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Thalidomide in combination with dexamethasone for pretreated patients with multiple myeloma: serum level of soluble interleukin-2 receptor as a predictive factor for response rate and for survival

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Abstract

The aim of this study was to assess the side effects and the efficacy of thalidomide alone or in combination with dexamethasone in relapsed multiple myeloma (MM) and to evaluate possible predictive factors for response rate and survival. Twenty-nine pretreated patients were enrolled, including 13 patients with a relapse after high-dose chemotherapy. The median number of relapses was 3 (range: 1–7). Twenty-two patients received thalidomide in combination with dexamethasone and seven patients thalidomide alone. The dosage of thalidomide was 400 mg/day and the dosage of dexamethasone 20 mg/m2 daily for 4 consecutive days every 3 weeks. Cycles of dexamethasone were given until maximal decline of myeloma protein was achieved, whereas therapy with thalidomide was maintained until disease progression. Responses occurred in 62% of patients, including 5 (17%) complete remissions and 13 (45%) partial remissions. The median event-free survival (EFS) was 7.2 months and the median overall survival (OS) 26.1 months. In multivariate analysis, pretreatment serum levels of soluble interleukin-2 receptor (sIL-2R) were a significant prognostic factor for EFS, and those of β2-microglobulin (β2M) and sIL-2R for OS. Serum levels of sIL-2R significantly increased after 3 weeks of treatment in 89% of patients, possibly representing lymphocyte activation induced by thalidomide. Two patients died of septic complications within 3 months after starting treatment with thalidomide and dexamethasone and one patient of herpes encephalitis after 26 months of treatment with thalidomide alone. Also, one case of pneumonia and one case of deep venous thrombosis of the lower limb occurred. Other side effects were somnolence, peripheral neuropathy, and bradycardia occurring in 35, 55, 38 and 55% of patients, respectively. The combination of thalidomide and dexamethasone is an effective therapy in heavily pretreated myeloma patients with a high response rate and acceptable toxicities. A powerful predictive factor both for EFS and OS was the pretreatment serum level of sIL-2R.

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References

  1. Akimoto Y, Ishiyama T, Ueno H, Hino K, Tomoyasu S, Tsuruoka N (1995) Clinical significance of soluble interleukin-2 receptor in multiple myeloma. Rinsho Ketsueki 36:1247–1251

    Google Scholar 

  2. Alexanian R, Weber D, Anagnostopoulos A, Delasalle K, Wang M, Rankin K (2003) Thalidomide with or without dexamethasone for refractory or relapsing multiple myeloma. Semin Hematol 40 (Suppl 4):3–7

    Google Scholar 

  3. Anagnostopoulos A, Weber D, Rankin K, Delasalle K, Alexanian R (2003) Thalidomide and dexamethasone for resistant multiple myeloma. Br J Haematol 121:768–771

    Article  CAS  PubMed  Google Scholar 

  4. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R (1996) A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 335:91–97

    Article  CAS  PubMed  Google Scholar 

  5. Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P, Testoni N, Tonelli M, De Vivo A, Palareti G, Tura S, Baccarani M (2004) First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica 89:826–831

    Google Scholar 

  6. Curley MJ, Hussein SA, Hassoun PM (2002) Disseminated herpes simplex virus and varicella zoster virus coinfection in a patient taking thalidomide for relapsed multiple myeloma. J Clin Microbiol 40:2302–2304

    Google Scholar 

  7. D’Amato RJ, Loughnan MS, Flynn E, Folkman J (1994) Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:4082–4085

    PubMed  Google Scholar 

  8. Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K, Gupta D, Chauhan D, Treon SP, Richardson PG, Schlossman RL, Morgan GJ, Muller GW, Stirling DI, Anderson KC (2001) Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 98:210–216

    Article  CAS  PubMed  Google Scholar 

  9. Desikan R, Barlogie B, Sawyer J, Ayers D, Tricot G, Badros A, Zangari M, Munshi NC, Anaissie E, Spoon D, Siegel D, Jagannath S, Vesole D, Epstein J, Shaughnessy J, Fassas A, Lim S, Roberson P, Crowley J (2000) Results of high-dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities. Blood 95:4008–4010

    Google Scholar 

  10. Dimopoulos MA, Zervas K, Kouvatseas G, Galani E, Grigoraki V, Kiamouris C, Vervessou E, Samantas E, Papadimitriou C, Economou O, Gika D, Panayiotidis P, Christakis I, Anagnostopoulos N (2001) Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol 12:991–995

