The Emerging Role of Novel Therapies for the Treatment of Relapsed Myeloma

Authors:
Paul G. RichardsonFrom the Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, and Harvard Medical School; Harvard Medical School, Dana-Farber Cancer Institute, and Brigham and Women's Hospital; and Jerome Lipper Multiple Myeloma Center, Kraft Family Donor Center, and Harvard Medical School, Boston, Massachusetts.

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Teru HideshimaFrom the Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, and Harvard Medical School; Harvard Medical School, Dana-Farber Cancer Institute, and Brigham and Women's Hospital; and Jerome Lipper Multiple Myeloma Center, Kraft Family Donor Center, and Harvard Medical School, Boston, Massachusetts.

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Constantine MitsiadesFrom the Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, and Harvard Medical School; Harvard Medical School, Dana-Farber Cancer Institute, and Brigham and Women's Hospital; and Jerome Lipper Multiple Myeloma Center, Kraft Family Donor Center, and Harvard Medical School, Boston, Massachusetts.

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Kenneth C. AndersonFrom the Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, and Harvard Medical School; Harvard Medical School, Dana-Farber Cancer Institute, and Brigham and Women's Hospital; and Jerome Lipper Multiple Myeloma Center, Kraft Family Donor Center, and Harvard Medical School, Boston, Massachusetts.

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Volume/Issue:
Volume 5: Issue 2
Online Publication Date:
Feb 2007
DOI:
https://doi.org/10.6004/jnccn.2007.0015
Full access

Despite advances in the first-line treatment of multiple myeloma, almost all patients eventually relapse, become chemoresistant, and die of the disease. Improved understanding of potential myeloma targets and molecular mechanisms of drug resistance, along with the development and clinical investigation of targeted antitumor agents, have led to new strategies for the treatment of relapsed myeloma. The proteasome inhibitor bortezomib, the immunomodulatory agent thalidomide, and the thalidomide derivative lenalidomide, are all recently approved treatment options for myeloma. Single-agent bortezomib has been shown to provide significantly greater efficacy than high-dose dexamethasone, and bortezomib has also been investigated in combination with other agents commonly used to treat myeloma, including thalidomide and lenalidomide, with high overall and complete response rates. The safety profile of bortezomib has been well characterized, and side effects have been shown to be generally predictable and manageable, including in high-risk and elderly patients and those with renal impairment. Thalidomide has been extensively studied alone and in combination in patients with relapsed myeloma, demonstrating substantial efficacy, and is therefore widely used in this setting. The toxicity profile is dose- and duration-linked, with lower doses appearing to be better tolerated. Lenalidomide plus dexamethasone has been shown to have significantly greater activity than dexamethasone alone in the relapsed setting, with impressive duration of disease control. Other combinations are also under investigation, with promising early results. Some aspects of the toxicity profile appear significantly reduced relative to thalidomide, although myelosuppression is increased. Other novel therapies at earlier stages of development are being studied and may provide further options in the treatment of relapsed myeloma. This review focuses on results from key phase II and III trials of bortezomib, thalidomide, and lenalidomide alone or in combination, and their emerging role in improving outcomes.

Correspondence: Paul G. Richardson, MD, Dana-Farber Cancer Institute, 44 Binney Street, Dana 1B02, Boston, MA 02115. E-mail: paul_richardson@dfci.harvard.edu
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  • Expand
  • 1.

    Sirohi B, Powles R. Multiple myeloma. Lancet 2004;363:875–887.

  • 2.

    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;102:1115–1123.

    • Search Google Scholar
    • Export Citation
  • 3.

    Durie BG, Harousseau JL, Miguel JS et al.. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467–1473.

  • 4.

    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.

    • Search Google Scholar
    • Export Citation
  • 5.

    Hideshima T, Chauhan D, Schlossman R et al.. The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene 2001;20:4519–4527.

    • Search Google Scholar
    • Export Citation
  • 6.

