Emerging therapies for multiple myeloma

American Journal of Cancer

Volumn 5, Issue 3, 2006, Pages 141-153

  Podar, Klaus ^a,b   Hideshima, Teru ^a   Tai, Yu Tzu ^a   Richardson, Paul G ^a   Chauhan, Dharminder ^a   Anderson, Kenneth C ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

^b DANA FARBER CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 (4 AMINO 1,3 DIHYDRO 1,3 DIOXO 2H ISOINDOL 2 YL)GLUTARIMIDE; 3 [4 METHYL 2 (2 OXO 3 INDOLINYLMETHYLIDENYL) 3 PYRROLYL]PROPIONIC ACID; 4 [N (2 HYDROXYETHYL) N [2 (3 INDOLYL)ETHYL]AMINOMETHYL]CINNAMOHYDROXAMIC ACID; ACETYLSALICYLIC ACID; ANTINEMATODAL AGENT; BEVACIZUMAB; BIBF 1000; BORTEZOMIB; CARMUSTINE; CHIR 258; CYCLOPHOSPHAMIDE; DEXAMETHASONE; DOXORUBICIN; GW 654652; HEAT SHOCK PROTEIN 90 INHIBITOR; LBH 589; LENALIDOMIDE; MELPHALAN; MIDOSTAURIN; PAZOPANIB; PD 173074; PREDNISONE; PROTEIN TYROSINE KINASE INHIBITOR; SCIO 469; SU 10991; THALIDOMIDE; UNCLASSIFIED DRUG; UNINDEXED DRUG; VATALANIB; VINCRISTINE; VORINOSTAT;

AUTOLOGOUS STEM CELL TRANSPLANTATION; BONE MARROW TRANSPLANTATION; CANCER GROWTH; CELL GROWTH; CELL MIGRATION; CELL SURVIVAL; CLINICAL EVALUATION; CLINICAL TRIAL; COLORECTAL CANCER; CONSTIPATION; CYTOGENETICS; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG MEGADOSE; DRUG TARGETING; DRY SKIN; EMBOLISM; HUMAN; IMMUNE DEFICIENCY; KIDNEY DISEASE; LOW DRUG DOSE; MULTIPLE MYELOMA; OSTEOLYSIS; OVERALL SURVIVAL; PLASMA CELL; PRIORITY JOURNAL; PRURITUS; REVIEW; SEDATION; SIDE EFFECT; STEM CELL TRANSPLANTATION; THROMBOSIS; TUMOR CELL; UNSPECIFIED SIDE EFFECT;

EID: 33846853306     PISSN: 11756357     EISSN: None     Source Type: Journal    
DOI: 10.2165/00024669-200605030-00001     Document Type: Review

References (180)

1. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004; 351 (18): 1860-73
2. Kyle RA. Five decades of therapy for multiple myeloma: a paradigm for therapeutic models. Leukemia 2005; 19 (6): 910-2
3. Alwall N. Urethane in multiple myeloma: I. Final report of a case treated more than four years with urethane. Acta Med Scand 1952; 144 (2): 114-8
4. Blokhin N, Larionov L, Perevodchikova N, et al. Clinical experiences with sarcolysin in neoplastic diseases. Ann N Y Acad Sci 1958; 68 (3): 1128-32
5. Bergsagel DE. Phase II trials of mitomycin C, AB-100, NSC-1026, L-sarcolysin, and meta-sarcolysin, in the treatment of multiple myeloma. Cancer Chemother Rep 1962; 16: 261-66
6. Alexanian R, Haut A, Khan AU, et al. Treatment for multiple myeloma: combination chemotherapy with different melphalan dose regimens. JAMA 1969 Jun 2; 208 (9): 1680-5
7. Myeloma-Trialists'-Collaborative-Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6633 patients from 27 randomized trials. Myeloma Trialists' Collaborative Group. J Clin Oncol 1998; 16 (12): 3832-42
8. Bergsagel DE, Bailey AJ, Langley GR, et al. The chemotherapy on plasma-cell myeloma and the incidence of acute leukemia. N Engl J Med 1979; 301 (14): 743-8
9. Bergsagel DE. Chemotherapy of myeloma: drug combinations versus single agents, an overview, and comments on acute leukemia in myeloma. Hematol Oncol 1988; 6 (2): 159-66
10. Finnish-Leukaemia-Group. Acute leukaemia and other secondary neoplasms in patients treated with conventional chemotherapy for multiple myeloma: a Finnish Leukaemia Group study. Eur J Haematol 2000; 65 (2): 123-7
11. Cuzick J, Erskine S, Edelman D, et al. A comparison of the incidence of the myelodysplastic syndrome and acute myeloid leukaemia following melphalan and cyclophosphamide treatment for myelomatosis: a report to the Medical Research Council's working party on leukaemia in adults. Br J Cancer 1987; 55 (5): 523-9
