Annals of Oncology 13:1116-1119, 2002
© 2002 European Society for Medical Oncology
Original Paper |
Consolidation therapy of multiple myeloma with thalidomide–dexamethasone after intensive chemotherapy
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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 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
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Background:
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 thalidomide–dexamethasone 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. Thalidomide–dexamethasone 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 1–4, 9–12 and 17–20, 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 thalidomide–dexamethasone 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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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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For newly diagnosed patients with multiple myeloma, improved outcomes have resulted from intensive therapy supported by autologous stem-cell transplantation [1–5]. Higher frequencies of remission and complete remission, as well as longer survival, have been observed in comparison with control patients who continued standard therapy [3, 4]. These results have been attributed to a dose-response effect with intensive therapy that frequently converted partial to complete remission, or induced remission in patients with resistant disease. Even after intensive therapy, the median duration of partial remission has been
2 years [6, 7]. There was no clear advantage from maintenance with 
-interferon [8].
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 thalidomide–dexamethasone 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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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Between July 1999 and September 2001, 21 patients were identified with overt multiple myeloma who had received intensive therapy supported by autologous stem-cell transplantation, and with reduced, stable myeloma protein for at least 4 months. Only patients with serum myeloma protein
0.2 g/dl and/or Bence Jones protein >100 mg/day were eligible in order to define occurrence and magnitude of further reduction. Clinical features are summarized in Table 1. All patients received primary therapy with intermittent high-dose dexamethasone (20 mg/m2 as a single oral dose on days 1–4, 9–12 and 17–20), either alone or as part of a vincristine–doxorubicin–dexamethasone (VAD) combination [13]. Autologous stem-cell supported therapies were given to all patients within 13 months of primary treatment as described previously [6]. Between 4 and 20 months after intensive therapy (median 7 months), thalidomide was begun in a dose of 100 mg each evening, with increments of 50 mg every 7 days to acceptable tolerance (maximum 300 mg); dexamethasone was given concurrently in the same dose regimen as used previously. The combined program was given for at least 3 months, during which period the median total dose for each patient was thalidomide 18 g (range 9–24 g) and dexamethasone 0.8 g (range 0.5–1.3 g). For patients with responsive disease, thalidomide alone was continued in a dose of 100–150 mg each evening until relapse.
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Tumor mass was defined prior to any therapy as high, intermediate or low by standard criteria: high tumor mass was either hemoglobin (Hgb) <8.5 g/dl or serum calcium >11.5 mg/dl; low tumor mass Hgb >10.5 g/dl and serum myeloma protein <4.5 g/dl; all others were rated as having intermediate tumor mass. Partial response to primary or intensive therapy was defined as >75% reduction of serum myeloma protein production and >95% reduction of Bence Jones protein, with reduction of marrow plasma cells to <10%; significant antitumor effect from thalidomide–dexamethasone required >90% further reduction of myeloma protein production to <0.5 g/dl or complete remission with disappearance of serum myeloma protein by immunofixation [14]. Relapse was defined as the earlier of either recurrent myeloma protein that had disappeared, increased myeloma protein by 25%, new lytic bone lesions or marrow plasmacytosis.
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Prior therapy
Among 21 patients treated with thalidomide–dexamethasone, the myeloma had responded to primary therapy in 10 patients and to subsequent intensive therapy supported by autologous stem cells in 11 additional patients. Residual myeloma protein persisted at a constant level for at least 4 months in all patients. Prior to thalidomide–dexamethasone, serum myeloma protein ranged from 0.2–2.2 g/dl (median 0.9 g/dl), representing a calculated median 3% of pre-treatment tumor mass; when present alone in two patients, Bence Jones protein was 0.13 and 0.47 g/day; marrow plasma cells ranged from 0% to 7% (median 1%).
Thalidomide–dexamethasone
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 thalidomide–dexamethasone despite stable myeloma status after intensive therapy.
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The myeloma has relapsed in six patients, among whom there were two deaths. Without further marked reduction of myeloma, recurrence occurred in two of nine patients after 4 and 10 months of maintenance (total remission 8 and 19 months). With further reduction, relapse occurred in four of 12 patients after a median of 13 months of maintenance (range 9–21 months) and median total remission of 26 months (range 18–31 months).
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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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The optimum maintenance therapy for patients with multiple myeloma that remains in partial remission despite intensive therapy remains unclear. Both survival and progression-free survival of patients with persistent partial remission remain significantly shorter than those of patients with complete remission [6, 7]. No improvement in survival has resulted from long-term maintenance with
-interferon [8].
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 thalidomide–dexamethasone 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 thalidomide–dexamethasone may have resulted from prior high-dose therapy, the abrupt, rapid and marked reduction of myeloma supported the dominant role of thalidomide–dexamethasone.
Thus, some myeloma cells were sensitive to thalidomide–dexamethasone despite prior treatments that included high-dose dexamethasone and intensive therapy. This observation extends the previously established effect of thalidomide–dexamethasone 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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We thank Rose Guevara for the careful preparation of the manuscript. This work was supported by the Lucille Murchison and Kay Laro research funds.
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Footnotes |
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+ Correspondence to: Dr R. Alexanian, The University of Texas M.D. Anderson Cancer Center, Box 429, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel: +1-713-792-2850; Fax: +1-713-796-9734; E-mail: ralexani@mdanderson.org
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References |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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1. Cunningham D, Pazares, Gore M et al. High-dose melphalan and autologous bone marrow transplantation as consolidation in previously untreated multiple myeloma. J Clin Oncol 1994; 12: 759–763.[Abstract]
2. Alexanian R, Dimopoulos M, Hester J et al. Early myeloablative therapy for multiple myeloma. Blood 1994; 84: 4278–4282.
3. Attal M, Harousseau J, Stoppa J et al. Autologous bone marrow transplantation versus conventional chemotherapy in multiple myeloma. N Engl J Med 1996; 335: 91–97.
4. Barlogie B, Jagannath S, Vesole D et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 1997; 89: 789–793.
5. Lenhoff S, Hjorth M, Holmberg E et al. Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma. Blood 2000; 95: 7–11.
6. Alexanian R, Weber D, Giralt S et al. Impact of complete remission with intensive therapy in patients with responsive multiple myeloma. Bone Marrow Transplant 2001; 27: 1037–1043.[Web of Science][Medline]
7. Lahuerta J, Martinez-Lopez J, de la Serna J et al. Remission status defined by immunofixation vs electrophoresis after autologous transplantation has a major impact on the outcome of multiple myeloma patients. Br J Haematol 2000; 109: 438–446.[Web of Science][Medline]
8. Cunningham D, Powles R, Malpas J et al. A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma. Br J Haematol 1998; 102: 495–502.[Web of Science][Medline]
9. Singhal S, Mehta J, Desikan R et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–1571.
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11. Weber D, Rankin K, Gavino M et al. Thalidomide with dexamethasone for resistant multiple myeloma. Blood 2000; 96: (Abstr 167a).
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