Thalidomide in Patients with Relapsed Multiple Myeloma

  • Ashraf Badros
Part of the Contemporary Hematology book series (CH)

The Dark Remedy “History of Thalidomide”

More than half a century ago, thalidomide began an astonishing journey of endurance where fate rather than science transformed a dreadful drug to a great remedy.1,2In 1953, a chemist at a German pharmaceutical company, Chemie Grünenthal, first synthesized thalidomide after heating a commercially available chemical phthaloylisoglutamine; the new molecule was called thalid-omide. The company patented the molecule and began searching for diseases thalidomide could treat. In absence of any scientific rationale, human clinical trials began. However, after extensive testing, they failed to establish pharmacological activity as an antibiotic, an anticonvulsant, or an antihistaminic. It is worth mentioning that thalidomide was evaluated in two clinical trials including 92 patients with advanced cancer, including two patients with multiple myeloma (MM). Many patients reported palliation of symptoms. However, with the lack of clinical responses, the...


Vascular Endothelial Growth Factor Overall Survival Multiple Myeloma Peripheral Neuropathy Hepatocyte Growth Factor 
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  1. 1.
    Stephens, T. & Brynner, R. (2001). Dark Remedy. First edn, Perseus Publishing Cambridge, Massachusetts.Google Scholar
  2. 2.
    Hales, B. F. (1999). Thalidomide on the comeback trail Nat Med5, 489–90.PubMedGoogle Scholar
  3. 3.
    Grabstald, H.& Golbey, R. (1965). Clinical experience with thaliomide in patients with cancer. Clin Pharmacol Ther40, 298–302.Google Scholar
  4. 4.
    Alson, K., Hall, T., Horton, J. et al. (1965). Thalidomide in treatment of advanced cancer Clin Pharmaco Ther40, 292–7.Google Scholar
  5. 5.
    Pagnini, G.&Dicarlo, R. (1963). [Treatment of experimental tumors with tha-lidomide]. Boll Soc Ital Biol Sper39, 1360–3.PubMedGoogle Scholar
  6. 6.
    Goldman, D. A. (2001). Thalidomide use: past history and current implications for practice. Oncol Nurs Forum 28, 471–7; quiz 478–9.PubMedGoogle Scholar
  7. 7.
    von Moos, R., Stolz, R., Cerny, T. & Gillessen, S. (2003). Thalidomide: from tragedy to promise Swiss Med Wkly 133, 77–87.Google Scholar
  8. 8.
    Okafor, M. C. (2003). Thalidomide for erythema nodosum leprosum and other applications. Pharmacotherapy 23, 481–93.PubMedGoogle Scholar
  9. 9.
    Matthews, S. J. & McCoy, C. (2003). Thalidomide: a review of approved and inves-tigational uses. Clin Ther25, 342–95.PubMedGoogle Scholar
  10. 10.
    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 Med341, 1565–71.PubMedGoogle Scholar
  11. 11.
    Jonsson, N. A. (1972). Chemical structure and teratogenic properties. IV. An outline of a chemical hypothesis for the teratogenic action of thalidomide. Acta Pharm Suec9, 543–62.PubMedGoogle Scholar
  12. 12.
    Izumi, H., Futamura, S., Tokita, N. & Hamada, Y. (2007). Flip like motion in the thalidomide dimer: conformational analysis of (R)-thalidomide using vibrational circular dichroism spectroscopy. J Org Chem72, 277–9.PubMedGoogle Scholar
  13. 13.
    Goosen, C., Laing, T. J., du Plessis, J., Goosen, T. C., Rao, T. B. & Flynn, G. L (2002). Chemical stabilities and biological activities of thalidomide and its N-alkyl analogs. Pharm Res19, 1232–5.PubMedGoogle Scholar
  14. 14.
    Figg, W. D., Raje, S., Bauer, K. S., Tompkins, A., Venzon, D., Bergan, R., Chen, A., Hamilton, M., Pluda, J. & Reed, E. (1999). Pharmacokinetics of thalidomide in an elderly prostate cancer population J Pharm Sci88, 121–5.PubMedGoogle Scholar
  15. 15.
    Chen, T. L., Vogelsang, G. B., Petty, B. G., Brundrett, R. B., Noe, D. A., Santos, G. W. & Colvin, O. M. (1989). Plasma pharmacokinetics and urinary excretion of thalidomide after oral dosing in healthy male volunteers. Drug Metab Dispos 17, 402–5.PubMedGoogle Scholar
  16. 16.
    Teo, S. K., Colburn, W. A., Tracewell, W. G., Kook, K. A., Stirling, D. I., Jaworsky, M. S., Scheffler, M. A., Thomas, S. D. & Laskin, O. L. (2004). Clinical pharma-cokinetics of thalidomide Clin Pharmacokinet43, 311–27.PubMedGoogle Scholar
  17. 17.
