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Treatment of relapsed and refractory myeloma

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Abstract

Treatment options for patients with relapsed and refractory myeloma have dramatically changed as a result of the approval of bortezomib, thalidomide, lenalidomide, and bortezomib/liposomal doxorubicin by the US Food and Drug Administration. These changes have resulted in improved responses to salvage therapy and, in many cases, improved overall survival. The challenge for clinicians is choosing which agent to use and deciding whether a single agent or combination therapy is the optimal treatment option for each patient. This article outlines some of the data underpinning the use of bortezomib, thalidomide, lenalidomide, or combinations of these agents in the setting of relapsed myeloma, as well as a number of potential future agents or combinations that may improve outcomes for patients with relapsed and refractory disease.

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References and Recommended Reading

  1. Kyle RA, Rajkumar SV: Multiple myeloma. N Engl J Med 2004, 351:1860–1873.

    Article  PubMed  CAS  Google Scholar 

  2. Harousseau JL, Shaughnessy J Jr, Richardson P: Multiple myeloma. Hematology Am Soc Hematol Educ Program 2004, 237–256.

  3. Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC: Advances in biology of multiple myeloma: clinical applications. Blood 2004, 104:607–618.

    Article  PubMed  CAS  Google Scholar 

  4. Hideshima T, Chauhan D, Hayashi T, et al.: Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma. Oncogene 2003, 22:8386–8393.

    Article  PubMed  CAS  Google Scholar 

  5. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al.: Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 2002, 20:4420–4427.

    Article  PubMed  CAS  Google Scholar 

  6. Richardson PG, Barlogie B, Berenson J, et al.: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003, 348:2609–2617.

    Article  PubMed  CAS  Google Scholar 

  7. 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, 127:165–172.

    Article  PubMed  CAS  Google Scholar 

  8. Liebross RH, Ha CS, Cox JD, et al.: Solitary bone plasmacytoma: outcome and prognostic factors following radiotherapy. Int J Radiat Oncol Biol Phys 1998, 41:1063–1067.

    PubMed  CAS  Google Scholar 

  9. Richardson PG, Sonneveld P, Schuster MW, et al.: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005, 352:2487–2498.

    Article  PubMed  CAS  Google Scholar 

  10. Richardson PG, 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, 110:3557–3560.

    Article  PubMed  CAS  Google Scholar 

  11. Richardson P, Schlossman R, McKenney M, et al.: Efficacy of bortezomib in the treatment of relapsed multiple myeloma: case history from the APEX phase III study. Am J Hematol Oncol 2008, 7:395–399.

    Google Scholar 

  12. Jagannath S, Richardson PG, Sonneveld P, et al.: Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia 2007, 21:151–157.

    Article  PubMed  CAS  Google Scholar 

  13. Harousseau JL, Mathiot C, Attal M, et al.: VELCADE/dexamethasone (Vel/D) versus VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM): updated results of the IFM 2005/01 trial [abstract 450]. Blood (ASH Annual Meeting Abstracts) 2007, 110.

  14. Cavo M, Patriarca F, Tacchetti P, et al.: Bortezomib (Velcade®)-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) in preparation for autologous stem-cell (SC) transplantation (ASCT) in newly diagnosed multiple myeloma (MM) [abstract 73]. Blood (ASH Annual Meeting Abstracts) 2007, 110.

  15. Dispenzieri A, Zhang L, Fonseca R, et al.: Single agent bortezomib is associated with a high response rate in patients with high risk myeloma. A phase II study from the Eastern Cooperative Oncology Group (E2A02) [abstract 3527]. Blood (ASH Annual Meeting Abstracts) 2006, 108.

  16. Lonial S, Waller EK, Richardson PG, et al.: Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 2005, 106:3777–3784.

    Article  PubMed  CAS  Google Scholar 

  17. Lonial S, Richardson PG, San Miguel J, et al.: Characterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma. Br J Haematol 2008, 143:222–229.

    Article  PubMed  CAS  Google Scholar 

  18. Richardson PG, 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, 24:3113–3120.

    Article  PubMed  CAS  Google Scholar 

  19. Orlowski RZ, Voorhees PM, Garcia RA, et al.: Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 2005, 105:3058–3065.

