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Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma

Leukemia volume 24, pages 22–32 (2010)Cite this article

Abstract

Immunomodulatory drugs (IMiDs) are thalidomide analogues, which possess pleiotropic anti-myeloma properties including immune-modulation, anti-angiogenic, anti-inflammatory and anti-proliferative effects. Their development was facilitated by an improved understanding in myeloma (MM) biology and initiated a profound shift in the therapeutic approach towards MM. Despite the diverse effects of IMiDs in vitro, the relative contribution of each effect towards their ultimate anti-MM activity is still unclear. Based on in vitro data, it appears that anti-proliferative effects and downregulation of crucial cytokines are their most important anti-MM attributes. Although the co-stimulatory effects on T and NK cells have been heralded as a unique and important property of IMiDs towards enhancing anti-MM immune activity, these in vitro effects have yet to be firmly corroborated in vivo. Much is yet to be elucidated regarding the complex interplay of immunomodulatory cytokines that occurs in vivo, which ultimately dictates the net effects of IMiDs in MM—the understanding of which is necessary to facilitate optimal manipulation of these drugs in future MM management.

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References

  1. van Rhee F, Dhodapkar M, Shaughnessy Jr JD, Anaissie E, Siegel D, Hoering A et al. First thalidomide clinical trial in multiple myeloma: a decade. Blood 2008; 112: 1035–1038.

    CAS  Google Scholar 

  2. Galustian C, Labarthe MC, Bartlett JB, Dalgleish AG . Thalidomide-derived immunomodulatory drugs as therapeutic agents. Exp Opin Biolog Ther 2004; 4: 1963–1970.

    CAS  Google Scholar 

  3. Lyer G . WHO co-ordinated short-term double-blind trial with thalidomide in the treatmetn of acute lepra reactions with male lepromatous patients. Bull World Health Organization 1971; 45: 719–732.

    Google Scholar 

  4. Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G . Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991; 173: 699–703.

    CAS  Google Scholar 

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

    Google Scholar 

  6. 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.

    CAS  Google Scholar 

  7. Corral LG, Muller GW, Moreira AL, Chen Y, Wu M, Stirling D et al. Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity. Mol Med (Cambridge, Mass) 1996; 2: 506–515.

    CAS  Google Scholar 

  8. Muller GW, Corral LG, Shire MG, Wang H, Moreira A, Kaplan G et al. Structural modifications of thalidomide produce analogs with enhanced tumor necrosis factor inhibitory activity. J Med Chem 1996; 39: 3238–3240.

    CAS  Google Scholar 

  9. Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 1999; 163: 380–386.

    CAS  Google Scholar 

  10. Zou W . Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev 2005; 5: 263–274.

    CAS  Google Scholar 

  11. Urashima M, Ogata A, Chauhan D, Hatziyanni M, Vidriales MB, Dedera DA et al. Transforming growth factor-beta1: differential effects on multiple myeloma versus normal B cells. Blood 1996; 87: 1928–1938.

    CAS  Google Scholar 

  12. Brimnes MK, Svane IM, Johnsen HE . Impaired functionality and phenotypic profile of dendritic cells from patients with multiple myeloma. Clin Exp Immunol 2006; 144: 76–84.

    CAS  Google Scholar 

  13. Smyth MJ, Godfrey DI, Trapani JA . A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol 2001; 2: 293–299.

    CAS  Google Scholar 

  14. Brown RD, Pope B, Murray A, Esdale W, Sze DM, Gibson J et al. Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-beta1 and interleukin-10. Blood 2001; 98: 2992–2998.

    CAS  Google Scholar 

  15. Rawstron AC, Davies FE, Owen RG, English A, Pratt G, Child JA et al. B-lymphocyte suppression in multiple myeloma is a reversible phenomenon specific to normal B-cell progenitors and plasma cell precursors. Br J Haematol 1998; 100: 176–183.

    CAS  Google Scholar 

  16. Ogawara H, Handa H, Yamazaki T, Toda T, Yoshida K, Nishimoto N et al. High Th1/Th2 ratio in patients with multiple myeloma. Leukaemia Res 2005; 29: 135–140.

