Advertisement
Review Article| Volume 21, ISSUE 6, P1007-1034, December 2007

The Role of the Bone Marrow Microenvironment in the Pathophysiology of Myeloma and Its Significance in the Development of More Effective Therapies

      Multiple myeloma (MM) is viewed as a prototypic disease state for the study of how neoplastic cells interact with their local bone marrow (BM) microenvironment. This interaction reflects not only the osteotropic clinical behavior of MM and the clinical impact of the lytic bone lesions caused by its tumor cells but also underlines the broadly accepted notion that nonneoplastic cells of the BM can attenuate the activity of cytotoxic chemotherapy and glucocorticoids. This article summarizes the recent progress in characterization, at the molecular and cellular levels, of how the BM milieu interacts with MM cells and modifies their biologic behavior.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.

      Subscribe:

      Subscribe to Hematology/Oncology Clinics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Mitsiades C.S.
        • Koutsilieris M.
        Molecular biology and cellular physiology of refractoriness to androgen ablation therapy in advanced prostate cancer.
        Expert Opin Investig Drugs. 2001; 10: 1099-1115
        • van Kempen L.C.
        • Ruiter D.J.
        • van Muijen G.N.
        • et al.
        The tumor microenvironment: a critical determinant of neoplastic evolution.
        Eur J Cell Biol. 2003; 82: 539-548
        • Munk Pedersen I.
        • Reed J.
        Microenvironmental interactions and survival of CLL B-cells.
        Leuk Lymphoma. 2004; 45: 2365-2372
        • Zhou J.
        • Mauerer K.
        • Farina L.
        • et al.
        The role of the tumor microenvironment in hematological malignancies and implication for therapy.
        Front Biosci. 2005; 10: 1581-1596
        • Paget S.
        The distribution of secondary growths in cancer of the breast.
        Lancet. 1889; 1: 571-573
        • Bataille R.
        • Harousseau J.L.
        Multiple myeloma.
        N Engl J Med. 1997; 336: 1657-1664
        • Mitsiades C.S.
        • Mitsiades N.
        • Munshi N.C.
        • et al.
        Focus on multiple myeloma.
        Cancer Cell. 2004; 6: 439-444
        • Chauhan D.
        • Uchiyama H.
        • Urashima M.
        • et al.
        Regulation of interleukin 6 in multiple myeloma and bone marrow stromal cells.
        Stem Cells. 1995; 13: 35-39
        • Chauhan D.
        • Uchiyama H.
        • Akbarali Y.
        • 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
        • 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
        • Damiano J.S.
        • Cress A.E.
        • Hazlehurst L.A.
        • et al.
        Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines.
        Blood. 1999; 93: 1658-1667
        • Akiyama M.
        • Hideshima T.
        • Hayashi T.
        • et al.
        Cytokines modulate telomerase activity in a human multiple myeloma cell line.
        Cancer Res. 2002; 62: 3876-3882
        • Chauhan D.
        • Li G.
        • Hideshima T.
        • et al.
        Blockade of ubiquitin-conjugating enzyme CDC34 enhances anti-myeloma activity of bortezomib/proteasome inhibitor PS-341.
        Oncogene. 2004; 23: 3597-3602
        • 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
        • Freund G.G.
        • Kulas D.T.
        • Mooney R.A.
        Insulin and IGF-1 increase mitogenesis and glucose metabolism in the multiple myeloma cell line, RPMI 8226.
        J Immunol. 1993; 151: 1811-1820
        • Mitsiades C.S.
        • Mitsiades N.S.
        • McMullan C.J.
        • et al.
        Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors.
        Cancer Cell. 2004; 5: 221-230
        • Vanderkerken K.
        • Asosingh K.
        • Braet F.
        • et al.
        Insulin-like growth factor-1 acts as a chemoattractant factor for 5T2 multiple myeloma cells.
        Blood. 1999; 93: 235-241
        • Asosingh K.
        • Gunthert U.
        • Bakkus M.H.
        • et al.
        In vivo induction of insulin-like growth factor-I receptor and CD44v6 confers homing and adhesion to murine multiple myeloma cells.
        Cancer Res. 2000; 60: 3096-3104
        • Podar K.
        • Anderson K.C.
        The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications.
        Blood. 2005; 105: 1383-1395
        • Podar K.
        • Catley L.P.
        • Tai Y.T.
        • et al.
        GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment.
        Blood. 2004; 103: 3474-3479
        • Podar K.
        • Tai Y.T.
        • Davies F.E.
        • et al.
        Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration.
        Blood. 2001; 98: 428-435
        • Podar K.
        • Tai Y.T.
        • Lin B.K.
        • et al.
        Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with beta 1 integrin- and phosphatidylinositol 3-kinase-dependent PKC alpha activation.
        J Biol Chem. 2002; 277: 7875-7881
        • Hideshima T.
        • Chauhan D.
        • Hayashi T.
        • et al.
        The biological sequelae of stromal cell-derived factor-1alpha in multiple myeloma.
        Mol Cancer Ther. 2002; 1: 539-544
        • Otsuki T.
        • Yamada O.
        • Yata K.
        • et al.
        Expression of fibroblast growth factor and FGF-receptor family genes in human myeloma cells, including lines possessing t(4;14)(q16.3;q32. 3) and FGFR3 translocation.
        Int J Oncol. 1999; 15: 1205-1212
        • 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
        • Novak A.J.
        • Darce J.R.
        • Arendt B.K.
        • et al.
        Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival.
        Blood. 2004; 103: 689-694
        • Moreaux J.
        • Legouffe E.
        • Jourdan E.
        • et al.
