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Treatment of myeloma in patients not eligible for transplantation

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Multiple myeloma (MM) remains an incurable disease for most patients, with a median survival of 4 to 5 years. High-dose chemotherapy followed by transplantation has resulted in improvement in response rates and survival compared with conventional therapy, but relapse is nearly universal and not all patients are candidates for this option of aggressive treatment. Standard therapeutic strategies for newly diagnosed patients not eligible for transplantation include pulsed high-dose dexamethasone, melphalan with prednisone, and vincristine in combination with doxorubicin and dexamethasone, as well as other combinations of alkylating agents. Emerging therapies under clinical investigation for first-line therapy include thalidomide, the thalidomide analog lenalidomide, and the proteasome inhibitor bortezomib alone and in combination with other agents, particularly dexamethasone. At an interim analysis, thalidomide combined with melphalan and prednisone was shown to induce a complete or near complete remission (CR) rate of 28% and overall (complete + partial) response rate of 77% in elderly patients generally not eligible for transplantation. These results are comparable to those obtained with high-dose therapy and may obviate transplantation in these patients. Induction therapy with bortezomib-based combinations induces complete and near complete remissions in a similar proportion of patients. These regimens include bortezomib and dexamethasone alone and in combination with doxorubicin, thalidomide, or melphalan. Use of thalidomide or bortezomib does not preclude stem cell harvest. Survival benefits need to be firmly established before these novel regimens emerge as the new standard of care for newly diagnosed disease. However, front-line treatment with combinations involving these agents is a promising strategy that may improve the standard of care for patients both eligible and ineligible for stem cell transplantation.

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References and Recommended Reading

  1. Jemal A, Tiwari RC, Murray T, et al.: Cancer statistics, 2004. CA Cancer J Clin 2004, 54:8–29.

    PubMed  Google Scholar 

  2. Attal M, Harousseau JL, Stoppa AM, et al.: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996, 335:91–97. A landmark prospective trial comparing autologous bone marrow transplantation with conventional chemotherapy that demonstrates the superiority of transplantation.

    Article  PubMed  CAS  Google Scholar 

  3. Child JA, Morgan GJ, Davies FE, et al.: High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003, 348:1875–1883.

    Article  PubMed  CAS  Google Scholar 

  4. Crowley J, Fonseca R, Greipp P, et al.: Comparable survival in newly diagnosed multiple myeloma (MM) after VAD induction with high-dose therapy using melphalan 140 mg/m2 + TBI 12 Gy (MEL+TBI) versus standard therapy with VBMCP and no benefit from interferon (IFN) maintenance: Final clinical results of Intergroup Trial S9321 in the context of IFM-90 and Medical Research Council (MRC)-VII trials. Blood 2004, 104:156a-157a.

    Google Scholar 

  5. Rajkumar SV, Gertz MA, Kyle RA, et al.: Current therapy for multiple myeloma. Mayo Clin Proc 2002, 77:813–822.

    Article  PubMed  CAS  Google Scholar 

  6. Durie BG, Kyle RA, Belch A, et al.: Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematol J 2003, 4:379–398. A review of key literature and summarized guidelines for myeloma management by the Scientific Advisors of the International Myeloma Foundation.

    Article  PubMed  Google Scholar 

  7. Myeloma Trialists’ Collaborative Group: Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6633 patients from 27 randomized trials. J Clin Oncol 1998, 16:3832–3842.

    Google Scholar 

  8. Palumbo A, Bringhen S, Petrucci MT, et al.: Intermediatedose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial. Blood 2004, 104:3052–3057.

    Article  PubMed  CAS  Google Scholar 

  9. Hernandez JM, 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, 127:159–164.

    Article  PubMed  CAS  Google Scholar 

  10. Segeren CM, Sonneveld P, Van der HB, et al.: Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol 1999, 105:127–130.

    Article  PubMed  CAS  Google Scholar 

  11. Segeren CM, Sonneveld P, Van HB, et al.: Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase III study. Blood 2003, 101:2144–2151.

    Article  PubMed  CAS  Google Scholar 

  12. Samson D, Gaminara E, Newland A, et al.: Infusion of vincristine and doxorubicin with oral dexamethasone as first-line therapy for multiple myeloma. Lancet 1989, 2:882–885.

