талидомид

Множественная миелома (лечение рецидивов и рефрактерных форм): обзор литературы и собственные данные. Часть III

КЛИНИКА, ДИАГНОСТИКА И ЛЕЧЕНИЕ ЛИМФОИДНЫХ ОПУХОЛЕЙ , , , , , , , , , , ,

С.С. Бессмельцев

ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург, Российская Федерация

РЕФЕРАТ

Использование новых подходов в лечении рецидивов/рефрактерных форм множественной миеломы (ММ) привело к существенному увеличению общей выживаемости больных, достижению качественного ответа и более длительной ремиссии по сравнению с пациентами, получавшими стандартную химиотерапию. Эти изменения связаны главным образом с применением новых препаратов: бортезомиба, талидомида, леналидомида, каждый из которых обладает выраженной противомиеломной активностью. Бортезомиб, талидомид и леналидомид используются в комбинации как с химиотерапевтическими препаратами, так и друг с другом, что существенно повышает эффективность лечения больных ММ. Однако, если больные не отвечают на бортезомиб и иммуномодуляторы, прогноз ухудшается. В настоящее время число препаратов, которые используются при ММ, достаточно большое, причем спектр их все более расширяется. Тем не менее результаты лечения больных с рецидивами/рефрактерными формами ММ не вполне удовлетворительные, что свидетельствует о трудностях разработки эффективных лекарственных средств. Появилось большое количество препаратов второго и третьего поколений, которые становятся все более доступными для клинического применения. Проводятся клинические исследования I, II и III фаз по оценке эффективности карфилзомиба, помалидомида, вориностата, панобиностата, ромидепсина, перифосина, танеспимицина, бендамустина и элотузумаба при рецидивах/рефрактерных формах ММ. В обзоре представлены современные подходы к ведению пациентов с рецидивами и рефрактерным течением ММ, основанные на результатах клинических исследований и собственных данных, целью которых было оптимизировать результаты лечения. Представлена эффективность различных классов новых лекарственных средств, обсуждены все «за» и «против», полученные в доклинических и клинических исследованиях. Подробно освещены побочные эффекты новых препаратов.

Ключевые слова: множественная миелома, рецидив, рефрактерное течение, бортезомиб, талидомид, леналидомид, карфилзомиб, помалидомид, лечение, полная ремиссия, общая выживаемость, нейропатия.

