The emerging role of carfilzomib combination therapy in the management of multiple myeloma

Expert Review of Hematology

Volumn 7, Issue 2, 2014, Pages 265-290

  Moreau, Philippe ^a  

^a HÔTEL DIEU   (France)

Author keywords

carfilzomib; drug combinations; multiple myeloma; newly diagnosed; relapsed refractory

Indexed keywords

ALKYLATING AGENT; ARRY 520; ASCORBIC ACID; BENDAMUSTINE; BORTEZOMIB; CARFILZOMIB; CISPLATIN; CLARITHROMYCIN; CYCLOPHOSPHAMIDE; DEXAMETHASONE; DOXORUBICIN; ETOPOSIDE; GLUCOCORTICOID; HISTONE DEACETYLASE INHIBITOR; IMMUNOMODULATING AGENT; KINESIN INHIBITOR; LENALIDOMIDE; MELPHALAN; PANOBINOSTAT; POMALIDOMIDE; PREDNISONE; PROTEASOME INHIBITOR; THALIDOMIDE; UNCLASSIFIED DRUG; VINCRISTINE; VORINOSTAT;

ANEMIA; AUTOLOGOUS STEM CELL TRANSPLANTATION; CANCER COMBINATION CHEMOTHERAPY; CREATININE BLOOD LEVEL; DRUG APPROVAL; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; DYSPNEA; EUROPEAN UNION; FATIGUE; FEVER; FOOD AND DRUG ADMINISTRATION; HUMAN; HYPERTENSION; LOW DRUG DOSE; LUNG INFECTION; MAXIMUM TOLERATED DOSE; MONOTHERAPY; MULTICENTER STUDY (TOPIC); MULTIPLE CYCLE TREATMENT; MULTIPLE MYELOMA; MYELOMA CELL; NAUSEA; NEUTROPENIA; OVERALL SURVIVAL; PERIPHERAL NEUROPATHY; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PNEUMONIA; PRACTICE GUIDELINE; PRIORITY JOURNAL; PROGNOSIS; PROGRESSION FREE SURVIVAL; RELAPSE; REVIEW; SIDE EFFECT; THROMBOCYTOPENIA; TREATMENT OUTCOME; UNITED STATES;

ALKYLATING AGENTS; CLINICAL TRIALS AS TOPIC; DRUG THERAPY, COMBINATION; GLUCOCORTICOIDS; HISTONE DEACETYLASE INHIBITORS; HUMANS; IMMUNOLOGIC FACTORS; MULTIPLE MYELOMA; OLIGOPEPTIDES; PROTEASOME INHIBITORS;

EID: 84896372314     PISSN: 17474086     EISSN: 17474094     Source Type: Journal    
DOI: 10.1586/17474086.2014.873699     Document Type: Review

References (122)