12. Govindarajan R, Jagannath S, Flick JT, et al. Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma. Br J Haematol 1996; 95 (2): 349-53
13. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996; 335 (2): 91-7
14. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348 (19): 1875-83
15. Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the group myelome-autogreffe. J Clin Oncol 2005; 23 (36): 9227-33
16. Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 2006 Feb 20; 24 (6): 929-36
17. Blade J, Rosinol L, Sureda A, et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 2005; 106 (12): 3755-9
18. Morris TC, Velangi M, Jackson G, et al. Less than half of patients aged 65 years or under with myeloma proceed to transplantation: results of a two region population-based survey. Br J Haematol 2005; 128 (4): 510-2
19. Saravanamuttu K, Byrne JL, Williams C, et al. Uptake of high-dose therapy and peripheral blood stem cell transplantation in myeloma patients <65 years: the role of the myeloma multi-disciplinary team. Br J Haematol 2005; 130 (2): 318-9
20. Barlogie B, Jagannath S, Vesole DH, et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 1997; 89 (3): 789-93
21. Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 1999; 93 (1): 55-65
22. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003; 349 (26): 2495-502
23. Cavo M, Zamagni E, Cellini C. Single versus double autologous stem cell transplantation for multiple myeloma: Italian experience [abstract]. Hematol J 2003; 4 Suppl. 1: 560
24. Sonneveld P, van der Holt B, Segeren CM. Intensive versus double intensive therapy in untreated multiple myeloma: updated analysis of the prospective phase III study Hovon 24-MM. Hematol J 2003; 4 Suppl. 1: 559-60
25. Fermand JP, Alberti C, Marolleau JP. Single versus double high dose therapy supported with autologous blood stem cell transplantation using unselected or CD34 enriched ABSC: results of a two designed randomized trial in 230 young patients with multiple myeloma. Hematol J 2003; 4 Suppl. 1: S59
26. Goldschmidt H. Single versus double high dose therapy in multiple myeloma: second analysis of the trial GMMG-HD2. Proceedings Multiple Myeloma 2004 Meeting; 2004 Apr 22-24; Torino, 119
27. Segeren CM, Sonneveld P, van der Holt B, et al. Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study. Blood 2003; 101 (6): 2144-51
28. Gahrton G, Tura S, Ljungman P, et al. Prognostic factors in allogeneic bone marrow transplantation for multiple myeloma. J Clin Oncol 1995; 13 (6): 1312-22
29. Bensinger WI, Buckner CD, Anasetti C, et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood 1996; 88 (7): 2787-93
30. Alyea E, Weller E, Schlossman R, et al. T-cell: depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. Blood 2001; 98 (4): 934-9
31. Lokhorst HM, Segeren CM, Verdonck LF, et al. Partially T-cell-depleted allogeneic stem-cell transplantation for first-line treatment of multiple myeloma: a prospective evaluation of patients treated in the phase III study HOVON 24 MM. J Clin Oncol 2003; 21 (9): 1728-33
32. Maloney DG, Sandmaier BM, Mackinnon S, et al. Non-myeloablative transplantation. Hematology (Am Soc Hematol Educ Program) 2002: 392-421
33. Badros A, Barlogie B, Siegel E, et al. Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 2002; 20 (5): 1295-303
34. Kroger N, Schwerdtfeger R, Kiehl M, et al. Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood 2002; 100 (3): 755-60
35. Maloney DG, Molina AJ, Sahebi F, et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102 (9): 3447-54
