Evolving therapeutic paradigms for multiple myeloma: Back to the future

Leukemia and Lymphoma

Volumn 54, Issue 3, 2013, Pages 451-463

  Cherry, Benjamin M ^a   Korde, Neha ^a   Kwok, Mary ^a   Roschewski, Mark ^a   Landgren, Ola ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

Author keywords

Extended dosing; Lenalidomide; Maintenance; Multiple myeloma; Thalidomide

Indexed keywords

BORTEZOMIB; CARFILZOMIB; DEXAMETHASONE; DIAMIDINE DERIVATIVE; DOXORUBICIN; GLUCOCORTICOID RECEPTOR; I KAPPA B; LENALIDOMIDE; MELPHALAN; PAMIDRONIC ACID; PLACEBO; PREDNISONE; QUININE; RECOMBINANT ALPHA INTERFERON; SARCOLYSIN; STILBAMIDINE; THALIDOMIDE; TRANSCRIPTION FACTOR AP 1; VINCRISTINE;

ALLOGENEIC STEM CELL TRANSPLANTATION; AUTOLOGOUS STEM CELL TRANSPLANTATION; BODY WEIGHT; BONE MARROW TUMOR; CANCER COMBINATION CHEMOTHERAPY; CANCER MORTALITY; CANCER RADIOTHERAPY; CANCER REGRESSION; CANCER SURVIVAL; CHEMOTHERAPY INDUCED ANEMIA; CHILL; COGNITION; CONSOLIDATION CHEMOTHERAPY; CONSTIPATION; DRUG DOSE COMPARISON; DRUG FEVER; DRUG INDUCED HEADACHE; DRUG MEGADOSE; DRUG TOLERABILITY; DRUG WITHDRAWAL; EDEMA; FLU LIKE SYNDROME; FOLLOW UP; GRAFT VERSUS HOST REACTION; HEALTH CARE COST; HEART ARRHYTHMIA; HUMAN; IMMUNE RESPONSE; IMMUNOSUPPRESSIVE TREATMENT; IN VITRO STUDY; IN VIVO STUDY; INFECTION; LEUKOPENIA; LIVER FUNCTION TEST; LOW DRUG DOSE; MALAISE; META ANALYSIS (TOPIC); MOOD; MOON FACE; MULTIPLE MYELOMA; MUSCLE WEAKNESS; MYALGIA; MYELODYSPLASTIC SYNDROME; NONHUMAN; PATIENT MONITORING; PERIPHERAL NEUROPATHY; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; QUALITY OF LIFE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; SOMNOLENCE; TACHYCARDIA; THROMBOCYTOPENIA; TREATMENT DURATION; VENOUS THROMBOEMBOLISM;

ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; COMBINED MODALITY THERAPY; GLUCOCORTICOIDS; HUMANS; INTERFERONS; MELPHALAN; MULTIPLE MYELOMA; PREDNISONE; STEM CELL TRANSPLANTATION; TRANSPLANTATION, AUTOLOGOUS;

EID: 84873354623     PISSN: 10428194     EISSN: 10292403     Source Type: Journal    
DOI: 10.3109/10428194.2012.717277     Document Type: Review

References (123)