        BAFF and APRIL protect myeloma cells from apoptosis induced by IL-6 deprivation and dexamethasone.
        Blood. 2004; 103: 3148-3157
        • Tai Y.T.
        • Li X.F.
        • Breitkreutz I.
        • et al.
        Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment.
        Cancer Res. 2006; 66: 6675-6682
        • Hideshima T.
        • Anderson K.C.
        Molecular mechanisms of novel therapeutic approaches for multiple myeloma.
        Nat Rev Cancer. 2002; 2: 927-937
        • Hideshima T.
        • Bergsagel P.L.
        • Kuehl W.M.
        • et al.
        Advances in biology of multiple myeloma: clinical applications.
        Blood. 2004; 104: 607-618
        • Kuehl W.M.
        • Bergsagel P.L.
        Multiple myeloma: evolving genetic events and host interactions.
        Nat Rev Cancer. 2002; 2: 175-187
        • Roodman G.D.
        Pathogenesis of myeloma bone disease.
        Blood Cells Mol Dis. 2004; 32: 290-292
        • Roodman G.D.
        Myeloma bone disease: pathogenesis and treatment.
        Oncology (Williston Park). 2005; 19 (986): 983-984
        • Ribatti D.
        • Nico B.
        • Vacca A.
        Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma.
        Oncogene. 2006; 25: 4257-4266
        • Ribatti D.
        • Scavelli C.
        • Roccaro A.M.
        • et al.
        Hematopoietic cancer and angiogenesis.
        Stem Cells Dev. 2004; 13: 484-495
        • Werts E.D.
        • DeGowin R.L.
        • Knapp S.K.
        • et al.
        Characterization of marrow stromal (fibroblastoid) cells and their association with erythropoiesis.
        Exp Hematol. 1980; 8: 423-433
        • Greenberg B.R.
        • Wilson F.Z.
        • Woo L.
        Granulopoietic effects of human bone marrow fibroblastic cells and abnormalities in the “granulopoietic microenvironment”.
        Blood. 1981; 58: 557-564
        • Reincke U.
        • Hannon E.C.
        • Rosenblatt M.
        • et al.
        Proliferative capacity of murine hematopoietic stem cells in vitro.
        Science. 1982; 215: 1619-1622
        • Kaneko S.
        • Motomura S.
        • Ibayashi H.
        Differentiation of human bone marrow-derived fibroblastoid colony forming cells (CFU-F) and their roles in haemopoiesis in vitro.
        Br J Haematol. 1982; 51: 217-225
        • Kawano M.
        • Hirano T.
        • Matsuda T.
        • et al.
        Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas.
        Nature. 1988; 332: 83-85
        • Kawano M.
        • Kuramoto A.
        • Hirano T.
        • et al.
        Cytokines as autocrine growth factors in malignancies.
        Cancer Surv. 1989; 8: 905-919
        • Kawano M.
        • Tanaka H.
        • Ishikawa H.
        • et al.
        Interleukin-1 accelerates autocrine growth of myeloma cells through interleukin-6 in human myeloma.
        Blood. 1989; 73: 2145-2148
        • Shimizu S.
        • Yoshioka R.
        • Hirose Y.
        • et al.
        Establishment of two interleukin 6 (B cell stimulatory factor 2/interferon beta 2)-dependent human bone marrow-derived myeloma cell lines.
        J Exp Med. 1989; 169: 339-344
        • Klein B.
        • Zhang X.G.
        • Jourdan M.
        • et al.
        Interleukin-6 is the central tumor growth factor in vitro and in vivo in multiple myeloma.
        Eur Cytokine Netw. 1990; 1: 193-201
        • Barut B.A.
        • Zon L.I.
        • Cochran M.K.
        • et al.
        Role of interleukin 6 in the growth of myeloma-derived cell lines.
        Leuk Res. 1992; 16: 951-959
        • Urashima M.
        • Chauhan D.
        • Uchiyama H.
        • et al.
        CD40 ligand triggered interleukin-6 secretion in multiple myeloma.
        Blood. 1995; 85: 1903-1912
        • Urashima M.
        • Ogata A.
        • Chauhan D.
        • et al.
        Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein.
        Blood. 1996; 88: 2219-2227
        • Chauhan D.
        • Kharbanda S.
        • Ogata A.
        • et al.
        Interleukin-6 inhibits Fas-induced apoptosis and stress-activated protein kinase activation in multiple myeloma cells.
        Blood. 1997; 89: 227-234
        • Uchiyama H.
        • Barut B.A.
        • Chauhan D.
        • et al.
        Characterization of adhesion molecules on human myeloma cell lines.
        Blood. 1992; 80: 2306-2314
        • Uchiyama H.
        • Barut B.A.
        • Mohrbacher A.F.
        • et al.
        Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion.
        Blood. 1993; 82: 3712-3720
        • Nefedova Y.
        • Landowski T.H.
        • Dalton W.S.
        Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms.
        Leukemia. 2003; 17: 1175-1182
        • Folkman J.
        Role of angiogenesis in tumor growth and metastasis.
        Semin Oncol. 2002; 29: 15-18
        • Naumov G.N.
        • Bender E.
        • Zurakowski D.
        • et al.
        A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype.
        J Natl Cancer Inst. 2006; 98: 316-325
        • Nawab R.A.
        • Azar H.A.
        The laboratory diagnosis of plasma cell myeloma and related disorders.
        Orthop Clin North Am. 1979; 10: 391-404
        • Rajkumar S.V.
        • Kyle R.A.
        Angiogenesis in multiple myeloma.
        Semin Oncol. 2001; 28: 560-564
        • Roccaro A.M.
        • Hideshima T.
        • Raje N.
