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Thalidomide With Continuous Low-Dose Dexamethasone for Multiple Myeloma

Golda Hasharon Campus, Rabin Medical Center, Petach Tikva, Israel

To the Editor:

I read with interest the excellent comprehensive review of thalidomide in plasma cell dyscrasia by Dimopoulos et al,¹ including their update regarding the improved response of combined therapy with thalidomide and dexamethasone in multiple myeloma.

Ever since the landmark report by Alexanian et al² on the melphalan plus prednisone protocol for myeloma, successful therapies for multiple myeloma have included glucocorticoid steroids. Invariably, with few exceptions, this treatment is given in the form of pulse therapy, usually prednisone 100 mg for 4 to 5 days per month or dexamethasone 40 mg for 4 days for up to three cycles per month. In the original melphalan-plus-prednisone study, prednisone was shown to be equally effective when given for short, large doses or continuous alternate-day therapy, but lower toxicity led to the adoption of treatment with larger doses of corticosteroids over a shorter course of time,² concomitantly with melphalan and later with vincristine and doxorubicin chemotherapy.

However, in the case of thalidomide therapy that is given continuously, dexamethasone in most cases is given as pulse therapy, thus for a considerable part of the treatment, the patient receives thalidomide only. There have been many mechanisms of action proposed for thalidomide, and the clinical relevance of each of these still remains undetermined,¹ whereas some of these mechanisms, especially the suppression of cytokines such as interleukin-6, interleukin-1ß, and inhibition of nuclear factor kappa B activity are shared by glucocorticoids.³ It would therefore seem more effective for both drugs to be given together, to allow them to exert their activity at the same time; indeed, in vitro, dexamethasone given together with thalidomide has been shown to enhance the antiproliferative effect of thalidomide on cultured myeloma cells.⁴

Maintenance therapy with alternate-day prednisone has also been found to improve progression-free and overall survival in myeloma, after induction with vincristine, doxorubicin, and dexamethasone.³ A recent report has also shown a 40% response rate with low-dose continuous dexamethasone in 15 patients who had experienced treatment failure previously. Median survival was 20 months with little toxicity.⁵ Myers et al⁶ have already treated several advanced myeloma patients with a combination of continuous low-dose dexamethasone and thalidomide; 43% of these had a further reduction of paraprotein of more than 50%. Relatively few adverse effects were noted. As reported by Dimopoulos et al,¹ a Canadian multicenter trial is currently evaluating alternate-day prednisone with thalidomide as maintenance therapy after autologous stem-cell transplantation.⁷

I believe the time has come to further assess continuous low-dose dexamethasone therapy with thalidomide, given that this corticosteroid regimen has so far shown little toxicity and may well ensure an even better response rate for this truly remarkable combination.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Dimopoulos MA, Anagnostopoulos A, Weber D: Treatment of plasma cell dyscrasias with thalidomide and its derivatives. J Clin Oncol 21:4444-4454, 2003[Abstract/Free Full Text]

2. Alexanian R, Haut A, Khan AU, et al: Treatment for multiple myeloma: Combination chemotherapy with different melphalan dose regimens. JAMA 208:1680-1685, 1969[Abstract/Free Full Text]

3. Berenson JR, Crowley JJ, Grogan TM, et al: Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 99:3163-3168, 2002[Abstract/Free Full Text]

4. Hideshima T, Chauhan D, Shima Y, et al: Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96:2943-2950, 2000[Abstract/Free Full Text]

5. Tiplady CW, Summerfield GP: Continuous low-dose dexamethasone in relapsed or refractory multiple myeloma. Br J Haematol 111:381, 2000[Medline]

6. Myers B, Grimley C, Dolan G: Thalidomide and low-dose dexamethasone in myeloma treatment. Br J Haematol 114:245, 2001

7. Stewart AK, Chen C, Howson-Jan K, et al: A multi-center randomized phase two trial of thalidomide and prednisone as maintenance therapy for multiple myeloma following autologous stem cell transplant. Hematol J 4:S208, 2003 (abstr 272; suppl)

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• Treatment of Plasma Cell Dyscrasias With Thalidomide and Its Derivatives
  Meletios A. Dimopoulos, Athanasios Anagnostopoulos, and Donna Weber
  JCO 2003 21: 4444-4454 [Abstract] [Full Text]

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