The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
Received 2 November 2001; revised 22 January 2002; accepted 11 February 2002
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Abstract |
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After myeloablative therapy for multiple myeloma, progression-free survival is shorter for disease in partial remission rather than complete remission. In an attempt to induce more frequent complete remission, we assessed thalidomidedexamethasone in patients with stable partial remission after intensive therapy.
Patients and methods:
Twenty-one patients with multiple myeloma were identified with disease in stable partial remission after prior intensive therapy. Thalidomidedexamethasone was given within 15 months after intensive therapy provided myeloma protein production had been reduced by >75% to a constant level for at least 4 months. Thalidomide was begun at a dose of 100 mg each evening, with increments of 50 mg every 7 days to a maximum of 300 mg. Dexamethasone was given concurrently in a dose of 20 mg/m2 each morning for 4 days on days 14, 912 and 1720, with resumption on day 35. The combination was continued for at least 3 months and patients with marked reduction of myeloma were maintained on thalidomide alone until disease progression.
Results:
Marked further reduction of myeloma by at least 90% occurred in 12 patients (57%), including four (19%) with disease converted to complete remission. Disease has progressed in six of 21 patients, whose median total remission was 22 months. Common side effects of constipation, fatigue, paresthesias and dry skin were mild, dose-related and reversible.
Conclusions:
The combination of thalidomidedexamethasone reduced tumor mass markedly in 57% of patients with stable, residual disease after myeloablative therapy. Such an effect may produce longer disease-free survival and/or preserve tumor sensitivity to later retreatment with previously effective drugs.
Key words: autologous stem-cell transplantation, multiple myeloma, thalidomide
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Introduction |
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Recently, thalidomide has been effective against myeloma, inducing partial remission in 25% of patients with disease resistant or relapsing despite standard and intensive treatments [9, 10]. The combination with intermittent high-dose dexamethasone has been effective in
40% of such patients, including those with disease resistant to prior sequential trials of dexamethasone and thalidomide [11, 12]. In an attempt to reduce myeloma more markedly in responsive disease, we evaluated a combination of thalidomidedexamethasone in 21 consecutive patients with stable partial remission after intensive chemotherapy supported by autologous stem-cell transplantation.
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Materials and methods |
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Results |
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Thalidomidedexamethasone
Significant further reduction of myeloma by >90% occurred in 12 of 21 patients with prior partial remission (57%), including four patients with complete remission (Table 2); serum myeloma protein was reduced to <0.5 g/dl in all patients with further disease response to a calculated median <0.1% of pretreatment tumor mass (Figure 1). Figure 2 depicts abrupt and rapid reduction of calculated tumor mass for two patients whose disease was responsive to thalidomidedexamethasone despite stable myeloma status after intensive therapy.
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Side effects
Acceptably tolerated doses of thalidomide (median 200 mg/day) and dexamethasone were given to all patients. The most common side effects included manageable constipation (86%), fatigue or tremor (67%), paresthesias of feet (14%) and dry skin or rash (5%), which were attributed to thalidomide. Ankle edema (17%) and indigestion (9%) were attributed to dexamethasone. All side effects cleared or were relieved by interruption of treatment for 3 days and resumption of slightly lower doses of either or both drugs. There were no serious drug-related complications such as deep venous thrombosis.
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Discussion |
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Thalidomide is an effective agent against multiple myeloma, reducing myeloma cell number by >50% in 25% of patients with resistant or relapsing disease [9, 10]. When combined with intermittent, high-dose dexamethasone, remissions have occurred in 40% of similar patients, including some who had not responded to prior sequential treatments with dexamethasone and thalidomide alone [11, 12]. The more frequent benefit, with rare serious side effects, justified our study of the combination rather than either drug alone.
The myeloma was reduced further by at least 90% in approximately one-half of patients with stable partial remission after high-dose therapy. Such an effect has not been observed in similar patients maintained on -interferon or on standard doses of alkylating agent, either alone or in combination with glucocorticoid [6, 8]. Because of the occasional slow reduction of myeloma that may occur after any treatment, we required long intervals of stable disease between primary therapy, intensive therapy and thalidomidedexamethasone in order to distinguish the antitumor effects of each program with clarity. We also required at least 90% reduction from pre-thalidomide level to a very low value in order to recognize an unequivocal and marked antitumor effect that might translate into potential survival benefit, as shown previously for patients who achieved complete remission [6, 7]. While we could not exclude the possibility that some of the effect attributed to thalidomidedexamethasone may have resulted from prior high-dose therapy, the abrupt, rapid and marked reduction of myeloma supported the dominant role of thalidomidedexamethasone.
Thus, some myeloma cells were sensitive to thalidomidedexamethasone despite prior treatments that included high-dose dexamethasone and intensive therapy. This observation extends the previously established effect of thalidomidedexamethasone against resistant or relapsing myeloma to subclones of plasma cells that persisted at a low, stable level despite intensive therapy. Conversion of partial to complete remission occurred in 20% of patients, adding further to the frequencies of complete remission achieved after primary therapy (10%) and intensive treatment (30%). Despite persistent partial remission and modest absolute reduction of myeloma for most patients, there is a potential for longer disease-free survival with fewer residual cells and/or preservation of tumor sensitivity to retreatment with previously effective drugs. Randomized trials in comparable groups of patients should clarify these questions.
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Acknowledgements |
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Footnotes |
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References |
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