    Hideshima T, Chauhan D, Richardson P et al.. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002;277:16639–16647.

  • 7.

    Mitsiades N, Mitsiades CS, Poulaki V et al.. Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications. Blood 2002;99:4079–4086.

    • Search Google Scholar
    • Export Citation
  • 8.

    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.

    • Search Google Scholar
    • Export Citation
  • 9.

    Hideshima T, Mitsiades C, Akiyama M et al.. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 2003;101:1530–1534.

    • Search Google Scholar
    • Export Citation
  • 10.

    Mitsiades CS, Treon SP, Mitsiades N et al.. TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 2001;98:795–804.

    • Search Google Scholar
    • Export Citation
  • 11.

    Mitsiades N, Mitsiades CS, Poulaki V et al.. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 2002;99:14374–14379.

    • Search Google Scholar
    • Export Citation
  • 12.

    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.

    • Search Google Scholar
    • Export Citation
  • 13.

    Orlowski RZ, Baldwin AS Jr. NF-kappaB as a therapeutic target in cancer. Trends Mol Med 2002;8:385–389.

  • 14.

    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.

    • Search Google Scholar
    • Export Citation
  • 15.

    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.

    • Search Google Scholar
    • Export Citation
  • 16.

    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.

    • Search Google Scholar
    • Export Citation
  • 17.

    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.

  • 18.

    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.

    • Search Google Scholar
    • Export Citation
  • 19.

    Richardson P, Sonneveld P, Schuster M et al.. Bortezomib continues to demonstrate superior efficacy compared with high-dose dexamethasone in relapsed multiple myeloma: updated results of the APEX trial [abstract]. Blood 2005;106:715a. Abstract 2547.

    • Search Google Scholar
    • Export Citation
  • 20.

    Weber DM, Chen C, Niesvizky R et al.. Lenalidomide plus high-dose dexamethasone provides improved survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma: results of a North American phase III study (MM-009) [abstract]. J Clin Oncol 2006;24:427s. Abstract 7521.

    • Search Google Scholar
    • Export Citation
  • 21.

    Dimopoulos MA, Anagnostopoulos A, Prince M et al.. Lenalidomide (Revlimid) combination with dexamethasone (DEX) is more effective than DEX alone in patients with relapsed or refractory multiple myeloma and independent of the number of previous treatments [abstract]. Haematologica 2006;91(Suppl 1):181. Abstract 494.

    • Search Google Scholar
    • Export Citation
  • 22.

    Hollmig K, Stover J, Talamo G et al.. Bortezomib (Velcade™) + Adriamycin™ + thalidomide + dexamethasone (VATD) as an effective regimen in patients with refractory or relapsed multiple myeloma (MM) [abstract]. Blood 2004;104:659a. Abstract 2399.

    • Search Google Scholar
    • Export Citation
  • 23.

    Leoni F, Casini C, Breschi C et al.. Low dose bortezomib, dexamethasone, thalidomide plus liposomal doxorubicin in relapsed and refractory myeloma [abstract]. Haematologica 2006;91(Suppl 1):281. Abstract 764.

    • Search Google Scholar
    • Export Citation
  • 24.

    Zangari M, Barlogie B, Burns MJ et al.. Velcade (V)-thalidomide (T)-dexamethasone (D) for advanced and refractory multiple myeloma (MM): long-term follow-up of phase I-II trial UARK 2001-37: superior outcome in patients with normal cytogenetics and no prior T [abstract]. Blood 2005;106:717a. Abstract 2552.

    • Search Google Scholar
    • Export Citation
  • 25.

    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.

    • Search Google Scholar
    • Export Citation
  • 26.

    Richardson P, Schlossman R, Munshi N et al.. A phase 1 trial of lenalidomide (REVLIMID®) with bortezomib (VELCADE®) in relapsed and refractory multiple myeloma [abstract]. Blood 2005;106:110a. Abstract 365.

