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

Hematology/Oncology Clinics of North America

Volumn 21, Issue 6, 2007, Pages 1007-1034

  Mitsiades, Constantine S ^a   McMillin, Douglas W ^a   Klippel, Steffen ^a   Hideshima, Teru ^a   Chauhan, Dharminder ^a   Richardson, Paul G ^a   Munshi, Nikhil C ^a   Anderson, Kenneth C ^a  

^a DANA FARBER CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BORTEZOMIB; CYTOKINE; INTERLEUKIN 6; LENALIDOMIDE; MITOGENIC AGENT; SOMATOMEDIN; THALIDOMIDE;

BONE MARROW; CANCER GENETICS; CELL INTERACTION; CELL SURVIVAL; ENDOTHELIUM CELL; GENE TARGETING; HUMAN; MICROENVIRONMENT; MYELOMA; MYELOMA CELL; NONHUMAN; OSTEOBLAST; OSTEOCLAST; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; STROMA CELL; TUMOR CELL;

BONE MARROW; CELL COMMUNICATION; HUMANS; MULTIPLE MYELOMA; OSTEOCLASTS; STROMAL CELLS;

EID: 35748930596     PISSN: 08898588     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.hoc.2007.08.007     Document Type: Review

References (227)

1. Mitsiades C.S., and Koutsilieris M. Molecular biology and cellular physiology of refractoriness to androgen ablation therapy in advanced prostate cancer. Expert Opin Investig Drugs 10 6 (2001) 1099-1115
2. 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 82 11 (2003) 539-548
3. Munk Pedersen I., and Reed J. Microenvironmental interactions and survival of CLL B-cells. Leuk Lymphoma 45 12 (2004) 2365-2372
4. Zhou J., Mauerer K., Farina L., et al. The role of the tumor microenvironment in hematological malignancies and implication for therapy. Front Biosci 10 (2005) 1581-1596
5. Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1 (1889) 571-573
6. Bataille R., and Harousseau J.L. Multiple myeloma. N Engl J Med 336 23 (1997) 1657-1664
7. Mitsiades C.S., Mitsiades N., Munshi N.C., et al. Focus on multiple myeloma. Cancer Cell 6 5 (2004) 439-444
8. Chauhan D., Uchiyama H., Urashima M., et al. Regulation of interleukin 6 in multiple myeloma and bone marrow stromal cells. Stem Cells 13 Suppl 2 (1995) 35-39
9. 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 87 3 (1996) 1104-1112
10. 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 61 7 (2001) 3071-3076
11. 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 93 5 (1999) 1658-1667
12. Akiyama M., Hideshima T., Hayashi T., et al. Cytokines modulate telomerase activity in a human multiple myeloma cell line. Cancer Res 62 13 (2002) 3876-3882
13. 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 23 20 (2004) 3597-3602
14. 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 107 10 (2006) 4053-4062
15. Freund G.G., Kulas D.T., and Mooney R.A. Insulin and IGF-1 increase mitogenesis and glucose metabolism in the multiple myeloma cell line, RPMI 8226. J Immunol 151 4 (1993) 1811-1820
16. 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 5 3 (2004) 221-230
17. Vanderkerken K., Asosingh K., Braet F., et al. Insulin-like growth factor-1 acts as a chemoattractant factor for 5T2 multiple myeloma cells. Blood 93 1 (1999) 235-241
18. 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 60 11 (2000) 3096-3104
19. Podar K., and Anderson K.C. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood 105 4 (2005) 1383-1395
20. 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 103 9 (2004) 3474-3479
21. 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 98 2 (2001) 428-435
22. 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 277 10 (2002) 7875-7881
23. Hideshima T., Chauhan D., Hayashi T., et al. The biological sequelae of stromal cell-derived factor-1alpha in multiple myeloma. Mol Cancer Ther 1 7 (2002) 539-544
24. 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 15 6 (1999) 1205-1212
25. 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 8 5 (2005) 407-419
26. 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 103 2 (2004) 689-694
27. Moreaux J., Legouffe E., Jourdan E., et al. BAFF and APRIL protect myeloma cells from apoptosis induced by IL-6 deprivation and dexamethasone. Blood 103 8 (2004) 3148-3157
28. 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 66 13 (2006) 6675-6682
29. Hideshima T., and Anderson K.C. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2 12 (2002) 927-937