    Eriksson, T., Bjorkman, S. & Hoglund, P. (2001). Clinical pharmacology of tha-lidomide. Eur J Clin Pharmacol 57, 365–76.PubMedGoogle Scholar
  18. 18.
    Chung, F., Lu, J., Palmer, B. D., Kestell, P., Browett, P., Baguley, B. C., Tingle, M. & Ching, L. M. (2004). Thalidomide pharmacokinetics and metabolite formation in mice, rabbits, and multiple myeloma patients Clin Cancer Res10, 5949–56.PubMedGoogle Scholar
  19. 19.
    Ando, Y., Fuse, E. & Figg, W. D. (2002). Thalidomide metabolism by the CYP2C subfamily. Clin Cancer Res8, 1964–73.PubMedGoogle Scholar
  20. 20.
    Lu, J., Helsby, N., Palmer, B. D., Tingle, M., Baguley, B. C., Kestell, P. & Ching, L. M. (2004). Metabolism of thalidomide in liver microsomes of mice, rabbits, and humans. J Pharmacol Exp Ther310, 571–7.PubMedGoogle Scholar
  21. 21.
    Lepper, E. R., Smith, N. F., Cox, M. C., Scripture, C. D. & Figg, W. D. (2006). Thalidomide metabolism and hydrolysis: mechanisms and implications Curr Drug Metab7, 677–85.PubMedGoogle Scholar
  22. 22.
    Thurmann, P. A. (2005). [Gender-related differences in pharmacokinetics and phar-macodynamics]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 48, 536–40.PubMedGoogle Scholar
  23. 23.
    Kamikawa, R., Ikawa, K., Morikawa, N., Asaoku, H., Iwato, K. & Sasaki, A (2006). The pharmacokinetics of low-dose thalidomide in Japanese patients with refractory multiple myeloma Biol Pharm Bull 29, 2331–4.PubMedGoogle Scholar
  24. 24.
    Barlogie, B., Desikan, R., Eddlemon, P., Spencer, T., Zeldis, J., Munshi, N., Badros, A., Zangari, M., Anaissie, E., Epstein, J., Shaughnessy, J., Ayers, D., Spoon, D. & Tricot, G. (2001). Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients Blood 98, 492–4.PubMedGoogle Scholar
  25. 25.
    Barlogie, B. (2003). Thalidomide and CC-5013 in multiple myeloma: the University of Arkansas experience. Semin Hematol 40, 33–8.PubMedGoogle Scholar
  26. 26.
    Glasmacher, A., Hahn, C., Hoffmann, F., Naumann, R., Goldschmidt, H., von Lilienfeld-Toal, M., Orlopp, K., Schmidt-Wolf, I. & Gorschluter, M. (2006). A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma Br J Haematol 132, 584–93.PubMedGoogle Scholar
  27. 27.
    Prince, H. M., Schenkel, B. & Mileshkin, L. (2007). An analysis of clinical trials assessing the efficacy and safety of single-agent thalidomide in patients with relapsed or refractory multiple myeloma Leuk Lymphoma 48, 46–55.PubMedGoogle Scholar
  28. 28.
    Thompson, J. L. & Hansen, L. A. (2003). Thalidomide dosing in patients with relapsed or refractory multiple myeloma Ann Pharmacother 37, 571–6.PubMedGoogle Scholar
  29. 29.
    Weber, D. (2003). Thalidomide and its derivatives: new promise for multiple myeloma. Cancer Control 10, 375–83.PubMedGoogle Scholar
  30. 30.
    Dimopoulos, M. A., 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 Oncol12, 991–5.PubMedGoogle Scholar
  31. 31.
    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 dex-amethasone is an effective salvage therapy for advanced myeloma Haematologica 86, 399–403.PubMedGoogle Scholar
  32. 32.
    Palumbo, A., Falco, P., Ambrosini, M. T., Petrucci, M. T., Musto, P., Caravita, T., Pregno, P., Bertola, A., Cavallo, F., Ciccone, G. & Boccadoro, M. (2005). Thalidomide plus dexamethasone is an effective salvage regimen for myeloma patients relapsing after autologous transplant Eur J Haematol 75, 391–5.PubMedGoogle Scholar
  33. 33.
    Coleman, M., Leonard, J., Lyons, L., Pekle, K., Nahum, K., Pearse, R., Niesvizky, R. & Michaeli, J. (2002). BLT-D (clarithromycin [Biaxin], low-dose thalidomide, and dexamethasone) for the treatment of myeloma and Waldenstrom's macroglob-ulinemia. Leuk Lymphoma 43, 1777–82.PubMedGoogle Scholar
  34. 34.
    Badros, A. Z., Goloubeva, O., Rapoport, A. P., Ratterree, B., Gahres, N., Meisenberg, B., Takebe, N., Heyman, M., Zwiebel, J., Streicher, H., Gocke, C. D., Tomic, D., Flaws, J. A., Zhang, B. & Fenton, R. G. (2005). Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients J Clin Oncol 23, 4089–99.PubMedGoogle Scholar
  35. 35.