1. Nerlich AG, Rohrbach H, Bachmeier B, et al. Malignant tumors in two ancient populations: an approach to historical tumor epidemiology. Oncol Rep 2006: 16: 197-202.
2. Raab MS, Podar K, Breitkreutz I, et al. Multiple myeloma. Lancet 2009;374: 324-339.
3. Perez-Persona E, Vidriales MB, Mateo G, et al. New criteria to identify risk of progression in monoclonal gammopathy of uncertain signif cance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells. Blood 2007;110: 2586-2592.
4. Landgren O, Kyle RA, Pfeifer RM, et al. Monoclonal gammopathy of undetermined signif cance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009;113: 5412-5417.
5. Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined signif cance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia 2010;24: 1121-1127.
6. Kyle RA, Steensma DP. History of multiple myeloma. Recent Results Cancer Res 2011: 183: 3-23.
7. McArthur JR, Athens JW, Wintrobe MM, et al. Melphalan and myeloma. Experience with a low-dose continuous regimen. Ann Intern Med 1970;72: 665-670.
8. Harrington WJ, Moloney WC. The treatment of multiple myeloma with urethane. Cancer 1950;3: 253-271.
9. Speed DE, Galton DA, Swan A. Melphalan in the treatment of myelomatosis. Br Med J 1964;1: 1664-1669.
10. Snapper I. On the inf uence of stilbamidine upon multiple myeloma. J Mt Sinai Hosp NY 1946: 13: 119-127.
11. Scott RB. Cancer chemotherapy-the first twenty-f ve years. Br Med J 1970;4: 259-265.
12. Blokhin N, Larionov L, Perevodchikova N, et al. [Clinical experiences with sarcolysin in neoplastic diseases]. Ann NY Acad Sci 1958;68: 1128-1132.
13. Myelomatosis: comparison of melphalan and cyclophosphamide therapy. Br Med J 1971;1: 640-641.
14. Alexanian R, Bergsagel DE, Migliore PJ, et al. Melphalan therapy for plasma cell myeloma. Blood 1968;31: 1-10.
15. Bergsagel DE, Grifth KM, Haut A, et al. The treatment of plasma cell myeloma. Adv Cancer Res 1967: 10: 311-359.
16. Alexanian R, Haut A, Khan AU, et al. Treatment for multiple myeloma. Combination chemotherapy with Different melphalan dose regimens. JAMA 1969;208: 1680-1685.
17. Costa G, Engle RL, Schilling A, et al. Melphalan and prednisone: an Effective combination for the treatment of multiple myeloma. Am J Med 1973;54: 589-599.
18. Remission maintenance therapy for multiple myeloma. Southwest Oncology Group Study. Arch Intern Med 1975;135: 147-152.
19. Trotta PP. Preclinical biology of alpha interferons. Semin Oncol 1986;13: 3-12.
20. Edwards BS, Hawkins MJ, Borden EC Comparative in vivo and in vitro activation of human natural killer cells by two recombinant alpha-interferons Differing in antiviral activity. Cancer Res 1984;44: 3135-3139.
21. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994: 264: 1415-1421.
22. Du Z, Wei L, Murti A, et al. Non-conventional signal transduction by type 1 interferons: the NF-kappaB pathway. J Cell Biochem 2007;102: 1087-1094.
23. Creasey AA, Bartholomew JC, Merigan TC. Role of G0-G1 arrest in the inhibition of tumor cell growth by interferon. Proc Natl Acad Sci USA 1980;77: 1471-1475.
24. Gutterman JU. Cytokine therapeutics: lessons from interferon alpha. Proc Natl Acad Sci USA 1994;91: 1198-1205.
25. Mellstedt H, Aahre A, Bjorkholm M, et al. Interferon therapy in myelomatosis. Lancet 1979;2: 697.
26. Ahre A, Bjorkholm M, Mellstedt H, et al. Human leukocyte interferon and intermittent high-dose melphalan-prednisone administration in the treatment of multiple myeloma: a randomized clinical trial from the Myeloma Group of Central Sweden. Cancer Treat Rep 1984;68: 1331-1338.
27. Khoo TL, Vangsted AJ, Joshua D, et al. Interferon-alpha in the treatment ofmultiple myeloma. Curr Drug Targets 2011;12: 437-446.
28. Mandelli F, Avvisati G, Amadori S, et al. Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med 1990;322: 1430-1434.
29. Corso A, Nozza A, Lazzarino M, et al. Plateau phase in multiple myeloma: an end-point of conventional-dose chemotherapy. Haematologica 1999: 84: 336-341.
30. Fritz E, Ludwig H. Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients. Ann Oncol 2000;11: 1427-1436.
31. Myeloma Trialists' Collaborative Group. Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 2001: 113: 1020-1034.
32. Quesada JR, Talpaz M, Rios A, et al. Clinicaltoxicityofinterferons in cancer patients: a review. J Clin Oncol 1986;4: 234-243.