30. Hideshima T., Bergsagel P.L., Kuehl W.M., et al. Advances in biology of multiple myeloma: clinical applications. Blood 104 3 (2004) 607-618
31. Kuehl W.M., and Bergsagel P.L. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer 2 3 (2002) 175-187
32. Roodman G.D. Pathogenesis of myeloma bone disease. Blood Cells Mol Dis 32 2 (2004) 290-292
33. Roodman G.D. Myeloma bone disease: pathogenesis and treatment. Oncology (Williston Park) 19 8 (2005) 983-984 986
34. Ribatti D., Nico B., and Vacca A. Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene 25 31 (2006) 4257-4266
35. Ribatti D., Scavelli C., Roccaro A.M., et al. Hematopoietic cancer and angiogenesis. Stem Cells Dev 13 5 (2004) 484-495
36. Werts E.D., DeGowin R.L., Knapp S.K., et al. Characterization of marrow stromal (fibroblastoid) cells and their association with erythropoiesis. Exp Hematol 8 4 (1980) 423-433
37. Greenberg B.R., Wilson F.Z., and Woo L. Granulopoietic effects of human bone marrow fibroblastic cells and abnormalities in the "granulopoietic microenvironment". Blood 58 3 (1981) 557-564
38. Reincke U., Hannon E.C., Rosenblatt M., et al. Proliferative capacity of murine hematopoietic stem cells in vitro. Science 215 4540 (1982) 1619-1622
39. Kaneko S., Motomura S., and Ibayashi H. Differentiation of human bone marrow-derived fibroblastoid colony forming cells (CFU-F) and their roles in haemopoiesis in vitro. Br J Haematol 51 2 (1982) 217-225
40. Kawano M., Hirano T., Matsuda T., et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332 6159 (1988) 83-85
41. Kawano M., Kuramoto A., Hirano T., et al. Cytokines as autocrine growth factors in malignancies. Cancer Surv 8 4 (1989) 905-919
42. Kawano M., Tanaka H., Ishikawa H., et al. Interleukin-1 accelerates autocrine growth of myeloma cells through interleukin-6 in human myeloma. Blood 73 8 (1989) 2145-2148
43. 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 169 1 (1989) 339-344
44. 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 1 4 (1990) 193-201
45. 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 16 10 (1992) 951-959
46. Urashima M., Chauhan D., Uchiyama H., et al. CD40 ligand triggered interleukin-6 secretion in multiple myeloma. Blood 85 7 (1995) 1903-1912
47. Urashima M., Ogata A., Chauhan D., et al. Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein. Blood 88 6 (1996) 2219-2227
48. 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 89 1 (1997) 227-234
49. Uchiyama H., Barut B.A., Chauhan D., et al. Characterization of adhesion molecules on human myeloma cell lines. Blood 80 9 (1992) 2306-2314
50. 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 82 12 (1993) 3712-3720
51. Nefedova Y., Landowski T.H., and 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 17 6 (2003) 1175-1182
52. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29 6 Suppl 16 (2002) 15-18
53. 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 98 5 (2006) 316-325
54. Nawab R.A., and Azar H.A. The laboratory diagnosis of plasma cell myeloma and related disorders. Orthop Clin North Am 10 2 (1979) 391-404
55. Rajkumar S.V., and Kyle R.A. Angiogenesis in multiple myeloma. Semin Oncol 28 6 (2001) 560-564
56. 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 66 1 (2006) 184-191
57. Singhal S., Mehta J., Desikan R., et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341 21 (1999) 1565-1571
58. D'Amato R.J., Loughnan M.S., Flynn E., et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91 9 (1994) 4082-4085
59. 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 23 23 (2005) 5334-5346
60. Vacca A., Ria R., Semeraro F., et al. Endothelial cells in the bone marrow of patients with multiple myeloma. Blood 102 9 (2003) 3340-3348
61. Anderson K.C. Moving disease biology from the lab to the clinic. Cancer 97 3 Suppl (2003) 796-801
62. 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 6 10 (2005) 1038-1046
63. 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 91 5 (2006) 605-612
64. 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 15 12 (2001) 1950-1961
65. 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 99 4 (2002) 1419-1427
66. 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 16 19 (2002) 2530-2543
67. 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 4 3 (2002) 204-217