    Rajkumar, S. V., Blood, E., Vesole, D., Fonseca, R. & Greipp, P. R. (2006). Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group J Clin Oncol 24, 431–6.PubMedGoogle Scholar
  36. 36.
    Richardson, P. & Anderson, K. (2006). Thalidomide and dexamethasone: a new standard of care for initial therapy in multiple myeloma J Clin Oncol24, 334–6.PubMedGoogle Scholar
  37. 37.
    Kropff, M. H., Lang, N., Bisping, G., Domine, N., Innig, G., Hentrich, M., Mitterer, M., Sudhoff, T., Fenk, R., Straka, C., Heinecke, A., Koch, O. M., Ostermann, H., Berdel, W. E. & Kienast, J. (2003). Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma Br J HaematoJ 122, 607–16.Google Scholar
  38. 38.
    Dimopoulos, M. A., Hamilos, G., Zomas, A., Gika, D., Efstathiou, E., Grigoraki, V., Poziopoulos, C., Xilouri, I.,Zorzou,M.P., Anagnostopoulos,N. & Anagnostopoulos, A. (2004). Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma Hematol J 5, 112–7.PubMedGoogle Scholar
  39. 39.
    Suvannasankha, A., Fausel, C., Juliar, B. E., Yiannoutsos, C. T., Fisher, W. B., Ansari, R. H., Wood, L. L., Smith, G. G., Cripe, L. D. & Abonour, R. (2007). Final report of toxicity and efficacy of a phase II study of oral cyclophosphamide, thalidomide, and prednisone for patients with relapsed or refractory multiple myeloma: a Hoosier Oncology Group Trial, HEM01–21 Oncologist 12, 99–106.PubMedGoogle Scholar
  40. 40.
    Moehler, T. M., Neben, K., Benner, A., Egerer, G., Krasniqi, F., Ho, A. D. & Goldschmidt, H. (2001). Salvage therapy for multiple myeloma with thalidomide and CED chemotherapy. Blood 98, 3846–8.PubMedGoogle Scholar
  41. 41.
    Lee, C. K., Barlogie, B., Munshi, N., Zangari, M., Fassas, A., Jacobson, J., van Rhee, F., Cottler-Fox, M., Muwalla, F. & Tricot, G. (2003). DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma J Clin Oncol21, 2732–9.PubMedGoogle Scholar
  42. 42.
    Badros, A. & Gahres, N. (2005). Bortezomib, thalidomide, and dexamethasone for relapsed multiple myeloma: add it up and wait. Clin Adv Hematol Oncol3, 916–7; discussion 918.PubMedGoogle Scholar
  43. 43.
    Chung, F., Wang, L. C., Kestell, P., Baguley, B. C. & Ching, L. M. (2004). Modulation of thalidomide pharmacokinetics by cyclophosphamide or 5,6-dimeth-ylxanthenone-4-acetic acid (DMXAA) in mice: the role of tumour necrosis factor. Cancer Chemother Pharmacol 53, 377–83.PubMedGoogle Scholar
  44. 44.
    Dimopoulos, M. A., Anagnostopoulos, A., Terpos, E., Repoussis, P., Zomas, A., Katodritou, E., Kyrtsonis, M. C., Delibasi, S., Vassou, A., Pouli, A., Zervas K., Anagnostopoulos, N. & Maniatis, A. (2006). Primary treatment with pulsed melphalan, dexamethasone and thalidomide for elderly symptomatic patients with multiple myeloma Haematologica 91, 252–4.PubMedGoogle Scholar
  45. 45.
    Palumbo, A., Bringhen, S., Caravita, T., Merla, E., Capparella, V., Callea, V., Cangialosi, C., Grasso, M., Rossini, F., Galli, M., Catalano, L., Zamagni, E., Petrucci, M. T., De Stefano, V., Ceccarelli, M., Ambrosini, M. T., Avonto, I., Falco, P., Ciccone, G., Liberati, A. M., Musto, P. & Boccadoro, M. (2006). Oral melpha-lan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 367, 825–31.PubMedGoogle Scholar
  46. 46.
    Srkalovic, G., Elson, P., Trebisky, B., Karam, M. A. & Hussein, M. A. (2002). Use of melphalan, thalidomide, and dexamethasone in treatment of refractory and relapsed multiple myeloma. Med Oncol19, 219–26.Google Scholar
  47. 47.
    Offidani, M., Marconi, M., Corvatta, L., Olivieri, A., Catarini, M. & Leoni, P. (2003). Thalidomide plus oral melphalan for advanced multiple myeloma: a phase II study. Haematologica 88, 1432–3.PubMedGoogle Scholar
  48. 48.