    Article  PubMed  CAS  Google Scholar 

  20. Orlowski RZ, Zhuang SH, Parekh T, et al.: The combination of pegylated liposomal doxorubicin and bortezomib significantly improves time to progression of patients with relapsed/refractory multiple myeloma compared with bortezomib alone: results from a planned interim analysis of a randomized phase III study [abstract 404]. Blood (ASH Annual Meeting Abstracts) 2006, 108.

  21. Orlowski RZ, 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, 25:3892–3901.

    Article  PubMed  CAS  Google Scholar 

  22. Singhal S, Mehta J, Desikan R, et al.: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999. 341:1565–1571.

    Article  PubMed  CAS  Google Scholar 

  23. Palumbo A, Facon T, Sonneveld P, et al.: Thalidomide for treatment of multiple myeloma: 10 years later. Blood 2008, 111:3968–3977.

    Article  PubMed  CAS  Google Scholar 

  24. Richardson PG, Mitsiades C, Hideshima T, Anderson KC: Lenalidomide in multiple myeloma. Expert Rev Anticancer Ther 2006, 6:1165–1173.

    Article  PubMed  CAS  Google Scholar 

  25. 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 

  26. Richardson P, Jagannath S, Hussein M, et al.: A multicenter, single-arm, open-label study to evaluate the efficacy and safety of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma; preliminary results [abstract 1565]. Blood (ASH Annual Meeting Abstracts) 2005, 106.

  27. Richardson PG, Blood E, Mitsiades CS, et al.: A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006, 108:3458–3464.

    Article  PubMed  CAS  Google Scholar 

  28. Weber DM, Chen C, Niesvizky R, et al.: Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007, 357:2133–2142.

    Article  PubMed  CAS  Google Scholar 

  29. Dimopoulos M, Spencer A, Attal M, et al.: Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007, 357:2123–2132.

    Article  PubMed  CAS  Google Scholar 

  30. Reece DE, Masih-Khan E, Chen C, et al.: Lenalidomide (Revlimid®) +/- corticosteroids in elderly patients with relapsed/refractory multiple myeloma [abstract 3550]. Blood (ASH Annual Meeting Abstracts) 2006, 108.

  31. Stadtmauer E, Weber D, Dimopolous M, et al.: Lenalidomide in combination with dexamethasone is more effective than dexamethasone at first relapse in relapsed multiple myeloma [abstract 3552]. Blood (ASH Annual Meeting Abstracts) 2006, 108.

  32. Wang M, Dimopoulos MA, 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, 112:4445–4451.

    Article  PubMed  CAS  Google Scholar 

  33. 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 [abstract 412]. Blood (ASH Annual Meeting Abstracts) 2007, 110.

  34. Jagannath S, Richardson P, Zeldenrust SR, et al.: Long-term responses observed with lenalidomide therapy for patients with relapsed or refractory multiple myeloma [abstract 8525]. J Clin Oncol 2008, 26(May 20 suppl).

  35. 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, 47:1466–1475.

    Article  PubMed  CAS  Google Scholar 

  36. Palumbo A, Rajkumar SV, Dimopoulos MA, et al.: Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008, 22:414–423.

    Article  PubMed  CAS  Google Scholar 

  37. Mitsiades CS, Mitsiades NS, McMullan CJ, et al.: Antimyeloma activity of heat shock protein-90 inhibition. Blood 2006, 107:1092–1100.

    Article  PubMed  CAS  Google Scholar 

  38. Richardson PG, Chanan-Khan A, Lonial S, et al.: Tanespimycin (T) + bortezomib (BZ) in multiple myeloma (MM): confirmation of the recommended dose using a novel formulation [abstract 1165]. Blood (ASH Annual Meeting Abstracts) 2007, 110.

  39. Catley L, Weisberg E, Kiziltepe T, et al.: Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 2006, 108:3441–3449.

    Article  PubMed  CAS  Google Scholar 

  40. Lonial S, Francis D, Karanes C, et al.: A phase I MMRC clinical trial testing the combination of bortezomib and tipifarnib in relapsed/refractory multiple myeloma [abstract 3706]. Blood (ASH Annual Meeting Abstracts) 2008, 112.