33. Valentine AD, Meyers CA, Kling MA, et al. Mood and cognitive side Effects of interferon-alpha therapy. Semin Oncol 1998: 25: 39-47.
34. Floyd JD, Nguyen DT, Lobins RL, et al. Cardiotoxicity of cancer therapy. J Clin Oncol 2005: 23: 7685-7696.
35. Weiss K. Safety profile of interferon-alpha therapy. Semin Oncol 1998;25: 9-13.
36. Case DC Jr, Sonneborn HL, Paul SD, et al. Phase II study of rDNA alpha-2 interferon (INTRON A) in patients with multiple myeloma utilizing an escalating induction phase. Cancer Treat Rep 1986: 70: 1251-1254.
37. Blade J, San Miguel JF, Escudero ML, et al. Maintenance treatment with interferon alpha-2b in multiple myeloma: a prospective randomized study from PETHEMA (Program for the Study and Treatment of Hematological Malignancies, Spanish Society of Hematology). Leukemia 1998;12: 1144-1148.
38. Schaar CG, Kluin-Nelemans HC, Te Marvelde C, et al. Interferon-alpha as maintenance therapy in patients with multiple myeloma. Ann Oncol 2005;16: 634-639.
39. Moalli PA, Rosen ST. Glucocorticoid receptors and resistance to glucocorticoids in hematologic malignancies. Leuk Lymphoma 1994;15: 363-374.
40. Gaynon PS, Carrel AL. Glucocorticosteroid therapy in childhood acute lymphoblastic leukemia. Adv Exp Med Biol 1999: 457: 593-605.
41. Alexanian R, Dimopoulos M. The treatment of multiple myeloma. NEngl JMed 1994;330: 484-489.
42. Greenstein S, Ghias K, Krett NL, et al. Mechanisms of glucocorticoid-mediated apoptosis in hematological malignancies. Clin Cancer Res 2002;8: 1681-1694.
43. Frankfurt O, Rosen ST. Mechanisms of glucocorticoid-induced apoptosis in hematologic malignancies: updates. Curr Opin Oncol 2004;16: 553-563.
44. Salmon SE, Crowley JJ, Balcerzak SP, et al. Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol 1998;16: 890-896.
45. Alexanian R, Weber D, Dimopoulos M, et al. Randomized trial of alpha-interferon or dexamethasone as maintenance treatment for multiple myeloma. Am J Hematol 2000;65: 204-209.
46. Berenson JR, Crowley JJ, Grogan TM, et al. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 2002;99: 3163-3168.
47. McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet 1983;2: 822-824.
48. Selby P, Zulian G, Forgeson G, et al. The development of high dose melphalan and of autologous bone marrow transplantation in the treatment of multiple myeloma: Royal Marsden and St Bartholomew's Hospital studies. Hematol Oncol 1988;6: 173-179.
49. Westbury G, Humble JG, Newton KA, et al. Disseminated malignant melanoma: response to treatment by massive dosage of a cytotoxic agent combined with autogenous marrow replacement. Lancet 1959;1: 968-969.
50. Ariel IM, Pack GT. Treatment of disseminated melanoma with phenylalanine mustard (melphelan) and autogenous bone marrow transplants. Surgery 1962;51: 583-591.
51. Barlogie B, Alexanian R, Dicke KA, et al. High-dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma. Blood 1987;70: 869-872.
52. Barlogie B, Hall R, Zander A, et al. High-dose melphalan with autologous bone marrow transplantation for multiple myeloma. Blood 1986;67: 1298-1301.
53. Barlogie B, Jagannath S, Naucke S, et al. Long-term follow-up after high-dose therapy for high-risk multiple myeloma. Bone Marrow Transplant 1998;21: 1101-1107.
54. 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: 91-97.
55. 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: 1875-1883.
56. Barlogie B, Tricot GJ, van Rhee F, et al. Long-term outcome results of the first tandem autotransplant trial for multiple myeloma. Br J Haematol 2006;135: 158-164.
57. Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol 2007;25: 2434-2441.
58. Gahrton G, Svensson H, Cavo M, et al. Progress in allogenic bone marrow and peripheral blood stem cell transplantation for multiple myeloma: a comparison between transplants performed 1983-93 and 1994-8 at European Group for Blood and Marrow Transplantation centres. Br JHaematol 2001;113: 209-216.
59. Bjorkstrand B, Iacobelli S, Hegenbart U, et al. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol 2011;29: 3016-3022.
60. Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol 2011;12: 1195-1203.
61. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 2006;108: 3289-3294.