    Offidani, M., Corvatta, L., Marconi, M., Olivieri, A., Catarini, M., Mele, A., Brunori, M., Candela, M., Malerba, L., Capelli, D., Montanari, M. & Leoni, P. (2004). Thalidomide plus oral melphalan compared with thalidomide alone for advanced multiple myeloma Hematol J5, 312–7.PubMedGoogle Scholar
  49. 49.
    Palumbo, A., Avonto, I., Bruno, B., Ambrosini, M. T., Bringhen, S., Cavallo, F., Falco, P. & Boccadoro, M. (2006). Intravenous melphalan, thalidomide and pred-nisone in refractory and relapsed multiple myeloma. Eur J Haematol 76, 273–7.PubMedGoogle Scholar
  50. 50.
    Economopoulos, T., Pappa, V., Panani, A., Stathakis, N., Dervenoulas, J., Papageorgiou, E., Asprou, N. & Raptis, S. (1991). Myelopathies during the course of multiple myeloma Haematologica 76, 289–92.PubMedGoogle Scholar
  51. 51.
    Badros, A., Morris, C., Zangari, M., Barlogie, B.&Tricot, G. (2002). Thalidomide paradoxical effect on concomitant multiple myeloma and myelodysplasia Leuk Lymphoma 43, 1267–71.PubMedGoogle Scholar
  52. 52.
    Hussein, M. A. (2003). Modifications to therapy for multiple myeloma: pegylated liposomal Doxorubicin in combination with vincristine, reduced-dose dexametha-sone, and thalidomide Oncologist8 Suppl 3, 39–45.PubMedGoogle Scholar
  53. 53.
    Hussein, M. A., Baz, R., Srkalovic, G., Agrawal, N., Suppiah, R., Hsi, E., Andresen, S., Karam, M. A., Reed, J., Faiman, B., Kelly, M.&Walker, E. (2006). Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dex-amethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma. Mayo Clin Proc81, 889–95.PubMedGoogle Scholar
  54. 54.
    Offidani, M., Bringhen, S., Corvatta, L., Falco, P., Marconi, M., Avonto, I., Piersantelli, M. N., Polloni, C., Boccadoro, M., Leoni, P.&Palumbo, A. (2007). Thalidomide-dexamethasone plus pegylated liposomal doxorubicin vs. thalido-mide-dexamethasone: a case-matched study in advanced multiple myeloma Eur J Haematol 78(4), 297–302.PubMedGoogle Scholar
  55. 55.
    Zangari, M., Barlogie, B., Hollmig, K., Fassas, A., Rasmussen, E., Thertulien, R., Talamo, G., Lee, C. K.&Tricot, G. (2004). Marked activity of velcade plus thalidomide (V plus T) in advanced and refractory multiple myeloma (MM) Blood 104, 413A–414A.Google Scholar
  56. 56.
    Zangari, M., Barlogie, B., Jacobson, J., Rasmussen, E., Burns, M., Kordsmeier, B., Shaughnessy, J. D., Anaissie, E. J., Thertulien, R., Fassas, A., Lee, C. K., Schenkein, D., Zeldis, J. B.&Tricot, G. (2003). VTD regimen comprising velcade (V) plus thalidomide (T) and added DEX (D) for non-responders to V + T effects a 57% PR rate among 56 patients with myeloma (M) relapsing after autologous transplant. Blood 102, 236A–236A.Google Scholar
  57. 57.
    Ciolli, S., Leoni, F., Gigli, F., Rigacci, L.&Bosi, A. (2006). Low dose Velcade, thalidomide and dexamethasone (LD-VTD): an effective regimen for relapsed and refractory multiple myeloma patients Leuk Lymphoma 47, 171–3.PubMedGoogle Scholar
  58. 58.
    Palumbo, A., Ambrosini, M. T., Benevolo, G., Pregno, P., Pescosta, N., Callea, V., Cangialosi, C., Caravita, T., Morabito, F., Musto, P., Bringhen, S., Falco, P., Avonto, I., Cavallo, F.&Boccadoro, M. (2007). Bortezomib, melphalan, pred-nisone and thalidomide for relapsed multiple myeloma. Blood 109, 2767–2772.PubMedGoogle Scholar
  59. 59.
    Palumbo, A., Avonto, I., Bruno, B., Falcone, A., Scalzulli, P. R., Ambrosini, M. T., Bringhen, S., Gay, F., Rus, C., Cavallo, F., Falco, P., Massaia, M., Musto, P.&Boccadoro, M. (2006). Intermediate-dose melphalan (100 mg/m2)/bortezomib/thalidomide/dexamethasone and stem cell support in patients with refractory or relapsed myeloma Clin Lymphoma Myeloma 6, 475–7.PubMedGoogle Scholar
  60. 60.
    Neben, K., Moehler, T., Benner, A., Kraemer, A., Egerer, G., Ho, A. D.&Goldschmidt, H. (2002). Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma Clin Cancer Res8, 3377–82.PubMedGoogle Scholar
  61. 61.
