editorial accompanying our report,1 several mechanisms may be involved in the antimyeloma activity of thalidomide, which, in turn, may be dose-related.

The minimal effective dose of thalidomide is unknown, but responses have been reported at doses as low as 50 to 100 mg in patients who had received less prior therapy than our patients had (Durie B: personal communication). We are now conducting a randomized trial to determine whether the inclusion of thalidomide at a dose of 400 mg during the induction, consolidation, and maintenance phases of a trial of high-dose chemotherapy improves results in patients with newly diagnosed multiple myeloma.2 In another trial involving previously treated patients, we are evaluating two doses of thalidomide (50 mg and 200 mg) as maintenance therapy; the results should provide information on the dose–response effects of thalidomide in multiple myeloma.3

Kishi et al. also ask about prognostic factors and how they influence the response to thalidomide. We reported a high response rate among patients with a low plasma-cell–labeling index. In addition, in an analysis of all 180 patients enrolled in the trial, event-free and overall survival were significantly longer when the degree of bone marrow plasmacytosis was low and deletion of chromosome 13 was not found.4

Bart Barlogie, M.D., Ph.D.
University of Arkansas for Medical Sciences, Little Rock, AR 72205

4 References

1. 1

   Raje N, Anderson K. Thalidomide -- a revival story. N Engl J Med 1999;341:1606-1608
   Full Text | Web of Science | Medline

2. 2

   Munshi N, Desikan R, Anaissie E, et al. Peripheral blood stem cell collection (PBSC) after CAD+ G-CSF as part of total therapy II in newly diagnosed multiple myeloma (MM): influence of thalidomide (THAL) administration. Blood 1999;94:Suppl 1:578a-578a abstract.
   Web of Science

3. 3

   Munshi N, Desikan R, Zangari M, et al. Chemoangiotherapy with DT-PACE for previously treated multiple myeloma (MM). Blood 1999;94:Suppl 1:123a-123a abstract.
   Web of Science

4. 4

   Desikan R, Munshi N, Zeldis J, et al. Activity of thalidomide (THAL) in multiple myeloma (MM) confirmed in 180 patients with advanced disease. Blood 1999;94:Suppl 1:603a-603a abstract.
   Web of Science

Citing Articles (3)

Citing Articles

1. 1

   Y. Cao, J. Arbiser, R. J. D'Amato, P. A. D'Amore, D. E. Ingber, R. Kerbel, M. Klagsbrun, S. Lim, M. A. Moses, B. Zetter, H. Dvorak, R. Langer. (2011) Forty-Year Journey of Angiogenesis Translational Research. Science Translational Medicine 3:114, 114rv3-114rv3
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2. 2

   Shufeng Zhou, Philip Kestell, Malcolm D. Tingle, James W. Paxton. (2002) Thalidomide in Cancer Treatment. Drugs & Aging 19:2, 85-100
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3. 3

   R.E. Johnston, S.H. Abdalla. (2002) Thalidomide in Low Doses is Effective for the Treatment of Resistant or Relapsed Multiple Myeloma and for Plasma Cell Leukaemia. Leukemia & Lymphoma 43:2, 351-354
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