    CAS  Google Scholar 

  17. Quach H, Ritchie D, Neeson P, Harrison S, Tai T, Tainton K et al. Regulatory T cells (Treg) are Depressed in Patients with Relapsed/Refractory Multiple Myeloma (MM) and Increases Towards Normal Range in Responding Patients Treated with Lenalidomide (LEN) [abstract]. Blood 2008; 112: 1696a.

    Google Scholar 

  18. Maecker B, Anderson KS, von Bergwelt-Baildon MS, Weller E, Vonderheide RH, Richardson PG et al. Viral antigen-specific CD8+ T-cell responses are impaired in multiple myeloma. Br J Haematol 2003; 121: 842–848.

    Google Scholar 

  19. Jarahian M, Watzl C, Issa Y, Altevogt P, Momburg F . Blockade of natural killer cell-mediated lysis by NCAM140 expressed on tumor cells. Int J Cancer 2007; 120: 2625–2634.

    CAS  Google Scholar 

  20. Dhodapkar MV, Geller MD, Chang DH, Shimizu K, Fujii S, Dhodapkar KM et al. A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma. J Exp Med 2003; 197: 1667–1676.

    CAS  Google Scholar 

  21. Ratta M, Fagnoni F, Curti A, Vescovini R, Sansoni P, Oliviero B et al. Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood 2002; 100: 230–237.

    CAS  Google Scholar 

  22. Takahashi A, Kono K, Ichihara F, Sugai H, Fujii H, Matsumoto Y . Vascular endothelial growth factor inhibits maturation of dendritic cells induced by lipopolysaccharide, but not by proinflammatory cytokines. Cancer Immunol Immunother 2004; 53: 543–550.

    CAS  Google Scholar 

  23. Prabhala RH, Neri P, Bae JE, Tassone P, Shammas MA, Allam CK et al. Dysfunctional T regulatory cells in multiple myeloma. Blood 2006; 107: 301–304.

    CAS  Google Scholar 

  24. Curiel TJ . Tregs and rethinking cancer immunotherapy. J Clin Invest 2007; 117: 1167–1174.

    CAS  Google Scholar 

  25. Curiel TJ . Regulatory T-cell development: is Foxp3 the decider? Nat Med 2007; 13: 250–253.

    CAS  Google Scholar 

  26. Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM . Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin's lymphoma. Cancer Res 2006; 66: 10145–10152.

    CAS  Google Scholar 

  27. Trzonkowski P, Szmit E, Mysliwska J, Dobyszuk A, Mysliwski A . CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction. Clin Immunol (Orlando, Fla) 2004; 112: 258–267.

    CAS  Google Scholar 

  28. Beyer M, Schultze JL . Regulatory T cells in cancer. Blood 2006; 108: 804–811.

    CAS  Google Scholar 

  29. Joshua DE, Brown RD, Ho PJ, Gibson J . Regulatory T cells and multiple myeloma. Clin Lymphoma Myeloma 2008; 8: 283–286.

    CAS  Google Scholar 

  30. Carreras J, Lopez-Guillermo A, Fox BC, Colomo L, Martinez A, Roncador G et al. High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood 2006; 108: 2957–2964.

    CAS  Google Scholar 

  31. Alvaro T, Lejeune M, Salvado MT, Bosch R, Garcia JF, Jaen J et al. Outcome in Hodgkin's lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res 2005; 11: 1467–1473.

    Google Scholar 

  32. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441: 235–238.

    CAS  Google Scholar 

  33. Beyer M, Kochanek M, Giese T, Endl E, Weihrauch MR, Knolle PA et al. In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma. Blood 2006; 107: 3940–3949.

    CAS  Google Scholar 

  34. Feyler S, von Lilienfeld-Toal M, Jarmin S, Marles L, Rawstron A, Ashcroft AJ et al. CD4(+)CD25(+)FoxP3(+) regulatory T cells are increased whilst CD3(+)CD4(−)CD8(−)alphabetaTCR(+) Double Negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden. Br J Haematol 2009; 144: 686–695.

    Google Scholar 

  35. Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001; 98: 210–216.

    CAS  Google Scholar 

  36. LeBlanc R, Hideshima T, Catley LP, Shringarpure R, Burger R, Mitsiades N et al. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. Blood 2004; 103: 1787–1790.

    CAS  Google Scholar 

  37. Corral LG, Kaplan G . Immunomodulation by thalidomide and thalidomide analogues. Ann Rheum Dis 1999; 58 (Suppl 1): 1107–1113.

