New drugs in multiple myeloma

Current Opinion in Supportive and Palliative Care

Volumn 2, Issue 3, 2008, Pages 204-210

  Berenson, James R ^a,b   Yellin, Ori ^a  

^a Oncotherapeutics   (United States)

^b Institute for Myeloma   (United States)

Author keywords

Bortezomib; Lenalidomide; Multiple myeloma; Thalidomide; Treatment

Indexed keywords

ANTINEOPLASTIC AGENT; ARSENIC TRIOXIDE; BORONIC ACID DERIVATIVE; BORTEZOMIB; DRUG DERIVATIVE; LENALIDOMIDE; ORGANOARSENIC DERIVATIVE; OXIDE; PYRAZINE DERIVATIVE; THALIDOMIDE;

CLINICAL TRIAL; HUMAN; MULTIPLE MYELOMA; REVIEW;

ANTINEOPLASTIC AGENTS; ARSENICALS; BORONIC ACIDS; CLINICAL TRIALS AS TOPIC; HUMANS; MULTIPLE MYELOMA; OXIDES; PYRAZINES; THALIDOMIDE;

EID: 54049134117     PISSN: 17514258     EISSN: 17514266     Source Type: Journal    
DOI: 10.1097/SPC.0b013e3283090475     Document Type: Article

References (115)