        • et al.
        Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells.
        Cancer Res. 2006; 66: 184-191
        • Singhal S.
        • Mehta J.
        • Desikan R.
        • et al.
        Antitumor activity of thalidomide in refractory multiple myeloma.
        N Engl J Med. 1999; 341: 1565-1571
        • D'Amato R.J.
        • Loughnan M.S.
        • Flynn E.
        • et al.
        Thalidomide is an inhibitor of angiogenesis.
        Proc Natl Acad Sci U S A. 1994; 91: 4082-4085
        • Vacca A.
        • Scavelli C.
        • Montefusco V.
        • et al.
        Thalidomide downregulates angiogenic genes in bone marrow endothelial cells of patients with active multiple myeloma.
        J Clin Oncol. 2005; 23: 5334-5346
        • Vacca A.
        • Ria R.
        • Semeraro F.
        • et al.
        Endothelial cells in the bone marrow of patients with multiple myeloma.
        Blood. 2003; 102: 3340-3348
        • Anderson K.C.
        Moving disease biology from the lab to the clinic.
        Cancer. 2003; 97: 796-801
        • Dar A.
        • Goichberg P.
        • Shinder V.
        • et al.
        Chemokine receptor CXCR4-dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells.
        Nat Immunol. 2005; 6: 1038-1046
        • Menu E.
        • Asosingh K.
        • Indraccolo S.
        • et al.
        The involvement of stromal derived factor 1alpha in homing and progression of multiple myeloma in the 5TMM model.
        Haematologica. 2006; 91: 605-612
        • Gupta D.
        • Treon S.P.
        • 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
        • Tai Y.T.
        • Podar K.
        • Gupta D.
        • et al.
        CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells.
        Blood. 2002; 99: 1419-1427
        • Baudino T.A.
        • McKay C.
        • Pendeville-Samain H.
        • et al.
        c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression.
        Genes Dev. 2002; 16: 2530-2543
        • Oh J.S.
        • Kucab J.E.
        • Bushel P.R.
        • et al.
        Insulin-like growth factor-1 inscribes a gene expression profile for angiogenic factors and cancer progression in breast epithelial cells.
        Neoplasia. 2002; 4: 204-217
        • Poulaki V.
        • Mitsiades C.S.
        • McMullan C.
        • et al.
        Regulation of vascular endothelial growth factor expression by insulin-like growth factor I in thyroid carcinomas.
        J Clin Endocrinol Metab. 2003; 88: 5392-5398
        • Tanaka Y.
        • Nakayamada S.
        • Okada Y.
        Osteoblasts and osteoclasts in bone remodeling and inflammation.
        Curr Drug Targets Inflamm Allergy. 2005; 4: 325-328
        • Taube T.
        • Beneton M.N.
        • McCloskey E.V.
        • et al.
        Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption.
        Eur J Haematol. 1992; 49: 192-198
        • Bataille R.
        • Chappard D.
        • Marcelli C.
        • et al.
        Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease.
        J Clin Oncol. 1989; 7: 1909-1914
        • Ashcroft A.J.
        • Davies F.E.
        • Morgan G.J.
        Aetiology of bone disease and the role of bisphosphonates in multiple myeloma.
        Lancet Oncol. 2003; 4: 284-292
        • Sezer O.
        • Heider U.
        • Zavrski I.
        • et al.
        RANK ligand and osteoprotegerin in myeloma bone disease.
        Blood. 2003; 101: 2094-2098
        • Hofbauer L.C.
        • Schoppet M.
        Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases.
        JAMA. 2004; 292: 490-495
        • Roux S.
        • Meignin V.
        • Quillard J.
        • et al.
        RANK (receptor activator of nuclear factor-kappaB) and RANKL expression in multiple myeloma.
        Br J Haematol. 2002; 117: 86-92
        • Pearse R.N.
        • Sordillo E.M.
        • Yaccoby S.
        • et al.
        Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression.
        Proc Natl Acad Sci U S A. 2001; 98: 11581-11586
        • Lacey D.L.
        • Timms E.
        • Tan H.L.
        • et al.
        Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.
        Cell. 1998; 93: 165-176
        • Kawano M.
        • Yamamoto I.
        • Iwato K.
        • et al.
        Interleukin-1 beta rather than lymphotoxin as the major bone resorbing activity in human multiple myeloma.
        Blood. 1989; 73: 1646-1649
        • Mundy G.R.
        Hypercalcemic factors other than parathyroid hormone-related protein.
        Endocrinol Metab Clin North Am. 1989; 18: 795-806
        • Nakamura M.
        • Merchav S.
        • Carter A.
        • et al.
        Expression of a novel 3.5-kb macrophage colony-stimulating factor transcript in human myeloma cells.
        J Immunol. 1989; 143: 3543-3547
        • Bataille R.
        • Chappard D.
        • Klein B.
        The critical role of interleukin-6, interleukin-1B and macrophage colony-stimulating factor in the pathogenesis of bone lesions in multiple myeloma.
        Int J Clin Lab Res. 1992; 21: 283-287
        • Nakagawa M.
        • Kaneda T.
        • Arakawa T.
        • et al.
        Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts.
        FEBS Lett. 2000; 473: 161-164
        • Niida S.
        • Kaku M.
        • Amano H.
        • et al.
        Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption.
        J Exp Med. 1999; 190: 293-298
        • Han J.H.
        • Choi S.J.
        • Kurihara N.
        • et al.
        Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand.
        Blood. 2001; 97: 3349-3353
        • Choi S.J.
        • Cruz J.C.
        • Craig F.
        • et al.
        Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma.
        Blood. 2000; 96: 671-675
        • Callander N.S.