Читать  статью в PDFpdficon

ЛИТЕРАТУРА

  1. Бессмельцев С.С., Абдулкадыров К.М. Множественная миелома. Современный взгляд на проблему. Алматы: Коста, 2007. [Bessmeltsev S.S., Abdulkadyrov K.M. Mnozhestvennaya miyeloma. Sovremennyy vzglyad na problemu (Multiple myeloma. Current view of the problem). Almaty: Kosta, 2007.]
  2. Harousseau J.L., Shaughnessy J.Jr., Richardson P. Multiple myeloma. Hematol. Am. Soc. Hematol. Educ. Program 2004: 237–56.
  3. Stewart A.K. Novel therapies for relapsed myeloma. Hematol. Am. Soc. Hematol. Educ. Program 2009: 555–65.
  4. Podar K., Tai Y.T., Hideshima T. et al. Emerging therapies for multiple myeloma. Expert. Opin. Emerg. Drugs 2009; 14: 99–127.
  5. Ругаль В.И., Бессмельцев С.С., Семенова Н.Ю. и др. Структурные особенности паренхимы и стромы костного мозга больных множественной миеломой. Medline.ru. 2012; 13: 515–23. [Rugal V.I., Bessmeltsev S.S., Semenova N.Yu., et al. Structural features of bone marrow parenchyma and stroma in patients with multiple myeloma. Medline.ru. 2012; 13: 515–23. (In Russ.)].
  6. Morgan G.J., Kaiser M.F. How to use new biology to guide therapy in multiple myeloma. ASH Educ. Book 2012; 2012(1): 342–9.
  7. Morgan G.J., Gregory W.M., Davies F.E. et al.; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood 2012; 119(1): 7–15.
  8. Fonseca R., Debes-Marun C.S., Picken E.B. et al. The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma. Blood 2003; 102(7): 2562–67.
  9. Hideshima T., Bergsagel P.L., Kuehl W.M., Anderson K.C. Advances in biology of multiple myeloma: clinical applications. Blood 2004; 104: 607–18.
  10. Rajkumar S.V., Harousseau J.-L., Durie B. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. Prepublished online Feb 3, 2011; doi: 10.1182/blood-2010-10-299487.
  11. Lonial S. Treatment of relapsed and refractory multiple myeloma. Hematol. Educ. Ann. Congr. Eur. Hematol. Assoc. 2013; 7: 216–26.
  12. Kumar S.K., Lee J.H., Lahuerta J.J. et al. Risk of progression and survival in multiple myeloma relapsed after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 2012; 26: 149–57.
  13. Durie B.G.M., Harousseau J.-L., Miguel J.S. et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20(9): 1467–73.
  14. Anderson K.C., Kyle R.A., Rajkumar S.V. et al. Clinically relevant end points and new drug approvals for myeloma. Leukemia 2008; 22(2): 231–9.
  15. Niesvizky R., Richardson P.G., Rajkumar S.V. et al. The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma. Br. J. Haematol. 2008; 143(1): 46–53.
  16. Dimopoulos M., Kyle R., Fermand J.-P. et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood 2011; 117(18): 4701–5.
  17. Avet-Loiseau H. Ultra high-risk myeloma. Hematol. Am. Soc. Hematol. Educ. Program 2010; 2010: 489–93.
  18. Mohty B., El-Cheikh J., Yakoub-Agha I. et al. Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and ‘retreatment’ approaches in the era of novel agents. Leukemia 2012; 26: 73–85.
  19. Kumar S., Mahmood S.T., Lacy M.Q. et al. Impact of early relapse after auto-SCT for multiple myeloma. Bone Marrow Transplant. 2008; 42: 413–20.
  20. Kroger N., Perez-Simon J.A., Myint H. et al. Relapse to prior autograft and chronic graft-versus-host disease are the strongest prognostic factors for outcome of melphalan/fludarabine-based dose reduced allogeneic stem cell transplantation in patients multiple myeloma. Biol. Blood Marrow Transplant. 2004; 10: 698–708.
  21. Kroger N., Shimoni A., Schilling G. et al. Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation. Br. J. Haematol. 2009; 148: 323–31.
  22. Garban F., Attal M., Michaller M. et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in highrisk de novo multiple myeloma. Blood 2006; 107: 3474–80.
  23. Lonial S. Relapsed multiple myeloma. Hematol. Am. Soc. Hematol. Educ. Program 2010: 303–9.
  24. Mikhael J.R., Goodwin J., Qi X. et al. p53 Deletion Yields High Response Rates but Rapid Progression and Poor Overall Survival in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation. ASH Ann. Meet. Abstr. 2007; 110: 953.
  25. Kaufman J., Nooka A., Muppidi S. et al. Survival outcomes of early autologous stem cell transplant (ASCT) followed by lenalidomide, bortezomib, and dexamethasone (RVD) maintenance in patients with high-risk multiple myeloma (MM). ASCO Ann. Meet. Abstr. 2012: 8100.
  26. Blade J., Samson D., Reece D. et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br. J. Haematol. 1998; 102(5): 1115–23.
  27. Alexanian R., Barlogie B., Dixon D. High-dose glucocorticoid treatment of resistant myeloma. Ann. Intern. Med. 1986; 105: 8–11.
  28. Gertz M.A., Garton J.P., Greipp P.R., Witzig T.E., Kyle R.A. A phase II study of high-dose methylprednisolone in refractory or relapsed multiple myeloma. Leukemia 1995; 9: 2115–8.
  29. Barlogie B., Smith L., Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N. Engl. J. Med. 1984; 310: 1353–6.
  30. Anderson H., Scarffe J.H., Ranson M. et al. VAD chemotherapies remission induction for multiple myeloma. Br. J. Cancer 1995; 71: 326–30.
  31. Phillips J.K., Sherlaw-Johnson C., Pearce R. et al. A randomized study of MOD versus VAD in the treatment of relapsed and resistant multiple myeloma. Leuk. Lymphoma 1995; 17: 465–72.
  32. Durie B.G., Dixon D.O., Carter S. et al. Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group Study. J. Clin. Oncol. 1986; 4: 1227–37.
  33. Giles F.J., Wickham N.R., Rapoport B.L. et al. Cyclophosphamide, etoposide, vincristine, adriamycin, and dexamethasone (CEVAD) regimen in refractory multiple myeloma: an International Oncology Study Group (IOSG) phase II protocol. Am. J. Hematol. 2000; 63: 125–30.
  34. Munshi N., Desikan K., Jagannath S. et al. Dexamethasone, cyclophosphamide, etoposide and cisplatinum (DCEP), an effective regimen for relapse after high-dose chemotherapy and autologous transplantation. Blood 1996; 88: Abstract 586a.
  35. Passweg J.R., Baldomero H., Bregni M. et al. Hematopoietic SCT in Europe: date and trends in 2011. Bone Marrow Transplant. Advance online publication 15 April 2013; doi: 10.1038/bmt.2013.51.
  36. Бессмельцев С.С., Абдулкадыров К.М. Возможности применения производных нитрозометилмочевины и вепезида в химиотерапии множе- ственной миеломы и злокачественных лимфом. Совр. онкол. 2002; 1: 25–9.  [Bessmeltsev S.S., Abdulkadyrov K.M. Potentials use of nitrosourea derivatives and VePesid in chemotherapy for multiple myeloma and malignant lymphomas. Sovr. onkol., 2002; 1: 25–9. (In Russ.)].
  37. Parameswaran R., Giles C., Boots M. et al. CCNU (lomustin), idsrubicin and dexamethasone (CIDEX): an effective oral regimen for the treatments of refractory or relapsed myeloma. Br. J. Haematol. 2000; 109: 571–5.
  38. Abdulkadyrov K.M., Bessmeltsev S.S. Use of VCAP, ARA-COP and VAD schedules in treatment of patients with multiple myeloma (MM). XVI International Cancer Congress. New Delhi (India), 1994: Abstract NA-02807.
  39. Бессмельцев С.С., Абдулкадыров К.М., Рукавицын О.А. Эффектив- ность некоторых программ полихимиотерапии при лечении больных множественной миеломой. Tер. арх. 1998; 3: 46–9. [Bessmeltsev S.S., Abdulkadyrov K.M., Rukavitsyn O.A. Efficacy of some polychemotherapy programs in management of patient with multiple myeloma. Ter. arkh., 1998; 3: 46–9. (In Russ.)].
  40. Бессмельцев С.С., Стельмашенко Л.В. Сравнительная оценка раз- личных методов лечения больных с множественной миеломой. Эфферент. тер. 2000; 2: 54–63. [Bessmeltsev S.S., Stelmashenko L.V. Comparative evaluation of various therapeutic methods in patients with multiple myeloma. Efferent. ter. 2000; 2: 54–63. (In Russ.)].
  41. Mohrbacher A.F., Gregory S.A., Gabriel D.A. et al. Liposomal daunorubicin (DaunoXome) plus dexamethasone for patients with multiple myeloma. A phase II International Oncology Study Group study. Cancer 2002; 94: 2645–52.
  42. Alexanian R., Dimopoulos M.A., Hester I. et al. Early myeloablative therapy for multiple myeloma. Blood 1994; 84(12): 4278–82.
  43. Pulsoni A., Villiva N., Cavalieri E. et al. Continuous low dose of melphalan and prednisone in patients with multiple myeloma of very old age or severe associated disease. Drugs Aging 2002; 19: 947–53.
  44. Бессмельцев С.С., Абдулкадыров К.М. a-2а-интерферон (Реаферон) в лечении больных множественной миеломой. Вопр. онкол. 1999; 4: 393–7. [Bessmeltsev S.S., Abdulkadyrov K.M. a-2a-interferon (Reaferon) in management of patients with multiple myeloma. Vopr. onkol., 1999; 4: 393–7. (In Russ.)].
  45. Joshua D.E., Penny R., Matthews J.P. et al. Australian Leukemia Study Group myeloma II: a randomized trial of intensive combination chemotherapy with or without interferon in patients with myeloma. Br. J. Haematol. 1997; 97: 38–45.
  46. Gertz M.A., Kalish L.A., Kyle R.A. et al. Phase III study comparing vincristine, doxorubicine (Adriamycin), and dexamethasone (VAD) chemotherapy with VAD plus recombinant interferon alfa-2 in refractory or relapsed multiple myeloma. An Eastern Cooperative Oncology Group study. Am. J Clin. Oncol. 1995; 18: 475–80.
  47. Peest D. The role of alpha-interferon in multiple myeloma. Pathol. Biol. (Paris) 1999; 47(2): 172–7.
  48. Бессмельцев С.С., Абдулкадыров К.М. Эффективность циклоспорина А при рефрактерных формах множественной миеломы и рецидиве заболевания. Актуальные вопросы гематологии и трансфузиологии. Мат-лы Рос. науч.-практ. конф., посвященной 70-летию Российского НИИ гематологии и трансфузиологии, Санкт-Петербург, 18–20 июня 2002 г. СПб., 2002: 98. [Bessmeltsev S.S., Abdulkadyrov K.M. Effektivnost tsiklosporina A pri refrakternykh formakh mnozhestvennoy mielomy i retsidive zabolevaniya. Aktualnye voprosy gematologii i transfuziologii. Mat-ly Ros. nauch.-prakt. konf., posvyashchennoy 70-letiyu Rossiyskogo NII gematologii i transfuziologii, (Efficacy of cyclosporine A in refractory forms and relapses of multiple myeloma. Current issues in hematology and transfusiology. In: Materials of Rus. scient.-pract. conference dedicated to 70th anniversary of the Russian Research Institute of Hematology and Transfusiology. Saint Petersburg, June 18-20, 2002, St. Petersburg, 2002: 98.]
  49. Бессмельцев С.С., Абдулкадыров К.М. Современные принципы лечения больных множественной миеломой. Гематол. i трансфузiол.: фунд. та приклад. пит. Мат-лы науч.-практ. конф., Киев, 13–14 октября 2005 г. Киев, 2005: 21–3. [Bessmeltsev S.S., Abdulkadyrov K.M. Sovremennye printsipy lecheniya bolnykh mnozhestvennoy mielomoy. Gematol. i transfuziol.: fund. ta priklad. pit. Mat-ly nauch.-prakt. konf. (Current principles of management of patients with multiple myeloma. Hematol. and transfuiol.: fund. and pract. issues. In: Material of scient.-pract. conference, Kiev, October 13-14, 2005), Kiev, 2005: 21–3.]
  50. Schwarzenbach H. Expression of MDR1/P-glycoprotein, the multidrug resistance protein MRP, and the lung-resistance protein LRP in multiple myeloma. Med. Oncol. 2002; 19: 87–104.
  51. Uchiyama-Kokubu N., Watanabe T., Nakajima M. A bioassay for the activity of PSC 833 in human serum for modulation of P-glycoprotein-mediated multidrug resistance. Anticancer Drugs 2000; 11: 583–90.
  52. Koskela K., Pelliniemi T.T., Pulkki K., Remes K. Treatment of multiple myeloma with all-trans retinoic acid alone and in combination with chemotherapy: a phase I/II trial. Leuk. Lymphoma 2004; 45: 749–54.
  53. Singhal S., Mehta J., Desikan R. et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 1999; 341: 1565–71.
  54. Barlogie B., Desikan R., Eddlemon P. et al. 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 2001; 98: 492–4.
  55. Kumar S., Gertz M.A., Dispenzieri A. et al. Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma. Mayo Clin. Proc. 2003; 78: 34–9.
  56. Yakoub-Agha I., Mary J., Hulin C. et al. Low-dose vs. high-dose thalidomide for advanced multiple myeloma: A prospective trial from the Intergroupe Francophone du Myelome. Eur. J. Haematol. 2012; 88: 249–5.
  57. Neben K., Moehler T., Benner A. et al. Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma. Clin. Cancer Res. 202; 8: 3377–80.
  58. Glasmacher A., Hahn C., Hoffmann F. et al. A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma. Br. J. Haematol. 2006; 132: 584–93.
  59. Kropff M., Baylon H.G., Hillengass J. et al. Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma: results from OPTIMUM, a randomized trial. Haematologica 2012; 97(5): 784–91.
  60. Mileshkin L., Stark R., Day B. et al. Development of neuropathy in patients with myeloma treated with thalidomide: patterns of occurrence and the role of electrophysiologic monitoring. J. Clin. Oncol. 2006; 24: 4507–14.
  61. Richardson P., Schlossman R., Jagannath S. et al. Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity. Mayo Clin. Proc. 2004; 79: 875–82.
  62. Dimopoulos M.A., Zervas K., Kouvatseas G. et al. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann. Oncol. 2001; 12: 991–5.
  63. Weber D. Thalidomide: a wide spectrum of activity. Myeloma Focus. Newslett. Multiple Myel. Res. Found. 2002; IV: 4.
  64. Palumbo A., Bertola A., Falco P. et al. Efficacy of low dose thalidomide as first salvage regimen in multiple myeloma. Hemat. J. 2004; 5: 318–24.
  65. Fermand J.P., Jaccard A., Macro M. et al. A randomized comparison of dexamethasone + thalidomide (Dex/Tal) vs Dex + Placebo (Dex/P) in patients (pts) with relapsing multiple myeloma (MM). Blood 2006; 108: Abstract 3563.
  66. Offidani M., Corvatta L., Marconi M. et al. Thalidomide plus oral melphalan compared with thalidomide alone for advanced multiple myeloma. Hematol. J. 2004; 5: 312–7.
  67. Palumbo A., Avonto I., Bruno B. et al. Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma. Eur. J. Hematol. 2006; 76: 273–7.
  68. Srakovic G., Elson P., Trebisky B. et al. Use of melphalan, thalidomide and dexamethasone in treatment of refractory and relapsed multiple myeloma. Med. Oncol. 2002; 19: 219–26.
  69. Kyriakou C., Thomson K., D’Sa S. et al. Low-dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma. Br. J. Haematol. 2005; 29: 763–5.
  70. Dimopoulos M.A., Hamilos G., Zomas A. et al. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regiment for previously treated patients with multiple myeloma. Hematol. J. 2004; 5: 112–7.
  71. Kropff M.N., Lang N., Bisping G. et al. Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCTD) in primary refractory or relapsed multiple myeloma. Br. J. Haematol. 2003; 122: 607–16.
  72. Garcia-Sanz R., Gonzales-Porras H.R., Hermandez J.M. et al. The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia 2004; 18: 856–63.
  73. Offidani M., Corvatta L., Marconi M. et al. Low dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/ refractory multiple myeloma: a prospective, multicenter, phase II study. Haematologica 2006; 91: 133–6.
  74. Hussein M.A., Baz R., Srkalovic G. et al. Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma. Mayo Clin. Proc. 2006; 81: 889–95.
  75. Husseun M.A. Thromboembalism risk reduction in multiple myeloma patients treated with immunomodulatory drug combinations. Tromb. Haemost. 2006; 95: 924–30.
  76. Pineda-Roman M., Zangari M., van Rhee F. et al. VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma. Leukemia 2008; 22: 1419–27.
  77. Biehn S.E., Moore D.T., Voorhees P.M. et al. Extended follow-up of outcome measures in multiple myeloma patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin. Ann. Hematol. 2007; 86: 211–6.
  78. Reece D.E., Rodriguez G.P., Chen C. et al. Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J. Clin. Oncol. 2008; 26(29): 4777–83.
