• 1
    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.
  • 2
    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.
  • 3
    Einsele H, Liebisch P, Langer C, et al. Velcade, intravenous cyclophosphamide and dexamethasone (VCD) induction for previously untreated multiple myeloma (German DSMM XIa Trial). ASH Annual Meeting Abstracts. 2009;114:59a. Abstract 131.
  • 4
    Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085.
  • 5
    Mateos MV, Oriol A, Martinez-Lopez J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010;11:934-941.
  • 6
    Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011;118:5752-5758.
  • 7
    Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28:5101-5109.
  • 8
    Rosinol L, Oriol A, Teruel AI, et al;rograma para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012;120:1589-1596.
  • 9
    San Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013;31:448-455.
  • 10
    Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 Trial. J Clin Oncol. 2012;30:2946-2955.
  • 11
    Adams J. Proteasome inhibition in cancer: development of PS-341. Semin Oncol. 2001;28:613-619.
  • 12
    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.
  • 13
    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.
  • 14
    Zwickl P, Voges D, Baumeister W. The proteasome: a macromolecular assembly designed for controlled proteolysis. Philos Trans R Soc Lond B Biol Sci. 1999;354:1501-1511.
  • 15
    Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649-683.
  • 16
    Richardson PG, Hideshima T, Anderson KC. Bortezomib (PS-341): a novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancers. Cancer Control. 2003;10:361-369.
  • 17
    Ondrey FG, Dong G, Sunwoo J, et al. Constitutive activation of transcription factors NF-(kappa)B, AP-1, and NF-IL6 in human head and neck squamous cell carcinoma cell lines that express pro-inflammatory and pro-angiogenic cytokines. Mol Carcinog. 1999;26:119-129.
  • 18
    Berenson JR, Ma HM, Vescio R. The role of nuclear factor-kappaB in the biology and treatment of multiple myeloma. Semin Oncol. 2001;28:626-633.
  • 19
    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.
  • 20
    Wang X, Luo H, Chen H, Duguid W, Wu J. Role of proteasomes in T cell activation and proliferation. J Immunol. 1998;160:788-801.
  • 21
    Wu J. On the role of proteasomes in cell biology and proteasome inhibition as a novel frontier in the development of immunosuppressants. Am J Transplant. 2002;2:904-912.
  • 22
    Orlowski RZ, Small GW, Shi YY. Evidence that inhibition of p44/42 mitogen-activated protein kinase signaling is a factor in proteasome inhibitor-mediated apoptosis. J Biol Chem. 2002;277:27864-27871.
  • 23
    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.
  • 24
    Sunwoo JB, Chen Z, Dong G, et al. Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res. 2001;7:1419-1428.
  • 25
    Terpos E, Dimopoulos MA. Myeloma bone disease: pathophysiology and management. Ann Oncol. 2005;16:1223-1231.
  • 26
    Roodman GD. Pathogenesis of myeloma bone disease. Leukemia. 2009;23:435-441.
  • 27
    Sezer O. Myeloma bone disease: recent advances in biology, diagnosis, and treatment. Oncologist. 2009;14:276-283.
  • 28
    Garrett IR, Chen D, Gutierrez G, et al. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest. 2003;111:1771-1782.
  • 29
    Zavrski I, Krebbel H, Wildemann B, et al. Proteasome inhibitors abrogate osteoclast differentiation and osteoclast function. Biochem Biophys Res Commun. 2005;333:200-205.
  • 30
    von Metzler I, Krebbel H, Hecht M, et al. Bortezomib inhibits human osteoclastogenesis. Leukemia. 2007;21:2025-2034.
  • 31
    Boissy P, Andersen TL, Lund T, Kupisiewicz K, Plesner T, Delaisse JM. Pulse treatment with the proteasome inhibitor bortezomib inhibits osteoclast resorptive activity in clinically relevant conditions. Leuk Res. 2008;32:1661-1668.
  • 32
    Pennisi A, Li X, Ling W, Khan S, Zangari M, Yaccoby S. The proteasome inhibitor, bortezomib suppresses primary myeloma and stimulates bone formation in myelomatous and nonmyelomatous bones in vivo. Am J Hematol. 2009;84:6-14.
  • 33
    Breitkreutz I, Raab MS, Vallet S, et al. Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. Leukemia. 2008;22:1925-1932.
  • 34
    Hongming H, Jian H. Bortezomib inhibits maturation and function of osteoclasts from PBMCs of patients with multiple myeloma by downregulating TRAF6. Leuk Res. 2009;33:115-122.