36. Bruno B, Rotta M, Patriarca F, et al. Double autologous transplant versus tandem autologus: non myeloablative allogeneic transplant for newly diagnosed multiple myeloma [abstract]. Blood 2005; 106 (11): 46
37. Carella AM, Spriano M, Corsetti MT, et al. Autografting followed closely by nonmyeloablative allografting as consolidation immunotherapy reduces disease progression compared to tandem autografting in multiple myeloma [abstract no. 112]. Blood 2005, 328a
38. Cavo M, Zamagni E, Tosi P, et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005; 106 (1): 35-9
39. Rajkumar SV, Gertz MA, Kyle RA, et al. Current therapy for multiple myeloma. Mayo Clin Proc 2002; 77 (8): 813-22
40. Facon T, Mary JY, Pegourie B, et al. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood 2006 Feb 15; 107 (4): 1292-8
41. Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 1996; 334 (8): 488-93
42. Ludwig H, Fritz E, Kotzmann H, et al. Erythropoietin treatment of anemia associated with multiple myeloma. N Engl J Med 1990; 322 (24): 1693-9
43. Bociek RG, Armitage JO. Hematopoietic growth factors. CA Cancer J Clin 1996; 46 (3): 165-84
44. Marx RE, Sawatari Y, Fortin M, et al. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005; 63 (11): 1567-75
45. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61 (9): 1115-7
46. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62 (5): 527-34
47. Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2002; 2 (12): 927-37
48. Podar K, Hideshima T, Chauhan D, et al. Targeting signalling pathways for the treatment of multiple myeloma. Expert Opin Ther Targets 2005; 9 (2): 359-81
49. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341 (21): 1565-71
50. Barlogie B, Desikan R, Eddlemon P, et al. Extended survival in advanced and fractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001; 98 (2): 492-4
51. Rajkumar SV, Fonseca R, Dispenzieri A, et al. Thalidomide in the treatment of relapsed multiple myeloma. Mayo Clin Proc 2000; 75 (9): 897-901
52. Dimopoulos MA, Anagnostopoulos A, Weber D. Treatment of plasma cell dyscrasias with thalidomide and its derivatives. J Clin Oncol 2003; 21 (23): 4444-54
53. D'Amato RJ, Lentzsch S, Anderson KC, et al. Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma. Semin Oncol 2001; 28 (6): 597-601
54. Sampaio EP, Sarno EN, Galilly R, et al. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991; 173 (3): 699-703
55. 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 (33): 4519-27
56. Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002; 99 (12): 4525-30
57. Hideshima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000; 96 (9): 2943-50
58. Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001; 98 (1): 210-6
59. Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 2004; 4 (4): 314-22
60. Weber D, Rankin K, Gavino M, et al. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol 2003; 21 (1): 16-9
61. Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002; 20 (21): 4319-23
62. Garcia-Sanz R, Gonzalez-Fraile MI, Sierra M, et al. The combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is feasible and can be an option for relapsed/refractory multiple myeloma. Hematol J 2002; 3 (1): 43-8
63. Coleman M, Leonard J, Lyons L, et al. BLT-D (clarithromycin [Biaxin], low-dose thalidomide, and dexamethasone) for the treatment of myeloma and Waldenstrom's macroglobulinemia. Leuk Lymphoma 2002; 43 (9): 1777-82
64. Osman K, Comenzo R, Rajkumar SV. Deep venous thrombosis and thalidomide therapy for multiple myeloma. N Engl J Med 2001; 344 (25): 1951-2
65. Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 2001; 98 (5): 1614-5
66. Baz R, Li L, Kottke-Marchant K, et al. The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 2005; 80 (12): 1568-74
67. Yakoub-Agha I, Attal M, Dumontet C, et al. Thalidomide in patients with advanced multiple myeloma: a study of 83 patients: report of the Intergroupe Francophone du Myelome (IFM). Hematol J 2002; 3 (4): 185-92
68. Neben K, Moehler T, Benner A, et al. Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma. Clin Cancer Res 2002; 8 (11): 3377-82
69. Palumbo A, Giaccone L, Bertola A, et al. Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica 2001; 86 (4): 399-403
70. Durie BG. Low-dose thalidomide in myeloma: efficacy and biologic significance. Semin Oncol 2002; 29 (6 Suppl. 17): 34-8
71. Leleu X, Magro L, Fawaz A, et al. Efficacy of a low dose of thalidomide in advanced multiple myeloma. Blood 2002; 100 (4): 1519-20
72. Johnston RE, Abdalla SH. Thalidomide in low doses is effective for the treatment of resistant or relapsed multiple myeloma and for plasma cell leukaemia. Leuk Lymphoma 2002; 43 (2): 351-4
73. Kees M, Dimou G, Sillaber C, et al. Low dose thalidomide in patients with relapsed or refractory multiple myeloma. Leuk Lymphoma 2003; 44 (11): 1943-6
74. Palumbo A, Bertola A, Falco P, et al. Efficacy of low-dose thalidomide and dexamethasone as first salvage regimen in multiple myeloma. Hematol J 2004; 5 (4): 318-24
75. Yakoub-Agha I, Hulin C, Doyen C, et al. A multicenter prospective randomized study testing non-inferiority of thalidomide 100mg/day as compared with 400mg/day in patients with refractory/relapsed multiple myeloma: first results of the final analysis of the IFM 01-02 study [abstract]. Blood 2005; 106 (11): 137
76. Catley L, Tai YT, Chauhan D, et al. Perspectives for combination therapy to overcome drug-resistant multiple myeloma. Drug Resist Updat 2005; 8 (4): 205-18
77. Dimopoulos MA, Repoussis P, Terpos E, et al. Primary treatment with pulsed melphalan, dexamethasone, thalidomide (MDT) for symptomatic patients with multiple myeloma ≥75 years of age [abstract]. Blood 2004; 104: 1482
78. Palumbo A, Bertola A, Musto P, et al. A prospective randomized trial of oral melphalan, prednisone, thalidomide (MPT) vs oral melphalan, prednisone (MP): an interim analysis [abstract]. Blood 2004; 104: 207
79. Facon T, Mary JY, Hulin C, et al. Randomized clinical trial comparing melphalanprednisone (MP), MP-thalidomide (MP-THAL) and high-dose therapy using melphalan 100 mg/mL (MEL100) for newly diagnosed myeloma patients aged 65-75 years: interim analysis of the IFM 99-06 Trial on 350 Patients [abstract]. Blood 2004; 104: 206
80. Palumbo A, Bringhen S, Musto P, et al. Oral melphalan, prednisone and thalidomide for multiple myeloma [abstract no. 779]. Blood 2005, 230a
81. Palumbo A, Ambrosini MT, Pregno P, et al. Velcade™ plus melphalan, prednisone, and thalidomide (V-MPT) for advanced multiple myeloma [abstract no. 2553]. Blood 2005; 106 (11): 717a
82. Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002; 100 (9): 3063-7
83. Schey SA, Fields P, Bartlett JB, et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol 2004; 22 (16): 3269-76
84. Richardson P, Jagannath S, Schlossman R, et al. A multi-center, randomized, phase II study to evaluate the efficacy and safety of two CDC-5013 dose regimens when used alone or in combination with dexamethasone (Dex) for the treatment of relapsed or refractory multiple myeloma (MM). Blood 2002; 100 (11): 105a