  79. Garderet L., Iacobelli S., Moreau P. et al. Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomized Phase III Trial From the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J. Clin. Oncol. 2012; 30: 2475–82.
  80. Richardson P.G., Schlossman R.L., Weller E. et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002; 100(9): 3063–7.
  81. Richardson P.G., Blood E., Mitsiades C.S. et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006; 108: 3458–64.
  82. Weber D., Knight R., Chen C. et al. Prolonged Overall Survival with Lenalidomide Plus Dexamethasone Compared with Dexamethasone Alone in Patients with Relapsed or Refractory Multiple Myeloma. ASH Ann. Meet. Abstr. 2007; 110: 412.
  83. Dimopoulos M., Spencer A., Attal M. et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N. Engl. J. Med. 2007; 357: 2123–32.
  84. Reece D.E., Masih-Khan E., Chen C. et al. Lenalidomide (Revlimid) +/- corticosteroids in elderly patients with relapsed/refractory multiple myeloma. Blood (ASH Ann. Meet. Abstr.); 2006; 108: Abstract 3550.
  85. Dimopoulos M.A., Chen C., Spencer A. et al. Long-term follow-up on overall survival from the MM-009 and MM-010 Phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia 2009; 23(11): 2147–52.
  86. Wang M., Dimopoulos M.A., Chen C. et al. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood 2008; 112(12): 4445–51.
  87. Stadtmauer E., Weber D., Dimopoulos M. et al. Lenalidomide in combination with dexamethasone is more effective than dexamethasone at first relapse in relapsed multiple myeloma. Blood (ASH Ann. Meet. Abstr.). 2006; 108: Abstract 3552.
  88. Chanan-Khan A.A., Yu Z., Weber D. et al. Lenalidomide (L) in combination with dexamethasone (D) improves time to progression (TTP) in non-stem cell transplant patients (pts) with relapsed or refractory (rel/ref) multiple myeloma (MM): analysis from MM-009 and MM-010 randomized phase III clinical trials. Blood (ASH Ann. Meet. Abstr.). 2006; 108: Abstract 3554.
  89. Kyle R.A., Gertz M.A., Witzig T.E. et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin. Proc. 2003; 78: 21–33.
  90. Chen N., Lau H., Kong L. et al. Pharmacokinetics of lenalidomide in subjects with various degrees of renal impairment and in subjects on hemodialysis. J. Clin. Pharmacol. 2007; 47(12): 1466–75.
  91. Weber D., Wang M., Chen C. et al. Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): results of 2 phase III studies (MM-009, MM-010) and subgroup analysis of patients with impaired renal function. Blood (ASH Ann. Meet. Abstr.). 2006; 108: Abstract 3547.
  92. Bahlis N.J., Song K., Trieu Y. et al. Lenalidomide overcomes poor prognosis conferred by del13q and t(4; 14) but not del17p13 in multiple myeloma: results of the Canadian MM016 trial. Blood 2007; 110: Abstract 3597.
  93. Knight R., De Lap R.J., Zeldis J.B. Lenalidomide and venous thrombosis in multiple myeloma. N. Engl. J. Med. 2006; 354: 2079–80.
  94. Nooka A.K., Kaufman J.L., Heffner L.T. et al. Thromboembolic Events (TEE) with Lenalidomide-Based Therapies for Multiple Myeloma (MM): Emory Experience. ASH Ann. Meet. Abstr. 2009; 114: Abstract 3888.
  95. Reece D.E., Masih-Khan E., Chen C. et al. Use of Lenalidomide (Revlimid(R) +/- Corticosteroids in Relapsed/Refractory Multiple Myeloma Patients with Elevated Baseline Serum Creatinine Levels. ASH Ann. Meet. Abstr. 2006; 108: Abstract 3548.
  96. Baz R., Walker E., Karam M.A. et al. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann. Oncol. 2006; 17: 1766–71.
  97. Knop S., Gerecke C., Topp M.S. et al. Lеnalidomide (revlimidTM), adriamicin and dexamethasone chemotherapy (RAD) is safe and effective in treatment of relapsed multiple myeloma — first results of a German multicentre phase I/II trial. ASH Ann. Meet. Abstr. 2006; 108: 408.
  98. Knop S., Gerecke C., Topp M.S. et al. RAD (Revlimid, Adriamycin, Dex) is a new treatment regimen for relapsed multiple myeloma. Haematologica 2007; 92(s2): Abstract PO-658.
  99. Morgan G.J., Schey S.A., Wu P. et al. Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated regimen for myeloma patients. Br. J. Haematol. 2007; 137: 268–9.
  100. Reece D.E., Masin-Khan E., Khan A. et al. Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide (revlimid (R) (CPR) for treatment of patients with relapsed and refractory multiple myeloma. ASH Ann. Meet. Abstr. 2009; 114: 1874.
  101. Richardson P.G., Weller E., Jagannath S. et al. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/ refractory multiple myeloma. J. Clin. Oncol. 2009; 27: 5713–9.
  102. Anderson K., Jagannath S., Jakubowiak A. et al. Lenalidomide, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma: Encouraging outcomes and tolerability in a phase II study. ASCO Annual Meeting Proceedings (Post-Meeting Edition). J. Clin. Oncol. 2009; 27(15S): 8536.
  103. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Эффективность леналидомида при рефрактерных/рецидивирующих формах множественной миеломы. Онкогематология 2012; 1: 6–14. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V. et al. Lenalidomide efficacy in refractory/relapsing forms of multiple myeloma. Onkogematologiya 2012; 1: 6–14. (In Russ.)].
  104. Orlowski R.Z., Stinchcombe T.E., Mitchell B.S. et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J. Clin. Oncol. 2002; 20: 4420–7.
  105. Richardson P.G., Barlogie B., Berenson J. et al. A phase 2 study f bortezomib in relapsed, refractory myeloma. N. Engl. J. Med. 2003; 348(26): 2609–17.
  106. Jagannath S., Barlogie B., Berenson J. et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br. J. Haematol. 2004; 127(2): 165–72.
  107. Jagannath S., Barlogie B., Berenson J.R. et al. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br. J. Haematol. 2008; 143(4): 537–40.
  108. Richardson P.G., Sonneveld P., Schuster M.W. et al. Bortezomib or highdose dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 2005; 352(24): 2487–98.
  109. Richardson P.G., Sonneveld P., Schuster M. et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007; 110(10): 3557–60.
  110. Richardson P., Sonneveld P., Schuster M. et al. Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed myeloma. Program and abstracts of the American Society of Clinical Oncology Annual Meeting, May 13–17, 2005; Orlando, Florida. Abstract 6533.
  111. Horton T.M., Gannavarapu A., Blaney S.M. et al. Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer Chemother. Pharmacol. 2006; 58(1): 13–23.
  112. Jagannath S., Richardson P.G., Barlogie B. et al. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/ or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica 2006; 91: 929–34.
  113. Kropff M.H., Bisping G., Wenning D. et al. Bortezomib in combination with dexamethasone for relapsed multiple myeloma. Leuk. Res. 2005; 29: 587–90.
  114. Mikhael J.R., Belch A.R., Prince H.M. et al. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br. J. Haematol. 2009; 144: 169–75.
  115. Chou T. Multiple Myeloma: Recent Progress in Diagnosis and Treatment. J. Clin. Exp. Hematopathol. 2012; 52(3): 149–59.
  116. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Бортезомиб (Велкейд) в комбинации с дексаметазоном в лечении рефрактерных/рецидивирующих форм множественной миеломы. Результаты заключительного анализа. Клин. онкогематол. 2009; 2(3): 236–44. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V., et al. Bortezomib (Velcade) in combination with dexamethasone in therapy for refractory/relapsing forms of multiple myeloma (final analysis results). Klin. onkogematol. 2009; 2(3): 236–44. (In Russ.)].
  117. Richardson P.G., Briemberg H., Jagannath S. et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J. Clin. Oncol. 2006; 24: 3113–20.
  118. Moreau P., Richardson P.G., Cavo M. et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood 2012; 120(5): 947–59.
  119. Moreau P., Coiteux V., Hulin C. et al. Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma. Haematologica 2008; 93(12): 1908–11.
  120. Moreau P., Pylypenko H., Grosicki S. et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011; 12(5): 431–40.
  121. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Бортезомиб (велкейд) и дексаметазон в лечении рефрактерных/рецидивирующих форм множественной миеломы (результаты промежуточного анализа). Вестн. гематол. 2008; 4: 14–22. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V., et al. Bortezomib (Velcade) in combination with dexamethasone in therapy for refractory/relapsing forms of multiple myeloma (interim analysis results). Vest. gematol. 2008; 4: 14–22. (In Russ.)].
  122. Mitsiades N., Mitsiades C.S., Richardson P.G. et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003; 101(6): 2377–80.
  123. Orlowski R.Z., Voorhees P.M., Garcia R.A. et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 2005; 105(8): 3058–65.
  124. Orlowski R.Z., Nagler A., Sonneveld P. et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J. Clin. Oncol. 2007; 25(25): 3892–901.
  125. Spencer A., Hajek R., Nagler A. et al. Doxil + velcade in previously treated high risk myeloma. Haematologica 2007; 92: 162. 126. San Miguel J., Hajek R., Nagler A. et al. Doxil + velcade in previously treated ³ 65y myeloma pts. Haematologica 2007; 92: 159.
  126. Palumbo A., Gay F., Bringhen S. et al. Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma. Ann. Oncol. 2008; 19(6): 1160–5.
  127. Pineda-Roman M., Zangari M., van Rhee F. et al. VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma. Leukemia 2008; 22: 1419–27.
  128. Cioli S., Leoni F., Gigli F. et al. Low dose velcade, thalidomide and dexamethasone (LD-VTD): An effective regimen for relapsed and refractory multiple myeloma patients. Leuk. Lymphoma 2006; 47: 171–3.
  129. Garderet L., Iacobelli S., Moreau P. et al. Bortezomib (VELCADE)-thalidomide-dexamethasone (VTD) is superior to thalidomide-dexamethasone (TD) in patients with multiple myeloma (MM) progressing or relapsing after autologous transplantation [abstract]. Haematologica 2011; 96(s2): 420–1. Abstract 1008.
  130. Reece D.E., Rodriguez G.P., Chen C. et al. Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. J. Clin. Oncol. 2008; 26(29): 4777–83.
  131. Kropff M., Bisping G., Liebisch P. et al. Bortezomib in combination with high dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Blood (ASH Ann. Meet. Abstr.) 2005; 106: 2549.
  132. Berenson J., Yang H., Swift R. et al. Bortezomib in Combination with Melphalan in the Treatment of Relapsed or Refractory Multiple Myeloma: A Phase I/II Study. Blood (ASH Ann. Meet. Abstr.) 2004; 104: Abstract 209.
  133. Terpos E., Anagnostopoulos A., Kastritis E. et al. The Combination of Bortezomib, Melphalan, Dexamethasone and Intermittent Thalidomide (VMDT) Is an Effective Treatment for Relapsed/Refractory Myeloma: Results of a Phase II Clinical Trial. ASH Ann. Meet. Abstr. 2005; 106: 363.
  134. Terpos E., Kastritis E., Roussou M. et al. The combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide is an effective regimen for relapsed/refractory myeloma and is associated with improvement of abnormal bone metabolism and angiogenesis. Leukemia 2008; 22: 2247–56.
  135. Palumbo A., Ambrosini M.T., Pregno P. et al. Velcade plus Melphalan, Prednisone and Thalidomide (V-MPT) for advanced multiple myeloma. Blood (ASH Ann. Meet. Abstr.) 2005; 106: 2553.
  136. Mitsiades N., Mitsiades C.S., Poulaki V. et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc. Natl. Acad. Sci. U S A 2002; 99(22): 14374–9.
  137. Richardson P., Jagannath S., Jakubowiak A. et al. Lenalidomide, bortezomib, and dexamethasone in patients with relapsed or relapsed/ refractory multiple myeloma (MM): encouraging response rates and tolerability with correlation of outcome and adverse cytogenetics in a phase II study. ASH Ann. Meet. Abstr. 2008; 112: Abstract 1742.
  138. Wolf J., Richardson P.G., Schuster M. et al. Utility of bortezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter case series. Clin. Adv. Hematol. Oncol. 2008; 6: 755–9.
  139. Hrusovsky I., Emmerich B., Enhgelhardt M. et al. Response to bortezomib retreatment is determined by duration of preceding treatment free interval — results from a retrospective multicenter survey. Haematologica 2008; 93(Suppl. 1): 259. Abstract 0645.
  140. Richardson P.G., Sonneveld P., Schuster M. et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007; 110: 3557–60.
  141. Conner Th.M., Doan Q.Ch.D., Walters I.B. et al. An Observational, Retrospective Analysis of Retreatment with Bortezomib for Multiple Myeloma. Clin. Lymph. Myel. 2008; 8(3): 140–5.
  142. Hrusovsky I., Emmerich B., von Rohr A. et al. Bortezomib retreatment in relapsed multiple myeloma: results from a retrospective multicentre survey in Germany and Switzerland. Oncology 2010; 79(3–4): 247–54.
  143. Petrucci M.T., Blau I., Corradini P. et al. Efficacy and safety of retreatment with bortezomib in patients with multiple myeloma: interim results from RETRIEVE, a prospective international phase 2 study. Haematologica 2010; 95(s2): 152. Abstract 0377.
  144. Бессмельцев С.С., Стельмашенко Л.В., Карягина Е.В. и др. Лечение рефрактерных/рецидивирующих форм множественной миеломы. Medline. ru. 2011; 12: 763–80. [Bessmeltsev S.S., Stelmashenko L.V., Karyagina Ye.V., et al. Management of refractory/relapsing forms of multiple myeloma. Medline.ru. 2011; 12: 763–80. (In Russ.)].
  145. Verhelle D., Corral L.G., Wong K. et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res. 2007; 67(2): 746–55.
  146. Mitsiades N., Mitsiades C.S., Poulaki V. et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99(12): 4525–30.
  147. Schey S., Ramasamy K. Pomalidomide therapy for myeloma. Expert. Opin. Investig. Drugs 2011; 20: 691–700.
  148. Terpos E., Kanellias N., Christoulas D. et al. Pomalidomide: a novel drug to treat relapsed and refractory multiple myeloma. Oncol. Targ. Ther. 2013; 6: 531–8.
  149. Schey S.A., Fields P., Bartlett J.B. et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J. Clin. Oncol. 2004; 22: 3269–76.
  150. Streetly M.J., Gyertson K., Daniel Y. et al. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation. Br. J. Haematol. 2008; 141(1): 41–51.
  151. Richardson P.G., Siegel D.S., Vij R. et al. Randomized, Open Label Phase 1/2 Study of Pomalidomide (POM) Alone or in Combination with Low-Dose Dexamethasone (LoDex) in Patients (Pts) with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide (LEN) and Bortezomib (BORT): Phase 2 Results. ASH Ann. Meet. Abstr. 2011; 118: 634.
  152. Richardson P.G., Siegel D., Baz R. et al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood 2013; 121(11): 1961–7.
  153. Leleu X., Attal M., Arnulf B. et al. High Response Rates to Pomalidomide and Dexamethasone in Patients with Refractory Myeloma, Final Analysis of IFM 2009-02. ASH Ann. Meet. Abstr. 2011; 118: 812.
  154. Leleu X., Attal M., Arnulf B. et al. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide– refractory multiple myeloma: Intergroupe Francophone du Myelome 2009-02. Published online before print January 14, 2013, doi: 10.1182/blood-2012-09- 452375. Blood 2013; 121(11): 1968–75.
  155. Lacy M.Q., Kumar S.K., LaPlant B.R. et al. Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Relapsed Myeloma: Long Term Follow up and Factors Predicting Outcome in 345 Patients. ASH Ann. Meet. Abstr. 2012; 120: 201.
  156. Vij R., Richardson P.G., Jagannath S. et al. Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): outcomes in pts refractory to lenalidomide (LEN) and/or bortezomib (BORT). J. Clin. Oncol. 2012; 30(Suppl.): Abstract 8016.