        • Roodman G.D.
        Myeloma bone disease.
        Semin Hematol. 2001; 38: 276-285
        • Choi S.J.
        • Oba Y.
        • Gazitt Y.
        • et al.
        Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease.
        J Clin Invest. 2001; 108: 1833-1841
        • Oba Y.
        • Lee J.W.
        • Ehrlich L.A.
        • et al.
        MIP-1alpha utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells.
        Exp Hematol. 2005; 33: 272-278
        • Urashima M.
        • Ogata A.
        • Chauhan D.
        • et al.
        Transforming growth factor-beta1: differential effects on multiple myeloma versus normal B cells.
        Blood. 1996; 87: 1928-1938
        • Franchimont N.
        • Rydziel S.
        • Canalis E.
        Transforming growth factor-beta increases interleukin-6 transcripts in osteoblasts.
        Bone. 2000; 26: 249-253
        • Ducy P.
        • Zhang R.
        • Geoffroy V.
        • et al.
        Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation.
        Cell. 1997; 89: 747-754
        • Karsenty G.
        • Ducy P.
        • Starbuck M.
        • et al.
        Cbfa1 as a regulator of osteoblast differentiation and function.
        Bone. 1999; 25: 107-108
        • Giuliani N.
        • Colla S.
        • Morandi F.
        • et al.
        Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation.
        Blood. 2005; 106: 2472-2483
        • Tian E.
        • Zhan F.
        • Walker R.
        • et al.
        The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma.
        N Engl J Med. 2003; 349: 2483-2494
        • Oshima T.
        • Abe M.
        • Asano J.
        • et al.
        Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2.
        Blood. 2005; 106: 3160-3165
        • Lee J.W.
        • Chung H.Y.
        • Ehrlich L.A.
        • et al.
        IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells.
        Blood. 2004; 103: 2308-2315
        • Ehrlich L.A.
        • Chung H.Y.
        • Ghobrial I.
        • et al.
        IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma.
        Blood. 2005; 106: 1407-1414
        • Standal T.
        • Abildgaard N.
        • Fagerli U.M.
        • et al.
        HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma.
        Blood. 2007; 109: 3024-3030
        • Mitsiades C.S.
        • Mitsiades N.S.
        • Munshi N.C.
        • et al.
        The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: interplay of growth factors, their receptors and stromal interactions.
        Eur J Cancer. 2006; 42: 1564-1573
        • Murray E.J.
        • Bentley G.V.
        • Grisanti M.S.
        • et al.
        The ubiquitin-proteasome system and cellular proliferation and regulation in osteoblastic cells.
        Exp Cell Res. 1998; 242: 460-469
        • Garrett I.R.
        • 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
        • 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
        • Zangari M.
        • Yaccoby S.
        • Cavallo F.
        • et al.
        Response to bortezomib and activation of osteoblasts in multiple myeloma.
        Clin Lymphoma Myeloma. 2006; 7: 109-114
        • Shimazaki C.
        • Uchida R.
        • Nakano S.
        • et al.
        High serum bone-specific alkaline phosphatase level after bortezomib-combined therapy in refractory multiple myeloma: possible role of bortezomib on osteoblast differentiation.
        Leukemia. 2005; 19: 1102-1103
        • Knobloch J.
        • Shaughnessy Jr., J.D.
        • Ruther U.
        Thalidomide induces limb deformities by perturbing the Bmp/Dkk1/Wnt signaling pathway.
        FASEB J. 2007; 21: 1410-1421
        • Bergsagel P.L.
        • Masellis Smith A.
        • Belch A.R.
        • et al.
        The blood B-cells and bone marrow plasma cells in patients with multiple myeloma share identical IgH rearrangements.
        Curr Top Microbiol Immunol. 1995; 194: 17-24
        • Bergsagel P.L.
        • Smith A.M.
        • Szczepek A.
        • et al.
        In multiple myeloma, clonotypic B lymphocytes are detectable among CD19+ peripheral blood cells expressing CD38, CD56, and monotypic Ig light chain.
        Blood. 1995; 85: 436-447
        • Kiel K.
        • Cremer F.W.
        • Rottenburger C.
        • et al.
        Analysis of circulating tumor cells in patients with multiple myeloma during the course of high-dose therapy with peripheral blood stem cell transplantation.
        Bone Marrow Transplant. 1999; 23: 1019-1027
        • Zojer N.
        • Schuster-Kolbe J.
        • Assmann I.
        • et al.
        Chromosomal aberrations are shared by malignant plasma cells and a small fraction of circulating CD19+ cells in patients with myeloma and monoclonal gammopathy of undetermined significance.
        Br J Haematol. 2002; 117: 852-859
        • Rasmussen T.
        • Lodahl M.
        • Hancke S.
        • et al.
        In multiple myeloma clonotypic CD38-/CD19+/CD27+ memory B cells recirculate through bone marrow, peripheral blood and lymph nodes.
        Leuk Lymphoma. 2004; 45: 1413-1417
        • Lin B.
        • Podar K.
        • Gupta D.
        • et al.
        The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment.
        Cancer Res. 2002; 62: 5019-5026
        • Hov H.
        • Holt R.U.
        • Ro T.B.
        • et al.
        A selective c-met inhibitor blocks an autocrine hepatocyte growth factor growth loop in ANBL-6 cells and prevents migration and adhesion of myeloma cells.
        Clin Cancer Res. 2004; 10: 6686-6694
        • Asosingh K.
        • De Raeve H.
        • Croucher P.
        • et al.
        In vivo homing and differentiation characteristics of mature (CD45-) and immature (CD45+) 5T multiple myeloma cells.