    Johnston, R. E.&Abdalla, S. H. (2002). Thalidomide in low doses is effective for the treatment of resistant or relapsed multiple myeloma and for plasma cell leukaemia. Leuk Lymphoma 43, 351–4.PubMedGoogle Scholar
  62. 62.
    Durie, B. G. (2002). Low-dose thalidomide in myeloma: efficacy and biologic significance Semin Oncol29, 34–8.PubMedGoogle Scholar
  63. 63.
    Cibeira, M. T., Rosinol, L., Ramiro, L., Esteve, J., Torrebadell, M.&Blade, J. (2006). Long-term results of thalidomide in refractory and relapsed multiple myeloma with emphasis on response duration Eur J Haematol 77, 486–92.PubMedGoogle Scholar
  64. 64.
    Kumar, S., Witzig, T. E., Dispenzieri, A., Lacy, M. Q., Wellik, L. E., Fonseca, R., Lust, J. A., Gertz, M. A., Kyle, R. A., Greipp, P. R.&Rajkumar, S. V. (2004). Effect of thalidomide therapy on bone marrow angiogenesis in multiple myeloma. Leukemia 18, 624–7.PubMedGoogle Scholar
  65. 65.
    Neben, K., Moehler, T., Egerer, G., Kraemer, A., Hillengass, J., Benner, A., Ho, A. D.&Goldschmidt, H. (2001). High plasma basic fibroblast growth factor concentration is associated with response to thalidomide in progressive multiple myeloma. Clin Cancer Res7, 2675–81.PubMedGoogle Scholar
  66. 66.
    Dmoszynska, A., Podhorecka, M., Manko, J., Bojarska-Junak, A., Rolinski, J.&Skomra, D. (2005). The influence of thalidomide therapy on cytokine secretion, immunophenotype, BCL-2 expression and microvessel density in patients with resistant or relapsed multiple myeloma Neoplasma 52, 175–81.PubMedGoogle Scholar
  67. 67.
    Schutt, P., Ebeling, P., Buttkereit, U., Brandhorst, D., Opalka, B., Poser, M., Muller, S., Flasshove, M., Moritz, T., Seeber, S.&Nowrousian, M. R. (2005). 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.PubMedGoogle Scholar
  68. 68.
    Blade, J., Perales, M., Rosinol, L., Tuset, M., Montoto, S., Esteve, J., Cobo, F., Villela, L., Rafel, M., Nomdedeu, B.&Montserrat, E. (2001). Thalidomide in multiple myeloma: lack of response of soft-tissue plasmacytomas. Br J Haematol 113, 422–4.PubMedGoogle Scholar
  69. 69.
    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.PubMedGoogle Scholar
  70. 70.
    Avigdor, A., Raanani, P., Levi, I., Hardan, I.&Ben-Bassat, I. (2001). Extramedullary progression despite a good response in the bone marrow in patients treated with tha-lidomide for multiple myeloma Leuk Lymphoma 42, 683–7.PubMedGoogle Scholar
  71. 71.
    Rosinol, L., Cibeira, M. T., Blade, J., Esteve, J., Aymerich, M., Rozman, M., Segarra, M., Cid, M. C., Filella, X.&Montserrat, E. (2004). Extramedullary multiple myeloma escapes the effect of thalidomide Haematologica 89, 832–6.PubMedGoogle Scholar
  72. 72.
    Barlogie, B., Tricot, G., Anaissie, E., Shaughnessy, J., Rasmussen, E., van Rhee, F., Fassas, A., Zangari, M., Hollmig, K., Pineda-Roman, M., Lee, C., Talamo, G., Thertulien, R., Kiwan, E., Krishna, S., Fox, M.&Crowley, J. (2006). Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med354, 1021–30.PubMedGoogle Scholar
  73. 73.
    Stirling, D. (2001). Thalidomide: a novel template for anticancer drugs Semin Oncol28, 602–6.PubMedGoogle Scholar
  74. 74.
    D'Amato, R. J., Lentzsch, S., Anderson, K. C.&Rogers, M. S. (2001). Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma Semin Oncol 28, 597–601.PubMedGoogle Scholar
  75. 75.
    Anderson, K. C.&Prince, H. M. (2005). Lenalidomide and thalidomide: an evolving paradigm for the management of multiple myeloma. Semin Hematol 4 2 S1–2.PubMedGoogle Scholar
  76. 76.
    Rajkumar, S. V.&Witzig, T. E. (2000). A review of angiogenesis and antiangiogenic therapy with thalidomide in multiple myeloma Cancer Treat Rev26, 351–62.PubMedGoogle Scholar
  77. 77.