68. 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 88 11 (2003) 5392-5398
69. Tanaka Y., Nakayamada S., and Okada Y. Osteoblasts and osteoclasts in bone remodeling and inflammation. Curr Drug Targets Inflamm Allergy 4 3 (2005) 325-328
70. 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 49 4 (1992) 192-198
71. 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 7 12 (1989) 1909-1914
72. Ashcroft A.J., Davies F.E., and Morgan G.J. Aetiology of bone disease and the role of bisphosphonates in multiple myeloma. Lancet Oncol 4 5 (2003) 284-292
73. Sezer O., Heider U., Zavrski I., et al. RANK ligand and osteoprotegerin in myeloma bone disease. Blood 101 6 (2003) 2094-2098
74. Hofbauer L.C., and Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 292 4 (2004) 490-495
75. Roux S., Meignin V., Quillard J., et al. RANK (receptor activator of nuclear factor-kappaB) and RANKL expression in multiple myeloma. Br J Haematol 117 1 (2002) 86-92
76. 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 98 20 (2001) 11581-11586
77. Lacey D.L., Timms E., Tan H.L., et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93 2 (1998) 165-176
78. 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 73 6 (1989) 1646-1649
79. Mundy G.R. Hypercalcemic factors other than parathyroid hormone-related protein. Endocrinol Metab Clin North Am 18 3 (1989) 795-806
80. 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 143 11 (1989) 3543-3547
81. Bataille R., Chappard D., and 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 21 4 (1992) 283-287
82. 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 473 2 (2000) 161-164
83. 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 190 2 (1999) 293-298
84. 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 97 11 (2001) 3349-3353
85. 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 96 2 (2000) 671-675
86. Callander N.S., and Roodman G.D. Myeloma bone disease. Semin Hematol 38 3 (2001) 276-285
87. 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 108 12 (2001) 1833-1841
88. 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 33 3 (2005) 272-278
89. Urashima M., Ogata A., Chauhan D., et al. Transforming growth factor-beta1: differential effects on multiple myeloma versus normal B cells. Blood 87 5 (1996) 1928-1938
90. Franchimont N., Rydziel S., and Canalis E. Transforming growth factor-beta increases interleukin-6 transcripts in osteoblasts. Bone 26 3 (2000) 249-253
91. Ducy P., Zhang R., Geoffroy V., et al. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89 5 (1997) 747-754
92. Karsenty G., Ducy P., Starbuck M., et al. Cbfa1 as a regulator of osteoblast differentiation and function. Bone 25 1 (1999) 107-108
93. 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 106 7 (2005) 2472-2483
94. 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 349 26 (2003) 2483-2494
95. Oshima T., Abe M., Asano J., et al. Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood 106 9 (2005) 3160-3165
96. 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 103 6 (2004) 2308-2315
97. Ehrlich L.A., Chung H.Y., Ghobrial I., et al. IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Blood 106 4 (2005) 1407-1414
98. Standal T., Abildgaard N., Fagerli U.M., et al. HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma. Blood 109 7 (2007) 3024-3030
99. 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 42 11 (2006) 1564-1573
100. 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 242 2 (1998) 460-469
101. 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 111 11 (2003) 1771-1782
102. Heider U., Kaiser M., Muller C., et al. Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment. Eur J Haematol 77 3 (2006) 233-238
103. Zangari M., Yaccoby S., Cavallo F., et al. Response to bortezomib and activation of osteoblasts in multiple myeloma. Clin Lymphoma Myeloma 7 2 (2006) 109-114
104. 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 19 6 (2005) 1102-1103
105. Knobloch J., Shaughnessy Jr. J.D., and Ruther U. Thalidomide induces limb deformities by perturbing the Bmp/Dkk1/Wnt signaling pathway. FASEB J 21 7 (2007) 1410-1421
106. 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 194 (1995) 17-24