1. RajkumarSV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc 2005; 80:1371-1382.
2. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23:3412-3420.
3. Barlogie B, Kyle RA, Anderson KC, etal. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 2006; 24:929-936.
4. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78:21-33.
5. 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 cooperativegroup PETHEMA. Blood 2005; 106:3755-3759.
6. Richardson PG, Barlogie B, Berenson J, etal. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348:2609-2617.
7. Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses of bortezomib in relapsed orrefractorymyeloma. Br JHaematol 2004; 127:165-172.
8. Richardson PG, Sonneveld P, Schuster MW, etal. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352:2487-2498.
9. Orlowski RZ, Voorhees PM, Garcia RA, etal. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 2005; 105:3058-3065.
10. Biehn SE, Moore DT, Voorhees PM, et al. Extended follow-up of outcome measures in multiple myeloma patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin. Ann Hematol 2007; 86:211-216.
11. Orlowski RZ, Zhuang SH, Parekh T, et al., DOXIL-MMY-3001 Study Investigators. The combination of pegylated liposomal doxorubicin and bortezomib significantly improves time to progression of patients with relapsed/refractory multiple myeloma compared with bortezomib alone: results from a planned interim analysis of a randomized phase III study. Blood 2006; 108:124a.
12. Friedman J, Al-Zoubi A, Kaminski M, et al. A new model predicting at least a very good partial response in patients with multiple myeloma after 2 cycles of velcade-based therapy. Haematologica 2006; 91:273.
13. Jakubowiak AJ, Brackett L, Kendall T, et al. Combination therapy with velcade, doxil, and dexamethasone (VDD) for patients with relapsed/ refractory multiple myeloma (MM). Blood 2005; 106:378b.
14. Hollmig K, Stover J, Talamo G, et al. Bortezomib (Velcade) adriamycin thalidomide dexamethasone (VATD) as an effective regimen in patients with refractory or relapsed multiple myeloma (MM). Blood 2004; 104:659a.
15. Leoni F, Casini C, Breschi C, etal. Low dose bortezomib, dexamethasone, thalidomide plus liposomal doxorubicin in relapsed and refractory myeloma. Haematologica 2006; 91:281.
16. Padmanabhan S, Miller K, Musiel L, etal. Bortezomib (Velcade) in combination with liposomal doxorubicin (Doxil) and thalidomide is an active salvage regimen in patients with relapsed or refractory multiple myeloma: final results of a phase II trial. Haematologica 2006; 91:277.
17. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 2007; 25:3892-3901.
18. Sonneveld P, Hajek R, Nagler A, et al. Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/ lenalidomide therapy. Cancer 2008; 112:1529-1537.
19. Mateos MV, Hernández JM, Hernández MT, et al. Bortezomib plus melphalan andprednisoneinelderlyuntreatedpatientswithmultiplemyeloma:resultsof a multicenter phase 1/2 study. Blood 2006; 108:2165-2172.
20. San Miguel JF, Schlag R, Khuageva N, et al. A phase 3 study comparing bortezomib-melphalan-prednisone (VMP) with melphalan-prednisone (MP) in newly diagnosed multiple myeloma. Blood 2007; 110:76.
21. Berenson JR, Yellin O, Woytowitz D, et al. Bortezomib, ascorbic acid and melphalan (BAM) therapy for patients (pts) with newly diagnosed multiple myeloma (MM): an effective and well tolerated frontline regimen. Blood 2007; 110:3602.
22. Grad AJ, Bahlis NJ, Reis I, et al. Ascorbic acid enhances arsenic trioxide- induced cytotoxicity in multiple myeloma cells. Blood 2001; 98:805-813.
23. May JM, Qu Z, Li X, etal. Requirement for GSH in recycling of ascorbic acid in endothelial cells. Biochem Pharmacol 2001; 62:873-881.
24. Gupta V, Singh SV, Ahmad H, et al. Glutathione and glutathione S-transferases in a human plasma cell line selected for resistance to melphalan. Biochem Pharmacol 1989; 38:1993-2000.
25. Bellamy WT, Dalton WS, Gleason MC, et al. Development and character- izationofamelphalanresistanthumanmultiplemyelomacellline.CancerRes 1991; 51:995-1002.
26. Campbell RA, SanchezE, Steinberg JA, etal.Antimyelomaeffectsofarsenic trioxide are enhanced by melphalan, bortezomib and ascorbic acid. Br J Haematol 2007; 138:467-478.
27. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 2006; 24:3113-3120.
28. San Miguel JF, Richardson P, Sonneveld P, et al. Frequency, characteristics, andreversibilityofperipheralneuropathy(PN)intheAPEXtrial. Blood2005;106:111a.
29. Anderson K, Richardson P, Chanan-Khan A, et al. Single-agentbortezomib in previouslyuntreatedmultiplemyeloma: resultsofaphaseIImulticenterstudy [Abstract 7504]. J Clin Oncol 2006; 24:423s.