    Du, W., Hattori, Y., Hashiguchi, A., Kondoh, K., Hozumi, N., Ikeda, Y., Sakamoto, M., Hata, J.&Yamada, T. (2004). Tumor angiogenesis in the bone marrow of multiple myeloma patients and its alteration by thalidomide treatment. Pathol Int54 285–94.PubMedGoogle Scholar
  78. 78.
    Jurczyszyn, A., Wolska-Smolen, T.&Skotnicki, A. B. (2003). [Multiple myeloma: the role of angiogenesis and therapeutic application of thalidomide]. Przegl Lek 60 542–7.PubMedGoogle Scholar
  79. 79.
    Rosinol, L., Cibeira, M. T., Segarra, M., Cid, M. C., Filella, X., Aymerich, M., Rozman, M., Arenillas, L., Esteve, J., Blade, J.&Montserrat, E. (2004). Response to thalidomide in multiple myeloma: impact of angiogenic factors. Cytokine 26 145–8.PubMedGoogle Scholar
  80. 80.
    Thompson, M. A., Witzig, T. E., Kumar, S., Timm, M. M., Haug, J., Fonseca, R., Greipp, P. R., Lust, J. A.&Rajkumar, S. V. (2003). Plasma levels of tumour necrosis factor alpha and interleukin-6 predict progression-free survival following thalidomide therapy in patients with previously untreated multiple myeloma Br J Haematol 123, 305–8.PubMedGoogle Scholar
  81. 81.
    Dredge, K., Marriott, J. B.&Dalgleish, A. G. (2002). Immunological effects of thalido-mide and its chemical and functional analogs Crit Rev Immunol 22, 425–37.PubMedGoogle Scholar
  82. 82.
    Schutt, P., Buttkereit, U., Brandhorst, D., Lindemann, M., Schmiedl, S., Grosse-Wilde, H., Seeber, S., Nowrousian, M. R., Opalka, B.&Moritz, T. (2005). In vitro dendritic cell generation and lymphocyte subsets in myeloma patients: influence of thalidomide and high-dose chemotherapy treatment. Cancer Immunol Immunother 54, 506–12.PubMedGoogle Scholar
  83. 83.
    Davies, F. E., Raje, N., Hideshima, T., Lentzsch, S., Young, G., Tai, Y. T., Lin, B., Podar, K., Gupta, D., Chauhan, D., Treon, S. P., Richardson, P. G., Schlossman, R. L., Morgan, G. J., Muller, G. W., Stirling, D. I.&Anderson, K. C. (2001). Thalidomide and immunomodulatory derivatives augment natural killer cell cyto-toxicity in multiple myeloma Blood 98, 210–6.PubMedGoogle Scholar
  84. 84.
    Neiger, B. L. (2000). The re-emergence of thalidomide: results of a scientific conference. Teratology 62, 432–5.PubMedGoogle Scholar
  85. 85.
    Chaudhry, V., Cornblath, D. R., Corse, A., Freimer, M., Simmons-O'Brien, E.&Vogelsang, G. (2002). Thalidomide-induced neuropathy. Neurology 59, 1872–5.PubMedGoogle Scholar
  86. 86.
    Crawford, C. L. (2002). Thalidomide-induced neuropathy. Author's reply Mayo Clin Proc77, 1395.PubMedGoogle Scholar
  87. 87.
    Isoardo, G., Bergui, M., Durelli, L., Barbero, P., Boccadoro, M., Bertola, A., Ciaramitaro, P., Palumbo, A., Bergamasco, B.&Cocito, D. (2004). Thalidomide neuropathy: clinical, electrophysiological and neuroradiological featuresActa Neurol Scand 109, 188–93.PubMedGoogle Scholar
  88. 88.
    Laaksonen, S., Remes, K., Koskela, K., Voipio-Pulkki, L. M.&Falck, B. (2005). Thalidomide therapy and polyneuropathy in myeloma patients Electromyogr Clin Neurophysiol 45, 75–86.PubMedGoogle Scholar
  89. 89.
    Mileshkin, L., Stark, R., Day, B., Seymour, J. F., Zeldis, J. B.&Prince, H. M (2006). Development of neuropathy in patients with myeloma treated with tha-lidomide: patterns of occurrence and the role of electrophysiologic monitoring. J Clin Oncol24, 4507–14.PubMedGoogle Scholar
  90. 90.
    Katan, M. B. (2005). [How much vitamin B6 is toxic?] Ned Tijdschr Geneeskd 149, 2545–6.PubMedGoogle Scholar
  91. 91.
    Levine, S.&Saltzman, A. (2004). Pyridoxine (vitamin B6) neurotoxicity: enhancement by protein-deficient diet. J Appl Toxicol24, 497–500.PubMedGoogle Scholar
  92. 92.