    • Search Google Scholar
    • Export Citation
  • 27.

    Padmanabhan S, Miller K, Musiel L et al.. Bortezomib (Velcade) in combination with liposomal doxorubicin (Doxil) and thalidomide is an active salvage regimen in patients with relpase or refractory multiple myeloma: final results of a phase II trial [abstract]. Haematologica 2006;91(Suppl 1):277. Abstract 752.

    • Search Google Scholar
    • Export Citation
  • 28.

    Palumbo A, Ambrosini MT, Benevolo G et al.. Bortezomib, melphalan, prednisone and thalidomide for relapsed multiple myeloma. Blood 2006; e-pub ahead of print.

    • Search Google Scholar
    • Export Citation
  • 29.

    Terpos E, Anagnostopoulos A, Kastritis E et al.. The combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide (VMTD) is an effective regimen for relapsed/refractory myeloma and reduces serum levels of RANKL, MIP-1 alpha and angiogenic cytokines [abstract]. Haematologica 2006;91(Suppl 1):84. Abstract 223.

    • Search Google Scholar
    • Export Citation
  • 30.

    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;98:492–494.

    • Search Google Scholar
    • Export Citation
  • 31.

    Palumbo A, Bertola A, Falco P et al.. Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma. Hematol J 2004;5:318–324.

    • Search Google Scholar
    • Export Citation
  • 32.

    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.

    • Search Google Scholar
    • Export Citation
  • 33.

    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.

    • Search Google Scholar
    • Export Citation
  • 34.

    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.

    • Search Google Scholar
    • Export Citation
  • 35.

    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.

    • Search Google Scholar
    • Export Citation
  • 36.

    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]. Blood 2005;106:449a. Abstract 1565.

    • Search Google Scholar
    • Export Citation
  • 37.

    Gerecke C, Knop S, Topp MS et al.. A multicenter phase I/II trial evaluating the safety and efficacy of lenalidomide [Revlimid ® CC-5013] in combination with doxorubicin and dexamethasone (RAD) in patients with relapsed or refractory multiple myeloma [abstract]. Blood 2005;106:367b. Abstract 5136.

    • Search Google Scholar
    • Export Citation
  • 38.

    Baz R, Walker E, Karam MA et al.. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol 2006;17:1766–1771.

    • Search Google Scholar
    • Export Citation
  • 39.

    Sonneveld P, Richardson PG, Schuster MW et al.. Bortezomib at first relapse is superior to high-dose dexamethasone and more effective than when given later in relapsed multiple myeloma [abstract]. Haematologica 2005;90:146–147. Abstract P140.721.

    • Search Google Scholar
    • Export Citation
  • 40.

    Vogl DT, Stadtmauer EA, Richardson PG et al.. Impact of prior autologous stem cell transplant (ASCT) in patients receiving bortezomib or dexamethasone for relapsed/refractory multiple myeloma in the APEX trial [abstract]. J Clin Oncol 2006;24(Suppl 1):433s. Abstract 7546.

    • Search Google Scholar
    • Export Citation
  • 41.

    Richardson PG, Sonneveld P, Schuster MW et al.. Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed myeloma [abstract]. J Clin Oncol 2005;23(Suppl 1):568s. Abstract 6533.

    • Search Google Scholar
    • Export Citation
  • 42.

    Knudsen LM, Hippe E, Hjorth M et al.. Renal function in newly diagnosed multiple myeloma—a demographic study of 1353 patients. The Nordic Myeloma Study Group. Eur J Haematol 1994;53:207–212.

    • Search Google Scholar
    • Export Citation
  • 43.

    Knudsen LM, Hjorth M, Hippe E. Renal failure in multiple myeloma: reversibility and impact on the prognosis. Nordic Myeloma Study Group. Eur J Haematol 2000;65:175–181.

    • Search Google Scholar
    • Export Citation
  • 44.