    Google Scholar 

  11. Durie BG, Salmon SE (1975) A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 36:842–854

    CAS  PubMed  Google Scholar 

  12. Geitz H, Handt S, Zwingenberger K (1996) Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade. Immunopharmacology 31:213–221

    Google Scholar 

  13. Haslett P, Hempstead M, Seidman C, Diakun J, Vasquez D, Freedman VH, Kaplan G (1997) The metabolic and immunologic effects of short-term thalidomide treatment of patients infected with the human immunodeficiency virus. AIDS Res Hum Retroviruses 13:1047–1054

    Google Scholar 

  14. Haslett PA, Corral LG, Albert M, Kaplan G (1998) Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. J Exp Med 187:1885–1892

    Article  CAS  PubMed  Google Scholar 

  15. Haslett PA, Hanekom WA, Muller G, Kaplan G (2003) Thalidomide and a thalidomide analogue drug costimulate virus-specific CD8+ T cells in vitro. J Infect Dis 187:946–955

    Article  CAS  PubMed  Google Scholar 

  16. Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT, Treon SP, Lin B, Schlossman RL, Richardson P, Muller G, Stirling DI, Anderson KC (2000) Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96:2943–2950

    Google Scholar 

  17. Hus M, Dmoszynska A, Soroka-Wojtaszko M, Jawniak D, Legiec W, Ciepnuch H, Hellmann A, Wolska-Smolen T, Skotnicki A, Manko J (2001) Thalidomide treatment of resistant or relapsed multiple myeloma patients. Haematologica 86:404–408

    Google Scholar 

  18. Juliusson G, Celsing F, Turesson I, Lenhoff S, Adriansson M, Malm C (2000) Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma. Br J Haematol 109:89–96

    Google Scholar 

  19. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481

    Google Scholar 

  20. Lauta VM (2001) Interleukin-6 and the network of several cytokines in multiple myeloma: an overview of clinical and experimental data. Cytokine 16:79–86

    Google Scholar 

  21. Lissoni P, Barni S, Rovelli F, Viviani S, Maestroni GJ, Conti A, Tancini G (1990) The biological significance of soluble interleukin-2 receptors in solid tumors. Eur J Cancer 26:33–36

    Google Scholar 

  22. Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170

    CAS  PubMed  Google Scholar 

  23. Niitsu N, Iijima K, Chizuka A (2001) A high serum-soluble interleukin-2 receptor level is associated with a poor outcome of aggressive non-Hodgkin’s lymphoma. Eur J Haematol 66:24–30

    Google Scholar 

  24. Palumbo A, Giaccone L, Bertola A, Pregno P, Bringhen S, Rus C, Triolo S, Gallo E, Pileri A, Boccadoro M (2001) Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica 86:399–403

    CAS  PubMed  Google Scholar 

  25. Parman T, Wiley MJ, Wells PG (1999) Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity. Nat Med 5:582–585

    Article  CAS  PubMed  Google Scholar 

  26. Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, Geyer S, Iturria N, Fonseca R, Lust JA, Kyle RA, Witzig TE (2002) Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 20:4319–4323

    Article  CAS  PubMed  Google Scholar 

  27. Rubin LA, Kurman CC, Fritz ME, Biddison WE, Boutin B, Yarchoan R, Nelson DL (1985) Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. J Immunol 135:3172–3177

    CAS  PubMed  Google Scholar 

  28. Rubin LA, Nelson DL (1990) The soluble interleukin-2 receptor: biology, function, and clinical application. Ann Intern Med 113:619–627

    CAS  PubMed  Google Scholar 

  29. Schutt P, Ebeling P, Buttkereit U, Brandhorst D, Opalka B, Hoiczyk M, Flasshove M, Hense J, Bojko P, Metz K, Moritz T, Seeber S, Nowrousian MR (2005) Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma. Eur J Haematol 74:40–46

    Google Scholar 

  30. Shannon E, Aseffa A, Pankey G, Sandoval F, Lutz B (2000) Thalidomide’s ability to augment the synthesis of IL-2 in vitro in HIV-infected patients is associated with the percentage of CD4+ cells in their blood. Immunopharmacology 46:175–179

    Article  CAS  PubMed  Google Scholar 

  31. Shannon EJ, Sandoval F (1995) Thalidomide increases the synthesis of IL-2 in cultures of human mononuclear cells stimulated with Concanavalin-A, Staphylococcal enterotoxin A, and purified protein derivative. Immunopharmacology 31:109–116