    Offidani, M., Corvatta, L., Marconi, M., Malerba, L., Mele, A., Olivieri, A., Brunori, M., Catarini, M., Candela, M., Capelli, D., Montanari, M., Rupoli, S.&Leoni, P. (2004). Common and rare side-effects of low-dose thalidomide in multiple myeloma: focus on the dose-minimizing peripheral neuropathy. Eur J Haematol 72, 403–9.PubMedGoogle Scholar
  93. 93.
    van de Donk, N. W., Kroger, N., Hegenbart, U., Corradini, P., San Miguel, J. F., Goldschmidt, H., Perez-Simon, J. A., Zijlmans, M., Raymakers, R. A., Montefusco, V., Ayuk, F. A., van Oers, M. H., Nagler, A., Verdonck, L. F.&Lokhorst, H. M. (2006). Remarkable activity of novel agents bortezomib and thalidomide in patients not responding to donor lymphocyte infusions following nonmyeloablative allogeneic stem cell transplantation in multiple myeloma. Blood 107, 3415–6.PubMedGoogle Scholar
  94. 94.
    Zangari, M., Saghafifar, F., Mehta, P., Barlogie, B., Fink, L.&Tricot, G. (2003). The blood coagulation mechanism in multiple myeloma Semin Thromb Hemost 29, 275–82.PubMedGoogle Scholar
  95. 95.
    Zangari, M., Anaissie, E., Barlogie, B., Badros, A., Desikan, R., Gopal, A. V., Morris, C., Toor, A., Siegel, E., Fink, L.&Tricot, G. (2001). Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 98, 1614–5.PubMedGoogle Scholar
  96. 96.
    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, 1168–71.PubMedGoogle Scholar
  97. 97.
    Bennett, C. L., Hussain, Z., Courtney, M., Yarnold, P., Raisch, D.&McKoy, J. M. (2006). RADAR update on thalidomide (Thal)- and lenalidomide (Len)-associated venous thromboembolism (VTE): safety concerns persist for multiple myeloma (MM) despite FDA approvals in this setting ASH Annual Meeting Abstracts 108, 3310A.Google Scholar
  98. 98.
    Zangari, M., Barlogie, B., Thertulien, R., Jacobson, J., Eddleman, P., Fink, L., Fassas, A., Van Rhee, F., Talamo, G., Lee, C. K.&Tricot, G. (2003). Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival. Clin Lymphoma 4, 32–5.PubMedGoogle Scholar
  99. 99.
    Zangari, M., Saghafifar, F., Anaissie, E., Badros, A., Desikan, R., Fassas, A., Mehta, P., Morris, C., Toor, A., Whitfield, D., Siegel, E., Barlogie, B., Fink, L.&Tricot, G. (2002). Activated protein C resistance in the absence of factor V Leiden mutation is a common finding in multiple myeloma and is associated with an increased risk of thrombotic complications Blood Coagul Fibrinolysis 13, 187–92.PubMedGoogle Scholar
  100. 100.
    Zangari, M., Cavallo, F., Prasad, K., Fink, L., Coon, S., Barlogie, B.&Tricot, G. (2006). Erythropoietin therapy and venous thromboembolic events in patients with multiple myeloma receiving chemotherapy with or without thalidomide. ASH Annual Meeting Abstracts 108, 3572A.Google Scholar
  101. 101.
    Durie, B. G. M., Richardson, P., Palumbo, A., Dimopoulos, M. A., Cavo, M., Hajek, R., Joshua, D. E., Shimizu, K., Tricot, G. J., Gertz, M., Tosi, P., Vesole, D. H., Hussein, M. A., Ludwig, H., Goldschmidt, H., Miguel, J. F. S., Sonneveld, P.&Rajkumar, S. V. (2006). Deep vein thrombosis in myeloma: estimate of prevelance and recommendations for therapy based upon a survey of members of the International Myeloma Working Group (IMWG) ASH Annual Meeting Abstracts 108, 3571Google Scholar
  102. 102.
    Baz, R., Li, L., Kottke-Marchant, K., Srkalovic, G., McGowan, B., Yiannaki, E., Karam, M. A., Faiman, B., Jawde, R. A., Andresen, S., Zeldis, J.&Hussein, M. A. (2005). The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma Mayo Clin Proc80, 1568–74.PubMedGoogle Scholar
  103. 103.
    Jimenez, V. H., Dominguez, V., Reynoso, E.&Lopez, I. (2006). Thromboprophylaxis with aspirin for newly diagnosed multiple myeloma treated with thalidomide plus dexamethasone: a preliminary report ASH Annual Meeting Abstracts 108, 5091A.Google Scholar
  104. 104.
    Zangari, M., Barlogie, B., Anaissie, E., Saghafifar, F., Eddlemon, P., Jacobson, J., Lee, C. K., Thertulien, R., Talamo, G., Thomas, T., Van Rhee, F., 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, 715–21.PubMedGoogle Scholar
  105. 105.