1. Becker N. Epidemiology of multiple myeloma. Recent Results Cancer Res 2011;183:25-35
2. Munshi NC, Anderson KC, Bergsagel PL, et al. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood 2011;117(18): 4696-700
3. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111(5):2516-20
4. Kyprolis prescribing information. 2012. Available from: www.accessdata.fda.gov/drugsatfda-docs/label/2012/202714lbl.pdf [Last accessed 22 August 2013]
5. Pomalyst prescribing information. 2013. Available from: www.accessdata.fda.gov/drugsatfda-docs/label/2013/204026lbl.pdf [Last accessed 22 August 2013]
6. Richardson PG, Siegel DS, Vij R, et al. Randomized, open label Phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): Phase 2 results. Presented at: 53rd American Society of Hematology (ASH) Annual Meeting and Exposition; 10-13 December 2011; San Diego, CA, USA
7. Lonial S, Mitsiades CS, Richardson PG. Treatment options for relapsed and refractory multiple myeloma. Clin Cancer Res 2011;17(6):1264-77
8. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood 2011;117(18): 4691-5
9. Nooka A, Lonial S. Sequential or combination therapy for multiple myeloma. Expert Rev Hematol 2012;5(5):533-45
10. Kapoor P, Ramakrishnan V, Rajkumar SV. Bortezomib combination therapy in multiple myeloma. Semin Hematol 2012; 49(3):228-42
11. Lonial S, Kaufman JL. The era of combination therapy in myeloma. J Clin Oncol 2012;30(20):2434-6
12. 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(25): 3892-901 (Pubitemid 47477266)
13. Moreau P, Richardson PG, Cavo M, et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood 2012;120(5):947-59
14. Rajkumar SV. Doublets, triplets, or quadruplets of novel agents in newly diagnosed myeloma? Hematology Am Soc Hematol Educ Program 2012;2012:354-61
15. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised Phase 3 study. Lancet 2010; 376(9758):2075-85
16. Mateos MV, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the Phase III VISTA trial. J Clin Oncol 2010;28(13): 2259-66
17. 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(9): 906-17
18. Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomidedexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 2012;30(20):2475-82
19. Velcade prescribing information. 2012. Available from: www.accessdata.fda.gov/drugsatfda-docs/label/2012/021602s031s032lbl.pdf [Last accessed 22 August 2013]
20. Velcade summary of product information.
21. Gentile M, Recchia AG, Mazzone C, Morabito F. Emerging biological insights and novel treatment strategies in multiple myeloma. Expert Opin Emerg Drugs 2012; 17(3):407-38
22. Broyl A, Jongen JL, Sonneveld P. General aspects and mechanisms of peripheral neuropathy associated with bortezomib in patients with newly diagnosed multiple myeloma. Semin Hematol 2012;49(3): 249-57
23. Mateos MV. How to maintain patients on long-term therapy: understanding the profile and kinetics of adverse events. Leuk Res 2012;36(Suppl 1):S35-43
24. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 2007;67(13):6383-91 (Pubitemid 47037522)
25. Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitinproteasome pathway, against preclinical models of multiple myeloma. Blood 2007; 110(9):3281-90 (Pubitemid 350106321)
26. Arastu-Kapur S, Anderl JL, Kraus M, et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res 2011;17(9):2734-43
27. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A Phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 2012;120(9):1801-9
28. Badros AZ, Vij R, Martin T, et al. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia 2013;27(8):1707-14
29. O'Connor OA, Stewart AK, Vallone M, et al. A Phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res 2009;15(22):7085-91
30. Papadopoulos KP, Lee P, Singhal S, et al. A Phase 1b/2 study of prolonged infusion carfilzomib in patients with relapsed and/or refractory (R/R) multiple myeloma: updated efficacy and tolerability from the completed 20/56 mg/m2 expansion cohort of PX-171-007. Presented at: 53rd American Society of Hematology (ASH) Annual Meeting and Exposition; 10-13 December 2011; San Diego, CA, USA
31. Siegel DS, Martin T, Wang M, et al. A Phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012;120(14):2817-25