    Article  PubMed  CAS  Google Scholar 

  13. Rifkin RM, Hussein MA, Gregory SA, et al.:Updated results from a randomized multicenter trial of DVd versus VAd in patients with newly diagnosed multiple myeloma.J Clin Oncol 2004, 22 (14S):560s.

    Google Scholar 

  14. Alexanian R, Dimopoulos MA, Delasalle K, et al.: Primary dexamethasone treatment of multiple myeloma. Blood 1992, 80:887–890.

    PubMed  CAS  Google Scholar 

  15. Alexanian R, Barlogie B, Tucker S: VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol 1990, 33:86–89.

    Article  PubMed  CAS  Google Scholar 

  16. Monconduit M, Menard JF, Michaux JL, et al.: VAD or VMBCP in severe multiple myeloma. The Groupe d’Etudes et de Recherche sur le Myelome (GERM). Br J Haematol 1992, 80:199–204.

    PubMed  CAS  Google Scholar 

  17. Anderson H, Scarffe JH, Ranson M, et al.: VAD chemotherapy as remission induction for multiple myeloma. Br J Cancer 1995, 71:326–330.

    PubMed  CAS  Google Scholar 

  18. Salmon SE, Crowley JJ, Grogan TM, et al.: Combination chemotherapy, glucocorticoids, and interferon-α in the treatment of multiple myeloma: a Southwest Oncology Group study. J Clin Oncol 1994, 12:2405–2414.

    PubMed  CAS  Google Scholar 

  19. Cavo M, Benni M, Ronconi S, et al.: Melphalan-prednisone versus alternating combination VAD/MP or VND/MP as primary therapy for multiple myeloma: final analysis of a randomized clinical study. Haematologica 2002, 87:934–942.

    PubMed  CAS  Google Scholar 

  20. Rajkumar SV, Hayman S, Gertz MA, et al.: Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002, 20:4319–4323. A key trial that demonstrated the activity of thalidomide plus dexamethasone in newly diagnosed multiple myeloma.

    Article  PubMed  CAS  Google Scholar 

  21. Alexanian R, Wang LW, Weber DM, et al.: VTD (Velcade, thalidomide, dexamethasone) as primary therapy for newly-diagnosed multiple myeloma. Blood 2004, 104:64a.

    Google Scholar 

  22. Rajkumar SV, Hayman SR, Lacy MQ, et al.: Combination therapy with CC-5013 plus dexamethasone for newly diagnosed myeloma (MM). Blood 2004, 104:98a.

    Google Scholar 

  23. Richardson PG, Chanan-Khan A, Schlossman RL, et al.:Phase II trial of single-agent bortezomib in patients with previously untreated multiple myeloma (MM). Blood 2004, 104:100a.

    Article  CAS  Google Scholar 

  24. Rajkumar SV, Blood E, Vesole DH, et al.: Thalidomide plus dexamethasone versus dexamethasone alone in newly diagnosed multiple myeloma (E1A00): results of a phase III trial coordinated by the Eastern Cooperative Oncology Group. Blood 2004, 104:63a.

    Google Scholar 

  25. Weber D, Rankin K, Gavino M, et al.: Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003, 21:16–19.

    Article  PubMed  CAS  Google Scholar 

  26. Mateos MV, Blade J, Diaz Mediavilla J, et al.: A phase I/II national, multicenter, open-label study of bortezomib plus melphalan and prednisone (V-MP) in elderly untreated multiple myeloma patients. Blood 2004, 104:943a.

    Google Scholar 

  27. Facon T, Mary JY, Hulin C, et al.: Randomized clinical trial comparing melphalan-prednisone (MP), MP-thalidomide (MP-thal), and high-dose therapy using melphalan 100 mg/m2 (MEL100) for newly diagnosed myeloma patients aged 65 to 75 years. Interim analysis of the IFM99-06 trial on 350 patients. Blood 2004, 104:63a.

    Google Scholar 

  28. Jagannath S, Durie B, Wolf JL, et al.: A phase II study of bortezomib as first-line therapy in patients with multiple myeloma. Br J Haematol 2005, In press.