  157. Dimopoulos M.A., Lacy M.Q., Moreau P. et al. Pomalidomide in combination with low-dose dexamethasone: demonstrates a significant progression free survival and overall survival advantage, in relapsed/refractory ММ: a phase 3, multicenter, randomized, open-label study. Blood (ASH Ann. Meet. Abstr.) 2012; 120: Abstract LBA-6.
  158. San-Miguel J.F., Weisel K.C., Moreau Ph. et al. MM-003: A phase III, multicenter, randomized, open-label study of pomalidomide (POM) plus lowdose dexamethasone (LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM). 2013 ASCO Annual Meeting. J. Clin. Oncol. 2013; 31(Suppl.): Abstract 8510.
  159. Palumbo A., Larocca A., Montefusco V. et al. Pomalidomide Cyclophosphamide and Prednisone (PCP) Treatment for Relapsed/Refractory Multiple Myeloma. ASH Ann. Meet. Abstr. 2012; 120: 446.
  160. Shah J.J., Stadtmauer E.A., Abonour R. et al. A Multi-Center Phase I/ II Trial of Carfilzomib and Pomalidomide with Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. ASH Ann. Meet. Abstr. 2012; 120: 74.
  161. Richardson P.G., Hofmeister C.C., Siegel D. et al. MM-005: A Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Determine the Maximum Tolerated Dose for the Combination of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone in Subjects with Relapsed or Refractory Multiple Myeloma. ASH Ann. Meet. Abstr. 2012; 120: 727.
  162. Mark T.M., Boyer A., Rossi A.C. et al. ClaPD (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma. Blood (ASH Ann. Meet. Abstr.) 2012; 120: Abstract 77.
  163. Jain S., Diefenbach C., Zain J., O’Connor O.A. Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma. Core Evid. 2011; 6: 43–57.
  164. Reece D.E. Carfilzomib in multiple myeloma: gold, silver, or bronze? Blood 2012; 120(14): 2776–7.
  165. Badros A.Z., Vij R., Martin T. et al. Phase I study of carfilzomib in patients (pts) with relapsed and refractory multiple myeloma (MM) and varying degrees of renal insufficiency [ASH abstract]. Blood 2009; 114: 3877.
  166. Jagannath S., Vij R., Stewart A.K. et al. An open-label single arm pilot phase II study (PX-171-003-A0) of low-dose, single agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin. Lymph. Myel. Leuk. 2012; 12: 310–8.
  167. Vij R., Wang M., Kaufman J.L. et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood 2012; 119: 5661–70.
  168. Siegel D.S., Martin T., Wang M. et al. Results of PX-171-003-A1, an open-label, single-arm, phase 2 (ph 2) study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). Blood (ASH Ann. Meet. Abstr.) 2010; 116(21): 433. Abstract 985.
  169. Siegel D.S., Martin T., Wang M. et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012; 120(14): 2817–25.
  170. Vij R., Siegel D.S., Kaufman J.L. et al. Results of an ongoing open-label, phase II study of carfilzomib in patients with relapsed and/or refractory multiple myeloma (R/R MM). J. Clin. Oncol. 2010; 28(15s): 573s. Abstract 8000.
  171. Vij R., Wang M., Kaufman J.L. et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma [published online ahead of print May 3, 2012]. Blood. doi: 10.1182/blood-2012-03-414359.
  172. Jakubowiak A.J., Martin T., Singhal S. et al. Responses to single-agent carfilzomib (CFZ) are not affected by cytogenetics in patients (pts) with relapsed and refractory multiple myeloma. Ann. Oncol. 2011; 22(Suppl. 4): iv122. Abstract 117.
  173. Singhal S., Siegel D.S., Martin T. et al. Integrated safety from phase 2 studies of monotherapy carfilzomib in patients with relapsed and refractory multiple myeloma (MM): an updated analysis [abstract]. Blood (ASH Ann. Meet. Abstr.) 2011; 118(21): 819. Abstract 1876.
  174. Badros A.Z., Vij R., Martin T. et al. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia 2013; 27: 1707–14.
  175. Niesvizky R., Wang L., Orlowski R.Z. et al. Phase Ib multicenter dose escalation study of carfilzomib plus lenalidomide and low dose dexamethasone (CRd) in relapsed and refractory multiple myeloma (MM) [abstract]. Blood (ASH Ann. Meet. Abstr.) 2009; 114(22): 128–9. Abstract 304.
  176. Wang M., Bensinger W., Martin T. et al. Interim results from PX-171-006, a phase (Ph) II multicenter dose-expansion study of carfilzomib (CFZ = CRd), lenalidomide (LEN), and low-dose dexamethasone (loDex) in relapsed and/or refractory multiple myeloma (R/R MM). ASCO Ann. Meet. 2011; 29(15): 8025.
  177. Hajek R., Bryce R., Ro S. et al. Design and rationale of FOCUS (PX- 171-011): a randomized, open-label, phase 3 study of carf lzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma (R/R MM). BMC Cancer 2012; 12: 415.
  178. Potts B.C., Albitar M.X., Anderson K.C. Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials. Curr. Cancer Drug Targ. 2011; 11(3): 254–84.
  179. Richardson P.G., Spencer A., Cannell P. et al. Phase 1 clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma (MM) [abstract]. Blood (ASH Ann. Meet. Abstr.) 2011; 118(21): 140–1. Abstract 302.
  180. Richardson P.G., Baz R., Wang L. et al. Investigational agent MLN9708, an oral proteasome inhibitor, in patients (pts) with relapsed and/or refractory multiple myeloma (MM): results from the expansion cohorts of a phase 1 doseescalation study. Blood (ASH Ann. Meet. Abstr.) 2011; 118(21): 140. Abstract 301.
  181. Kumar S., Bensinger W.I., Reeder C.B. et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients with relapsed and/ or refractory multiple myeloma: results from a phase 1 dose-escalation study [abstract]. Blood (ASH Ann. Meet. Abstr.) 2011; 118(21): 371–2. Abstract 816.
  182. Hideshima T., Catley L., Yasui H. et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 2006; 107: 4053–62.
  183. Mitsiades C.S., Mitsiades N., Poulaki V. et al. Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene 2002; 21: 5673–83.
  184. Jakubowiak A., Richardson P., Zimmerman T.M. et al. Phase I results of perifosine (KRX-0401) in combination with lenalidomide and dexamethasone in patients with relapse or refractory multiple myeloma (mm) [ASH abstract]. Blood 2008; 112: 3691.
  185. Richardson P., Lonial S., Jakubowiak A. et al. Multi-center phase II study of perifosine (KRX-0401) alone and in combination with dexamethasone (dex) for patients with relapsed or relapsed/refractory multiple myeloma: promising activity as combination therapy with manageable toxicity [ASH abstract]. Blood 2007; 110: 1164.
  186. Richardson P., Wolf J.L., Jakubowiak A. et al. Perifosine in combination with bortezomib and dexamethasone extends progression-free survival and overall survival in relapsed/refractory multiple myeloma patients previously treated with bortezomib: updated phase I/II trial results [ASH abstract]. Blood 2009; 114: 1869.
  187. Khan N., Jeffers M., Kumar S. et al. Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem. J. 2008; 409: 581–9.
  188. Wolf J.L., Siegel D., Matous J. et al. A phase II study of oral panobinostat (LBH589) in adult patients with advanced refractory multiple myeloma [ASH abstract]. Blood 2008; 112: 2774.
  189. Spencer A., Taylor K.M., Lonial S. et al. Panobinostat plus lenalidomide and dexamethasone phase I trial in multiple myeloma (MM) [ASCO abstract]. J. Clin. Oncol. 2009; 27: 8542.
  190. Berenson J.R., Yellin O., Boccia R.V. et al. A phase I study of oral melphalan combined with LBH589 for patients with relapsed or refractory multiple myeloma (MM) [ASH abstract]. Blood 2009; 114: 1855.
  191. Siegel D., Sezer O., San Miguel J. et al. A phase IB, multicenter, openlabel, dose-escalation study of oral panobinostat (LBH589) and I.V. bortezomib in patients with relapsed multiple myeloma [ASH abstract]. Blood 2008; 112: 2781.
  192. San Miguel J., Sezer O., Siegel D. et al. A phase IB, multi-center, openlabel dose-escalation study of oral panobinostat (LBH589) and I.V. bortezomib in patients with relapsed multiple myeloma [ASH abstract]. Blood 2009; 114: 3852.
  193. Alsina M., Schlossman R., Weber D.M. et al. PANORAMA 2: a phase II study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma. J. Clin. Oncol. 2012; 30(Suppl.): Abstract 8012.
  194. Richardson P.G., Schlossman R.L., Alsina M. et al. PANORAMA 2: Panobinostat in Combination With Bortezomib and Dexamethasone in Patients With Relapsed and Bortezomib-Refractory Myeloma. Blood 2013. doi: 10.1182/blood- 2013-01-481325 (Epub Ahead of Print: bloodjournal.hematologylibrary.org).
  195. Prince M., Quach H., Neeson P. et al. Safety and efficacy of the combination of bortezomib with the deacetylase inhibitor romidepsin in patients with relapsed or refractory multiple myeloma: preliminary results of a phase I trial [ASH abstract]. Blood 2007; 110: 1167.
  196. Berenson J.R., Yellin O., Mapes R. et al. A phase II study of a 1-hour infusion of romidepsin combined with bortezomib for multiple myeloma (MM) patients with relapsed or refractory disease. [ASCO abstract]. J. Clin. Oncol 2009; 27: e19508.
  197. Harrison S.J., Quach H., Yuen K. et al. High response rates with the combination of bortezomib, dexamethasone and the pan-histone deacetylase inhibitor romidepsin in patients with relapsed or refractory multiple myeloma in a phase I/II clinical trial [ASH abstract]. Blood 2008; 112: 3698.
  198. Mann B.S., Johnson J.R., Cohen M.H. et al. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007; 12: 1247–52.
  199. Badros A., Burger A.M., Philip S. et al. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin. Cancer Res. 2009; 15: 5250–7.
  200. Jagannath S., Weber D., Sobecks R. et al. The combination of vorinostat and bortezomib provides long-term responses in patients with relapsed or refractory multiple myeloma [ASH abstract]. Blood 2009; 114: 3886.
  201. Siegel D., Jagannath S., Lonial S. et al. Update on the phase IIb, openlabel study of vorinostat in combination with bortezomib in patients with relapsed and refractory multiple myeloma [ASH abstract]. Blood 2009; 114: 3890.
  202. Siegel D., Weber D.M., Mitsiades C. et al. Combined vorinostat, lenalidomide and dexamethasone therapy in patients with relapsed or refractory multiple myeloma: a phase I study [ASH abstract]. Blood 2009; 114: 305.
  203. Voorhees P.M., Gasparetto C., Richards K.L. et al. Vorinostat in combination with pegylated liposomal doxorubicin and bortezomib for patients with relapsed/refractory multiple myeloma: results of a phase I study [ASH abstract]. Blood 2009; 114: 306.
  204. Siegel D.S., Dimopoulos M.A., Yoon S.-S. et al. VANTAGE 095: vorinostat in combination with bortezomib in salvage multiple myeloma patients: final study results of a global phase 2b trial. ASH Ann. Meet. Abstr. 2011; 118: 480.
  205. Siegel D., Munster P.N., Rubin E.H. et al. The combined safety and tolerability profile of vorinostat-based therapy for solid or hematologic malignancies [ASH abstract]. Blood 2009; 114: 1710.
  206. Raje N., Hari P.N., Vogl D.T. et al. Rocilinostat (ACY-1215), a selective HDAC6 inhibitor, alone and in combination with bortezomib in multiple myeloma: preliminary results from the first-in-humans phase I/II study. ASH Ann. Meet. Abstr. 2012; 120: 4061.
  207. Kapoor T.M., Mayer T.U., Coughlin M.L. et al. Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J. Cell Biol. 2000; 150: 975–88.
  208. Sawin K.E., LeGuellec K., Philippe M. et al. Mitotic spindle organization by a plus-end-directed microtubule motor. Nature 1992; 359: 540–3.
  209. Shah J.J., Zonder J., Cohen A. et al. ARRY-520 Shows Durable Responses in Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Dose-Escalation Study. ASH Ann. Meet. Abstr. 2011; 118: 1860.
  210. Shah J.J., Zonder J.A., Cohen A. et al. The Novel KSP Inhibitor ARRY- 520 Is Active Both with and without Low-Dose Dexamethasone in Patients with Multiple Myeloma Refractory to Bortezomib and Lenalidomide: Results From a Phase 2 Study. ASH Ann. Meet. Abstr. 2012; 120: 449.
  211. Leoni L.M., Bailey B., Reifert J. et al. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin. Cancer Res. 2008; 14: 309–17.
  212. Michael M., Bruns I., Bolke E. et al. Bendamustine in patients with relapsed or refractory multiple myeloma. Eur. J. Med. Res. 2010; 15: 13–9.
  213. Knop S., Straka C., Haen M. et al. The efficacy and toxicity of bendamustine in recurrent multiple myeloma after high-dose chemotherapy. Haematologica 2005; 90: 1287–8.
  214. Ponisch W., Rozanski M., Goldschmidt H. et al. Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a Phase I clinical trial. Br. J. Haematol. 2008; 143: 191–200.
  215. Fenk R., Michael M., Zohren F. et al. Escalation therapy with bortezomib, dexamethasone and bendamustine for patients with relapsed or refractory multiple myeloma. Leuk. Lymphoma 2007; 48: 2345–51.
  216. Havasi A., Li Z., Wang Z. et al. Hsp27 inhibits Bax activation and apoptosis via a phosphatidylinositol 3-kinase-dependent mechanism. J. Biol. Chem. 2008; 283: 12305–13.
  217. Ciocca D.R., Calderwood S.K. Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 2005; 10: 86–103.
  218. Chauhan D., Li G., Hideshima T. et al. Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance. Blood 2003; 102: 3379–86.
  219. Chauhan D., Li G., Shringarpure R. et al. Blockade of Hsp27 overcomes bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res. 2003; 63: 6174–7.
  220. Badros A.Z., Richardson P.G., Albitar M. et al. Tanespimycin + bortezomib in relapsed/refractory myeloma patients: results from the Time-2 study. Blood 2009; 114: 1871 (ASH abstract).
  221. Richardson P., Chanan-Khan A.A., Lonial S. et al. Tanespimycin + bortezomib demonstrates safety, activity, and effective target inhibition in relapsed/refractory myeloma patients: updated results of a phase 1/2 study [ASH abstract]. Blood 2009; 114: 2890.
  222. Badros A.Z., Richardson P.G., Albitar M. et al. Tanespimycin + bortezomib in relapsed/refractory myeloma patients: results from the Time-2 study (ASH abstract). Blood 2009; 114: 1871.
  223. Lonial S., Jagannath S. Monoclonal antibodies in the treatment of multiple myeloma. Haematologica. 13th International Myeloma Workshop, Paris, France, May 3–6, 2011; Abstract Book: S22–3.
  224. Plesner T., Lokhorst H.M., Gimsing P. et al. Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma — date from a doseescalation phase I/II study. 54th American Society Hematology Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA.
  225. Харченко М.Ф., Бессмельцев С.С. Значение протеогликанов в патогенезе множественной миеломы. Medline.ru. 2010; 11: 404–23. [Kharchenko M.F., Bessmeltsev S.S. Significance of proteoglycans in pathogenesis of multiple myeloma. Medline.ru. 2010; 11: 404–23. (In Russ.)].
  226. Dimopoulos M.A., San-Miguel J.F., Anderson K.C. Emerging therapies for the treatment of relapsed or refractory multiple myeloma. Eur. J. Haematol. 2010; 86: 1–15.
  227. Tai Y.T., Dillon M., Song W. et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 2008; 112: 1329–37.
  228. Hsi E.D., Steinle R., Balasa B. et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin. Cancer Res. 2008; 14: 2775–84.
  229. Van Rhee F., Szmania S.M., Dillon M. et al. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Mol. Cancer Ther. 2009; 8: 2616–24.
  230. Lonial S., Vij R., Harousseau J. et al. Multiple Myeloma Research Consortium. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma: a phase I/II study. J. Clin. Oncol. 2010; 28: 8020.
  231. Richardson P.G., Jagannath S., Moreau P. et al. A phase 2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma: update results: 54th American Society of Hematology Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA.