32. Siegel DS, Wang M, Martin TG III, et al. A Phase 2 study of prolonged carfilzomib therapy in patients with multiple myeloma previously enrolled in carfilzomib clinical trials. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
33. Fostier K, De Becker A, Schots R. Carfilzomib: a novel treatment in relapsed and refractory multiple myeloma. Onco Targets Ther 2012;5:237-44
34. Khan RZ, Badros A. Role of carfilzomib in the treatment of multiple myeloma. Expert Rev Hematol 2012;5(4):361-72 . A drug profile review article that summarizes the published data that have been obtained with carfilzomib.
35. Kortuem KM, Stewart AK. Carfilzomib. Blood 2013;121:893-7 . Recent review article that nicely summarizes the preclinical and clinical studies that have been conducted with carfilzomib.
36. Jakubowiak AJ, Siegel DS, Martin T, et al. Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003- A1 study. Leukemia 2013. [Epub ahead of print]
37. Hajek R, Bryce R, Ro S, Klencke B, Ludwig H. Design and rationale of FOCUS. (PX-171-011): a randomized, open-label, Phase 3 study of carfilzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma (R/R MM). BMC Cancer 2012;12:415
38. Dasmahapatra G, Lembersky D, Kramer L, et al. The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. Blood 2010; 115(22):4478-87
39. Di Liberto M, Huang X, Bretz J, et al. Induction of metabolic impairment in prolonged early G1 arrest induced by CDK4/CDK6 inhibition sensitizes myeloma cells for proteasome inhibitor killing during subsequent S phase synchronization. Presented at: 52nd American Society of Hematology (ASH) Annual Meeting and Exposition; 4-7 December 2010; Orlando, FL, USA
40. Gu J, Hernandez-Ilizaliturri FJ, Kaufman GP, Mavis C, Czuczman MS. Carfilzomib (CFZ): a novel proteasome inhibitor that induces cell cycle arrest and cell death in rituximab-chemotherapy resistant lymphoma and potentiates the antitumor activity of chemotherapeutic agents. Presented at: 52nd American Society of Hematology (ASH) Annual Meeting and Exposition; 4-7 December 2010; Orlando, FL, USA
41. Kaufman GP, Hernandez-Ilizaliturri FJ, Mavis C, Patil R, Czuczman MS. Evaluation of carfilzomib to disrupt the apoptotic threshold of B-cell lymphomas by targeting Bcl-2 family members and overcome rituximab (R) chemotherapy resistance. Presented at: American Society of Clinical Oncology (ASCO) 2010 Annual Meeting; 4-8 June 2010; Chicago, IL, USA
42. Rao R, Fiskus W, Balusu R, et al. Treatment with histone deacetylase 6-specific inhibitor WT-161 disrupts hsp90 function, abrogates aggresome formation and sensitizes human mantle cell lymphoma cells to lethal ER stress induced by proteasome inhibitor carfilzomib. Presented at: 52nd American Society of Hematology (ASH) Annual Meeting and Exposition; 4-7 December 2010; Orlando, FL, USA
43. 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(11):2034-42
44. Woessner R, Tunquist B, Walker D, et al. Combination of the KSP inhibitor ARRY-520 with bortezomib causes sustained tumor regressions and significantly increased time to regrowth in bortezomib sensitive and resistant models of multiple myeloma. Presented at: 102nd American Association for Cancer Research (AACR) Annual Meeting; 2-6 April 2011; Orlando, FL, USA
45. Jagannath S, Richardson PG, Barlogie B, et al. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica 2006; 91(7):929-34 (Pubitemid 44023146)
46. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a Phase II clinical trial. Leukemia 2009;23(7):1337-41
47. Richardson PG, Jagannath S, Jakubowiak AJ, et al. Phase II trial of lenalidomide, bortezomib, and dexamethasone in patients (pts) with relapsed and relapsed/refractory multiple myeloma (MM): updated efficacy and safety data after >2 years of follow-up. Presented at: 52nd American Society of Hematology (ASH) Annual Meeting and Exposition; 4-7 December 2010; Orlando, FL, USA
48. Wang Z, Yang J, Kirk C, et al. Clinical pharmacokinetics, metabolism, and drug-drug interaction of carfilzomib. Drug Metab Dispos 2013;41(1):230-7
49. Yang J, Wang Z, Fang Y, et al. Pharmacokinetics, pharmacodynamics, metabolism, distribution, and excretion of carfilzomib in rats. Drug Metab Dispos 2011;39(10):1873-82