  29. Cavenagh J, Popat R, Curry N, et al.: PAD combination therapy (PS-341/bortezomib, Adriamycin, and dexamethasone) for previously untreated patients with multiple myeloma. Blood 2004, 104:413a.

    Google Scholar 

  30. Palumbo A, Bertola A, Musto P, et al.: Oral melphalan, prednisone, and thalidomide for newly diagnosed myeloma patients. J Clin Oncol 2004, 22 (14S):569s.

    Google Scholar 

  31. Palumbo A, Bertola A, Musto P, et al.: A prospective randomized trial of oral melphalan, prednisone, thalidomide (MPT) versus oral melphalan, prednisone (MP): An interim analysis. Blood 2004, 104:63a.

    Article  CAS  Google Scholar 

  32. Kane RC, Bross PF, Farrell AT, et al.: US Food and Drug Administration approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 2003, 8:508–513.

    Article  PubMed  Google Scholar 

  33. Ma MH, Yang HH, Parker K, et al.: The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 2003, 9:1136–1144.

    PubMed  CAS  Google Scholar 

  34. Mitsiades N, Mitsiades CS, Richardson PG, et al.: The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003, 101:2377–2380.

    Article  PubMed  CAS  Google Scholar 

  35. Jagannath S, Barlogie B, Berenson J, et al.: A phase II study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 2004, 127:165–172. One of two important trials that resulted in the approval of bortezomib for the treatment of relapsed and refractory multiple myeloma in patients who have received at least two prior therapies and have demonstrated disease progression on the most recent therapy.

    Article  PubMed  CAS  Google Scholar 

  36. Richardson PG, Barlogie B, Berenson J, et al.: A phase II study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003, 348:2609–2617. One of two important trials that resulted in the approval of bortezomib for the treatment of relapsed and refractory multiple myeloma in patients who have received at least two prior therapies and have demonstrated disease progression on the most recent therapy.

    Article  PubMed  CAS  Google Scholar 

  37. Richardson P, Sonneveld P, Schuster MW, et al.: Bortezomib versus dexamethasone in relapsed multiple myeloma: a phase III randomized study. Proc Am Soc Clin Oncol 2004, 22:560s.

    Google Scholar 

  38. Bladé 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, 102:1115–1123.

    Article  PubMed  Google Scholar 

  39. Richardson PG, Barlogie B, Berenson J, et al.: Survival, duration of response, and time to progression with bortezomib in patients with relapsed and refractory multiple myeloma: An update with additional followup. Hematol J 2004, 5:S129.

    Google Scholar 

  40. Hideshima T, Richardson P, Chauhan D, et al.: The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001, 61:3071–3076.

    PubMed  CAS  Google Scholar 

  41. Jagannath S, Richardson P, Barlogie B, et al.: Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma. Hematol J 2004, 5(Suppl 2):S130.

    Google Scholar 

  42. Harousseau J, Attal M, Leleu X, et al.: Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: preliminary results of an IFM phase II study. Blood 2004, 104:416a.

    Google Scholar 

  43. 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 2004, 104:64a.

    Google Scholar 

  44. Orlowski R, Voorhees P, Garcia R, et al.: Phase I study of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with refractory hematologic malignancies. Hematol J 2004, 5(Suppl 2):S131.

    Google Scholar 

  45. Alexanian R, Weber D, Delasalle K, et al.: Clinical outcomes with intensive therapy for patients with primary resistant multiple myeloma. Bone Marrow Transplant 2004, 34:229–234.

    Article  PubMed  CAS  Google Scholar 

  46. Ross DM, To LB, Horvath N: Assessment of early paraprotein response to vincristine-doxorubicin-dexamethasone chemotherapy may help guide therapy in multiple myeloma. Intern Med J 2004, 34:576–578.

    Article  PubMed  CAS  Google Scholar 

  47. Schaar CG, Kluin-Nelemans JC, le Cessie S, et al.: Early response to therapy and survival in multiple myeloma. Br J Haematol 2004, 125:162–166.