107. 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 85 2 (1995) 436-447
108. 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 23 10 (1999) 1019-1027
109. 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 117 4 (2002) 852-859
110. 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 45 7 (2004) 1413-1417
111. 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 62 17 (2002) 5019-5026
112. 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 10 19 (2004) 6686-6694
113. 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 29 1 (2001) 77-84
114. 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 63 18 (2003) 5850-5858
115. Anderson K. Advances in the biology of multiple myeloma: therapeutic applications. Semin Oncol 26 5 Suppl 13 (1999) 10-22
116. 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 87 3 (1994) 483-493
117. Asosingh K. Migration, adhesion and differentiation of malignant plasma cells in the 5T murine model of myeloma. Verh K Acad Geneeskd Belg 65 2 (2003) 127-134
118. 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 61 7 (2001) 2862-2865
119. 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 22 16 (2003) 2417-2421
120. Damiano J.S., and Dalton W.S. Integrin-mediated drug resistance in multiple myeloma. Leuk Lymphoma 38 1-2 (2000) 71-81
121. 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 19 38 (2000) 4319-4327
122. 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 63 22 (2003) 7900-7906
123. 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 90 4 (1997) 1649-1655
124. Flomenberg N., DiPersio J., and Calandra G. Role of CXCR4 chemokine receptor blockade using AMD3100 for mobilization of autologous hematopoietic progenitor cells. Acta Haematol 114 4 (2005) 198-205
125. Roodman G.D. Role of the bone marrow microenvironment in multiple myeloma. J Bone Miner Res 17 11 (2002) 1921-1925
126. Koutsilieris M., Mitsiades C., Lembessis P., et al. Cancer and bone repair mechanism: clinical applications for hormone refractory prostate cancer. J Musculoskelet Neuronal Interact 1 1 (2000) 15-17
127. 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 66 4 (2006) 2338-2345
128. 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 24 2B (2004) 935-941
129. 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 3 4 (2003) 377-386
130. Sausville E.A. The challenge of pathway and environment-mediated drug resistance. Cancer Metastasis Rev 20 1-2 (2001) 117-122
131. Mudry R.E., Fortney J.E., York T., et al. Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy. Blood 96 5 (2000) 1926-1932
132. Taylor S.T., Hickman J.A., and Dive C. Survival signals within the tumour microenvironment suppress drug-induced apoptosis: lessons learned from B lymphomas. Endocr Relat Cancer 6 1 (1999) 21-23
133. 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 5 6 (1999) 662-668
134. Taylor S.T., Hickman J.A., and Dive C. Epigenetic determinants of resistance to etoposide regulation of Bcl-X(L) and Bax by tumor microenvironmental factors. J Natl Cancer Inst 92 1 (2000) 18-23
135. 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 97 15 (2000) 8658-8663
136. Huff C.A., Matsui W., Smith B.D., et al. The paradox of response and survival in cancer therapeutics. Blood 107 2 (2006) 431-434
137. Matsui W., Huff C.A., Wang Q., et al. Characterization of clonogenic multiple myeloma cells. Blood 103 6 (2004) 2332-2336
138. Lemischka I.R. Microenvironmental regulation of hematopoietic stem cells. Stem Cells 15 Suppl 1 (1997) 63-68
139. Bissell M.J., and Labarge M.A. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment?. Cancer Cell 7 1 (2005) 17-23
140. Shain K.H., Landowski T.H., and 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 168 5 (2002) 2544-2553
141. Hideshima T., Nakamura N., Chauhan D., et al. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 20 42 (2001) 5991-6000
142. Hideshima T., Chauhan D., Richardson P., et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277 19 (2002) 16639-16647
143. 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 109 4 (2000) 823-828
144. 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 3 6 (1997) 1017-1022
145. Ogata A., Chauhan D., Teoh G., et al. IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade. J Immunol 159 5 (1997) 2212-2221