50. Badros A, Papadopoulos KP, Zojwalla N, Lee JR, Siegel DS. 30-min infusion of high dose carfilzomib plus dexamethasone in patients with relapsed and/or refractory multiple myeloma. Presented at: 14th International Myeloma Workshop; 3-7 April 2013; Kyoto, Japan
51. Badros AZ, Papadopoulos KP, Zojwalla N, Lee JR, Siegel DS. A Phase 1b study of 30-minute infusion carfilzomib 20/45 and 20/56 mg/m2 plus 40 mg weekly dexamethasone in patients with relapsed and/or refractory (R/R) multiple myeloma. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
52. Lendvai N, Landau H, Lesokhin A, et al. Phase II study of infusional carfilzomib in patients with relapsed or refractory multiple myeloma. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
53. Berdeja JG, Mace J, Lamar RE, et al. A single-arm, open-label, multicenter Phase I/II study of the combination of panobinostat (pan) and carfilzomib (cfz) in patients (pts) with relapsed/refractory multiple myeloma (RR MM). Presented at: American Society of Clinical Oncology (ASCO) 2012 Annual Meeting; 1-5 June 2012; Chicago, IL, USA
54. Berdeja JG, Hart L, Lamar R, et al. Phase I/II study of panobinostat and carfilzomib in patients (pts) with relapsed or refractory multiple myeloma (MM), interim Phase I safety analysis. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
55. Kaufman J, Zimmerman T, Jakubowiak A, et al. Phase I study of the combination of carfilzomib and panobinostat for patients with relapsed and refractory myeloma: a multicenter MMRC clinical trial. Presented at: 18th Congress of the European Hematology Association (EHA); 13-16 June 2013; Stockholm, Sweden
56. Shah JJ, Thomas SK, Weber DM, et al. Phase 1/1b study of the efficacy and safety of the combination of panobinostat + carfilzomib in patients with relapsed and/or refractory multiple myeloma. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
57. Shah JJ, Weber DM, Thomas SK, et al. Phase 1 study of the novel kinesin spindle protein inhibitor ARRY-520 + carfilzomib in patients with relapsed and/or refractory multiple myeloma. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
58. Shah J, Thomas S, Weber D, Wang M, Orlowski R. Phase 1 study of the novel kinesin spindle protein inhibitor ARRY-520 + carfilzomib (Car) in patients with relapsed and/or refractory multiple myeloma (RRMM). Presented at: 18th Congress of the European Hematology Association (EHA); 13-16 June 2013; Stockholm, Sweden
59. Array BioPharma reports financial results for the first quarter of fiscal 2014 and announces ARRY-520 development strategy. Available from: http://phx.corporate-ir.net/phoenix.zhtml?c=123810&p=irolnewsArticle&ID= 1870705 [Last accessed 12 November 2013]
60. Shah JJ, Stadtmauer EA, Abonour R, et al. A multi-center Phase I/II trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
61. Stadtmauer E, Shah J, Abonour R, et al. Carfilzomib, pomalidomide and dexamethasone (CPomd) for relapsed/refractory multiple myeloma (RRMM): a Phase I/II trial. Presented at: 14th International Myeloma Workshop; 3-7 April 2013; Kyoto, Japan
62. Bilotti E, Vesole D, Richter J, et al. Preliminary results of a Phase I/II study of carfilzomib, lenalidomide, vorinostat and dexamethasone (QUAD) in relapsed and/or refractory multiple myeloma. Presented at: 18th Congress of the European Hematology Association (EHA); 13-16 June 2013; Stockholm, Sweden
63. Usmani S, Szymonifka J, Sexton R, et al. Phase II study of carfilzomib (CFZ) combined with other anti-myeloma agents in relapsed-refractory multiple myeloma (RRMM) - updates on the UARK compassionate use protocol. Presented at: 53rd American Society of Hematology (ASH) Annual Meeting and Exposition; 10-13 December 2011; San Diego, CA, USA
64. Atrash S, Tullos A, Panozzo S, et al. Retrospective analysis of cardiovascular (CV) events following compassionate use of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (RRMM). Presented at: American Society of Clinical Oncology (ASCO) 2013 Annual Meeting; 31 May-4 June 2013; Chicago, IL, USA
65. Siegel DS, Wang M, Martin T, et al. Phase 2 study of prolonged carfilzomib therapy in patients previously enrolled in carfilzomib Phase 1 and 2 trials. Presented at: 14th International Myeloma Workshop; 3-7 April 2013; Kyoto, Japan