62. Kotla V, Goel S, Nischal S, et al. Mechanism of action ofilenalidomide in hematological malignancies. J Hematol Oncol 2009;2: 36.
63. D'Amato RJ, Loughnan MS, Flynn E, et al. T alidomide is an inhibitor ofangiogenesis. Proc Natl Acad Sci USA 1994;91: 4082-4085.
64. Kenyon BM, Browne F, D'Amato RJ. Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization. Exp Eye Res 1997;64: 971-978.
65. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341: 1565-1571.
66. Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002;20: 4319-4323.
67. List AF. Lenalidomide-the phoenix rises. N Engl J Med 2007;357: 2183-2186.
68. Barlogie B, Tricot G, Anaissie E, et al. T alidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006;354: 1021-1030.
69. Lokhorst HM, Schmidt-Wolf I, Sonneveld P, et al. T alidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma. Haematologica 2008;93: 124-127.
70. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol 2009;27: 1788-1793.
71. Barlogie B, Pineda-Roman M, van Rhee F, et al. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood 2008;112: 3115-3121.
72. Hahn-Ast C, von Lilienfeld-Toal M, van Heteren P, et al. Improved progression-free survival and overall survival with thalidomide maintenance therapy in multiple myeloma: a meta-analysis of randomized trials in 2274 patients. Haematologica 2010: 95(Suppl. 2): Abstract 0942.
73. Beksac M, Haznedar R, Firatli-Tuglular T, et al. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol 2011: 86: 16-22.
74. 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.
75. Waage A, Gimsing P, Fayers P, et al. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood 2010;116: 1405-1412.
76. Wijermans P, Schaafsma M, Termorshuizen F, et al. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol 2010;28: 3160-3166.
77. Palumbo A, Bringhen S, Liberati AM, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood 2008;112: 3107-3114.
78. Lonial S, Mitsiades CS, Richardson PG. Treatment options for relapsed and refractory multiple myeloma. Clin Cancer Res 2011;17: 1264-1277.
79. Laubach J, Richardson P, Anderson K. Multiple myeloma. Annu Rev Med 2011;62: 249-264.
80. Barlogie B, Attal M, Crowley J, et al. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol 2010;28: 1209-1214.
81. Stewart AK, Chen CI, Howson-Jan K, et al. Resultsofamulticenter randomized phase II trial of thalidomide and prednisone maintenance therapy for multiple myeloma after autologous stem cell transplant. Clin Cancer Res 2004;10: 8170-8176.
82. Stewart AK, Trudel S, Bahlis N, et al. A randomized phase III trial of thalidomide and prednisone as maintenance therapy following autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM): the NCIC CTG MY. 10 trial. Blood 2010: 116(Suppl. 1): Abstract 2039.
83. Abdelkef A, Ladeb S, Torjman L, et al. Singleautologousstem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood 2008: 111: 1805-1810.
84. Retraction in Blood 2009;113: 6265.
85. Morgan GJ, Gregory WM, Davies FE, et al. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood 2012;119: 7-15.
86. Ludwig H, Adam Z, Tothova E, et al. Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica 2010;95: 1548-1554.
87. Barlogie B, Anaissie E, van Rhee F, et al. Reiterative survival analyses of total therapy 2 for multiple myeloma elucidate follow-up time dependency of prognostic variables and treatment arms. J Clin Oncol 2010;28: 3023-3027.
88. Lokhorst HM, van der Holt B, Zweegman S, et al. A randomized phase 3 study on the Effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood 2010: 115: 1113-1120.
89. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111: 2516-2520.
90. Dimopoulos MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials ofilenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia 2009;23: 2147-2152.
91. Palumbo A, Delforge M, Catalano J, et al. Aphase3studyevaluating the Effcacy and safety ofilenalidomide combined with melphalan and prednisone in patients ≥65 years with newly diagnosed multiple myeloma (NDMM): continuous use ofilenalidomide vs fixed-duration regimens. Blood 2010;116(Suppl. 1): Abstract 2310.
92. Palumbo A, Gay F, Falco P, et al. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation- maintenance in untreated multiple myeloma patients. J Clin Oncol 2010;28: 800-807.