85. Richardson PG, Jagannath S, Hussein MA, et al. A multicenter, single-arm, open-label study to evaluate the safety and efficacy of single-agent lenalidomide in subjects with relapsed and refractory multiple myeloma [abstract no. PO.737]. Hematol J 2005; 90 Suppl. 1: 154
86. Weber DM, Chen C, Niesvizky R, et al. A multicenter, randomized, parallel-group, double-blind, placebo-controlled study of lenalidomide plus dexamethasone versus dexamethasone alone in previously treated subjects with multiple myeloma [abstract]. Hematol J 2005; 90 Suppl. 1: 155
87. Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with CC-5013 (lenalidomide; Revlimid™) plus dexamethasone (Rev/Dex) for newly diagnosed myeloma (MM) [abstract]. Blood 2004; 104: 331
88. Palumbo A, Falco P, Musto P, et al. Oral Revlimid plus melphalan and prednisone (R-MP) for newly diagnosed multiple myeloma [abstract no. 785]. Blood 2005; 11: 173
89. Richardson PG, Schlossman R, Munshi N, et al. A phase 1 trial of lenalidomide (REVLIMID®) with bortezomib (VELCADE®) in relapsed and refractory multiple myeloma [abstract no. 365]. Blood 2005; 106 (11): 137
90. Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer 2004; 4 (5): 349-60
91. 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 (7): 3071-6
92. Lee AH, Iwakoshi NN, Anderson KC, et al. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc Natl Acad Sci U S A 2003; 100 (17): 9946-51
93. Hideshima T, Mitsiades C, Akiyama M, et al. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 2003; 101 (4): 1530-4
94. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 2002; 20 (22): 4420-7
95. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348 (26): 2609-17
96. Richardson P, Sonneveld P, Schuster M, et al. Bortezomib demonstrates superior efficacy to high-dose dexamethasone in relapsed multiple myeloma: final report of the APEX Study [abstract]. Blood 2004; 104 (11): 336
97. Richardson P, Sonneveld P, Schuster M, et al. Bortezomib continues to demonstrate superior efficacy compared with high-dose dexamethasone in relapsed multiple myeloma: updated results of the APEX trail [abstract no. 2547]. Blood 2005; 106 (11): 715a
98. Anderson KC. Bortezomib therapy for myeloma. Curr Hematol Rep 2004; 3 (1): 65
99. Chauhan D, Hideshima T, Mitsiades C, et al. Proteasome inhibitor therapy in multiple myeloma. Mol Cancer Ther 2005; 4 (4): 686-92
100. Paterson JL, Li Z, Wen XY, et al. Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma. Br J Haematol 2004; 124 (5): 595-603
101. Grand EK, Chase AJ, Heath C, et al. Targeting FGFR3 in multiple myeloma: inhibition of t (4;14)-positive cells by SU5402 and PD173074. Leukemia 2004; 18 (5): 962-6
102. 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 (9): 3521-8
103. Trudel S, Li ZH, 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 (7): 2941-8
104. Chen J, Lee BH, Williams IR, et al. FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies. Oncogene 2005; 24 (56): 8259-67
105. Negri J, Mitsiades N, Deng Q, et al. PKC412 Is a multi-targeting kinase inhibitor with activity against multiple myeloma in vitro and in vivo [abstract no. 247]. Blood 2005; 106 (11): 128
106. Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6 (1): 38-51
107. Mitsiades N, Mitsiades CS, Richardson PG, et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 2003; 101 (10):4055-62
108. Catley L, Weisberg E, Tai YT, et al. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood 2003; 102 (7): 2615-22
109. Catley L, Tai YT, Hideshima T, et al. Novel hydroxamic acid-derived HDAC inhibitor LBH589 potently activates intrinsic and extrinsic apoptotic pathways, and induces tubulin hyperacetylation in multiple myeloma [abstract]. Blood 2005; 106: 1578