        Exp Hematol. 2001; 29: 77-84
        • Tai Y.T.
        • Podar K.
        • Catley L.
        • et al.
        Insulin-like growth factor-1 induces adhesion and migration in human multiple myeloma cells via activation of beta1-integrin and phosphatidylinositol 3′-kinase/AKT signaling.
        Cancer Res. 2003; 63: 5850-5858
        • Anderson K.
        Advances in the biology of multiple myeloma: therapeutic applications.
        Semin Oncol. 1999; 26: 10-22
        • Kim I.
        • Uchiyama H.
        • Chauhan D.
        • et al.
        Cell surface expression and functional significance of adhesion molecules on human myeloma-derived cell lines.
        Br J Haematol. 1994; 87: 483-493
        • Asosingh K.
        Migration, adhesion and differentiation of malignant plasma cells in the 5T murine model of myeloma.
        Verh K Acad Geneeskd Belg. 2003; 65: 127-134
        • Asosingh K.
        • Gunthert U.
        • De Raeve H.
        • et al.
        A unique pathway in the homing of murine multiple myeloma cells: CD44v10 mediates binding to bone marrow endothelium.
        Cancer Res. 2001; 61: 2862-2865
        • Landowski T.H.
        • Olashaw N.E.
        • Agrawal D.
        • et al.
        Cell adhesion-mediated drug resistance (CAM-DR) is associated with activation of NF-kappa B (RelB/p50) in myeloma cells.
        Oncogene. 2003; 22: 2417-2421
        • Damiano J.S.
        • Dalton W.S.
        Integrin-mediated drug resistance in multiple myeloma.
        Leuk Lymphoma. 2000; 38: 71-81
        • Hazlehurst L.A.
        • Damiano J.S.
        • Buyuksal I.
        • et al.
        Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR).
        Oncogene. 2000; 19: 4319-4327
        • Hazlehurst L.A.
        • Enkemann S.A.
        • Beam C.A.
        • et al.
        Genotypic and phenotypic comparisons of de novo and acquired melphalan resistance in an isogenic multiple myeloma cell line model.
        Cancer Res. 2003; 63: 7900-7906
        • Barille S.
        • Akhoundi C.
        • Collette M.
        • et al.
        Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells.
        Blood. 1997; 90: 1649-1655
        • Flomenberg N.
        • DiPersio J.
        • Calandra G.
        Role of CXCR4 chemokine receptor blockade using AMD3100 for mobilization of autologous hematopoietic progenitor cells.
        Acta Haematol. 2005; 114: 198-205
        • Roodman G.D.
        Role of the bone marrow microenvironment in multiple myeloma.
        J Bone Miner Res. 2002; 17: 1921-1925
        • Koutsilieris M.
        • Mitsiades C.
        • Lembessis P.
        • et al.
        Cancer and bone repair mechanism: clinical applications for hormone refractory prostate cancer.
        J Musculoskelet Neuronal Interact. 2000; 1: 15-17
        • Hazlehurst L.A.
        • Argilagos R.F.
        • Emmons M.
        • et al.
        Cell adhesion to fibronectin (CAM-DR) influences acquired mitoxantrone resistance in U937 cells.
        Cancer Res. 2006; 66: 2338-2345
        • Mougel L.
        • Tarpin M.
        • Albert P.
        • et al.
        Three-dimensional culture and multidrug resistance: effects on immune reactivity of MCF-7 cells by monocytes.
        Anticancer Res. 2004; 24: 935-941
        • Sherman-Baust C.A.
        • Weeraratna A.T.
        • Rangel L.B.
        • et al.
        Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells.
        Cancer Cell. 2003; 3: 377-386
        • Sausville E.A.
        The challenge of pathway and environment-mediated drug resistance.
        Cancer Metastasis Rev. 2001; 20: 117-122
        • Mudry R.E.
        • Fortney J.E.
        • York T.
        • et al.
        Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy.
        Blood. 2000; 96: 1926-1932
        • Taylor S.T.
        • Hickman J.A.
        • Dive C.
        Survival signals within the tumour microenvironment suppress drug-induced apoptosis: lessons learned from B lymphomas.
        Endocr Relat Cancer. 1999; 6: 21-23
        • Sethi T.
        • Rintoul R.C.
        • Moore S.M.
        • et al.
        Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo.
        Nat Med. 1999; 5: 662-668
        • Taylor S.T.
        • Hickman J.A.
        • Dive C.
        Epigenetic determinants of resistance to etoposide regulation of Bcl-X(L) and Bax by tumor microenvironmental factors.
        J Natl Cancer Inst. 2000; 92: 18-23
        • Song S.
        • Wientjes M.G.
        • Gan Y.
        • et al.
        Fibroblast growth factors: an epigenetic mechanism of broad spectrum resistance to anticancer drugs.
        Proc Natl Acad Sci U S A. 2000; 97: 8658-8663
        • Huff C.A.
        • Matsui W.
        • Smith B.D.
        • et al.
        The paradox of response and survival in cancer therapeutics.
        Blood. 2006; 107: 431-434
        • Matsui W.
        • Huff C.A.
        • Wang Q.
        • et al.
        Characterization of clonogenic multiple myeloma cells.
        Blood. 2004; 103: 2332-2336
        • Lemischka I.R.
        Microenvironmental regulation of hematopoietic stem cells.
        Stem Cells. 1997; 15: 63-68
        • Bissell M.J.
        • Labarge M.A.
        Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment?.
        Cancer Cell. 2005; 7: 17-23
        • Shain K.H.
        • Landowski T.H.
        • Dalton W.S.
        Adhesion-mediated intracellular redistribution of c-Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein-long confers resistance to CD95-induced apoptosis in hematopoietic cancer cell lines.