66. Berenson JR, Yellin O, Dichmann R, et al. A Phase I/II study of carfilzomib (CFZ) as a replacement for bortezomib (BTZ) for multiple myeloma (MM) patients (pts) progressing while receiving a BTZ-containing combination regimen. Presented at: American Society of Clinical Oncology (ASCO) 2012 Annual Meeting; 1-5 June 2012; Chicago, IL, USA
67. Berenson JR, Hilger JD, Dichmann R, et al. A Phase 1/2 study of carfilzomib as a replacement for bortezomib for multiple myeloma (MM) patients (pts) refractory to a bortezomib-containing combination regimen. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
68. Berenson JR, Hilger J, Dichmann R, et al. Phase 1/2 study of carfilzomib replacing bortezomib for multiple myeloma (MM) pts refractory to a BTZ-containing regimen. Presented at: 14th International Myeloma Workshop; 3-7 April 2013; Kyoto, Japan
69. Berenson JR, Hilger JD, Dichmann R, et al. Results of a Phase I/II study (NCT01365559) of carfilzomib (CFZ) replacing bortezomib (BTZ) in BTZcontaining regimens for BTZ-treated patients (pts) with relapsed and refractory multiple myeloma (MM). Presented at: American Society of Clinical Oncology (ASCO) 2013 Annual Meeting; 31 May-4 June 2013; Chicago, IL, USA
70. Niesvizky R, Wang M, Martin T, et al. Final results from the Phase 1b/2 study (PX-171-006) of carfilzomib (CFZ) in combination with lenalidomide and low-dose dexamethasone (CRd) for patients with relapsed or progressive multiple myeloma. Presented at: 18th Congress of the European Hematology Association (EHA); 13-16 June 2013; Stockholm, Sweden
71. Niesvizky R, Martin TG III, Bensinger WI, et al. Phase Ib dose-escalation study (PX- 171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Clin Cancer Res 2013;19(8):2248-56
72. Wang M, Martin T, Bensinger W, et al. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood 2013;122(18): 3122-8
73. Moreau P, Palumbo AP, Stewart AK, et al. A randomized, multicenter, Phase (Ph) III study comparing carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (Dex) to LEN and Dex in patients (Pts) with relapsed multiple myeloma (MM). Presented at: American Society of Clinical Oncology (ASCO) 2011 Annual Meeting; 3-7 June 2011; Chicago, IL, USA
74. NCCN clinical practice guidelines in oncology: multiple myeloma, version 2.
75. Jakubowiak AJ, Dytfeld D, Jasielec J, et al. Carfilzomib, lenalidomide, low-dose dexamethasone (CRd) in elderly patients with newly diagnosed multiple myeloma (NDMM). Presented at: 14th International Myeloma Workshop; 3-7 April 2013; Kyoto, Japan
76. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up. Presented at: American Society of Clinical Oncology (ASCO) 2013 Annual Meeting; 31 May-4 June 2013; Chicago, IL, USA
77. Moreau P, Avet-Loiseau H, Harousseau JL, Attal M. Current trends in autologous stem-cell transplantation for myeloma in the era of novel therapies. J Clin Oncol 2011; 29(14):1898-906
78. Korde N, Zingone A, Kwok M, et al. Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone (CRd) in newly diagnosed multiple myeloma (MM) patients. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
79. Korde N, Zingone A, Kwok M, et al. Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide extended dosing (CRD-R) in newly diagnosed multiple myeloma (MM) patients. Presented at: 18th Congress of the European Hematology Association (EHA); 13-16 June 2013; Stockholm, Sweden
80. Sonneveld P, Hacker E, Zweegman S, et al. Carfilzomib combined with thalidomide and dexamethasone (CARTHADEX) as induction treatment prior to high-dose melphalan (HDM) in newly diagnosed patients with multiple myeloma (MM). A trial of the European myeloma network EMN. Presented at: 53rd American Society of Hematology (ASH) Annual Meeting and Exposition; 10-13 December 2011; San Diego, CA, USA
81. Sonneveld P, Asselbergs E, Zweegman S, et al. Carfilzomib combined with thalidomide and dexamethasone (CTD) is an highly effective induction and consolidation treatment in newly diagnosed patients with multiple myeloma (MM) who are transplant candidate. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
82. Mikhael J, Reeder CB, Libby EN, et al. A Phase I/II trial of cyclophosphamide, carfilzomib, thalidomide, and dexamethasone (CYCLONE) in patients with newly diagnosed multiple myeloma. Presented at: American Society of Clinical Oncology (ASCO) 2012 Annual Meeting; 1-5 June 2012; Chicago, IL, USA