110. Podar K, Anderson KC. The pathophysiological role of VEGF in hematological malignancies: therapeutic implications. Blood 2005; 105 (4): 1383-95
111. Bisping G, Leo R, Wenning D, et al. Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma. Blood 2003; 101 (7): 2775-83
112. Casanovas O, Hicklin DJ, Bergers G, et al. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005; 8 (4): 299-309
113. Thomas AL, Morgan B, Drevs J, et al. Vascular endothelial growth factor receptor tyrosine kinase inhibitors. PTK787/ZK 222584. Semin Oncol 2003; 30 (3 Suppl. 6): 32-8
114. 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 (17): 5019-26
115. Kumar R, Hopper TM, Miller CG, et al. Discovery and biological evaluation of GW654652: a pan inhibitor of VEGF receptors [abstract]. Proc Am Assoc Cancer Res 2003; 44 (9): 9
116. Ferrara N, Hillan KJ, Gerber HP, et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004; 3 (5): 391-400
117. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349 (5): 427-34
118. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003; 21 (16): 3127-32
119. Bisping G, Kropff M, Wenning D, et al. Targeting receptor kinases by a novel indolinone derivative in multiple myeloma. abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups. Blood 2006; 105 (5): 2079-89
120. Tai YT, Catley LP, Mitsiades CS, et al. Mechanisms by which SGN-40, a humanized anti-CD40 antibody, induces cytotoxicity in human multiple myeloma cells: clinical implications. Cancer Res 2004; 64 (8): 2846-52
121. Tai YT, Catley L, Li XF, et al. Immunomodulatory drug Lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications [abstract]. Blood 2005; 106: 150
122. Bezieau S, Avet-Loiseau H, Moisan JP, et al. Activating Ras mutations in patients with plasma-cell disorders. a reappraisal. Blood 2002; 100 (3): 1101-2; 1103
123. Bezieau S, Devilder MC, Avet-Loiseau H, et al. High incidence of N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis. Hum Mutat 2001; 18 (3): 212-24
124. Rowley M, Liu P, Van Ness B. Heterogeneity in therapeutic response of genetically altered myeloma cell lines to interleukin 6, dexamethasone, doxorubicin, and melphalan. Blood 2000; 96 (9): 3175-80
125. Ochiai N, Uchida R, Fuchida S, et al. Effect of farnesyl transferase inhibitor R115777 on the growth of fresh and cloned myeloma cells in vitro. Blood 2003; 102 (9): 3349-53
126. Adjei AA, Davis JN, Bruzek LM, et al. Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines. Clin Cancer Res 2001; 7 (5): 1438-45
127. Cortes J, Albitar M, Thomas D, et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood 2003; 101 (5): 1692-7
128. Beaupre DM, Cepero E, Obeng EA, et al. R115777 induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways. Mol Cancer Ther 2004; 3 (2): 179-86
129. Alsina M, Fonseca R, Wilson EF, et al. Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. Blood 2004; 103 (9): 3271-7
130. Chauhan D, Li G, Shringarpure R, et al. Blockade of Hsp27 overcomes bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 2003; 63 (19): 6174-7
131. Chauhan D, Li G, Hideshima T, et al. Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance. Blood 2003; 102 (9): 3379-86
132. Chauhan D, Auclair D, Robinson EK, et al. Identification of genes regulated by dexamethasone in multiple myeloma cells using oligonucleotide arrays. Oncogene 2002; 21 (9): 1346-58
133. Hideshima T, Podar K, Chauhan D, et al. p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene 2004 Nov 18; 23 (54): 8766-76
134. Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 2002; 99 (22): 14374-9
135. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Anti-myeloma activity of heat shock protein-90 inhibition. Blood 2006 Feb 1; 107 (3): 1092-100
136. Abraham RT. Identification of TOR signaling complexes: more TORC for the cell growth engine. Cell 2002; 111 (1): 9-12
137. Hosoi H, Dilling MB, Liu LN, et al. Studies on the mechanism of resistance to rapamycin in human cancer cells. Mol Pharmacol 1998; 54 (5): 815-24
138. Nelsen CJ, Rickheim DG, Tucker MM, et al. Evidence that cyclin D1 mediates both growth and proliferation downstream of TOR in hepatocytes. J Biol Chem 2003; 278 (6): 3656-63
139. Hu L, Shi Y, Hsu JH, et al. Downstream effectors of oncogenic ras in multiple myeloma cells. Blood 2003; 101 (8): 3126-35
140. Gera JF, Mellinghoff IK, Shi Y, et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem 2004; 279 (4): 2737-46
141. Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 2000; 19 (56): 6680-6
142. Frost P, Moatomed F, Hoang B, et al. In vivo anti-tumor effects of the mTOR inhibitor, CCI-779, against human multiple myeloma cells in a xenograft model. Blood 2004 Dec 15; 104 (13): 4181-7
143. Raje N, Kumar S, Hideshima T, et al. Combination of the mTOR inhibitor rapamycin and Revlimid™ (CC-5013) has synergistic activity in multiple myeloma. Blood 2004 Dec 15; 104 (13): 4188-93
144. 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 (MM) cells [abstract no. 250]. Blood 2005; 106 (11): 128
145. Huston A, Singha U, Alsayed Y, et al. The role of the AKT inhibitor perifosine in migration and adhesion in multiple myeloma (MM) [abstract no. 2509]. Blood 2005; 106 (11): 267
146. Huston A, Francis L, Alsayed Y, et al. Combination of the AKT inhibitor perifosine with the HSP90 inhibitor 17-(dimethylaminoethylamino)-17- demethoxygeldanamycin (17-DMAG) has synergistic activity in multiple myeloma (MM) [abstract no. 1592]. Blood 2005; 106 (11): 219
147. Sinha R, David E, Zeilter E, et al. Combination of Akt/PKB inhibition (perifosine) and farnesyl transferase inhibition (tipifarnib) results in increased cell death in myeloma cell lines [abstract no. 1568]. Blood 2005; 106 (11): 218
148. Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A 2005; 102 (24): 8567-72
149. Macherla VR, Mitchell SS, Manam RR, et al. Structure-activity relationship studies of salinosporamide A (NPI-0052), a novel marine derived proteasome inhibitor. J Med Chem 2005; 48 (11): 3684-7
150. 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 (5): 407-19
151. Ishitsuka K, Hideshima T, Hamasaki M, et al. Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway. Oncogene 2005; 24 (38): 5888-96
152. Raje N, Kumar S, Hideshima T, et al. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood 2005; 106 (3): 1042-7
153. Boissy P, Andersen TL, Abdallah BM, et al. Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation. Cancer Res 2005; 65 (21): 9943-52
154. Yasui H, Hideshima T, Hamasaki M, et al. SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma. Blood 2005; 106 (2): 706-12
155. Hamasaki M, Hideshima T, Tassone P, et al. Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo. Blood 2005; 105 (11): 4470-6
156. Yasui H, Hideshima T, Raje N, et al. FTY720 induces apoptosis in multiple myeloma cells and overcomes drug resistance. Cancer Res 2005; 65 (16): 7478-84
157. Akiyama M, Hideshima T, Hayashi T, et al. Cytokines modulate telomerase activity in a human multiple myeloma cell line. Cancer Res 2002; 62 (13): 3876-82
158. Akiyama M, Hideshima T, Shammas MA, et al. Effects of oligonucleotide N3′->P5′ thio-phosphoramidate (GRN163) targeting telomerase RNA in human multiple myeloma cells. Cancer Res 2003; 63 (19): 6187-94