    Google Scholar 

  38. Schafer PH, Gandhi AK, Loveland MA, Chen RS, Man HW, Schnetkamp PP et al. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J Pharmacol Exp Therap 2003; 305: 1222–1232.

    CAS  Google Scholar 

  39. Dredge K, Marriott JB, Todryk SM, Muller GW, Chen R, Stirling DI et al. Protective antitumor immunity induced by a costimulatory thalidomide analog in conjunction with whole tumor cell vaccination is mediated by increased Th1-type immunity. J Immunol 2002; 168: 4914–4919.

    CAS  Google Scholar 

  40. Study CC-4047-1398/142: A Phase-1, Single-blind, placebo controlled, Ascending Single Oral Dose, Safety, Tolerability, Pharmakokinetic and Pharmacodynamic Study in Healthy Male Subjects. Pomalidomide Investigators’ Brochure, Celgene Corporation 2008; version 11: 1–164.

  41. Lu J, Palmer BD, Kestell P, Browett P, Baguley BC, Muller G et al. Thalidomide metabolites in mice and patients with multiple myeloma. Clin Cancer Res 2003; 9: 1680–1688.

    CAS  Google Scholar 

  42. Quach H, Ritchie D, Neeson P, Tai T, Tainton K, Lynch K et al. Lymphoid subsets and regulatory T cell profiles in patients with relapsed multiple myeloma in a subset of patients enrolled in the REVLITE trial [abstract]. Haematology Society of Australia and New Zealand Annual Scientific Meeting, Perth, Australia 2008.

  43. Schafer P, Gandhi AK, Zhang L, Kang J, Capone L, Bartlett JB . Opposing Effects of Dexamethasone on Lenalidomide Activity in Multiple Myeloma: Additive/Synergistic Effects on Anti-Proliferative Activity on Myeloma Cells and Antagonistic Effects on Immune Function [abstract]. Blood 2008; 112: 2761a.

    Google Scholar 

  44. Quach H, Hsu A, Ritchie D, Neeson P, Lynch K, Harrison S et al. In Vivo Antagonistic Effects of Dexamethasone on Lenalidomide-Induced NK cell Activation [abstract]. 51st Annual Meeting of the American Society of Hematology New Orleans, LA 2009: Abstract 1639.

  45. Payvandi F, Wu L, Naziruddin SD, Haley M, Parton A, Schafer PH et al. Immunomodulatory drugs (IMiDs) increase the production of IL-2 from stimulated T cells by increasing PKC-theta activation and enhancing the DNA-binding activity of AP-1 but not NF-kappaB, OCT-1, or NF-AT. J Interferon Cytokine Res 2005; 25: 604–616.

    CAS  Google Scholar 

  46. Hayashi T, Hideshima T, Akiyama M, Podar K, Yasui H, Raje N et al. Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol 2005; 128: 192–203.

    CAS  Google Scholar 

  47. Gandhi AK, Rogovitz A, Lopez-Girona A, Mendy D, Peter HS . Stimulation of T cells by Lenalidomide Involves Putative Lenalidomide Binding Protein Cd3-Epsilon-Associated Protein and GDP-Mannose Pyrophosphorylase a [abstract]. Blood 2008; 112: 2606a.

    Google Scholar 

  48. Galustian C, Meyer B, Labarthe MC, Dredge K, Klaschka D, Henry J et al. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol Immunother 2009; 58: 1033–1045.

    CAS  Google Scholar 

  49. Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood 2007; 109: 2708–2717.

    CAS  Google Scholar 

  50. Galustian C, Klaschka D, Labarthe MC, Bartlett JB, Dalgleish AG . The immunomodulatory drug (IMID(R)) CC-4047 enhances the proliferation and anti-tumour fuction of gamma delta T cells. J Immunother 2004; 27: S50.

    Google Scholar 

  51. Kronenberg M . Toward an understanding of NKT cell biology: progress and paradoxes. Ann Rev Immunol 2005; 23: 877–900.

    CAS  Google Scholar 

  52. Fujii S, Shimizu K, Steinman RM, Dhodapkar MV . Detection and activation of human Valpha24+ natural killer T cells using alpha-galactosyl ceramide-pulsed dendritic cells. J Immunolog Methods 2003; 272: 147–159.

