Correspondence

Life-Threatening Toxic Epidermal Necrolysis with Thalidomide Therapy for Myeloma

N Engl J Med 2000; 343:972-973September 28, 2000

Article

To the Editor:

Thalidomide has recently been shown to be effective for the treatment of refractory myeloma.1,2 We report a case of life-threatening toxic epidermal necrolysis with the combined use of thalidomide and dexamethasone in a patient with previously untreated myeloma.

A 64-year-old man with newly diagnosed myeloma presented with multiple lytic bone lesions, anemia, and hypercalcemia, with a serum IgA-lambda monoclonal protein level of 41 g per liter and 90 percent plasma cells in the bone marrow. After obtaining informed consent, we initiated treatment with thalidomide and dexamethasone as part of an ongoing phase 2 trial. The patient received 200 mg of thalidomide per day for 14 days and had no adverse effects. The dose was then increased to 400 mg per day. Ten days after the dose was increased, the patient noticed a rash, and the thalidomide was discontinued. Within three days, he had diffuse erythema of the trunk, extremities, and face, with blistering skin lesions and large areas with a scalded-skin appearance due to biopsy-proven, full-thickness epidermal necrosis — findings that are characteristic of toxic epidermal necrolysis (Figure 1Figure 1Toxic Epidermal Necrolysis in a Patient Treated with Thalidomide and Dexamethasone for Newly Diagnosed Myeloma.). There was also ulceration of the mouth and oropharynx. The patient was hospitalized and recovered after two weeks of intensive therapy.

Two additional patients in the group of eight patients who have thus far received thalidomide and dexamethasone for newly diagnosed myeloma have had unexpectedly severe dermatologic toxic effects, including one patient who required urgent hospitalization for generalized erythroderma. Both patients recovered fully after the thalidomide had been discontinued.

Toxic epidermal necrolysis is the result of drug-induced interactions between Fas and Fas ligand in keratinocytes, resulting in the separation of large areas of the epidermis from the dermis.3 Interestingly, thalidomide was recently studied as a treatment for toxic epidermal necrolysis in a randomized, placebo-controlled trial.4 However, the study was terminated because of an excess number of deaths in the thalidomide group.

Although rashes and a minor degree of exfoliation are seen in 20 to 25 percent of patients receiving thalidomide,1 toxic epidermal necrolysis has been reported only rarely.5 We have treated 55 other patients with thalidomide alone, and none of them have had toxic epidermal necrolysis. We are therefore concerned about the possibility of an adverse interaction between dexamethasone and thalidomide. Thalidomide undergoes spontaneous nonenzymatic cleavage to a variety of metabolites, the levels of which may be affected by dexamethasone.

Dexamethasone is often used alone or in combination with other agents in patients with myeloma, and there is interest in combining it with thalidomide for the treatment of this disease. Although the combination appears to be very effective and merits study, we recommend that until a safe dose schedule has been determined, dexamethasone (or other corticosteroids) not be used in combination with thalidomide for the treatment of newly diagnosed myeloma, except in closely monitored trials. Caution should be exercised when combining thalidomide with other drugs known to cause serious skin reactions, such as sulfonamides and allopurinol.

S. Vincent Rajkumar, M.D.
Morie A. Gertz, M.D.
Thomas E. Witzig, M.D.
Mayo Clinic, Rochester, MN 55905

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