    Chanan-Khan AA, Kaufman JL, Mehta J et al.. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 2006; e-pub ahead of print.

    • Search Google Scholar
    • Export Citation
  • 45.

    Jagannath S, Barlogie B, Berenson JR et al.. Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impared renal function. Cancer 2005;103:1195–1200.

    • Search Google Scholar
    • Export Citation
  • 46.

    Mohrbacher A, Levine AM. Reversal of advanced renal dysfunction on bortezomib treatment in multiple myeloma patients [abstract]. J Clin Oncol 2005;23(Suppl 1):612s. Abstract 6714.

    • Search Google Scholar
    • Export Citation
  • 47.

    Mulkerin D, Remick S, Ramanathan R et al.. A dose-escalating and pharmacologic study of bortezomib in adult cancer patients with impaired renal function [abstract]. J Clin Oncol 2006;24(Suppl 1):87s. Abstract 2032.

    • Search Google Scholar
    • Export Citation
  • 48.

    Nozza A, Siracusano L, Armando S. Bortezomib-dexamethasone combination in a patient with refractory multiple myeloma and impaired renal function. Clin Ther 2006;28:953–959.

    • Search Google Scholar
    • Export Citation
  • 49.

    Lonial S, Richardson P, Sonneveld P et al.. Hematologic profiles in the phase 3 APEX trial [abstract]. Blood 2005;106:970a. Abstract 3474.

  • 50.

    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.

    • Search Google Scholar
    • Export Citation
  • 51.

    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.

    • Search Google Scholar
    • Export Citation
  • 52.

    San Miguel JF, Richardson P, Sonneveld P et al.. Frequency, characteristics, and reversibility of peripheral neuropathy (PN) in the APEX trial [abstract]. Blood 2005;106:111a. Abstract 366.

    • Search Google Scholar
    • Export Citation
  • 53.

    Anderson KC. Lenalidomide and thalidomide: mechanisms of action—similarities and differences. Semin Hematol 2005;42:S3–8.

  • 54.

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

  • 55.

    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.

    • Search Google Scholar
    • Export Citation
  • 56.

    D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994;91:4082–4085.

  • 57.

    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.

    • Search Google Scholar
    • Export Citation
  • 58.

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

    • Search Google Scholar
    • Export Citation
  • 59.

    Rajkumar SV, Fonseca R, Dispenzieri A et al.. Thalidomide in the treatment of relapsed multiple myeloma. Mayo Clin Proc 2000;75:897–901.

  • 60.

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

    • Search Google Scholar
    • Export Citation
  • 61.

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

  • 62.

    Yakoub-Agha I, Attal M, Dumontet C et al.. Thalidomide in patients with advanced multiple myeloma: a study of 83 patients—report of the Intergroupe Francophone du Myelome (IFM). Hematol J 2002;3:185–192.

    • Search Google Scholar
    • Export Citation
  • 63.

    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;132:584–593.

    • Search Google Scholar
    • Export Citation
  • 64.

    Juliusson G, Celsing F, Turesson I et al.. Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma. Br J Haematol 2000;109:89–96.

    • Search Google Scholar
    • Export Citation
  • 65.

    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;79:875–882.

    • Search Google Scholar
    • Export Citation
  • 66.

    Matthews SJ, McCoy C. Thalidomide: a review of approved and investigational uses. Clin Ther 2003;25:342–395.

  • 67.

    Candelaria D, Armijo B, Montgomery R et al.. Thalidomide increases thrombin generation in multiple myeloma patients [abstract]. J Clin Oncol 2006;24(Suppl 1):447s. Abstract 7602.

    • Search Google Scholar
    • Export Citation
  • 68.

    Naina HVK, Lacy MQ, Dispenzieri A et al.. Incidence and clinical course of peripheral neuropathy in patients receiving thalidomide for the treatment of multiple myeloma [abstract]. Blood 2005;106:970a. Abstract 3475.