146. 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 202 1 (1994) 596-605
147. 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 21 37 (2002) 5673-5683
148. 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 103 9 (2004) 3503-3510
149. 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 14 12 (1999) 2048-2056
150. Jourdan M., Tarte K., Legouffe E., et al. Tumor necrosis factor is a survival and proliferation factor for human myeloma cells. Eur Cytokine Netw 10 1 (1999) 65-70
151. 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 20 33 (2001) 4519-4527
152. Sehgal P.B., Walther Z., and 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 84 11 (1987) 3663-3667
153. 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 90 3 (1995) 707-710
154. Chauhan D., Pandey P., Ogata A., et al. Dexamethasone induces apoptosis of multiple myeloma cells in a JNK/SAP kinase independent mechanism. Oncogene 15 7 (1997) 837-843
155. 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 90 1 (1997) 279-289
156. Chauhan D., Hideshima T., Pandey P., et al. RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells. Oncogene 18 48 (1999) 6733-6740
157. 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 275 36 (2000) 27845-27850
158. 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 6 3 (2000) 1180-1189
159. 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 162 3 (1989) 1546-1552
160. Bataille R., Barlogie B., Lu Z.Y., et al. Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma. Blood 86 2 (1995) 685-691
161. Klein B., Wijdenes J., Zhang X.G., et al. Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood 78 5 (1991) 1198-1204
162. 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 86 8 (1995) 3123-3131
163. 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 85 4 (1995) 917-924
164. Richardson P.G., Barlogie B., Berenson J., et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348 26 (2003) 2609-2617
165. 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 100 9 (2002) 3063-3067
166. Richardson P.G., Sonneveld P., Schuster M.W., et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352 24 (2005) 2487-2498
167. Rajkumar S.V., Hayman S., Gertz M.A., et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 20 21 (2002) 4319-4323
168. Weber D., Rankin K., Gavino M., et al. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 21 1 (2003) 16-19
169. 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 24 3 (2006) 431-436
170. Rajkumar S.V., Hayman S.R., Lacy M.Q., et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 106 13 (2005) 4050-4053
171. 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 351 9113 (1998) 1393-1396
172. Chan J.M., Stampfer M.J., Giovannucci E., et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 279 5350 (1998) 563-566
173. LeRoith D., and Roberts C.T. The insulin-like growth factor system and cancer. Cancer Lett 195 2 (2003) 127-137
174. 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 14 6 (1994) 3604-3612
175. 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 14 7 (1994) 4588-4595
176. 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 12 11 (1992) 5069-5077
177. Mitsiades C.S., and Mitsiades N. Treatment of hematologic malignancies and solid tumors by inhibiting IGF receptor signaling. Expert Rev Anticancer Ther 5 3 (2005) 487-499
178. 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 57 7 (2000) 1050-1093
179. 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 63 5 (1986) 1181-1185
180. Flier J.S., Usher P., and 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 83 3 (1986) 664-668
181. Kull Jr. F.C., Jacobs S., Su Y.F., et al. Monoclonal antibodies to receptors for insulin and somatomedin-C. J Biol Chem 258 10 (1983) 6561-6566
182. 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 61 4 (1985) 728-734
183. 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 5 3 (2004) 231-239
184. 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 64 1 (2004) 236-242
185. 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 107 2 (2006) 669-678
186. 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 107 2 (2006) 655-660