83. Mikhael JR, Reeder CB, Libby EN III, et al. Results from the Phase II dose expansion of cyclophosphamide, carfilzomib, thalidomide and dexamethasone (CYCLONE) in patients with newly diagnosed multiple myeloma. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
84. Kolb B, Hulin C, Caillot D, et al. Phase I/II study of carfilzomib plus melphalanprednisone (CMP) in elderly patients with de novo multiple myeloma. Presented at: American Society of Clinical Oncology (ASCO) 2012 Annual Meeting; 1-5 June 2012; Chicago, IL, USA
85. Moreau P, Kolb B, Hulin C, et al. Carfilzomib plus melphalan-prednisone induces very high response rates in elderly patients with newly diagnosed myeloma. Presented at: 14th International Myeloma Workshop; 3-7 April 2013; Kyoto, Japan
86. Moreau P, Kolb B, Hulin C, et al. CMPcarfilzomib (CFZ) plus melphalanprednisone (MP)-in elderly patients (pts) with newly diagnosed multiple myeloma (NDMM): results of a Phase (Ph) I/II trial. Presented at: 18th Congress of the European Hematology Association (EHA); 13-16 June 2013; Stockholm, Sweden
87. Touzeau C, Kolb B, Hulin C, et al. Effect of CMP, carfilzomib (CFZ) plus melphalan-prednisone (MP), on response rates in elderly patients (pts) with newly diagnosed multiple myeloma (NDMM): results of a Phase (Ph) I/II trial. Presented at: American Society of Clinical Oncology (ASCO) 2013 Annual Meeting; 31 May-4 June 2013; Chicago, IL, USA
88. 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. Lancet 2007;370(9594): 1209-18 (Pubitemid 47516593)
89. Palumbo A, Falco P, Corradini P, et al. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA - Italian Multiple Myeloma Network. J Clin Oncol 2007;25(28):4459-65 (Pubitemid 350063804)
90. 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(1):29-37
91. Bringhen S, Federica C, Petrucci M, et al. Carfilzomib, cyclophosphamide and dexamethasone (CCD) for newly diagnosed multiple myeloma (MM) patients: initial results of a multicenter, open label Phase II study. Presented at: 18th Congress of the European Hematology Association (EHA); 13-16 June 2013; Stockholm, Sweden
92. Palumbo A, Bringhen S, Villani O, et al. Carfilzomib, cyclophosphamide and dexamethasone (CCd) for newly diagnosed multiple myeloma (MM) patients. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
93. Palumbo A, Bringhen S, Petrucci MT, et al. A Phase II trial of carfilzomib, cyclophosphamide and dexamethasone (CCd) for newly diagnosed multiple myeloma patients. Presented at: 14th International Myeloma Workshop; 3-7 April 2013; Kyoto, Japan
94. Fassas A, Shaughnessy J, Barlogie B. Cure of myeloma: hype or reality? Bone Marrow Transplant 2005;35(3):215-24 (Pubitemid 40268291)
95. San-Miguel JF, Mateos MV. Can multiple myeloma become a curable disease? Haematologica 2011;96(9):1246-8
96. Kumar SK, Dispenzieri A, Gertz MA, et al. Continued improvement in survival in multiple myeloma and the impact of novel agents. Presented at: 54th American Society of Hematology (ASH) Annual Meeting and Exposition; 8-11 December 2012; Atlanta, GA, USA
97. Harousseau JL, Dreyling M. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21(Suppl 5): v155-7
98. Bird JM, Owen RG, D'Sa S, et al. Guidelines for the diagnosis and management of multiple myeloma 2011. Br J Haematol 2011;154(1):32-75
99. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 Phase III trial. J Clin Oncol 2010;28(30):4621-9
100. Kumar S, Flinn I, Richardson PG, et al. Randomized, multicenter, Phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012;119(19):4375-82
101. Sonneveld P, Schmidt-Wolf IG, Van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized Phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol 2012;30(24):2946-55
102. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010;116(5):679-86
103. Roussel M, Avet-Loiseau H, Moreau P, et al. Frontline therapy with bortezomib, lenalidomide, and dexamethasone (VRD) induction followed by autologous stem cell transplantation, VRD consolidation and lenalidomide maintenance in newly diagnosed multiple myeloma patients: primary results of the IFM 2008 Phase II study. Presented at: 52nd American Society of Hematology (ASH) Annual Meeting and Exposition; 4-7 December 2010; Orlando, FL, USA