Множественная миелома (лечение первичных больных): обзор литературы и собственные данные. Часть II

КЛИНИКА, ДИАГНОСТИКА И ЛЕЧЕНИЕ ЛИМФОИДНЫХ ОПУХОЛЕЙ , , , , , , , ,

С.С. Бессмельцев

ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства», Санкт-Петербург, Российская Федерация

РЕФЕРАТ

В последние десятилетия в результате широкого применения аутологичной трансплантации гемопоэтических стволовых клеток (аутоТГСК) и новых, весьма эффективных лекарственных средств существенно улучшились показатели выживаемости пациентов с множественной миеломой (ММ) в возрасте до 65 лет (молодые пациенты). У пациентов с ММ в возрасте старше 65 лет традиционно используется комбинация мелфалана и преднизолона (MP). Внедрение новых препаратов, в частности иммуномодулирующих средств (ИМС) и ингибиторов протеасомы, значительно изменило подходы к лечению этого заболевания. У больных с впервые выявленной ММ была изучена эффективность многих двух-, трех- и четырехкомпонентных комбинаций. Установлено, что достижение полной ремиссии (ПР) служит независимым предиктором длительной выживаемости (ВБП, ОВ). Результаты проведенных проспективных исследований свидетельствуют о том, что для достижения высокого значения ПР и увеличения ее продолжительности необходимо индукционное лечение с использованием трехкомпонентных режимов, содержащих бортезомиб или иммуномодуляторы, с последующей аутоТГСК, консолидацией/поддерживающей терапией ИМС или ингибиторами протеасомы. В преобладающем большинстве случаев пожилые пациенты не являются кандидатами на аутоТГСК. Внедрение в лечебную практику новых препаратов — талидомида, бортезомиба, леналидомида — значительно улучшило результаты лечения этих больных. Программы MP + талидомид (MPT), MP + бортезомиб (VMP) и MP + леналидомид с последующей поддерживающей терапией леналидомидом (MPR-R) в настоящее время рассматриваются в качестве новых стандартов лечения пожилых пациентов с ММ. Прогноз ММ зависит от множества факторов, которые следует учитывать до начала терапии. В обзоре представлены современные подходы к ведению пациентов с впервые выявленной ММ, основанные на проводимых в настоящее время исследованиях, цель которых заключается в оптимизации результатов лечения.

Ключевые слова: множественная миелома, бортезомиб, талидомид, леналидомид, лечение, полная ремиссия, общая выживаемость, нейропатия, аутологичная трансплантация гемопоэтических стволовых клеток.