        J Immunol. 2002; 168: 2544-2553
        • Hideshima T.
        • Nakamura N.
        • Chauhan D.
        • et al.
        Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma.
        Oncogene. 2001; 20: 5991-6000
        • 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
        • De Vos J.
        • Jourdan M.
        • Tarte K.
        • et al.
        JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells.
        Br J Haematol. 2000; 109: 823-828
        • Ogata A.
        • Chauhan D.
        • Urashima M.
        • et al.
        Blockade of mitogen-activated protein kinase cascade signaling in interleukin 6-independent multiple myeloma cells.
        Clin Cancer Res. 1997; 3: 1017-1022
        • Ogata A.
        • Chauhan D.
        • Teoh G.
        • et al.
        IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade.
        J Immunol. 1997; 159: 2212-2221
        • Berger L.C.
        • Hawley T.S.
        • Lust J.A.
        • et al.
        Tyrosine phosphorylation of JAK-TYK kinases in malignant plasma cell lines growth-stimulated by interleukins 6 and 11.
        Biochem Biophys Res Commun. 1994; 202: 596-605
        • Mitsiades C.S.
        • Mitsiades N.
        • Poulaki V.
        • et al.
        Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications.
        Oncogene. 2002; 21: 5673-5683
        • Nefedova Y.
        • Cheng P.
        • Alsina M.
        • et al.
        Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines.
        Blood. 2004; 103: 3503-3510
        • Derenne S.
        • Amiot M.
        • Barille S.
        • et al.
        Zoledronate is a potent inhibitor of myeloma cell growth and secretion of IL-6 and MMP-1 by the tumoral environment.
        J Bone Miner Res. 1999; 14: 2048-2056
        • Jourdan M.
        • Tarte K.
        • Legouffe E.
        • et al.
        Tumor necrosis factor is a survival and proliferation factor for human myeloma cells.
        Eur Cytokine Netw. 1999; 10: 65-70
        • 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
        • Sehgal P.B.
        • Walther Z.
        • Tamm I.
        Rapid enhancement of beta 2-interferon/B-cell differentiation factor BSF-2 gene expression in human fibroblasts by diacylglycerols and the calcium ionophore A23187.
        Proc Natl Acad Sci U S A. 1987; 84: 3663-3667
        • Juge-Morineau N.
        • Francois S.
        • Puthier D.
        • et al.
        The gp 130 family cytokines IL-6, LIF and OSM but not IL-11 can reverse the anti-proliferative effect of dexamethasone on human myeloma cells.
        Br J Haematol. 1995; 90: 707-710
        • Chauhan D.
        • Pandey P.
        • Ogata A.
        • et al.
        Dexamethasone induces apoptosis of multiple myeloma cells in a JNK/SAP kinase independent mechanism.
        Oncogene. 1997; 15: 837-843
        • Urashima M.
        • Teoh G.
        • Chauhan D.
        • et al.
        Interleukin-6 overcomes p21WAF1 upregulation and G1 growth arrest induced by dexamethasone and interferon-gamma in multiple myeloma cells.
        Blood. 1997; 90: 279-289
        • Chauhan D.
        • Hideshima T.
        • Pandey P.
        • et al.
        RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells.
        Oncogene. 1999; 18: 6733-6740
        • Chauhan D.
        • Pandey P.
        • Hideshima T.
        • et al.
        SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells.
        J Biol Chem. 2000; 275: 27845-27850
        • Hideshima T.
        • Chauhan D.
        • Teoh G.
        • et al.
        Characterization of signaling cascades triggered by human interleukin-6 versus Kaposi's sarcoma-associated herpes virus-encoded viral interleukin 6.
        Clin Cancer Res. 2000; 6: 1180-1189
        • Lowik C.W.
        • van der Pluijm G.
        • Bloys H.
        • et al.
        Parathyroid hormone (PTH) and PTH-like protein (PLP) stimulate interleukin-6 production by osteogenic cells: a possible role of interleukin-6 in osteoclastogenesis.
        Biochem Biophys Res Commun. 1989; 162: 1546-1552
        • Bataille R.
        • Barlogie B.
        • Lu Z.Y.
        • et al.
        Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma.
        Blood. 1995; 86: 685-691
        • Klein B.
        • Wijdenes J.
        • Zhang X.G.
        • et al.
        Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia.
        Blood. 1991; 78: 1198-1204
        • Lu Z.Y.
        • Brailly H.
        • Wijdenes J.
        • et al.
        Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments.
        Blood. 1995; 86: 3123-3131
        • Montero-Julian F.A.
        • Klein B.
        • Gautherot E.
        • et al.
        Pharmacokinetic study of anti-interleukin-6 (IL-6) therapy with monoclonal antibodies: enhancement of IL-6 clearance by cocktails of anti-IL-6 antibodies.
        Blood. 1995; 85: 917-924
        • Richardson P.G.
        • Barlogie B.
        • Berenson J.
        • et al.
        A phase 2 study of bortezomib in relapsed, refractory myeloma.
        N Engl J Med. 2003; 348: 2609-2617
        • Richardson P.G.
        • Schlossman R.L.
        • 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
        • Richardson P.G.
        • Sonneveld P.
        • Schuster M.W.
        • et al.
        Bortezomib or high-dose dexamethasone for relapsed multiple myeloma.
        N Engl J Med. 2005; 352: 2487-2498
        • Rajkumar S.V.
        • Hayman S.
        • Gertz M.A.
        • et al.
        Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma.
        J Clin Oncol. 2002; 20: 4319-4323
        • 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
        • Rajkumar S.V.