    • Search Google Scholar
    • Export Citation
  • 69.

    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;24:4507–4514.

    • Search Google Scholar
    • Export Citation
  • 70.

    Yakoub-Agha I, Doyen C, Hulin C et al.. A multicenter prospective randomized study testing non-inferiority of thalidomide 100 mg/day as compared with 400 mg/day in patients with refractory/relapsed multiple myeloma: Results of the final analysis of the IFM 01-02 study [abstract]. J Clin Oncol 2006;24(Suppl 1):427s. Abstract 7520.

    • Search Google Scholar
    • Export Citation
  • 71.

    Celgene Corporation. THALOMID (thalidomide) Product Information. Summit, NJ; 2006. Available at www.celgene.com. Accessed February 9, 2007.

    • Search Google Scholar
    • Export Citation
  • 72.

    Hussein MA. Thromboembolism risk reduction in multiple myeloma patients treated with immunomodulatory drug combinations. Thromb Haemost 2006;95:924–930.

    • Search Google Scholar
    • Export Citation
  • 73.

    Rajkumar SV, 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;24:431–436.

    • Search Google Scholar
    • Export Citation
  • 74.

    Rajkumar SV, Hussein M, Catalano J et al.. A multicenter, randomized, double-blind, placebo-controlled trial of thalidomide plus dexamethasone versus dexamethasone alone as initial therapy for newly diagnosed multiple myeloma [abstract]. J Clin Oncol 2006;24(Suppl 1):426s. Abstract 7517.

    • Search Google Scholar
    • Export Citation
  • 75.

    Baz R, Kottke-Marchant K, Srkalovic G et al.. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 2005;80:1568–1574.

    • Search Google Scholar
    • Export Citation
  • 76.

    Rajkumar SV. Thalidomide therapy and deep venous thrombosis in multiple myeloma. Mayo Clin Proc 2005;80:1549–1551.

  • 77.

    Hatjiharissi E, Terpos E, Papaioannou M et al.. The combination of intermediate doses of thalidomide and dexamethasone reduces bone marrow micro-vessel density but not serum levels of angiogenic cytokines in patients with refractory/relapsed multiple myeloma. Hematol Oncol 2004;22:159–168.

    • Search Google Scholar
    • Export Citation
  • 78.

    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.

    • Search Google Scholar
    • Export Citation
  • 79.

    Palumbo A, Falco P, Ambrosini MT et al.. Thalidomide plus dexamethasone is an effective salvage regimen for myeloma patients relapsing after autologous transplant. Eur J Haematol 2005;75:391–395.

    • Search Google Scholar
    • Export Citation
  • 80.

    Terpos E, Mihou D, Szydlo R et al.. The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio. Leukemia 2005;19:1969–1976.

    • Search Google Scholar
    • Export Citation
  • 81.

    Glasmacher A, Hahn C, Hoffmann F et al.. Thalidomide in relapsed or refractory patients with multiple myeloma: monotherapy or combination therapy? A report from systematic reviews [abstract]. Blood 2005;106:364b. Abstract 5125.

    • Search Google Scholar
    • Export Citation
  • 82.

    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.

    • Search Google Scholar
    • Export Citation
  • 83.

    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.

    • Search Google Scholar
    • Export Citation
  • 84.

    Sidra G, Williams CD, Russell NH et al.. Combination chemotherapy with cyclophosphamide, thalidomide and dexamethasone for patients with refractory, newly diagnosed or relapsed myeloma. Haematologica 2006;91:862–863.

    • Search Google Scholar
    • Export Citation
  • 85.

    Massimo MO, Bringhen S, Corvatta L et al.. Thalidomide-dexamethasone vs thalidomide-dexamethasone-pegylated liposomal doxorubicin: a case-matched study in patients with advanced multiple myeloma [abstract]. Haematologica 2006;91(Suppl 1):89. Abstract 236.