    CAS  Google Scholar 

  53. Carnaud C, Lee D, Donnars O, Park SH, Beavis A, Koezuka Y et al. Cutting edge: Cross-talk between cells of the innate immune system: NKT cells rapidly activate NK cells. J Immunol 1999; 163: 4647–4650.

    CAS  Google Scholar 

  54. Wu L, Adams M, Carter T, Chen R, Muller G, Stirling D et al. lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res 2008; 14: 4650–4657.

    CAS  Google Scholar 

  55. Tai YT, Li XF, Catley L, Coffey R, Breitkreutz I, Bae J et al. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer research 2005; 65: 11712–11720.

    CAS  Google Scholar 

  56. Lapalombella R, Yu B, Triantafillou G, Liu Q, Butchar JP, Lozanski G et al. Lenalidomide down-regulates the CD20 antigen and antagonizes direct and antibody-dependent cellular cytotoxicity of rituximab on primary chronic lymphocytic leukemia cells. Blood 2008; 112: 5180–5189.

    CAS  Google Scholar 

  57. Roda JM, Parihar R, Magro C, Nuovo GJ, Tridandapani S, Carson III WE . Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Cancer Res 2006; 66: 517–526.

    CAS  Google Scholar 

  58. Hideshima T, Chauhan D, Hayashi T, Podar K, Akiyama M, Gupta D et al. The biological sequelae of stromal cell-derived factor-1alpha in multiple myeloma. Mol Cancer Therap 2002; 1: 539–544.

    CAS  Google Scholar 

  59. Li ZW, Chen H, Campbell RA, Bonavida B, Berenson JR . NF-kappaB in the pathogenesis and treatment of multiple myeloma. Curr Opin Hematol 2008; 15: 391–399.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  61. Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto K, Libermann TA et al. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 1996; 87: 1104–1112.

    CAS  Google Scholar 

  62. Dankbar B, Padro T, Leo R, Feldmann B, Kropff M, Mesters RM et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 2000; 95: 2630–2636.

    CAS  Google Scholar 

  63. Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT 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.

    CAS  Google Scholar 

  64. Ogata A, Chauhan D, Teoh G, Treon SP, Urashima M, Schlossman RL et al. IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade. J Immunol 1997; 159: 2212–2221.

    CAS  Google Scholar 

  65. Chauhan D, Kharbanda S, Ogata A, Urashima M, Teoh G, Robertson M et al. Interleukin-6 inhibits Fas-induced apoptosis and stress-activated protein kinase activation in multiple myeloma cells. Blood 1997; 89: 227–234.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  67. Uchiyama H, Barut BA, Chauhan D, Cannistra SA, Anderson KC . Characterization of adhesion molecules on human myeloma cell lines. Blood 1992; 80: 2306–2314.

    CAS  Google Scholar 

  68. Mileshkin L, Honemann D, Gambell P, Trivett M, Hayakawa Y, Smyth M et al. Patients with multiple myeloma treated with thalidomide: evaluation of clinical parameters, cytokines, angiogenic markers, mast cells and marrow CD57+ cytotoxic T cells as predictors of outcome. Haematologica 2007; 92: 1075–1082.

    CAS  Google Scholar 

  69. Dredge K, Marriott JB, Macdonald CD, Man HW, Chen R, Muller GW et al. Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer 2002; 87: 1166–1172.

    CAS  Google Scholar 

  70. Price DK, Ando Y, Kruger EA, Weiss M, Figg WD . 5′-OH-thalidomide, a metabolite of thalidomide, inhibits angiogenesis. Ther Drug Monit 2002; 24: 104–110.

    CAS  Google Scholar 

  71. Dredge K, Horsfall R, Robinson SP, Zhang LH, Lu L, Tang Y et al. Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvascular Res 2005; 69: 56–63.

    CAS  Google Scholar 

  72. Costes V, Portier M, Lu ZY, Rossi JF, Bataille R, Klein B . Interleukin-1 in multiple myeloma: producer cells and their role in the control of IL-6 production. BrJ Haematol 1998; 103: 1152–1160.

    CAS  Google Scholar 

  73. Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1306–1311.

    CAS  Google Scholar 

  74. Prince HM, Mileshkin L, Roberts A, Ganju V, Underhill C, Catalano J et al. A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma. Clin Cancer Res 2005; 11: 5504–5514.