187. Holt R.U., Baykov V., Ro T.B., et al. Human myeloma cells adhere to fibronectin in response to hepatocyte growth factor. Haematologica 90 4 (2005) 479-488
188. 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 5 2 (2004) 191-199
189. Bergsagel P.L., Kuehl W.M., Zhan F., et al. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 106 1 (2005) 296-303
190. 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 79 7 (2004) 875-882
191. 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 108 10 (2006) 3458-3464
192. 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 108 11 (2006) 124A
193. Kenyon B.M., Browne F., and D'Amato R.J. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res 64 6 (1997) 971-978
194. D'Amato R.J., Lentzsch S., Anderson K.C., et al. Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma. Semin Oncol 28 6 (2001) 597-601
195. Stirling D.I. The pharmacology of thalidomide. Sem in Hematol 37 (2000) 5-14
196. 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 98 3 (1997) 665-672
197. Aparicio A., Gardner A., Tu Y., et al. In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia 12 2 (1998) 220-229
198. Uhlman D.L., Verfaillie C., Jones R.B., et al. BCNU treatment of marrow stromal monolayers reversibly alters haematopoiesis. Br J Haematol 78 3 (1991) 304-309
199. 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 101 2 (2004) 540-545
200. Mitsiades N., Mitsiades C.S., Richardson P.G., et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 101 10 (2003) 4055-4062
201. Sordillo E.M., and Pearse R.N. RANK-Fc: a therapeutic antagonist for RANK-L in myeloma. Cancer 97 3 Suppl (2003) 802-812
202. 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 63 2 (2003) 287-289
203. Holash J., Davis S., Papadopoulos N., et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 99 17 (2002) 11393-11398
204. Mori Y., Shimizu N., Dallas M., et al. Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood 104 7 (2004) 2149-2154
205. 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 103 9 (2004) 3521-3528
206. 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 105 7 (2005) 2941-2948
207. 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 4 5 (2005) 787-798
208. Sebti S.M., and Hamilton A.D. Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy: lessons from mechanism and bench-to-bedside translational studies. Oncogene 19 56 (2000) 6584-6593
209. Le Gouill S., Pellat-Deceunynck C., Harousseau J.L., et al. Farnesyl transferase inhibitor R115777 induces apoptosis of human myeloma cells. Leukemia 16 9 (2002) 1664-1667
210. 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 17 2 (2003) 451-457
211. 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 103 9 (2004) 3271-3277
212. Mitsiades N., Mitsiades C.S., Poulaki V., et al. Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications. Blood 99 11 (2002) 4079-4086
213. 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 104 13 (2004) 4181-4187
214. 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 104 11s (2004) 418a
215. Raje N., Kumar S., Hideshima T., et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood 104 13 (2004) 4188-4193
216. Stromberg T., Dimberg A., Hammarberg A., et al. Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood 103 8 (2004) 3138-3147
217. 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 4 10 (2005) 1533-1540
218. 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 2 9 (2003) 825-833
219. 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 10 2 (2004) 770-776
220. 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 106 11 (2005) 75a
221. Deng Q.W., Mitsiades N., Negri J., et al. Dasatinib (BMS-354825): a multi-targeted kinase inhibitor with activity against multiple myeloma. Blood 106 11 (2005) 451A-451A
222. Xu W., and 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 13 6 (2007) 1625-1629
223. Mitsiades C.S., Mitsiades N.S., McMullan C.J., et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood 107 3 (2006) 1092-1100
224. 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 109 2 (2007) 720-728
225. 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 103 46 (2006) 17408-17413
226. 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 106 11 (2005) 109a
227. 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.