    • Search Google Scholar
    • Export Citation
  • 86.

    Davies FE, Raje N, Hideshima T et al.. Thalidomide and immunomodulatory derivatives augment natural killer cell cytoxicity in multiple myeloma. Blood 2001;98:210–216.

    • Search Google Scholar
    • Export Citation
  • 87.

    Gupta D, Treon SP, Shima Y et al.. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 2001;15:1950–1961.

    • Search Google Scholar
    • Export Citation
  • 88.

    Lentzsch S, LeBlanc R, Podar K et al.. Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo. Leukemia 2003;17:41–44.

    • Search Google Scholar
    • Export Citation
  • 89.

    Zangari M, Elice F, Tricot G. Immunomodulatory drugs in multiple myeloma. Expert Opin Investig Drugs 2005;14:1411–1418.

  • 90.

    Richardson PG, Blood E, Mitsiades C 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.

    • Search Google Scholar
    • Export Citation
  • 91.

    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.

    • Search Google Scholar
    • Export Citation
  • 92.

    Stadtmauer EA, Weber D, Dimopoulos MA et al.. Lenalidomide (Len) in combination with dexamethasone (Dex) is more effective than Dex alone at first relapse and provides better outcomes when used early rather than as later salvage therapy in relapsed multiple myeloma (MM) [abstract]. J Clin Oncol 2006;24(Suppl 1):446s. Abstract 7600.

    • Search Google Scholar
    • Export Citation
  • 93.

    Wang M, Knight R, Dimopoulos M et al.. Comparison of lenalidomide in combination with dexamethasone to dexamethasone alone in patients who have received prior thalidomide in relpased or refractory multiple myeloma [abstract]. J Clin Oncol 2006;24(Suppl 1):427s. Abstract 7522.

    • Search Google Scholar
    • Export Citation
  • 94.

    Knight R, DeLap RJ, Zeldis JB. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med 2006;354:2079–2080.

  • 95.

    Niesvizky R, Spencer A, Wang M et al.. Increased risk of thrombosis with lenalidomide in combination with dexamethasone and erythropoietin [abstract]. J Clin Oncol 2006;24(Suppl 1):423s. Abstract 7506.

    • Search Google Scholar
    • Export Citation
  • 96.

    Zonder JA, Durie BGM, McCoy J et al.. High incidence of thrombotic events observed in patients receiving lenalidomide (L) + dexamethasone (D) (LD) as first-line therapy for multiple myeloma (MM) without aspirin (ASA) prophylaxis [abstract]. Blood 2005;106:964a. Abstract 3455.

    • Search Google Scholar
    • Export Citation
  • 97.

    Berenson JR, Matous JV, Ferretti D et al.. A phase I/II study of arsenic trioxide, bortezomib and ascorbic acid in relapsed or refactory multiple myeloma [abstract]. J Clin Oncol 2006;24(Suppl 1):449s.

    • Search Google Scholar
    • Export Citation
  • 98.

    Hussein MA, Saleh M, Ravandi F et al.. Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol 2004;125:470–476.

    • Search Google Scholar
    • Export Citation
  • 99.

    Munshi NC, Tricot G, Desikan R et al.. Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia 2002;16:1835–1837.

  • 100.

    Qazilbash MH, Davis MS, Ana A et al.. Arsenic trioxide with ascorbic acid and high-dose melphalan: a new preparative regimen for autologous hematopoietic stem cell transplantation for multiple myeloma [abstract]. Blood 2005;106:338a. Abstract 1159.

    • Search Google Scholar
    • Export Citation
  • 101.

    Rousselot P, Larghero J, Arnulf B et al.. A clinical and pharmacological study of arsenic trioxide in advanced multiple myeloma patients. Leukemia 2004;18:1518–1521.

    • Search Google Scholar
    • Export Citation
  • 102.