    Article  PubMed  CAS  Google Scholar 

  48. Hideshima T, Chauhan D, Shima Y, et al.: Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000, 96:2943–2950.

    PubMed  CAS  Google Scholar 

  49. Kumar S, Witzig TE, Dispenzieri A, et al.: Effect of thalidomide therapy on bone marrow angiogenesis in multiple myeloma. Leukemia 2004, 18:624–627.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  51. 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 II study of 169 patients. Blood 2001, 98:492–494.

    Article  PubMed  CAS  Google Scholar 

  52. Schey SA, Cavenagh J, Johnson R, et al.: An UK myeloma forum phase II study of thalidomide; long-term followup and recommendations for treatment. Leuk Res 2003, 27:909–914.

    Article  PubMed  CAS  Google Scholar 

  53. Dimopoulos MA, Zervas K, Kouvatseas G, et al.: Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol 2001, 12:991–995.

    Article  PubMed  CAS  Google Scholar 

  54. Palumbo A, Giaccone L, Bertola A, et al.: Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica 2001, 86:399–403.

    PubMed  CAS  Google Scholar 

  55. Barlogie B: Thalidomide and CC-5013 in multiple myeloma: the University of Arkansas experience. Semin Hematol 2003, 40:33–38.

    Article  PubMed  CAS  Google Scholar 

  56. Richardson PG, Schlossman RL, Weller E, et al.: Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002, 100:3063–3067.

    Article  PubMed  CAS  Google Scholar 

  57. Dexamethasone with or without CC-5013 in treating patients with newly diagnosed multiple myeloma. Accessible at http://clinicaltrials.gov/ct/gui/search;jsessionid= CC5FBB82945184BC0E4CA577E932E8C9?term =lenalidomide+myeloma&submit=Search 2004. Accessed January 27, 2005.

  58. Berenson J, Crowley J, Grogan TM, et al.: Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 2002, 99:3163–3168.

    Article  PubMed  CAS  Google Scholar 

  59. Shustik C, Belch A, Robinson S, et al.: Dexamethasone (dex) maintenance versus observation (obs) in patients with previously untreated multiple myeloma: A National Cancer Institute of Canada Clinical Trials Group Study: MY.7. J Clin Oncol 2004, 22:560s.

    Google Scholar 

  60. Berenson JR, Jagannath S, Barlogie B, et al.: The safety of prolonged therapy with the proteasome inhibitor bortezomib (VELCADE) in relapsed and/or refractory multiple myeloma (MM). Hematol J 2004, 5:S129.

    Google Scholar 

  61. Attal M, Harousseau J, Leyvraz S, et al.: Maintenance treatment with thalidomide after autologous transplantation for myeloma: first analysis of a prospective randomized study of the IFM 9902. Blood 2004, 104:155a.

    Google Scholar 

  62. Steurer M, Spizzo G, Mitterer M, et al.: Low-dose thalidomide for multiple myeloma: interim analysis of a compassionate use program. Onkologie 2004, 27:150–154.

    Article  PubMed  CAS  Google Scholar 

  63. Stewart AK, Chen CI, Howson-Jan K, et al.: Results of a multicenter randomized phase II trial of thalidomide and prednisone maintenance therapy for multiple myeloma after autologous stem cell transplant. Clin Cancer Res 2004, 10:8170–8176.

    Article  PubMed  CAS  Google Scholar 

  64. Schey SA, Fields P, Bartlett JB, et al.: Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol 2004, 22:3269–3276.

    Article  PubMed  CAS  Google Scholar 

  65. Hussein MA, Saleh M, Ravandi F, et al.: Phase II study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol 2004, 125:470–476.

    Article  PubMed  CAS  Google Scholar 

  66. Zangari M, Anaissie E, Stopeck A, et al.: Phase II study of SU5416, a small molecule vascular endothelial growth factor tyrosine kinase receptor inhibitor, in patients with refractory multiple myeloma. Clin Cancer Res 2004, 10:88–95.

    Article  PubMed  CAS  Google Scholar 

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Jagannath, S. Treatment of myeloma in patients not eligible for transplantation. Curr. Treat. Options in Oncol. 6, 241–253 (2005). https://doi.org/10.1007/s11864-005-0007-0

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