  • 35
    Giuliani N, Morandi F, Tagliaferri S, et al. The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood. 2007;110:334-338.
  • 36
    Mukherjee S, Raje N, Schoonmaker JA, et al. Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice. J Clin Invest. 2008;118:491-504.
  • 37
    Munemasa S, Sakai A, Kuroda Y, et al. Osteoprogenitor differentiation is not affected by immunomodulatory thalidomide analogs but is promoted by low bortezomib concentration, while both agents suppress osteoclast differentiation. Int J Oncol. 2008;33:129-136.
  • 38
    De Matteo M, Brunetti AE, Maiorano E, Cafforio P, Dammacco F, Silvestris F. Constitutive down-regulation of osterix in osteoblasts from myeloma patients: in vitro effect of bortezomib and lenalidomide. Leuk Res. 2010;34:243-249.
  • 39
    Oyajobi BO, Garrett IR, Gupta A, et al. Stimulation of new bone formation by the proteasome inhibitor, bortezomib: implications for myeloma bone disease. Br J Haematol. 2007;139:434-438.
  • 40
    Qiang YW, Hu B, Chen Y, et al. Bortezomib induces osteoblast differentiation via Wnt-independent activation of beta-catenin/TCF signaling. Blood. 2009;113:4319-4330.
  • 41
    Eda H, Aoki K, Kato S, et al. The proteasome inhibitor bortezomib inhibits FGF-2-induced reduction of TAZ levels in osteoblast-like cells. Eur J Haematol. 2010;85:68-75.
  • 42
    Hurchla MA, Garcia-Gomez A, Hornick MC, et al. The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects. Leukemia. 2013;27:430-440.
  • 43
    Zangari M, Esseltine D, Lee CK, et al. Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. Br J Haematol. 2005;131:71-73.
  • 44
    Heider U, Kaiser M, Muller C, et al. Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment. Eur J Haematol. 2006;77:233-238.
  • 45
    Terpos E, Heath DJ, Rahemtulla A, et al. Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma. Br J Haematol. 2006;135:688-692.
  • 46
    Terpos E, Kastritis E, Roussou M, et al. The combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide is an effective regimen for relapsed/refractory myeloma and is associated with improvement of abnormal bone metabolism and angiogenesis. Leukemia. 2008;22:2247-2256.
  • 47
    Ozaki S, Tanaka O, Fujii S, et al. Therapy with bortezomib plus dexamethasone induces osteoblast activation in responsive patients with multiple myeloma. Int J Hematol. 2007;86:180-185.
  • 48
    Terpos E, Christoulas D, Kastritis E, et al. The addition of bortezomib to the combination of lenalidomide and dexamethasone increases bone formation in relapsed/refractory myeloma: a prospective study in 91 patients. ASH Annual Meeting Abstracts. 2009;114:721a. Abstract 1815.
  • 49
    Uy GL, Trivedi R, Peles S, et al. Bortezomib inhibits osteoclast activity in patients with multiple myeloma. Clin Lymphoma Myeloma. 2007;7:587-589.
  • 50
    Terpos E, Christoulas D, Kokkoris P, et al. Increased bone mineral density in a subset of patients with relapsed multiple myeloma who received the combination of bortezomib, dexamethasone and zoledronic acid. Ann Oncol. 2010;21:1561-1562.
  • 51
    Lund T, Soe K, Abildgaard N, et al. First-line treatment with bortezomib rapidly stimulates both osteoblast activity and bone matrix deposition in patients with multiple myeloma, and stimulates osteoblast proliferation and differentiation in vitro. Eur J Haematol. 2010;85:290-299.
  • 52
    Zangari M, Yaccoby S, Pappas L, et al. A prospective evaluation of the biochemical, metabolic, hormonal and structural bone changes associated with bortezomib response in multiple myeloma patients. Haematologica. 2011;96:333-336.
  • 53
    Delforge M, Terpos E, Richardson PG, et al. Fewer bone disease events, improvement in bone remodeling, and evidence of bone healing with bortezomib plus melphalan-prednisone vs. melphalan-prednisone in the phase III VISTA trial in multiple myeloma. Eur J Haematol. 2011;86:372-384.
  • 54
    Lee SE, Min CK, Yahng SA, et al. Bone scan images reveal increased osteoblastic function after bortezomib treatment in patients with multiple myeloma. Eur J Haematol. 2011;86:83-86.