  41. Hideshima T, Bradner JE, Wong J, et al.: Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A 2005, 102:8567–8572.

    Article  PubMed  CAS  Google Scholar 

  42. Weber D, Badros AZ, Jagannath S, et al.: Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: early clinical experience [abstract 871]. Blood (ASH Annual Meeting Abstracts) 2008, 112.

  43. Harrison SJ, 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 [abstract 3698]. Blood (ASH Annual Meeting Abstracts) 2008, 112.

  44. 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, 107:4053–4062.

    Article  PubMed  CAS  Google Scholar 

  45. Richardson P, Jakubowiak A, Wolf J, et al.: Phase I/II report from a multicenter trial of perifosine (KRX-0401) + bortezomib in patients with relapsed or relapsed/refractory multiple myeloma previously treated with bortezomib [abstract 1170]. Blood (ASH Annual Meeting Abstracts) 2007, 110.

  46. Ghobrial IM, Munshi N, Schlossman R, et al.: Phase I trial of CCI-779 (temsirolimus) and weekly bortezomib in relapsed and/or refractory multiple myeloma [abstract 3696]. Blood (ASH Annual Meeting Abstracts) 2008, 112.

  47. David E, Peng X, Barwick BG, et al.: SF1126, a novel PI3K inhibitor, results in downstream inhibition of the PI3K axis and displays sequence specific synergy when combined with bortezomib in multiple myeloma cells [abstract 5167]. Blood (ASH Annual Meeting Abstracts) 2008, 112.

  48. Rossi, JF, Manges RF, Sutherland HJ, et al.: Preliminary results of CNTO 328, an anti-interleukin-6 monoclonal antibody, in combination with bortezomib in the treatment of relapsed or refractory multiple myeloma [abstract 867]. Blood (ASH Annual Meeting Abstracts) 2008, 112.

  49. Mitsiades N, Mitsiades CS, Poulaki V, et al.: Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002, 99:4525–4530.

    Article  PubMed  CAS  Google Scholar 

  50. 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 [abstract 1742]. Blood (ASH Annual Meeting Abstracts) 2008, 112.

  51. Richardson P, Jagannath S, Raje N, et al.: Lenalidomide, bortezomib, and dexamethasone (Rev/Vel/Dex) as frontline therapy for patients with multiple myeloma (MM): preliminary results of a phase 1/2 study [abstract 187]. Blood (ASH Annual Meeting Abstracts) 2007, 110.

  52. Richardson P, Anderson K: Immunomodulatory analogs of thalidomide: an emerging new therapy in myeloma. J Clin Oncol 2004, 22:3212–3214.

    Article  PubMed  CAS  Google Scholar 

  53. Chang DH, Liu N, Klimek V, et al.: Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood 2006, 108:618–621.

    Article  PubMed  CAS  Google Scholar 

  54. Tai YT, Li XF, Catley L, et al.: Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res 2005, 65:11712–11720.

    Article  PubMed  CAS  Google Scholar 

  55. Orlowski RZ, Stewart K, Vallone M, et al.: Safety and antitumor efficacy of the proteasome inhibitor carfilzomib (PR-171) dosed for five consecutive days in hematologic malignancies: phase 1 results [abstract 409]. Blood (ASH Annual Meeting Abstracts) 2007, 110.

  56. Alsina M, Trudel S, Vallone M, et al.: Phase 1 single agent antitumor activity of twice weekly consecutive day dosing of the proteasome inhibitor carfilzomib (PR-171) in hematologic malignancies [abstract 411]. Blood (ASH Annual Meeting Abstracts) 2007, 110.

  57. Vij R, Wang M, Orlowski R, et al.: Initial results of PX-171-004, an open-label, single-arm, phase ii study of carfilzomib (CFZ) in patients with relapsed myeloma (MM) [abstract 865]. Blood (ASH Annual Meeting Abstracts) 2008, 112.