    CAS  Google Scholar 

  75. Hinson RM, Williams JA, Shacter E . Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2. Proc Natl Acad Sci USA 1996; 93: 4885–4890.

    CAS  Google Scholar 

  76. Zhang M, Abe Y, Matsushima T, Nishimura J, Nawata H, Muta K . Selective cyclooxygenase 2 inhibitor NS-398 induces apoptosis in myeloma cells via a Bcl-2 independent pathway. Leuk lymphoma 2005; 46: 425–433.

    CAS  Google Scholar 

  77. Payvandi F, Wu L, Haley M, Schafer PH, Zhang LH, Chen RS et al. Immunomodulatory drugs inhibit expression of cyclooxygenase-2 from TNF-alpha, IL-1beta, and LPS-stimulated human PBMC in a partially IL-10-dependent manner. Cell Immunol 2004; 230: 81–88.

    CAS  Google Scholar 

  78. Muller GW, Chen R, Huang SY, Corral LG, Wong LM, Patterson RT et al. Amino-substituted thalidomide analogs: potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett 1999; 9: 1625–1630.

    CAS  Google Scholar 

  79. Akobeng AK, Stokkers PC . Thalidomide and thalidomide analogues for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev, 2009(2): p CD007351.

  80. 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.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  82. Breitkreutz I, Raab MS, Vallet S, Hideshima T, Raje N, Mitsiades C et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia 2008; 22: 1925–1932.

    CAS  Google Scholar 

  83. Rieman DJ, McClung HA, Dodds RA, Hwang SM, Holmes MW, James IE et al. Biosynthesis and processing of cathepsin K in cultured human osteoclasts. Bone 2001; 28: 282–289.

    CAS  Google Scholar 

  84. Anderson G, Gries M, Kurihara N, Honjo T, Anderson J, Donnenberg V et al. Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1. Blood 2006; 107: 3098–3105.

    CAS  Google Scholar 

  85. Heider U, Kaiser M, Muller C, Jakob C, Zavrski I, Schulz CO et al. Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment. Euro J Haematol 2006; 77: 233–238.

    CAS  Google Scholar 

  86. Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai YT et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000; 96: 2943–2950.

    CAS  Google Scholar 

  87. Pellagatti A, Jadersten M, Forsblom AM, Cattan H, Christensson B, Emanuelsson EK et al. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc Natl Acad Sci USA 2007; 104: 11406–11411.

    CAS  Google Scholar 

  88. Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH, Ballard DW . Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control. Proc Natl Acad Sci USA 1997; 94: 10057–10062.

    CAS  Google Scholar 

  89. Kreuz S, Siegmund D, Scheurich P, Wajant H . NF-kappaB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Mol Cell Biol 2001; 21: 3964–3973.

    CAS  Google Scholar 

  90. Mitsiades N, Mitsiades CS, Poulaki V, Anderson KC, Treon SP . Intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human multiple myeloma cells. Blood 2002; 99: 2162–2171.

    CAS  Google Scholar 

  91. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin Jr AS . NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science (New York, NY) 1998; 281: 1680–1683.

    CAS  Google Scholar 

  92. Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, Hideshima T et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99: 4525–4530.

    CAS  Google Scholar 

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Acknowledgements

We acknowledge the insightful comments and critical review of the article by A/Prof S Opat, P Schafer, and Dr H Tran. Dr Hang Quach received funding support from the Vincent Fairfax Scholarship (Royal Australasian College of Physicians), and the Peter MacCallum Foundation (Morris Family Grant).

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  1. Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Victoria, Australia

    H Quach, D Ritchie, S Harrison & H M Prince

  2. Department of Medicine, University of Melbourne, Victoria, Australia

    H Quach, D Ritchie & H M Prince

  3. Haematology Immunology Translational Research Laboratory, Peter MacCallum Cancer Centre, Victoria, Australia

    H Quach, D Ritchie, P Neeson, S Harrison & H M Prince

  4. Division of Hematology-Oncology, Mayo Clinic, Arizona, USA

    A K Stewart

  5. Cancer Immunology Research, Peter MacCallum Cancer Centre, Victoria, Australia

    M J Smyth

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Quach, H., Ritchie, D., Stewart, A. et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia 24, 22–32 (2010). https://doi.org/10.1038/leu.2009.236

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