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      A systematic review of phase II trials of thalidomide/dexamethasone combination therapy in patients with relapsed or refractory multiple myeloma

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          Abstract

          Thalidomide monotherapy in relapsed/refractory multiple myeloma (MM) has a response rate of 30%. The combination of thalidomide with dexamethasone (Thal/Dex) is expected to improve responses, but it is unknown if the combination increases the rate of adverse events. Here, we conducted a systematic review of studies evaluating Thal/Dex in relapsed/refractory MM. Twelve studies were included, comprising 451 patients. The response rate (CR and PR) was 46% (95% CI 42–51%). Therapy-related toxicity was comparable to thalidomide monotherapy and included somnolence (26%, 95% CI 22–31%), constipation (37%, 95% CI 32–42%) and peripheral neuropathy (27%, 95% CI 23–32%). Only venous thromboembolism appeared to occur more often with Thal/Dex (5%, 95% CI 3–8%). Thus, using Thal/Dex results in an improved response rate in relapsed/refractory MM, with a toxicity rate comparable to thalidomide monotherapy.

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          A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma.

          The activity of thalidomide in relapsed or refractory multiple myeloma is widely accepted but not yet demonstrated in a randomised-controlled trial. A systematic review of the published clinical trials of these patients could reduce the possible bias of single phase-II studies. A systematic search identified 42 communications reporting on 1674 patients. Thirty-two trials used an escalating dosing regimen and four a fixed dose regimen (one dose with 50 mg/d, three doses with 200 mg/d). The target dose in the dose escalating trials was 800 mg/d in 17 trials, 400-600 mg/d in 10 and 200 mg/d in one trial. The intention-to-treat population for efficacy was 1629 patients with a median age of 62 years. The complete and partial (>50% reduction in monoclonal protein) response rate was 29.4% (95%-confidence interval, 27-32%). The rates for minor responses or stable disease were 13.8% (12-16%) and 11.0% (9-13%). Progressive disease was reported in 9.9% (8-11%). The median overall survival from all trials was reported at 14 months. Severe adverse events (grade III-IV) included somnolence 11%, constipation 16%, neuropathy 6%, rash 3%, thrombo-embolism 3%, cardiac 2%. In conclusion, thalidomide monotherapy achieved complete and partial responses in 29.4% of patients with relapsed or refractory multiple myeloma.
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            Thalidomide and dexamethasone combination for refractory multiple myeloma.

            Thalidomide is effective in approximately 30% of patients with refractory multiple myeloma. Dexamethasone is active in 25% of patients with disease resistant to alkylating agents. We investigated the combination of thalidomide with dexamethasone as salvage treatment for heavily pretreated patients with multiple myeloma, in order to assess its efficacy and toxicity. Forty-four patients with refractory myeloma were treated with thalidomide, 200 mg p.o. daily at bedtime, with dose escalation to 400 mg after 14 days, and dexamethasone, which was administered intermittently at a dose of 20 mg/m2 p.o. daily for four days on day 1-4, 9-12, 17-20, followed by monthly dexamethasone for four days. Patients' median age was 67 years. All patients were resistant to standard chemotherapy, 77% were resistant to dexamethasone-based regimens and 32% had previously received high-dose therapy. On an intention-to-treat basis twenty-four patients (55%) achieved a partial response with a median time to response of 1.3 months. The thalidomide and dexamethasone combination was equally effective in patients with or without prior resistance to dexamethasone-based regimens and in patients with or without prior high-dose therapy. Toxicities were mild or moderate and consisted primarily of constipation, morning somnolence, tremor, xerostomia and peripheral neuropathy. The median time to progression for responding patients is expected to exceed 10 months and the median survival for all patients is 12.6 months. The combination of thalidomide with dexamethasone appears active in patients with refractory multiple myeloma. If this activity is confirmed, further studies of this combination as second-line treatment for patients resistant to conventional chemotherapy, and as primary treatment for patients with active myeloma, should be considered.
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              Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer.

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                Author and article information

                Journal
                Eur J Haematol
                ejh
                European Journal of Haematology
                Blackwell Publishing Ltd
                0902-4441
                1600-0609
                October 2008
                : 81
                : 4
                : 247-252
                Affiliations
                [1 ]Medizinische Klinik und Poliklinik III, Rheinische Friedrich Wilhelms Universität Bonn, Germany
                [2 ]BMTU, St James's University Hospital Leeds, UK
                [3 ]Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus Dresden, Germany
                [4 ]Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg Germany
                Author notes
                correspondence Dr Marie von Lilienfeld-Toal, Medizinische Klinik und Poliklinik III, Uniklinik Bonn, Sigmund Freud Str. 25, 53105 Bonn, Germany. Tel: +1 49 228 28714003; Fax: +1 49 228 28714003; e-mail: m.lilienfeld.toal@ 123456uni-bonn.de
                Article
                10.1111/j.1600-0609.2008.01121.x
                2613233
                18637031
                e620023d-5210-4cc0-ab17-889f3255f391
                © The Authors Journal compilation © 2008 Blackwell Munksgaard

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                : 30 June 2008
                Categories
                Review Article

                Hematology
                multiple myeloma,systematic review,dexamethasone,relapsed/refractory,thalidomide
                Hematology
                multiple myeloma, systematic review, dexamethasone, relapsed/refractory, thalidomide

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