159. Shammas MA, Shmookler Reis RJ, Akiyama M, et al. Telomerase inhibition and cell growth arrest by G-quadruplex interactive agent in multiple myeloma. Mol Cancer Ther 2003; 2 (9): 825-33
160. Hideshima T, Chauhan D, Richardson P, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277 (19): 16639-47
161. Hideshima T, Chauhan D, Hayashi T, et al. Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma. Cancer Res 2003; 63 (23): 8428-36
162. Chauhan D, Li G, Podar K, et al. The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance. Blood 2004; 103 (8): 3158-66
163. van de Donk NW, Kamphuis MM, Lokhorst HM, et al. The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells. Leukemia 2002; 16 (7): 1362-71
164. van de Donk NW, Kamphuis MM, van Kessel B, et al. Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels. Blood 2003; 102 (9): 3354-62
165. Hideshima T, Akiyama M, Hayashi T, et al. Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood 2003; 101 (2): 703-5
166. Chauhan D, Catley L, Hideshima T, et al. 2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells. Blood 2002; 100 (6): 2187-94
167. Chauhan D, Li G, Auclair D, et al. Identification of genes regulated by 2-methoxyestradiol (2ME2) in multiple myeloma cells using oligonucleotide arrays. Blood 2003; 101 (9): 3606-14
168. Pelliniemi TT, Irjala K, Mattila K, et al. Immunoreactive interleukin-6 and acute phase proteins as prognostic factors in multiple myeloma. Finnish Leukemia Group. Blood 1995; 85 (3): 765-71
169. Bataille R, Klein B. The bone-resorbing activity of interleukin-6. J Bone Miner Res 1991; 6 (10): 1143-6
170. Klein B, Wijdenes J, Zhang XG, et al. Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood 1991; 78 (5): 1198-204
171. Brochier J, Legouffe E, Liautard J, et al. Immunomodulating IL-6 activity by murine monoclonal antibodies. Int J Immunopharmacol 1995; 17 (1): 41-8
172. Kyrstsonis MC, Dedoussis G, Baxevanis C, et al. Serum interleukin-6 (IL-6) and interleukin-4 (IL-4) in patients with multiple myeloma (MM). Br J Haematol 1996; 92 (2): 420-2
173. Levy Y, Tsapis A, Brouet JC. Interleukin-6 antisense oligonucleotides inhibit the growth of human myeloma cell lines. J Clin Invest 1991; 88 (2): 696-9
174. Sporeno E, Savino R, Ciapponi L, et al. Human interleukin-6 receptor super-antagonists with high potency and wide spectrum on multiple myeloma cells. Blood 1996; 87 (11): 4510-9
175. Villunger A, Egle A, Kos M, et al. Constituents of autocrine IL-6 loops in myeloma cell lines and their targeting for suppression of neoplastic growth by antibody strategies. Int J Cancer 1996; 65 (4): 498-505
176. Tassone P, Forciniti S, Galea E, et al. Synergistic induction of growth arrest and apoptosis of human myeloma cells by the IL-6 super-antagonist Sant7 and dexamethasone. Cell Death Differ 2000; 7 (3): 327-8
177. Tassone P, Galea E, Forciniti S, et al. The IL-6 receptor super-antagonist Sant7 enhances antiproliferative and apoptotic effects induced by dexamethasone and zoledronic acid on multiple myeloma cells. Int J Oncol 2002; 21 (4): 867-73
178. Mitsiades CS, Mitsiades NS, McMullan CJ, 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 (3): 221-30
179. Gerth K, Bedorf N, Hofle G, et al. Epothilons A and B. antifungal and cytotoxic compounds from sorangium cellulosum (myxobacteria): production, physicochemical and biological properties. J Antibiot (Tokyo) 1996; 49 (6): 560-3
180. Lin B, Catley L, LeBlanc R, et al. Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo. Blood 2005 Jan 1; 105 (1): 350-7