30. Oakervee HE, Popat R, Curry N, et al. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol 2005; 129:755-762.
31. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341:1565-1571.
32. Barlogie B, Desikan R, Eddlemon P, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 studyof169 patients. Blood 2001; 98:492-494.
33. Rajkumar SV, Fonseca R, Dispenzieri A, et al. Thalidomide in the treatmentof relapsed multiple myeloma. Mayo Clin Proc 2000; 75:897-901.
34. Schey SA, Cavenagh J, Johnson R, etal. An UK myeloma forum phase II study of thalidomide: long term follow-up and recommendations for treatment.Leuk Res 2003; 27:909-914.
35. 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; 3:185-192.
36. 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; 5:318-324.
37. Hatjiharissi E, Terpos E, Papaioannou M, et al. The combination of intermediate doses of thalidomide and dexamethasone reduces bone marrow micro-vesseldensitybutnotserumlevelsofangiogeniccytokinesinpatients with refractory/relapsed multiple myeloma. Hematol Oncol 2004; 22:159-168.
38. Palumbo A, Giaccone L, Bertola A, et al. Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica 2001; 86:399-403.
39. Palumbo A, Falco P, Ambrosini MT, et al. Thalidomide plus dexamethasone is an effective salvage regimen for myeloma patients relapsing after autologous transplant. Eur J Haematol 2005; 75:391-395.
40. TerposE, Mihou D, SzydloR, etal.Thecombination ofintermediatedosesof thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio. Leukemia 2005; 19:1969-1976.
41. Murakami H, Handa H, Abe M, et al. Low-dose thalidomide plus low-dose dexamethasone therapy in patients with refractory multiple myeloma. Eur J Haematol 2007; 79:234-239.
42. Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thali- domide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002; 20:4319-4323.
43. Cavo M, Zamagni E, Tosi P, et al. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica 2004; 89:826-831.
44. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006; 24:431-436.
45. Cavo M, Patriarca F, Tacchetti P, et al. Bortezomib (Velcade)-thalidomide- dexamethasone (VTD) vs thalidomide-dexamethasone (TD) in preparation for autologous stem-cell (SC) transplantation (ASCT) in newly diagnosedmultiple myeloma (MM). Blood 2007; 110:73.
46. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalido- mide improves survival in patients with multiple myeloma. Blood 2006; 108:3289-3294.
47. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 2006; 367:825-831.
48. Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet2007; 370:1209-1218.
49. Martino M, Console G, Callea V, et al. Low tolerance and high toxicity of thalidomide as maintenance therapy after double autologous stem cell transplant in multiple myeloma patients. Eur J Haematol 2007; 78:35-40.
50. Mileshkin L, Stark R, DayB, et al. Developmentofneuropathyin patients with myeloma treated with thalidomide: patterns of occurrence and the role of electrophysiologic monitoring. J Clin Oncol 2006; 24:4507-4514.
51. Naina HVK, Lacy MQ, Dispenzieri A, et al. Incidence and clinical course of peripheral neuropathy in patients receiving thalidomide for the treatment of multiple myeloma. Blood 2005; 106:970a.
52. Celgene Corporation. THALOMID- (Thalidomide) Capsules [prescribing information]. Available at http://www.celgene.com/PDF/Thalomid-PI.pdf [Accessed 9 October 2006].
53. Hussein MA. Thromboembolism risk reduction in multiple myeloma patients treated with immunomodulatory drug combinations. Thromb Haemost 2006; 95:924-930.
54. Rajkumar SV. Thalidomide therapy and deep venous thrombosis in multiple myeloma. Mayo Clin Proc 2005; 80:1549-1551.
55. 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; 80:1568-1574.
56. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22:414-423.
57. Richardson PG, Blood E, Mitsiades CS, 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.
58. Richardson PG, MitsiadesCS, Hideshima T, etal. The emerging role ofnovel therapies for the treatment of relapsed myeloma. J Natl Compr Canc Netw 2007; 5:149-162.
59. Weber DM, Chen C, NiesvizkyR, etal. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. Lenalidomide plus dexametha- sone for relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133-2142.
60. Dimopoulos MA, Spencer T, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007; 357:21232132.
61. Baz R, Walker E, Karam MA, et al. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol 2006; 17:1766-1771.