93. Davies F, Baz R. Lenalidomide mode of action: linking bench and clinical fndings. Blood Rev 2010;24(Suppl. 1): S13-S19.
94. Lopez-Girona A, Heintel D, Zhang LH, et al. Lenalidomide downregulates the cell survival factor, interferon regulatory factor-4, providing a potential mechanistic link for predicting response. Br J Haematol 2011;154: 325-336.
95. Heintel D, Zojer N, Schreder M, et al. Expression ofMUM1/IRF4 mRNA as a prognostic marker in patients with multiple myeloma. Leukemia 2008: 22: 441-445.
96. Lioznov M, El-Cheikh J Jr, Hofmann F, et al. Lenalidomide as salvage therapy after allo-SCT for multiple myeloma is Effective and leads to an increase of activated NK (NKp44(+)) and T (HLA-DR(+)) cells. Bone Marrow Transplant 2010;45: 349-353.
97. van Heteren P, Renz O, Hahn-Ast C, et al. Activation of innate immunity in patients receiving combination therapy with lenalidomide (Revlimid), cyclophosphamide and low-dose dexamethasone (RCd) for newly diagnosed or relapsed/refractory myeloma. Haematologica 2010: 95(Suppl. 2): Abstract 0352.
98. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366: 1770-1781.
99. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. NEngl JMed 2012;366: 1782-1791.
100. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 2012;366: 1759-1769.
101. Landgren O, Tomas A, Mailankody S. Myeloma and second primary cancers. N Engl J Med 2011;365: 2241-2242.
102. Tomas A, Mailankody S, Korde N, et al. Second malignan-cies after multiple myeloma: from 1960s to 2010s. Blood 2012: 119: 2731-2737.
103. Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and Effective antitumor agents. Cancer Res 1999: 59: 2615-2622.
104. Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer 2004: 4: 349-360.
105. Hideshima T, Chauhan D, Schlossman R, et al. The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene 2001;20: 4519-4527.
106. LeBlanc R, Catley LP, Hideshima T, et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 2002: 62: 4996-5000.
107. Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001;61: 3071-3076.
108. Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther 2011;10: 2034-2042.
109. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003;348: 2609-2617.
110. Mateos MV, Hernandez JM, Hernandez MT, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood 2006;108: 2165-2172.
111. Hernandez JM, Garcia-Sanz R, Golvano E, et al. Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma. Br J Haematol 2004;127: 159-164.
112. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359: 906-917.
113. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352: 2487-2498.
114. Mateos MV, Oriol A, Martinez-Lopez J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 2010;11: 934-941.
115. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone- thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol 2010;28: 5101-5109.
116. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al. HOVON-65/GMMG-HD4 randomized phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly diagnosed multiple myeloma (MM). Blood 2010: 116(Suppl. 1): Abstract 2040.
117. Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clash of philosophies. Blood 2011;118: 3205-3211.
118. van Rhee F, Szymonifka J, Anaissie E, et al. Total Therapy 3 for multiple myeloma: prognostic implications of cumulative dosing and premature discontinuation of VTD maintenance components, bortezomib, thalidomide, and dexamethasone, relevant to all phases oftherapy. Blood 2010;116: 1220-1227.
119. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11: 29-37.
120. Tan D, Ong KH, Koh LP, et al. The impact of frontline risk-adapted strategy on the overall survival of patients with newly diagnosed multiple myeloma: an analysis of the Singapore multiple myeloma study group. Eur J Haematol 2012: 89: 136-144.
121. Moreau P, Rajkumar SV. "Should all eligible patients with multiple myeloma receive autologous stem-cell transplant as part of initial treatment? ". Leuk Res 2012: 36: 677-681.
122. Badros AZ. Lenalidomide in myeloma-a high-maintenance friend. N Engl J Med 2012;366: 1836-1838.
123. Waxman AJ, Kuehl WM, Balakumaran A, et al. Smoldering (asymptomatic) multiple myeloma: revisiting the clinical dilemma and looking into the future. Clin Lymphoma Myeloma Leuk 2010: 10: 248-257.