    Zangari, M., Cavallo, F., Fink, L. M., Barlogie, B., Bolejack, V., Burns, M. J., Anaissie, E., Hollmig, K. A., Mohiuddin, A., Pineda-Roman, M.&Tricot, G. J. (2006). Treatment associated venous thromboembolism (VTE) and survival in multiple myeloma patients ASH Annual Meeting Abstracts 108, 3573Google Scholar
  106. 106.
    Rajkumar, S. V., Jacobus, S., Callander, N., Fonseca, R., Vesole, D.&Greipp, P. (2006). A randomized phase III trial of lenalidomide plus high-dose dexametha-sone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. ASH Annual Meeting Abstracts 108, 799A.Google Scholar
  107. 107.
    Hall, V. C., El-Azhary, R. A., Bouwhuis, S.&Rajkumar, S. V. (2003). Dermatologic side effects of thalidomide in patients with multiple myeloma. J Am Acad Dermatol 48, 548–52.PubMedGoogle Scholar
  108. 108.
    Rajkumar, S. V., Gertz, M. A.&Witzig, T. E. (2000). Life-threatening toxic epidermal necrolysis with thalidomide therapy for myeloma N Engl J Med343, 972–3.PubMedGoogle Scholar
  109. 109.
    Fahdi, I. E., Gaddam, V., Saucedo, J. F., Kishan, C. V., Vyas, K., Deneke, M. G., Razek, H., Thorn, B., Bissett, J. K., Anaissie, E. J., Barlogie, B.&Mehta, J. L (2004). Bradycardia during therapy for multiple myeloma with thalidomide. Am J Cardiol 93, 1052–5.PubMedGoogle Scholar
  110. 110.
    Coutsouvelis, J.&Corallo, C. E. (2004). Thalidomide-induced bradycardia and its management Med J Aust180, 366–7.PubMedGoogle Scholar
  111. 111.
    Haslett, P., Tramontana, J., Burroughs, M., Hempstead, M.&Kaplan, G. (1997). Adverse reactions to thalidomide in patients infected with human immunodeficiency virus Clin Infect Dis 24, 1223–7.PubMedGoogle Scholar
  112. 112.
    Dispenzieri, A., Lacy, M. Q., Rajkumar, S. V., Geyer, S. M., Witzig, T. E., Fonseca, R., Lust, J. A., Greipp, P. R., Kyle, R. A.&Gertz, M. A. (2003). Poor tolerance to high doses of thalidomide in patients with primary systemic amy-loidosis. Amyloid 10, 257–61.PubMedGoogle Scholar
  113. 113.
    Dimopoulos, M. A.&Eleutherakis-Papaiakovou, V. (2004). Adverse effects of thalidomide administration in patients with neoplastic diseases Am J Med117, 508–15.PubMedGoogle Scholar
  114. 114.
    Ghobrial, I. M.&Rajkumar, S. V. (2003). Management of thalidomide toxicity. J Support Oncol1, 194–205.PubMedGoogle Scholar
  115. 115.
    Hattori, Y., Kakimoto, T., Okamoto, S., Sato, N.&Ikeda, Y. (2004). Thalidomide-induced severe neutropenia during treatment of multiple myeloma Int J Hematol 79, 283–8.PubMedGoogle Scholar
  116. 116.
    McCarthy, D. A., Macey, M. G., Streetly, M., Schey, S. A.&Brown, K. A. (2006). The neutropenia induced by the thalidomide analogue CC-4047 in patients with multiple myeloma is associated with an increased percentage of neutrophils bearing CD64. Int Immunopharmacol 6, 1194–203.PubMedGoogle Scholar
  117. 117.
    Badros, A. Z., Siegel, E., Bodenner, D., Zangari, M., Zeldis, J., Barlogie, B.&Tricot, G. (2002). Hypothyroidism in patients with multiple myeloma following treatment with thalidomide Am J Med112, 412–3.PubMedGoogle Scholar
  118. 118.
    Hattori, Y., Shimoda, M., Okamoto, S., Satoh, T., Kakimoto, T.&Ikeda Y (2005). Pulmonary hypertension and thalidomide therapy in multiple myeloma. Br J Haematol 128, 885–7; author reply 887–8.PubMedGoogle Scholar
  119. 119.
    Younis, T. H., Alam, A., Paplham, P., Spangenthal, E.&McCarthy, P. (2003). Reversible pulmonary hypertension and thalidomide therapy for multiple myeloma. Br J Haematol 121, 191–2.PubMedGoogle Scholar
  120. 120.
    Behrens, R. J., Gulley, J. L.&Dahut, W. L. (2003). Pulmonary toxicity during prostate cancer treatment with docetaxel and thalidomide Am J Ther10, 228–32.PubMedGoogle Scholar
  121. 121.
    Carrion Valero, F.&Bertomeu Gonzalez, V. (2002). [Lung toxicity due to tha-lidomide]. Arch Bronconeumol 38, 492–4.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Ashraf Badros
    • 1
  1. 1.Greenebaum Cancer CenterUniversity of MarylandBaltimoreUSA

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