    Wu K, van Droogenbroeck J, Beksac M et al.. Treatment with arsenic trioxide, ascorbic acid and dexamethasone in advanced myeloma patients: preliminary findings of a multicenter, phase II study [abstract]. Blood 2005;106:367a. Abstract 5135.

    • Search Google Scholar
    • Export Citation
  • 103.

    Berenson J, Boccia R, Siegel D et al.. A multicenter phase II study of combination treatment with melphalan, arsenic trioxide and vitamin C (MAC) for patients with relapsed or refractory multiple myeloma [abstract]. Blood 2005;106:720a. Abstract 2564.

    • Search Google Scholar
    • Export Citation
  • 104.

    Chauhan D, Catley L, Hideshima T et al.. 2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells. Blood 2002;100:2187–2194.

  • 105.

    Chauhan D, Li G, Auclair D et al.. 2-Methoxyestardiol and bortezomib/proteasome-inhibitor overcome dexamethasone-resistance in multiple myeloma cells by modulating Heat Shock Protein-27. Apoptosis 2004;9:149–155.

    • Search Google Scholar
    • Export Citation
  • 106.

    Dingli D, Timm M, Russell SJ et al.. Promising preclinical activity of 2-methoxyestradiol in multiple myeloma. Clin Cancer Res 2002;8:3948–3954.

  • 107.

    Mateos MV, Blade J, Prosper F et al.. Preliminary report from an exploratory phase II trial with plitidepsin (Aplidin(R)) in patients with refractory/relapsed multiple myeloma [abstract]. Blood 2005;106:722a. Abstract 2569.

    • Search Google Scholar
    • Export Citation
  • 108.

    Lust JA, Lacy MQ, Zeldenrust SR et al.. In smoldering/indolent (SMM/IMM) myeloma patients treated with interleukin-1 receptor antagonist (IL-1Ra), responders demonstrate a significantly increased time to progression (TTP) and a decreased C-reactive protein (CRP) compared with nonresponders [abstract]. Blood 2005;106:721a. Abstract 2567.

    • Search Google Scholar
    • Export Citation
  • 109.

    van de Donk NW, de WO, Veth G et al.. G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD refractory myeloma. Leukemia 2004;18:1078–1084.

    • Search Google Scholar
    • Export Citation
  • 110.

    Richardson PG, Chanan-Khan AA, Alsina M et al.. Safety and activity of KOS-953 in patients with relapsed refractory multiple myeloma (MM): interim results of a phase 1 trial [abstract]. Blood 2005;106:109a. Abstract 361.

    • Search Google Scholar
    • Export Citation
  • 111.

    Alsina M, Fonseca R, Wilson EF et al.. Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. Blood 2004;103:3271–3277.

    • Search Google Scholar
    • Export Citation
  • 112.

    Nguyen AN, Young GO, Quon D et al.. SCIO-469, a potent and selective inhibitor of the p38a MAPK, inhibits TNFa-induced adhesion of multiple myeloma cells to bone marrow stromal cells via downregulation of chemokines CXCL10/IP-10 and CCL8 [abstract]. Blood 2005;106:450a. Abstract 1569.

    • Search Google Scholar
    • Export Citation
  • 113.

    Catley L, Weisberg E, Tai YT et al.. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood 2003;102:2615–2622.

    • Search Google Scholar
    • Export Citation
  • 114.

    Mitsiades CS, Mitsiades NS, McMullan CJ et al.. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA 2004;101:540–545.

    • Search Google Scholar
    • Export Citation
Copyright:
Copyright © 2007 by the National Comprehensive Cancer Network
Page Numbers:
14
Article Category:
Research Article
Received:
26 Oct 2006
Accepted:
21 Dec 2006
Print Publication Date:
01 Feb 2007
Online Publication Date:
Feb 2007
Keywords:
Bortezomib; proteasome inhibitor; thalidomide; immunomodulatory drug (IMiD); lenalidomide; multiple myeloma; relapsed
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