Читать статью в PDFpdficon

Литература

  1. Бессмельцев С.С., Абдулкадыров К.М. Множественная миелома. Со- временный взгляд на проблему. Алматы: Коста, 2007. [Bessmeltsev S.S., Abdulkadyrov K.M. Mnozhestvennaya miyeloma. Sovremennyy vzglyad na problemu (Multiple myeloma. Current view of the problem). Almaty: Kosta, 2007.]
  2. Kumar S.K., Rajkumar S.V., Dispenzieri A. et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008; 111(5): 2516–20.
  3. San-Miguel J.F., Mateos M.-V. How to treat a newly diagnosed young patient with multiple myeloma. Hematology (American Society of Hematology Education Program Book, New Orleans, Louisiana, December 508, 2009) 2009: 555–65.
  4. Rajkumar S. V., Harousseau J.-L., Durie B. et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International myeloma workshop consensus panel 1. Blood, prepublished online Feb 3, 2011; doi:10.1182/blood-2010-10-299487.
  5. Dimopoulos M., Kyle R., Fermand J.-P. et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood 2011; 117(18): 4701–5.
  6. Landgren O., Katzmann J.A., Hsing A.W. et al. Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana. Mayo Clin. Proc. 2007; 82(12): 1468–73.
  7. Iwanaga M., Tagawa M., Tsukasaki K. et al. Prevalence of monoclonal gammopathy of undetermined significance: study of 52,802 persons in Nagasaki City, Japan. Mayo Clin. Proc. 2007; 82(12): 1474–9.
  8. Kyle R.A., Remstein E.D., Therneau T.M. et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. New Engl. J. Med. 2007; 356(25): 2582–90.
  9. Kumar S. K., Mikhael J.R., Buadi F.K. et al. Management of Newly Diagnosed Symptomatic Multiple Myeloma: Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines. Mayo Clin. Proc. 2009; 84(12): 1095–110.
  10. Euler H.H., Schmitz N., Loffler H. Plasmapheresis in Paraproteinemia. Blut 1985; 50(6): 321–30.
  11. Attal M., Huguet F., Schlaifer D. et al. Intensive combined therapy for previously untreated aggressive myeloma. Blood 1992; 79: 1130–6.
  12. Alexanian R., Dimopoulos M.A., Hester I. et al. Early myeloablative therapy for multiple myeloma. Blood 1994; 84(12): 4278–82.
  13. Abdulkadyrov K.M., Bessmeltsev S.S. Use of VCAP, ARA-COP and VAD schedules in treatment of patients with multiple myeloma. Abstracts of the XVI International Cancer Congress. New Delhi (India), 1995. Abstract NA-02807.
  14. Bergsagel D.E., Pruzanski P.W. Some unusual manifestations of plasma cell neoplasma. In: Neoplastic disease of the Blood. Ed. by P.H. Wiernik. New York, 1985: 553–73.
  15. Абдулкадыров К.М., Бессмельцев С.С. Сравнительная оценка эффективности программ моно- и полихимиотерапии больных множественной миеломой. Клин. мед. 1992; 9(10): 57–60. [Abdulkadyrov K.M., Bessmeltsev S.S. Sravnitelnaya otsenka effektivnosti programm mono- i polikhimioterapii bolnykh mnozhestvennoy miyelomoy (Comparative evaluation of efficacy of mono- and polychemotherapy programs in patients with multiple myeloma. In: Clin. med.). Klin. med. 1992; 9(10): 57–60.]
  16. Birgens H.S., Hansen O.P., Clausen N.T. et al. A methodological evaluation of 14 controlled clinical trials in myelomatosis. Scand. J. Haematol. 1985; 35: 26–34.
  17. Merlini G., Riccardi A., Riccardi R.G. et al. Peptichemio, vincristine, prednisone induction treatment in multiple myeloma. Tumors 1985; 71: 581–8.
  18. Бессмельцев С.С., Стельмашенко Л.В. Сравнительная оценка различных методов лечения больных с множественной миеломой. Эфферентная тер. 2000; 2: 54–63. [Bessmeltsev S.S., Stelmashenko L.V. Sravnitelnaya otsenka razlichnykh metodov lecheniya bolnykh s mnozhestvennoy miyelomoy (Comparative evaluation of various therapeutic methods in patients with multiple myeloma. In: Efferent ther.). Efferentnaya ter. 2000; 2: 54–63.]
  19. Palva I.P., Ahrenberg P., Ala-Harja K. et al. Treatment of multiple myeloma in old patients. Eur. J. Haematol. 1989; 43: 328–31.
  20. Hernandez J.M., Garcia-Sanz R., Golvano E. et al. Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma. Br. J. Haematol. 2004; 127(2): 159–64.
  21. Facon T., Mary J.Y., Pegourie B. et al. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood 2006; 107: 1292–8.
  22. Riccardi A., Ucci G., Luoni R. et al. Treatment of multiple myeloma according to the extension of the disease: a prospective, randomized study comparing a less with a more aggressive cytostatic policy. Cooperative Group of Study and Treatment of Multiple myeloma. Br. J. Cancer 1994; 70: 1203–10.
  23. Бессмельцев С.С. Современные подходы к химиотерапии множе- ственной миеломы. Медико-фармацевтический форум (29 октября — 2 но- ября): Тезисы докладов. М., 2002: 36–7. [Bessmeltsev S.S. Sovremennyye podkhody k khimioterapii mnozhestvennoy miyelomy. Mediko-farmatsevticheskiy forum (29 oktyabrya — 2 noyabrya): Tezisy dokladov (Current approaches to chemotherapy for multiple myeloma. Medico-pharmaceutical forum (October 29–November 2): talking points in presentations). M., 2002: 36–7.]
  24. Oken M.M., Kyle R.A., Greipp P.R. et al. Complete remission induction with combined VBMCP chemotherapy and interferon in patients with multiple myeloma. Leuk. Lymphoma 1996; 20: 447–52.
  25. Oken M.M., Harrington D.P., Abramson N. et al. Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479. Cancer 1997; 79: 1561–7.
  26. Finnish Leukemia Group. Treatment of multiple myeloma in old patients. Eur. J Haematol. 1989; 43: 328–31.
  27. Kumar S., Lacy M.Q., Dispenzieri A. et al. Single agent dexamethasone for pre-stem cell transplant induction therapy for multiple myeloma. Bone Marrow Transplant. 2004, advance online publication 2 August 2004; doi:10.1038/ sj.bmt. 1704633.
  28. Cook G., Clark R.E., Morris T.C. A randomized study (WOS MM1) comparing the oral regime Z-Dex (idarubicin and dexamethasone) with vincristine, adriamycin and dexamethasone as induction therapy for newly diagnosed patients with multiple myeloma. Br. J. Haematol. 2004; 126: 792–8.
  29. Munshi N.C., Anderson K.C., Bergsagel P.L. et al. Guidelines for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood, Prepublished online Feb 3, 2011; doi:10.1182/ blood-2010-10-300970.
  30. Kyle R.A., Rajkumar S.V. Multiple myeloma. N. Engl. J. Med. 2004; 351: 1060–77.
  31. Barlogie B., Shaughnessy J., Tricot G. et al. Treatment of multiple myeloma. Blood 2004; 103: 20–32.
  32. Palumbo A., Gay F. How to treat elderly patients with multiple myeloma: combination of therapy or sequencing. Hematology 2009 (American Society of Hematology Eduction Program Book, New Orleans, Louisiana, December 508, 2009): 566–77.
  33. Blade J., Samson D., Reece D. et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br. J. Haematol. 1998; 102(5): 1115–23.
  34. Durie B.G.M., Harousseau J.-L., San-Miguel J. et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20(9): 1467–73.
  35. Paiva B., Vidriales M.B., Cervero J. et al. Multiparameter flow cytometry remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood 2008; 112: 4017–23.
  36. Corradini P., Cavo M., Lokhorst H. et al. Molecular remission after myeloablative allogeneic stem cell transplantation predicts a better relapse-free survival in patients with multiple myeloma. Blood 2003; 102: 1927–9.
  37. Brenner H., Gondos A., Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood 2008; 111(5): 2521–6.
  38. D’Amato R.J., Loughnan M.S., Flynn E. et al. Thalidomide is an inhibitor of angiogenesis. Proc. Natl. Acad. Sci. U S A 1994; 91: 4082–5.
  39. Mitsiades N., Mitsiades C.S., Poulaki V. et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99(12): 4525–30.
  40. Kyle R.A., Rajkumar S.V. Therapeutic application of thalidomide in multiple myeloma. Semin. Oncol. 2001; 28: 583–7.
  41. Rajkumar S.V., Blood E., Vesole D. et al. 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. 2006; 24: 431–6.
  42. Rajkumar S.V., Rosinol L., Hussein M. et al. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J. Clin. Oncol. 2008; 26: 2171–7.
  43. Cavo M., Zamagni E., Tosi P. et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005; 106: 35–9.
  44. Lokhorst H.M., Schmidt-Wolf I., Sonneveld P. et al. Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma. Haematologica 2008; 93: 124–7.
  45. Zervas K., Mihou D., Katodritou E. et al. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek myeloma study group. Ann. Oncol. 2007; 18: 1369–75.
  46. Marco M., Divine M., Uzunhan Y. et al. Dexamethasone+thalidomide (Dex/Thal) compared to VAD as a pre-transplant treatment in newly diagnosed multiple myeloma: a randomized trial. Blood 2006; 108: 57a (abstr.).
  47. Morgan G.J., Faith D., Roger O. et al. Thalidomide combinations improve response rates; results from the MRC IX study. Blood 2007; 110: 3593 (abstr.).
  48. Schafer P.H., Gandhi A.K., Loveland M.A. et al. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J. Pharmacol. Exp. Ther. 2003; 305(3): 1222–32.
  49. Breitkreutz I., Raab M.S., Vallet S. et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia 2008; 22(10): 1925–32.
  50. Rajkumar S.V., Hayman S.R., Lacy M.Q. et al. Combination therapy with lenalidomide plus dexamethasone for newly diagnosed myeloma. Blood 2005; 106: 4050–3.
  51. Lacy M.Q., Gertz M.A., Dispenzieri A. et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin. Proc. 2007; 82(10): 1179–84.
  52. Kumar S., Dispenzieri A., Lacy M.Q. et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment postperipheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia 2007; 21: 2035–42.
  53. Kumar S., Giralt S., Stadtmauer E.A. et al. Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens. Blood 2009; 114: 1724–35.
  54. Zonder J.A., Crowley J., Hussein M.A. et al. Lenalidomide and highdose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Published online before print September 27, 2010, doi:10.1182/blood-2010- 08-303487.
  55. Rajkumar S.V., Jacobus S., Callander N.S. et al. Randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed myeloma, a trial coordinated by the Eastern Cooperative Oncology Group: analysis of response, survival, and outcome. J. Clin. Oncol. 2008; 26: 8504 (abstr.).
  56. Rajkumar S.V., Jacobus S., Callander N.S. et al. Lenalidomide plus highdose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma. An open-label randomised controlled trial. Lancet Oncol. 2010; 11: 29–37. 57. Kumar S.K., Lacy M.Q., Hayman S.R. et al. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: Results from a phase 2 trial. Am. J. Hematol. 2011; 86(8): 640–5.
  57. Niesvizky R., Jayabalan D.S., Christos P.J. et al. ViRD (Biaxian [clarithromycyn]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in highe complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood 2008; 111: 1101–9.
  58. Ohara T., Morishita T., Suzuki H. et al. Antibiotics directly induce apoptosis in B cell lymphoma cells derived from BALB/c mice. Anticancer Res. 2004; 24(6): 3723–30.
  59. Karin M., Cao Y., Greten F.R., Li Z.W. NF-kappaB in cancer: from innocent bystander to major culprit. Nat. Rev. Cancer 2002; 2: 301–10.
  60. Mitsiades N., Mitsiades C.S., Richardson P.G. et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003; 101: 2377–80.
  61. Bessmeltsev S., Rugal V. Stromal microenvironment and stem cells niches in multiple myeloma. Hematologica (15th Congress of the European Hematology Association, Spain, Barcelona, June 10–13, 2010, Abstract Book): 569–70 (abstr. 1422).
  62. Hideshima T., Mitsiades C., Akiyama M. et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 2003; 101: 1530–4.
  63. Terpos E., Heath D.J., Rahemtulla A. et al. Bortezomib reduced serum dick-kopf-1 and receptor activator of nuclear factor-kappaB ligand concentration and normalizes indices of bone remodelling in patients with relapsed multiple myeloma. Br. J. Haematol. 2006; 135: 688–92.
  64. Von Metzler H., Krebbel M., Hecht R.A. et al. Bortezomib inhibits human osteoclastogenesis. Leukemia 2007; 21(9): 2025–34.
  65. Zangari M., Terpos E., Zhan F., Tricot G. Impact of bortezomib on bone health in myeloma: A review of current evidence. Cancer Treatment Rev. 2012; 38: 968–80.
  66. Jagannath S., Brian D., Wolf J.L. et al. A Phase 2 Study of Bortezomib as First-Line Therapy in Patients with Multiple Myeloma. Blood (ASH Annual Meeting Abstracts) 2004; 104: Abstract 333.
  67. Harrousseau J., Mathiot C., Attal M. Bortezomib/dexamethasone versus VAD as induction prior to autologous stem cell transplantation in previously untreated multiple myeloma: Updated date from IFM 2005/01 trial (Abstract). J. Clin. Oncol. 2008; 26: 8505.
  68. Harrousseau J., Avet-Loiseau H., Attal M. et al. High complete and very good partial response rates with bortezomib-dexamethasone as induction prior to ASCT in newly diagnosed patients with high-risk myeloma: results of the IFM2005-01 phase 3 trial. ASH Annual Meeting Abstracts 2009; 114: 353.
  69. Бессмельцев С.С., Стельмашенко Л.В., Карягина Е.В. и др. Новые подходы к лечению множественной миеломы. Вестн. Рос. воен.-мед. акад. 2010; 3: 149–54. [Bessmeltsev S.S., Stelmashenko L.V., Karyagina Ye.V. i dr. Novyye podkhody k lecheniyu mnozhestvennoy miyelomy (Novel approaches to treatment of multiple myeloma. In: Bull. of Rus. Mil. Med. Acad.). Vestn. Ros. voyen.-med. akad. 2010; 3: 149–54.]