  58. Jagannath S, Vij R, Stewart AK, et al.: Initial results of PX-171-003, an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients with relapsed and refractory multiple myeloma (MM) [abstract 864]. Blood (ASH Annual Meeting Abstracts) 2008, 112.

  59. Chauhan D, Catley L, Li G, et al.: A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from bortezomib. Cancer Cell 2005, 8:407–419.

    Article  PubMed  CAS  Google Scholar 

  60. 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 

  61. Lacy MQ, Hayman SR, Gertz MA, et al.: Pomalidomide (CC4047) plus low-dose dexamethasone (pom/dex) is highly effective therapy in relapsed multiple myeloma [abstract 866]. Blood (ASH Annual Meeting Abstracts) 2008, 112.

  62. 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, 22:1419–1427.

    Article  PubMed  CAS  Google Scholar 

  63. Chanan-Khan AA, Padmanabhan S, Miller KC, et al.: Final results of a phase ii study of bortezomib (Velcade) in combination with liposomal doxorubicin (Doxil) and thalidomide (VDT) demonstrate a sustained high response rates in patients (pts) with relapsed (rel) or refactory (ref) multiple myeloma [abstract 3539]. Blood (ASH Annual Meeting Abstracts) 2006, 108.

  64. Jakubowiak AJ, Brackett L, Kendall T, et al.: Combination therapy with Velcade, Doxil, and dexamethasone (VDD) for patients with relapsed/refractory multiple myeloma (MM) [abstract 5179]. Blood (ASH Annual Meeting Abstracts) 2005, 106.

  65. Biehn SE, Moore DT, Voorhees PM, 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, 86:211–216.

    Article  PubMed  CAS  Google Scholar 

  66. Popat R, Oakervee HE, Foot N, et al.: A phase I/II study of bortezomib and low dose intravenous melphalan (BM) for relapsed multiple myeloma [abstract 2555]. Blood (ASH Annual Meeting Abstracts) 2005, 106.

  67. Palumbo A, Ambrosini MT, Benevolo G, et al.: Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood 2007, 109:2767–2772.

    PubMed  CAS  Google Scholar 

  68. Kropff M, Bisping G, Schuck E, et al.: Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol 2007, 138:330–337.

    Article  PubMed  CAS  Google Scholar 

  69. Reece DE, Rodriguez GP, 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, 26:4777–4783.

    Article  PubMed  CAS  Google Scholar 

  70. Garcia-Sanz R, Gonzalez-Porras JR, Hernandez JM, et al.: The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia 2004, 18:856–863.

    Article  PubMed  CAS  Google Scholar 

  71. Dimopoulos MA, Hamilos G, Zomas A, et al.: Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma. Hematol J 2004, 5:112–117.

    Article  PubMed  CAS  Google Scholar 

  72. 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, 129:763–770.

    Article  PubMed  CAS  Google Scholar 

  73. Hussein MA, 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, 81:889–895.

    Article  PubMed  CAS  Google Scholar 

  74. 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, 91:133–136.

    PubMed  CAS  Google Scholar 

  75. Palumbo A, Avonto I, Bruno B, et al.: Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma. Eur J Haematol 2006, 76:273–277.

    Article  PubMed  CAS  Google Scholar 

  76. Suvannasankha A, Fausel C, Juliar BE, et al.: Final report of toxicity and efficacy of a phase II study of oral cyclophosphamide, thalidomide, and prednisone for patients with relapsed or refractory multiple myeloma: a Hoosier Oncology Group Trial, HEM01-21. Oncologist 2007, 12:99–106.

    Article  PubMed  CAS  Google Scholar 

  77. Richardson P, Wolf J, Jakubowiak A, et al.: Phase I/II results of a multicenter trial of perifosine (KRX-0401) + bortezomib in patients with relapsed or relapsed/refractory multiple myeloma who were previously relapsed from or refractory to bortezomib [abstract 870] Blood (ASH Annual Meeting Abstracts) 2008, 112.

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Correspondence to Sagar Lonial.

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Kaufman, J., Gleason, C. & Lonial, S. Treatment of relapsed and refractory myeloma. Curr Hematol Malig Rep 4, 99–107 (2009). https://doi.org/10.1007/s11899-009-0014-5

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