62. Morgan GJ, Schey SA, Wu P, et al. Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated regimen for myelomapatients. Br JHaematol 2007; 137:268-269.
63. Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005; 106:4050-4053.
64. Rajkumar SV, Jacobus S, Callander N, et al. A randomized trial of lenalido- mide plus high-dose dexamethasone (RD) versus lenalidomide plus low-dose dexamethasone (Rd) in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. Blood 2007; 110:74.
65. Richardson P, Jagannath S, Raje N, et al. Lenalidomide, bortezomib, and dexamethasone (Rev/Vel/Dex) in patients with relapsed or relapsed/ refractory multiple myeloma (MM): preliminary results of a phase II study.Blood 2007; 110:2714.
66. Richardson P, Jagannath S, Raje N, et al. Lenalidomide, bortezomib, and dexamethasone (Rev/Vel/Dex) as front-line therapy for patients with multiple myeloma (MM): preliminary results of a phase 1/2 study. Blood 2007;110:187.
67. BartlettJB, DredgeK, Dalgleish AG. The evolution ofthalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 2004; 4:314-322.
68. 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; 100:3063-3067.
69. Richardson P, Jagannath S, Hussein M, etal. Amulticenter, single-arm, open- label study to evaluate the efficacy and safety of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma: preliminary results. Blood 2005; 106:449a.
70. Wang M, Knight R, Dimopoulos M, et al. Comparison of lenalidomide in combination with dexamethasone to dexamethasone alone in patients who have received prior thalidomide in relapsed or refractory multiple myeloma.J Clin Oncol 2006; 24:427s.
71. Knight R, DeLap RJ, Zeldis JB. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med 2006; 354:2079-2080.
72. Zonder JA, Durie BGM, McCoy J, et al. High incidence of thrombotic events observed in patients receiving lenalidomide (L)-dexamethasone (D) (LD) as first-line therapy for multiple myeloma (MM) without aspirin (ASA) prophylaxis. Blood 2005; 106:964a.
73. Palumbo A, Rus C, Zeldis JB, et al. Enoxaparin or aspirin for the prevention of recurrent thromboembolism in newly diagnosed myeloma patients treated with melphalan and prednisone plus thalidomide or lenalidomide. J Thromb Haemost 2006; 4:1842-1845.
74. Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J Med 2006; 354:2079-2080.
75. Niesvizky R, Spencer A, Wang M, et al. Increased risk of thrombosis with lenalidomide in combination with dexamethasone and erythropoietin [Abstract 7506]. J Clin Oncol 2006; 24:423s.
76. Munshi NC, Tricot G, Desikan R, et al. Clinical activity of arsenic trioxide for the treatment of multiple myeloma. Leukemia 2002; 16:1835-1837.
77. Hussein MA, Saleh M, Ravandi F, et al. Phase 2 study of arsenic trioxide in patients with relapsed or refractory multiple myeloma. Br J Haematol 2004; 125:470-476.
78. Rousselot P, Larghero J, ArnulfB, et al. A clinical and pharmacological study of arsenic trioxide in advanced multiple myeloma patients. Leukemia 2004;18:1518-1521.
79. Bahlis NJ, Cafferty-Grad J, Jordan-McMurry I, et al. Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of elapsed/refractory multiple myeloma. Clin Cancer Res 2002; 8:3658-3668.
80. Wu K, van Droogenbroeck J, Beksac M, et al. Treatment with arsenic trioxide, ascorbic acid and dexamethasone in advanced myeloma patients: preliminary findings of a multicenter, phase II study. Blood 2005; 106:5135.
81. Berenson J, Boccia R, Siegel D, et al. Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single-arm study. Br J Haematol 2006; 135:174-183.
82. Berenson J, Matous J, Swift RA, et al. A phase I/II study of arsenic trioxide/ bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma. Clin Cancer Res 2007; 13:1762-1768.
83. Berenson JR, Yeh HS. Arsenic compounds in the treatment of multiple myeloma: a new role for a historical remedy. Clin Lymphoma Myeloma 2006; 7:192-198.
84. Huang CH, Chen WJ, Wu CC, et al. Complete atrioventricular block after arsenic trioxide treatment in an acute promyelocytic leukemic patient. Pacing Clin Electrophysiol 1999; 22:965-967.
85. Westervelt P, Brown RA, Adkins DR, et al. Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood 2001;98:266-271.
86. Trisenox (arsenic trioxide) [product insert]. Frazer, PA: Cephalon, Inc; 2005.
87. Chauhan D, Singh A, Brahmandam M, et al. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 2008; 111:1654-1664.
88. Orlowski RZ, Stewart K, Vallone M, etal. Safety and Antitumor Efficacy of the Proteasome Inhibitor Carfilzomib (PR-171) Dosed for Five Consecutive Days in Hematologic Malignancies: Phase 1 Results. Blood 2007; 110:409.