  70. Jagannath S., Durie B., Wolf J. et al. First-line therapy with bortezomib (formerly PS-341) in patients with multiple myeloma. Proc. Am. Soc. Clin. Oncol. 2004; 23: 568 (abstr. 6551).
  71. Oakervee H.E., Popat R., Curry N. et al. PAD combination therapy (PS- 341/bortezomib, doxorubicib and dexamethasone) for previously untreated patients with multiple myeloma. Br. J. Haematol. 2005; 129: 755–62.
  72. Sonneveld P., van der Holt B., Schmidt-Wolf I.G.H. First analysis of HOVON-65/GMMG-HD4 randomized phase III trial comparing bortezomib, adriamycine, dexamethasone (PAD) vs VAD as induction treatment prior to high dose melphalan (HDM) in patients with newly diagnosed multiple myeloma. Blood 2008; 112: 653 (abstr.)
  73. Бессмельцев С.С., Стельмашенко Л.В., Карягина Е.В. и др. Борте- зомиб в терапии 1-й линии при лечении множественной миеломы. Рос. мед. вести 2009; XIV(4): 29–37. [Bessmeltsev S.S., Stelmashenko L.V., Karyagina Ye.V. i dr. Bortezomib v terapii 1-y linii pri lechenii mnozhestvennoy miyelomy (Bortezomib in first-line therapy for multiple myeloma. In: Rus. med. news). Ros. med. vesti 2009; XIV(4): 29–37.]
  74. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Лечение молодых пациентов с впервые выявленной множественной миеломой. Украiн. журн. гематол. и трансфузiол. 2010; 5: 5–14. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V. i dr. Lecheniye molodykh patsiyentov s vpervyye vyyavlennoy mnozhestvennoy miyelomoy (Management of young patients with newly diagnosed multiple myeloma. In: Ukraine journ. of hematol. & transfusiol.) Ukrain. zhurn. gematol. i transfuziol. 2010; 5: 5–14.]
  75. Jakubowiak A.J., Friedman J., Kendall T. et al. A phase II study of combination of bortezomib, liposomal doxorubicin and dexamethasone (VDD) as first line therapy for multiple myeloma. J. Clin. Oncol. (ASCO Meeting Abstracts) 2006; 24: 18S (abstr. 17504).
  76. Moreau P., Pylypenko H., Grosicki S. et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomized, phase 3, non-inferiority study. Lancet 2011; 12(5): 431–40.
  77. Alexanian R., Wang L.M., Weber D.M., Delasalle K.B. VTD (Velcade, Thalidomide, Dexamethasone) as Primary Therapy for Newly-Diagnosed Multiple Myeloma. Blood 2004; 104: Abstract 210.
  78. Cavo M., Patriarca F., Tacchetti P. Superior complete response rate and progression-free survival after autologous transplantation with up-front velcadethalidomide-dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma. Blood 2008; 112: 158 (abstr.).
  79. Cavo M., Pantani L., Petrucci M.T. et al. Bortezomib-thalidomidedexamethasone is superior to thalidomide-dexamethasone as consolidation therapy following autologous hematopoietic stem-cell transplantation in patients with newly diagnosed multiple myeloma. Blood 2012; 120(1): 9–18.
  80. Rosinol L., Cibera M.T., Martinez J. Thalidomide/dexamethasone (TD) vs. bortesomib/thalidomide/dexamethasone (VTD) vs. VBMCP/VBAD/Velcade regimens prior autologous stem cell transplantation (ASCT) in younger patients with multiple myeloma: first results of a prospective phase III PETHEMA/Gem Trial. Blood 2008; 112: 654 (abstr.).
  81. Richardson P.G., Weller E., Lonial S. et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010; 116(5): 679–86.
  82. Reeder C.B., Reece D.E., Kukreti V. et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia 2009; 23(7): 1337–41.
  83. Kumar S., Flinn I.W., Noga S.J. et al. Safety and efficacy of novel combination therapy with bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in newly diagnosed multiple myeloma: initial results from the phase I/II multi-center EVOLUTION Study. Blood 2008; 112: 93 (abstr.).
  84. Kumar S., Flinn I.W., Paul G. et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012; 119(19): 4375–82.
  85. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Эффек- тивность леналидомида при рефрактерных/рецидивирующих формах множественной миеломы. Онкогематология 2012; 1: 6–14. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V. i dr. Effektivnost lenalidomida pri refrakternykh/retsidiviruyushchikh formakh mnozhestvennoy miyelomy (Lenalidomide efficacy in refractory/relapsing forms of multiple myeloma. In: Oncohematology). Onkogematologiya 2012; 1: 6–14.]
  86. Siegel D.S., Martin T., Wang M. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012; 120(14): 2817–25.
  87. Demo S.D., Kirk C.J., Aujay M.A. et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007; 67(13): 6383–91.
  88. Kuhn D.J., Chen Q., Voorhees P.M. et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 2007; 110(9): 3281–90.
  89. Arastu-Kapur S., Anderl J.L., Kraus M. et al. Non-proteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin. Cancer Res. 2011; 17(9): 2734–43.
  90. Bruna J., Udina E., Ale A. et al. Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice. Exp. Neurol. 2010; 223(2): 599–608.
  91. Korde N., Zingone A., Kwok M. et al. Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone (CRd) in Newly Diagnosed Multiple Myeloma (MM) Patients. Blood (ASH Annual Meeting Abstracts) 2012; 120: Abstract 732.
  92. Barlogie B., Alexanian R., Docke K.A. High-dose chemoradiotherapy with autologous bone marrow transplantation for resistant multiple myeloma. Blood 1987; 70: 869–72.
  93. Attal M., Harousseau J.L., Stoppa A.M. et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myeloma. N. Engl. J. Med. 1996; 335: 91–7.
  94. Child J.A., Morgan G.J., Davies F.E. et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N. Engl. J. Med. 2003; 348: 1875–83.
  95. Gale K. Intensive Therapy Improves Survival in Patients With Multiple Myeloma. N. Engl. J. Med. 2003; 348: 1875–83.
  96. Barlogie B., Kyle R.A., Anderson K.S. et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J. Clin. Oncol. 2006; 24: 929–36.
  97. Fermand J.P., Katsahian S., Divine M. et al. High-dose therapy and autologous blood stem-cell transplantation high-dose therapy conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J. Clin. Oncol. 2005; 23: 9227–33.
  98. Blade J., Rosinol L., Sureda A. et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 2005; 106: 3755–9.
  99. Levy V., Katsahian S., Fermand J.P. et al. A meta-analysis on data from 575 patients with multiple myeloma randomly assigned to either high-dose therapy or conventional therapy. Medicine (Baltimore) 2005; 84(4): 250–60.
  100. Sirohi B., Powles R., Mehta J. et al. Single-center results of 200 mg/ m2 melphalan and autograft in 451 myeloma patients: identifying patients with prolonged survival based upon albumin and B2-microglobulin at transplant. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting. 2002, Orlando, Florida. Abstract 1072.
  101. Tribalto M., Amadori S., Cudillo L. Autologous peripheral blood stem cell transplantation as first line treatment of multiple myeloma: an Italian Multicenter Study. Haematologica 2000; 85: 52–8.
  102. Roussel M., Huynh A., Moreau P. Bortezomib and high dose melphalan as conditioning regimen before autologous stem cell transplantation for de novo multiple myeloma: final results of the IFM Phase II Study VEL/MEL. Blood 2008; 112: 160 (abstr.)
  103. Van de Velde H.J., Liu X., Chen G. et al. Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica 2007; 92(10): 1399–406.
  104. Gay F., Larocca A., Wijermans P. et al. Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: analysis of 1175 patients. Blood 2011; 117(11): 3025–31.
  105. Martinez-Lopez J., Blade J., Mateos M.V. et al. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood 2011; 118(3): 529–34.
  106. Dispenzieri A., Rajkumar S.V., Gertz M.A. et al. Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin. Proc. 2007; 82(3): 323–41.
  107. Kumar S.K., Lacy M.Q., Dispenzieri A. et al. Early versus delayed autologous transplantation after immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple myeloma. Cancer 2012; 118(6): 1585–92.
  108. Marjanovic S., Stamatovic D., Elez M. et al. Autologous stem cell transplantation in the treatment of patients with multiple myeloma: our experience. Bone Marrow Transplant. 2013; 48(Suppl. 2): S212 (abstr. P730).
  109. Barlogie B., Attal M., Crowley J. et al. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J. Clin. Oncol. 2010; 28(7): 1209–14.
  110. Barlogie B., Jagannath S., Vesole D.H. et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 1997; 89: 789–93.
  111. Barlogie B., Jagannath S., Desikan K.R. et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 1999; 93: 55–65.
  112. Cavo M., Tosi P., Zamagni E. et al. A multicentric randomized clinical trial comparing single vs double autologous peripheral blood stem cell transplantation for patients with newly diagnosed multiple myeloma: results of an interim analysis. Bone Marrow Transplant. 2000; 25(Suppl. 1): S54.
  113. Lahuerta J.J., Grande C., Martinez-Lopez J. et al. Tandem transplants with different high-dose regimens improve the complete remission rates in multiple myeloma. Results of a Grupo Espanol de Sindromes Linfoproliferativos/Trasplante Autologo de Medula Osea phase II trial. Br. J. Haematol. 2003; 120: 296–303.
  114. Barlogie B., Tricot G., Anaissie E. et al. Thalidomide and hematopoieticcell transplantation for multiple myeloma. N. Engl. J. Med. 2006; 354: 1021–30.
  115. Barlogie B., Anaissie E.J., Schaughnessy J.D. et al. Ninety percent sustained complete response (CR) projected 4 years after onset of CR in gene expression profiling (GEP)-defined low-risk multiple myeloma treated with Total Therapy 3 (TT3): basis for GEP-risk-adapted TT4 and TT5. Blood 2008; 12: 162 (abstr).
  116. Sonneveld P., Schmidt-Wolf I.G.H., van der Holt B. et al. HOVON-65/ GMMG-HD4 randomized phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts) 2010; 116(21): Abstract 40.
  117. Attal M., Harousseau J.L., Facon T. et al. InterGroupe Francophone du myeloma. Single versus double autologous stem-cell transplantation for multiple myeloma. N. Engl. J. Med. 2003; 249(26): 2495–502.
  118. Gerull S., Stem M., Ben Aissa A. et al. Allogeneic haematopoietic stem cell transplantation for multiple myeloma — the Swiss experience. Bone Marrow Transplant. 2012; 47(Suppl. 1): S326 (abstr. P899).
  119. Benakil M., Ahmed Nacer R., Talbi A. et al. Allogeneic stem cell transplantation in patients with multiple myeloma: long term follow-up in a single centre. Bone Marrow Transplant. 2012; 47(Suppl. 1): S327 (abstr. P901).
  120. Garban F., Attal M., Michallet M. et al. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in highrisk de novo multiple myeloma. Blood 2006; 107: 3477–80.
  121. Bruno B., Rotta M., Patriarca F. et al. A comparison of allografting with autografting for newly diagnosed myeloma. N. Engl. J. Med. 2007; 356: 1110–20.
  122. Rosinol L., Perez-Simin J.A., Sureda A. et al. A prospective PETEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood 2008; 112: 3591–3.
  123. Lokhorst H., Sonneveld P., van der Holt B. et al. Donor versus no donor analysis of newly diagnosed myeloma patients included in the HOVON 50/50 Study. Blood 2008; 112: 461 (abstr.).
  124. Bjorkstrand B., Lacobelli S., Hegenbart A. Autologous stem cell transplantation (ASCT) versus ASCT followed by reduced-intensity conditioning (RIC) allogeneic SCT with identical sibling donor in previously untreated multiple myeloma: a prospective controlled trial by the EBMT. Bone Marrow Transplant. 2009; 43: 223 (abstr.).
  125. Kroger N., Zabelina T., Ayuk F. et al. Molecular remission after autologous-allogeneic tandem transplantation in patients with multiple myeloma. Bone Marrow Transplant. 2012; 47(Suppl. 1): S45 (abstr. O256).
  126. Kharfan-Dabaja M., Hamadani M., Reljic T. Comparative efficacy of tandem autologous-autologous versus tandem autologous-reduced intensity allogeneic haematopoietic cell transplantation in multiple myeloma: results of a systematic review and meta-analysis. Bone Marrow Transplant. 2012; 47(Suppl. 1): S44 (abstr. O254).
  127. Ludwig H., Hajek R., Tothova E. et al. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood 2009; 113: 3435–42.
  128. Zonder J.A., Crowley J.J., Bolejack V. et al. A randomized Southwest Oncology Group study comparing dexamethasone (D) to lenalidomide+dexamethasone (LD) as treatment of newly diagnosed multiple myeloma: impact of cytogenetic abnormalities on efficacy of LD, and updated overall study results. J. Clin. Oncol. 2008; 26: 8521 (abstr.)
  129. Rajkumar S.V., Jacobus S., Callander N. et al. Randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide+low-dose dexamethasone in newly diagnosed myeloma (E4A03), a trial coordinated by Eastern Cooperative Oncology Group: analysis of response, survival, and outcome. J. Clin. Oncol. 2008; 26: 8504 (abstr.).
  130. Gulbrandsen N., Waage A., Gimsing P. et al. A randomized placebo controlled study with melphalan/prednisone vs melphalan/prednisone/thalidomide: quality of life and toxicity. Haematologica 2008; 93: 93 (abstr. 0209).
  131. Palumbo A., Bringhen S., Caravita T. et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomized controlled trial. Lancet 2006; 367: 825–31.