        • Blood E.
        • Vesole D.
        • et al.
        A randomized phase III clinical trial of thalidomide plus dexamethasone versus dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group.
        J Clin Oncol. 2006; 24: 431-436
        • Rajkumar S.V.
        • Hayman S.R.
        • Lacy M.Q.
        • et al.
        Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma.
        Blood. 2005; 106: 4050-4053
        • Hankinson S.E.
        • Willett W.C.
        • Colditz G.A.
        • et al.
        Circulating concentrations of insulin-like growth factor-I and risk of breast cancer.
        Lancet. 1998; 351: 1393-1396
        • Chan J.M.
        • Stampfer M.J.
        • Giovannucci E.
        • et al.
        Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study.
        Science. 1998; 279: 563-566
        • LeRoith D.
        • Roberts C.T.
        The insulin-like growth factor system and cancer.
        Cancer Lett. 2003; 195: 127-137
        • Sell C.
        • Dumenil G.
        • Deveaud C.
        • et al.
        Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts.
        Mol Cell Biol. 1994; 14: 3604-3612
        • Coppola D.
        • Ferber A.
        • Miura M.
        • et al.
        A functional insulin-like growth factor I receptor is required for the mitogenic and transforming activities of the epidermal growth factor receptor.
        Mol Cell Biol. 1994; 14: 4588-4595
        • Porcu P.
        • Ferber A.
        • Pietrzkowski Z.
        • et al.
        The growth-stimulatory effect of simian virus 40 T antigen requires the interaction of insulinlike growth factor 1 with its receptor.
        Mol Cell Biol. 1992; 12: 5069-5077
        • Mitsiades C.S.
        • Mitsiades N.
        Treatment of hematologic malignancies and solid tumors by inhibiting IGF receptor signaling.
        Expert Rev Anticancer Ther. 2005; 5: 487-499
        • Adams T.E.
        • Epa V.C.
        • Garrett T.P.
        • et al.
        Structure and function of the type 1 insulin-like growth factor receptor.
        Cell Mol Life Sci. 2000; 57: 1050-1093
        • Chaiken R.L.
        • Moses A.C.
        • Usher P.
        • et al.
        Insulin stimulation of aminoisobutyric acid transport in human skin fibroblasts is mediated through both insulin and type I insulin-like growth factor receptors.
        J Clin Endocrinol Metab. 1986; 63: 1181-1185
        • Flier J.S.
        • Usher P.
        • Moses A.C.
        Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts.
        Proc Natl Acad Sci U S A. 1986; 83: 664-668
        • Kull Jr., F.C.
        • Jacobs S.
        • Su Y.F.
        • et al.
        Monoclonal antibodies to receptors for insulin and somatomedin-C.
        J Biol Chem. 1983; 258: 6561-6566
        • Poretsky L.
        • Grigorescu F.
        • Seibel M.
        • et al.
        Distribution and characterization of insulin and insulin-like growth factor I receptors in normal human ovary.
        J Clin Endocrinol Metab. 1985; 61: 728-734
        • Garcia-Echeverria C.
        • Pearson M.A.
        • Marti A.
        • et al.
        In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase.
        Cancer Cell. 2004; 5: 231-239
        • Girnita A.
        • Girnita L.
        • del Prete F.
        • et al.
        Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth.
        Cancer Res. 2004; 64: 236-242
        • Stromberg T.
        • Ekman S.
        • Girnita L.
        • et al.
        IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells.
        Blood. 2006; 107: 669-678
        • Menu E.
        • Jernberg-Wiklund H.
        • Stromberg T.
        • et al.
        Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model.
        Blood. 2006; 107: 655-660
        • Holt R.U.
        • Baykov V.
        • Ro T.B.
        • et al.
        Human myeloma cells adhere to fibronectin in response to hepatocyte growth factor.
        Haematologica. 2005; 90: 479-488
        • Hurt E.M.
        • Wiestner A.
        • Rosenwald A.
        • et al.
        Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma.
        Cancer Cell. 2004; 5: 191-199
        • Bergsagel P.L.
        • Kuehl W.M.
        • Zhan F.
        • et al.
        Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma.
        Blood. 2005; 106: 296-303
        • 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
        • Richardson P.G.
        • Blood E.
        • Mitsiades C.S.
        • 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
        • Richardson P.G.
        • Jagannath S.
        • Avigan D.E.
        • et al.
        Lenalidomide plus bortezomib (Rev-Vel) in relapsed and/or refractory multiple myeloma (MM): final results of a multicenter phase 1 trial.
        Blood. 2006; 108 (124A)
        • Kenyon B.M.
        • Browne F.
        • D'Amato R.J.
        Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization.
        Exp Eye Res. 1997; 64: 971-978
        • D'Amato R.J.
        • Lentzsch S.
        • Anderson K.C.
        • et al.
        Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma.
        Semin Oncol. 2001; 28: 597-601
        • Stirling D.I.
        The pharmacology of thalidomide.
        Sem in Hematol. 2000; 37: 5-14
        • Shipman C.M.
        • Rogers M.J.
        • Apperley J.F.
        • et al.
        Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity.
        Br J Haematol. 1997; 98: 665-672
        • Aparicio A.
        • Gardner A.
        • Tu Y.
        • et al.
        In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates.
        Leukemia. 1998; 12: 220-229
        • Uhlman D.L.
        • Verfaillie C.
        • Jones R.B.
        • et al.
        BCNU treatment of marrow stromal monolayers reversibly alters haematopoiesis.
        Br J Haematol. 1991; 78: 304-309
        • Mitsiades C.S.
        • Mitsiades N.S.
        • McMullan C.J.
        • et al.
        Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications.
        Proc Natl Acad Sci U S A. 2004; 101: 540-545
        • Mitsiades N.
        • Mitsiades C.S.
        • Richardson P.G.
        • et al.
        Molecular sequelae of histone deacetylase inhibition in human malignant B cells.
        Blood. 2003; 101: 4055-4062
        • Sordillo E.M.
        • Pearse R.N.
        RANK-Fc: a therapeutic antagonist for RANK-L in myeloma.
        Cancer. 2003; 97: 802-812
        • Vanderkerken K.
        • De Leenheer E.
        • Shipman C.
        • et al.
        Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma.
        Cancer Res. 2003; 63: 287-289
        • Holash J.
        • Davis S.
        • Papadopoulos N.
        • et al.
        VEGF-Trap: a VEGF blocker with potent antitumor effects.
        Proc Natl Acad Sci U S A. 2002; 99: 11393-11398
        • Mori Y.
        • Shimizu N.
        • Dallas M.
        • et al.
        Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis.
        Blood. 2004; 104: 2149-2154
        • Trudel S.
        • Ely S.
        • Farooqi Y.
        • et al.
        Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma.
        Blood. 2004; 103: 3521-3528
        • Trudel S.
        • Li Z.H.
        • Wei E.
        • et al.
        CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma.
        Blood. 2005; 105: 2941-2948
        • Zhu L.
        • Somlo G.
        • Zhou B.
        • et al.
        Fibroblast growth factor receptor 3 inhibition by short hairpin RNAs leads to apoptosis in multiple myeloma.
        Mol Cancer Ther. 2005; 4: 787-798
        • Sebti S.M.
        • Hamilton A.D.
        Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies.
        Oncogene. 2000; 19: 6584-6593
        • Le Gouill S.
        • Pellat-Deceunynck C.
        • Harousseau J.L.
        • et al.
        Farnesyl transferase inhibitor R115777 induces apoptosis of human myeloma cells.
        Leukemia. 2002; 16: 1664-1667
        • Bolick S.C.
        • Landowski T.H.
        • Boulware D.
        • et al.
        The farnesyl transferase inhibitor, FTI-277, inhibits growth and induces apoptosis in drug-resistant myeloma tumor cells.
        Leukemia. 2003; 17: 451-457
        • Alsina M.
        • Fonseca R.
        • Wilson E.F.
        • 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
        • Mitsiades N.
        • Mitsiades C.S.
        • Poulaki V.
        • et al.
        Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications.
        Blood. 2002; 99: 4079-4086
        • Frost P.
        • Moatamed F.
        • Hoang B.
        • et al.
        In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model.
        Blood. 2004; 104: 4181-4187
        • Mitsiades N.S.
        • McMullan C.J.
        • Poulaki V.
        • et al.
        The mTOR inhibitor RAD001 (everolimus) is active against multiple myeloma cells in vitro and in vivo.
        Blood. 2004; 104: 418a
        • Raje N.
        • Kumar S.
        • Hideshima T.
        • et al.
        Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma.
        Blood. 2004; 104: 4188-4193
        • Stromberg T.
        • Dimberg A.
        • Hammarberg A.
        • et al.
        Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone.
        Blood. 2004; 103: 3138-3147
        • Shi Y.
        • Yan H.
        • Frost P.
        • et al.
        Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade.
        Mol Cancer Ther. 2005; 4: 1533-1540
        • Shammas M.A.
        • Shmookler Reis R.J.
        • Akiyama M.
        • et al.
        Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma.
        Mol Cancer Ther. 2003; 2: 825-833
        • Shammas M.A.
        • Shmookler Reis R.J.
        • Li C.
        • et al.
        Telomerase inhibition and cell growth arrest after telomestatin treatment in multiple myeloma.
        Clin Cancer Res. 2004; 10: 770-776
        • Negri J.
        • Mitsiades N.
        • Deng Q.W.
        • et al.
        PKC412 is a multi-targeting kinase inhibitor with activity against multiple myeloma in vitro and in vivo.
        Blood. 2005; 106: 75a
        • Deng Q.W.
        • Mitsiades N.
        • Negri J.
        • et al.
        Dasatinib (BMS-354825): a multi-targeted kinase inhibitor with activity against multiple myeloma.
        Blood. 2005; 106 (451A–451A)
        • Xu W.
        • Neckers L.
        Targeting the molecular chaperone heat shock protein 90 provides a multifaceted effect on diverse cell signaling pathways of cancer cells.
        Clin Cancer Res. 2007; 13: 1625-1629
        • Mitsiades C.S.
        • Mitsiades N.S.
        • McMullan C.J.
        • et al.
        Antimyeloma activity of heat shock protein-90 inhibition.
        Blood. 2006; 107: 1092-1100
        • Chatterjee M.
        • Jain S.
        • Stuhmer T.
        • et al.
        STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90alpha and beta in multiple myeloma cells, which critically contribute to tumor-cell survival.
        Blood. 2007; 109: 720-728
        • Sydor J.R.
        • Normant E.
        • Pien C.S.
        • et al.
        Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90.
        Proc Natl Acad Sci U S A. 2006; 103: 17408-17413
        • Richardson P.G.
        • Chanan-Khan A.A.
        • 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.
        Blood. 2005; 106: 109a
      1. Richardson P, Chanan-Khan A, Lonial S, et al. A multicenter Phase 1 clinical trial of tanespimycin (KOS-953) + Bortezomib (BZ): encouraging activity and manageable toxicity in heavily pre-treated patients with relapsed refractory multiple myeloma (MM). Paper presented at the 2006 Annual Meeting of the American Society of Hematology. Orlando (FL), December 2006.