    Article  CAS  PubMed  Google Scholar 

  32. Shannon EJ, Sandoval F, Krahenbuhl JL (1997) Hydrolysis of thalidomide abrogates its ability to enhance mononuclear cell synthesis of IL-2 as well as its ability to suppress the synthesis of TNF-alpha. Immunopharmacology 36:9–15

    Article  CAS  PubMed  Google Scholar 

  33. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B (1999) Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565–1571

    Article  CAS  PubMed  Google Scholar 

  34. Takamatsu T, Yasuda N, Ohno T, Kanoh T, Uchino H, Fujii H (1989) Soluble interleukin-2 receptors in plasma cell dyscrasias. Nippon Ketsueki Gakkai Zasshi 52:749–755

    Google Scholar 

  35. Tartour E, Deneux L, Mosseri V, Jaulerry C, Brunin F, Point D, Validire P, Dubray B, Fridman WH, Rodriguez J (1997) Soluble interleukin-2 receptor serum level as a predictor of locoregional control and survival for patients with head and neck carcinoma: results of a multivariate prospective study. Cancer 79:1401–1408

    Google Scholar 

  36. Tartour E, Mosseri V, Jouffroy T, Deneux L, Jaulerry C, Brunin F, Fridman WH, Rodriguez J (2001) Serum soluble interleukin-2 receptor concentrations as an independent prognostic marker in head and neck cancer. Lancet 357:1263–1264

    Google Scholar 

  37. Tosi P, Zamagni E, Cellini C, Cangini D, Tacchetti P, Tura S, Baccarani M, Cavo M (2004) Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure. Eur J Haematol 73:98–103

    Google Scholar 

  38. Vacca A, Di Stefano R, Frassanito A, Iodice G, Dammacco F (1991) A disturbance of the IL-2/IL-2 receptor system parallels the activity of multiple myeloma. Clin Exp Immunol 84:429–434

    Google Scholar 

  39. Wakao D, Murohashi I, Tominaga K, Yoshida K, Kishimoto K, Yagasaki F, Itoh Y, Itoh K, Sakata T, Kawai N, Kayano H, Suzuki T, Matsuda A, Hirashima K, Bessho M (2002) Serum thymidine kinase and soluble interleukin-2 receptor predict recurrence of malignant lymphoma. Ann Hematol 81:140–146

    Google Scholar 

  40. Wang LS, Chow KC, Li WY, Liu CC, Wu YC, Huang MH (2000) Clinical significance of serum soluble interleukin 2 receptor-alpha in esophageal squamous cell carcinoma. Clin Cancer Res 6:1445–1451

    Google Scholar 

  41. Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R (2003) Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21:16–19

    Article  PubMed  Google Scholar 

  42. Wolfler A, Bauer F, Zollner G, Weber K, Sill H, Linkesch W (2003) Fatal sepsis after thalidomide/dexamethasone treatment in two patients with multiple myeloma. Haematologica 88:ELT12

    Google Scholar 

  43. Zangari M, Barlogie B, Anaissie E, Saghafifar F, Eddlemon P, Jacobson J, Lee CK, Thertulien R, Talamo G, Thomas T, Rhee FV, Fassas A, Fink L, Tricot G (2004) Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation. Br J Haematol 126:715–721

    Google Scholar 

  44. Zangari M, Siegel E, Barlogie B, Anaissie E, Saghafifar F, Fassas A, Morris C, Fink L, Tricot G (2002) Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy. Blood 100:1168–1171

    Article  CAS  PubMed  Google Scholar 

  45. Zeimet AG, Natoli C, Herold M, Fuchs D, Windbichler G, Daxenbichler G, Iacobelli S, Dapunt O, Marth C (1996) Circulating immunostimulatory protein 90K and soluble interleukin-2-receptor in human ovarian cancer. Int J Cancer 68:34–38

    Google Scholar 

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Acknowledgments

We thank Mrs. C. Wartchow for her help in preparing the manuscript and the Grünenthal Company for providing us with thalidomide.

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Authors and Affiliations

  1. Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Hufelandstrasse 55, 45122, Essen, Germany

    Philipp Schütt, Peter Ebeling, Ulrike Buttkereit, Dieter Brandhorst, Bertram Opalka, Miriam Poser, Siemke Müller, Michael Flasshove, Thomas Moritz, Siegfried Seeber & Mohammad Resa Nowrousian

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Schütt, P., Ebeling, P., Buttkereit, U. et al. Thalidomide in combination with dexamethasone for pretreated patients with multiple myeloma: serum level of soluble interleukin-2 receptor as a predictive factor for response rate and for survival. Ann Hematol 84, 594–600 (2005). https://doi.org/10.1007/s00277-005-1007-7

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