104. Rosinol L, Cibeira MT, Mateos MV, et al. A Phase III PETHEMA/GEM study of induction therapy prior autologous stem cell transplantation (ASCT) in multiple myeloma: superiority of VTD (bortezomib/thalidomide/dexamethasone) over TD and VBMCP/VBAD plus bortezomib. Presented at: 52nd American Society of Hematology (ASH) Annual Meeting and Exposition; 4-7 December 2010; Orlando, FL, USA
105. Niesvizky R, Flinn IW, Rifkin RM, et al. Phase 3b UPFRONT study: safety and efficacy of weekly bortezomib maintenance therapy after bortezomib-based induction regimens in elderly, newly diagnosed multiple myeloma patients. Presented at: 52nd American Society of Hematology (ASH) Annual Meeting and Exposition; 4-7 December 2010; Orlando, FL, USA
106. Niesvizky R, Flinn IW, Rifkin R, et al. Efficacy and safety of three bortezomibbased combinations in elderly, newly diagnosed multiple myeloma patients: results from all randomized patients in the community-based, Phase 3b UPFRONT study. Presented at: 53rd American Society of Hematology (ASH) Annual Meeting and Exposition; 10-13 December 2011; San Diego, CA, USA
107. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352(24): 2487-98 (Pubitemid 41007864)
108. Richardson PG, Sonneveld P, Schuster M, et al. Extended follow-up of a Phase 3 trial in relapsed multiple myeloma: final time-toevent results of the APEX trial. Blood 2007; 110(10):3557-60 (Pubitemid 350159621)
109. Jagannath S, Barlogie B, Berenson J, et al. A Phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 2004;127(2):165-72 (Pubitemid 39371809)
110. Mikhael JR, Belch AR, Prince HM, et al. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global Phase 3b expanded access program. Br J Haematol 2009;144(2): 169-75
111. Anderson KC, Jagannath S, Jakubowiak A, et al. Lenalidomide, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma (MM): encouraging outcomes and tolerability in a Phase II study. Presented at: American Society of Clinical Oncology (ASCO) 2009 Annual Meeting; 29 May-2 June 2009; Orlando, FL, USA
112. Richardson PG, Weller E, Jagannath S, et al. Multicenter, Phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol 2009;27(34):5713-9
113. Kropff M, Bisping G, Schuck E, et al. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol 2007;138(3):330-7 (Pubitemid 47035389)
114. Nair B, van Rhee F, Shaughnessy JD Jr, et al. Superior results of Total Therapy 3 (2003-33) in gene expression profilingdefined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance. Blood 2010;115(21): 4168-73
115. Richardson PG, Alsina M, Weber DM, et al. Phase II study of the pan-deacetylase inhibitor panobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomib-refractory multiple myeloma (PANORAMA 2). Presented at: 53rd American Society of Hematology (ASH) Annual Meeting and Exposition; 10-13 December 2011; San Diego, CA, USA
116. Lonial S, Cohen A, Zonder J, et al. The novel KSP inhibitor ARRY-520 demonstrates single-agent activity in refractory myeloma: results from a Phase 2 trial in patients with relapsed/refractory multiple myeloma (MM). Presented at: 53rd American Society of Hematology (ASH) Annual Meeting and Exposition; 10-13 December 2011; San Diego, CA, USA
117. Shah JJ, Zonder J, Cohen A, et al. ARRY-520 shows durable responses in patients with relapsed/refractory multiple myeloma in a Phase 1 dose-escalation study. Presented at: 53rd American Society of Hematology (ASH) Annual Meeting and Exposition; 10-13 December 2011; San Diego, CA, USA
118. Morgan GJ, Davies FE, Gregory WM, et al. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica 2012;97(3):442-50
119. Richter JR, Bilotti E, McBride L, et al. Salvage therapy with vorinostat, lenalidomide, and dexamethasone (ZRD) in lenalidomide/dexamethasone relapsed/refractory multiple myeloma. Presented at: 53rd American Society of Hematology (ASH) Annual Meeting and Exposition; 10-13 December 2011; San Diego, CA, USA
120. Bringhen S, Mateos MV, Zweegman S, et al. Age and organ damage correlate with poor survival in myeloma patients: metaanalysis of 1435 individual patient data from 4 randomized trials. Haematologica 2013;98(6):980-7
121. ClinicalTrials.gov. Available from: www.ClinicalTrials.gov
122. Nederlands Trial Register. Available from: www.trialregister.nl