89. Alsina M, Trudel S, Vallone M, etal. Phase 1 single agentantitumor activityof twice weekly consecutive day dosing of the proteasome inhibitor carfilzomib (PR-171) in hematologic malignancies. Blood 2007; 110:411.
90. 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; 102:2615-2622.
91. Catley L, Weisberg E, Kiziltepe T, etal. Aggresome induction byproteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacety- lase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 2006; 108:3441-3449.
92. Maiso P, Carvajal-Vergara X, Ocio EM, etal. The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. Cancer Res 2006; 66:5781 -5789.
93. Hideshima T, Bradner JE, Wong ZG, 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; 102:8567-8572.
94. Richardson P, Mitsiades C, Colson K, et al. Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leuk Lymphoma 2008; 49:502-507.
95. Weber DM, Jagannath S, Mazumder A, et al. Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in combination with bortezomib in patients with advanced multiple myeloma. Blood 2007; 110:1172.
96. Badros A, Philip S, NiesvizkR, etal. Phase I trial of suberoylanilide hydroxamic acid (SAHA) + bortezomib (Bort) in relapsed multiple myeloma (MM) patients (pts). Blood 2007; 110:1168.
97. Mitsiades CS, Mitsiades NS, McMullan CJ, etal. Antimyeloma activityofheat shock protein-90 inhibition. Blood 2006; 107:1092-1100.
98. Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of protea- some inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 2002; 99:14374-14379.
99. Duus J, Bahar HI, Venkataraman G, etal. Analysisofexpression ofheatshock protein-90 (HSP90) and the effects ofHSP90 inhibitor (17-AAG) in multiple myeloma. Leuk Lymphoma 2006; 47:1369-1378.
100. Sydor JR, Normant E, Pien CS, 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.
101. Chatterjee M, Jain S, Stuhmer T, et al. STAT3 and MAPK signaling maintain overexpression ofheatshockproteins 90 alpha and beta in multiple myeloma cells, which critically contribute to tumor-cell survival. Blood 2007; 109:720-728.
102. Francis LK, Alsayed Y, Leleu X, et al. Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17- demethoxygeldanamycin has synergistic activity in multiple myeloma. Clin Cancer Res 2006; 12:6826-6835.
103. Richardson PG, Chanan-Khan AA, AlsinaM, etal. Safetyand activityofKOS- 953 in patients with relapsed refractory multiple myeloma (MM): interim results of a phase I trial. Blood 2005; 106:109a.
104. Richardson PG, Chanan-Khan AA, Lonial S, et al. Tanespimycin (T) + bortezomib (BZ) in multiple myeloma (MM): confirmation of the recommended dose using a novel formulation. Blood 2007; 110:1165.
105. HideshimaT, NakamuraN, Chauhan D, etal. Biologic sequelae ofinterleukin- 6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 2001;20:5991 -6000.
106. Hsu J, Shi Y, Krajewski S, et al. The AKT kinase is activated in multiple myeloma tumor cells. Blood 2001; 98:2853-2855.
107. Hsu JH, Shi Y, Hu L, et al. Role of the AKT kinase in expansion of multiple myeloma clones: effects on cytokine-dependent proliferative and survival responses. Oncogene 2002; 21:1391-1400.
108. Mitsiades CS, Mitsiades N, Poulaki V, et al. Activation of NF-kappaB and upregulation ofintracellular antiapoptotic proteins viatheIGF-1/Aktsignaling in human multiple myeloma cells: therapeutic implications. Oncogene 2002; 21:5673-5683.
109. 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.
110. Kiziltepe T, Hideshima T, Ishitsuka K, et al. JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells. Blood 2007; 110:709-718.
111. Richardson PG, Jakubowiak A, Wolf J, et al. A multicenter phase I/II trial of perifosine (KRX-0401) + bortezomib in relapsed and refractory multiple myeloma patients treated with bortezomib: Preliminary results. Haematolo- gica 2007; 92:155-156.
112. Richardson PG, Lonial S, Jakubowiak A, et al. Perifosine (KRX-0401) plus low dose dexamethasone is active in patients with relapsed and refractory multiple myeloma (MM): perifosine MM investigator group phase II multi- center study update. Haematologica 2007; 92:155.
113. JakubowiakA, Richardson P, Zimmerman T, etal. Amulticenter phase I trial of perifosine (KRX-0401) in combination with lenalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma: preliminary results. Multiple myeloma research consortium (MMRC) trial. Haematologica 2007; 92:154-155.
114. Frost P, Moatamed F, Hoang B, et al. In vivo antitumor effects of the mTOR inhibitorCCI-779 againsthuman multiplemyelomacells in axenograftmodel. Blood 2004; 104:4181 -4187.
115. 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.