  132. Palumbo A., Bringhen S., Liberaty A.M. et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood 2008; 112: 3107–14.
  133. Facon T., Mary J.Y., Hulin C. et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomized trial. Lancet 2007; 370: 1209–18.
  134. Hulin C., Facon T., Rodon P. et al. Melphalan-prednisone-thalidomide (MP-T) demonstrates a significant survival advantage in elderly patients 75 years with multiple myeloma compared with melphalan-prednisone (MP) in a randomized, double-blind, placebo-controlled trial, IFM 01/01. Blood 2007; 110: 75 (abstr.).
  135. Wijermans P., Schaafsma M., van Norden Y. et al. Melphalan+prednisone vs melphalan+prednisone+thalidomide in induction therapy for multiple myeloma in elderly patients: final analysis of the Dutch cooperative group HOVON 49 study. Blood 2008; 112: 649 (abstr.).
  136. San Miguel J.F., Schlag R., Khuageva N.K. et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N. Engl. J. Med. 2008; 359: 906–17.
  137. Mateos M.V., Hernandez J.M., Hernandez M.T. et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica 2008; 93(4): 560–5.
  138. Бессмельцев С.С., Стельмашенко Л.В., Карягина Е.В. и др. Бор- тезомиб (Велкейд) в индукционной терапии множественной миеломы. Клиническая Онкогематология 2008; 1(4): 315–22.  [Bessmeltsev S.S., Stelmashenko L.V., Karyagina Ye.V. i dr. Bortezomib (Velkeyd) v induktsionnoy terapii mnozhestvennoy miyelomy (Bortezomib (Velcade) in induction therapy for multiple myeloma. In: Clinical Oncohematology). Klinicheskaya Onkogematologiya 2008; 1(4): 315–22.]
  139. Бессмельцев С.С., Стельмашено Л.В., Степанова Н.В. и др. Борте- зомиб (велкейд) и мелфалан с преднизолоном в лечении множественной миеломы у пожилых больных. Онкогематология 2010; 2: 40–5.
  140. [Bessmeltsev S.S., Stelmashenko L.V., Stepanova N.V. i dr. Bortezomib (velkeyd) i melfalan s prednizolonom v lechenii mnozhestvennoy miyelomy u pozhilykh bolnykh (Bortezomib (Velcade) and melphalan with prednisolone in therapy for multiple myeloma in elderly patients. In: Oncohematology). Onkogematologiya 2010; 2: 40–5.]
  141. Бессмельцев С.С., Стельмашенко Л.В., Карягина Е.В. и др. Лечение пожилых пациентов с множественной миеломой на современном этапе. Онкогематология 2010; 4: 6–13. [Bessmeltsev S.S., Stelmashenko L.V., Karyagina Ye.V. i dr. Lecheniye pozhilykh patsiyentov s mnozhestvennoy miyelomoy na sovremennom etape (Current management of elderly patients with multiple myeloma. In: Oncohematology). Onkogematologiya 2010; 4: 6–13.]
  142. Palumbo A., Bringhen S., Rossi D. et al. A prospective, randomized, phase III study of bortezomib, melphalan, prednisone, and thalidomide (VMPT) versus bortezomib, melphalan and prednisone (VMP) in elderly newly diagnosed myeloma patients. Blood 2008; 112: 652 (abstr.)
  143. Morgan G.J., Davies F.E., Owen R.G. et al. Thalidomide combinations improve response rates: results from the MRC IX Study. Blood 2007; 110: 3593 (abstr.).
  144. Palumbo A., Falco P., Corradini P. et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA-Italian Multiple Myeloma Network. J. Clin. Oncol. 2007; 25: 4459–65.
  145. Gay F., Bringhen S., Offidani M. et al. Efficacy and safety of 3 lenalidomidebased combinations in elderly newly diagnosed multiple myeloma patients: results from the phase 3 community based emn01 trial. 18th Congress of the European Hematology Association, June 13–16, 2013, Stockholm. Abstract B 221.
  146. Paiva B., Martinez-Lopez J. Vidriales M.B. et al. Comparison of immunofixation, serum free light chain, and immunophenotyping for response evaluation and prognostication in multiple myeloma. J. Clin. Oncol. 2011; 29(12): 1627–33.
  147. Ladetto M., Pagliano G., Ferrero S. et al. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J. Clin. Oncol. 2010; 28(12): 2077–84.
  148. Hoering A., Crowley J., Shaughnessy J.D. Jr. et al. Complete remission in multiple myeloma examined as time-dependent variable in terms of both onset and duration in total therapy protocols. Blood 2009; 114(7): 1299–305.
  149. Myeloma Trialists’ Collaborative Group. Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br. J. Haematol. 2001; 113(4): 1020–34.
  150. Attal M., Harousseau J.L., Leyvraz S. et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 2006; 108: 3289–94.
  151. Hahn-Ast C., von Lilienfeld-Toal M., van Heteren P. et al. Improved progression-free survival and overall survival with thalidomide maintenance therapy in multiple myeloma: a meta-analyis of randomized trials in 2274 patients. Haematologica 2010; 95(2): Abstract 0942.
  152. Morgan G.J., Gregory W.M., Davies F.E. et al. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and metaanalysis. Blood 2012; 119(1): 7–15.
  153. Barlogie B., Pineds-Roman M., van Rhee F. et al. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood 2008; 112: 3115–21.
  154. Sonneveld P., Schmidt-Wolf I., van der Holt B. et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J. Clin. Oncol. 2012; 30(24): 2946–55.
  155. Mellqvist U.-H., Gimsing P., Hjertner O. et al. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood 2013; 121(23): 4647–54.
  156. Attal M., Lauwers-Cances V., Marit G. et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N. Engl. J. Med. 2012; 366(19): 1782–91.
  157. McCarthy P.L., Owzar K., Hofmeister C.C. et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N. Engl. J. Med. 2012; 366(19): 1770–81.
  158. Palumbo A., Gay F., Caravita di Toritto T. et al. Melphalan/prednisone/ lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (mel200) in newly diagnosed multiple myeloma patients. 18th Congress of the European Hematology Association, June 13–16, 2013, Stockholm. Abstract B 222.
  159. Cavo M., Pantani L., Petrucci M.T. et al. GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) Italian Myeloma Network. Bortezomibthalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood 2012; 120(1): 9–19.
  160. Palumbo A., Hajek R., Delforge M. et al. Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma. N. Engl. J. Med. 2012; 366: 1759–69.
  161. Mateos M.-V., Oriol A., Martinez-Lopez J. et al. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood 2012; 120(13): 2581–8.
  162. Bergsagel P.L., Mateos M.V., Gutierrez N.C. et al. Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma. Blood 2013; 121: 884–92.
  163. Rajkumar S.V. Treatment of multiple myeloma. Nat. Rev. Clin. Oncol. 2011; 8(8): 479–91.
  164. Nair B., van Rhee F., Shaughnessy J.D. et al. Superior results of Total Therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance. Blood 2010; 115(21): 4168–73.
  165. Goldschmidt H., Neben K., Bertsch U. et al. Bortezomib-based induction therapy followed by autologous stem cell transplantation and maintenance therapy with bortezomib improves outcome in myeloma patients with gain 1q21 and t(4;14): a subgroup analysis of the HOVON-65/GMMG-HD4 trial. Blood (ASH Annual Meeting Abstracts) 2010; 116(21): 305.
  166. Kapoor P., Kumar S., Fonseca R. et al. Impact of risk stratification on outcome among patients with multiple myeloma receiving initial therapy with lenalidomide and dexamethasone. Blood 2009; 114(3): 518–21.
  167. Jagannath S., Richardson P. G., Sonneveld P. et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 2007; 21(1): 151–7.
  168. San-Miguel J., Harousseau J.L., Joshua D., Anderson K.C. Individualizing treatment of patients with myeloma in the era of novel agents. J. Clin. Oncol. 2008; 26(16): 2761–6.
  169. Barlogie B., Anaissie E., van Rhee F. et al. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3. Br. J. Haematol. 2007; 138(2): 176–85.
  170. Kaufman J.L., Nooka A.K., Muppidi S. et al. Survival outcomes of early autologous stem cell transplantation followed by lenalidomide, bortezomib, and dexamethasone (RVD) maintenance and patients with high-risk multiple myeloma. J. Clin. Oncol. 2012; 30: Abstract 8100.
  171. Rajkumar S.V. Doublets, triplets, or quadruplets of novel agents in newly diagnosed myeloma?. Hematology doi: 10.1182/asheducation-2012.1.354 ASH Education Book 2012; 1: 354–61.
  172. Palumbo A., Cavallo F. Have drug combinations supplanted stem cell transplantation in myeloma?. Hematology doi: 10.1182/asheducation-2012.1.354 ASH Education Book 2012; 1: 335–41.
  173. Стельмашенко Л.В., Абдулкадыров К.М., Бессмельцев С.С. и др. Роль поддерживающей терапии в посттрансплантационном периоде больных множественной миеломой. Вестн. гематол. 2012; 4: 36–7.
  174. Siegel D.S., Desikan K.R., Mehta J. et al. Age is not a prognostic variable with autotransplantants for multiple myeloma. Blood 1999; 93: 51–4.
  175. Sirohi B., Powles R., Treleaven J. et al. The role of autologous transplantation in patients with multiple myeloma aged 65 years and over. Bone Marrow Transplant. 2000; 25: 533–9.
  176. Reece D.E., Bredeson C., Perez W.S. et al. Autologous stem cell transplantation in multiple myeloma patients < 60 vs >/= 60 years of age. Bone Marrow Transplant. 2003; 32: 1135–43.
  177. Palumbo A., Bringhen S., Petrucci M.T. et al. Intermediate-dose melphalan improves survival of myeloma patients ages 50 to 70: results of randomized controlled trial. Blood 2004; 104: 3052–3057.
  178. Rajkumar S.V. Thalidomide in the treatment of multiple myeloma. Expert. Rev. Anticancer Ther. 2001; 1(1): 20–8.
  179. Weber D., Rankin K., Gavino M. et al. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J. Clin. Oncol. 2003; 21: 16–9.
  180. Dimopoulos M.A., Eleutherakis V. Adverse effects of thalidomide administration in patients with neoplastic disease. Am. J. Med. 2004; 117: 508–15.
  181. Hall V.C., El-Azhary R.A., Bouwhuis S. et al. Dermatologic side effects of thalidomide in patients with multiple myeloma. J. Am. Acad. Dermatol. 2003; 48: 548–52.
  182. Palumbo A., Facon T., Sonneveld P. et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood 2008; 111: 3968–77.
  183. Gunzler V. Thalidomide in human immunodeficiency virus (HIV) patients: a review of safety considerations. Drug Safety 1992; 7: 116–34.
  184. Teo S., Morgan M., Stirling D. et al. Assessment of the in vitro and in vivo genotoxicity of thalomid (thalidomide). Terat. Carcin. Mutagen. 2000; 20: 301–11.
  185. Sonneveld P., Dimopoulos M., San Miguel J. et al. Recommended management of cytopenia for len/dex in MM. Haematologica 2007; 92: 217 (abstr. PO-1122).
  186. Palumbo A., Rajkumar S.V., Dimopoulos M.A. et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma . Leukemia 2008; 22(2): 414–23.
  187. Musallam K.M., Dahdaleh F.S., Shamseddine A.I., Taher A.T. Incidence and prophylaxis of venous thromboembolic events in multiple myeloma patients receiving immunomodulatory therapy. Thromb. Res. 2009; 123(5): 679–86.
  188. Cavo M., Palumbo A., Brighen S. et al. A phase III study of enoxaparin versus low-dose warfarin versus aspirin as thromboprophylaxis for patients with newly diagnosed multiple myeloma treated up-front with thalidomide-containing regimens. Blood 2008; 112: 3017 (abstr.)
  189. Larocca A., Cavallo F., Bringhen S. et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 2012; 119(4): 933–9.
  190. Faiman B.M., Spong J., Tariman J.D. Renal Complications in Multiple Myeloma and Related Disorders: Survivorship Care Plan of the International Myeloma Foundation Nurse Leadership Board. Clin. J. Oncol. Nurs. 2011; 15(4): 66–76.
  191. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Частота, характеристика и методы лечения периферической нейропатии у больных множественной миеломой, получающих бортезомиб (велкейд). Онкогема- тология 2008; 3: 52–62. [Bessmeltsev S.S., Karyagina Ye.V., Stelmashenko L.V. i dr. Chastota, kharakteristika i metody lecheniya perifericheskoy neyropatii u bolnykh mnozhestvennoy miyelomoy, poluchayushchikh bortezomib (velkeyd) (Incidence, characteristics, and therapeutic methods for management of peripheral neuropathy in patients with multiple myeloma treated with bortezomib (Velcade). In: Oncohematology). Onkogematologiya 2008; 3: 52–62.]
  192. Barohn R. Approach to peripheral neuropathy and neuronopathy. Semin. Neurol. 1998; 18: 7–18.
  193. Lopate G., Parks B., Goldstein J. et al. Polyneuropathies associated with high titre antisulphatide antibodies: characteristics of patients with and without serum monoclonal proteins. J. Neurol. Neurosurg. Psychiat. 1997; 62: 581–5.
  194. Ropper A.H., Gorson K.C. Neuropathies associated with paraproteinemia. N. Engl. J. Med. 1998; 338: 1601–7.
  195. Rajkumar S.V. MGUS and Smoldering Multiple Myeloma: Update on Pathogenesis, Natural History, and Management. Hematology (The American Society of Hematology) 2005; 1: 340.
  196. Richardson P.G., Delforge M., Beksac M. et al. Management of treatment-emergent peripheral neuropathy in multiple myeloma. Leukemia 2012; 26: 595–8.
  197. Dispenzieri A., Jacobus S., Vesole D.H. et al. Primary therapy with single agent bortezomib as induction, maintenance and re-induction in patients with high-risk myeloma: results of the ECOG E2A02 trial. Leukemia 2010; 24: 1406–11.
  198. Palumbo A., Anderson K. Multiple myeloma. Engl. J. Med. 2011; 364(11): 1046–60.