Current Phase II investigational proteasome inhibitors for the treatment of multiple myeloma

Expert Opinion on Investigational Drugs

Volumn 23, Issue 9, 2014, Pages 1193-1209

  Bringhen, Sara ^a   Gay, Francesca ^a   Donato, Francesca ^a   Troia, Rossella ^a   Mina, Roberto ^a   Palumbo, Antonio ^a  

^a CITTÀ DELLA SALUTE E DELLA SCIENZA HOSPITAL   (Italy)

Author keywords

Bortezomib; Multiple myeloma; Novel agents; Proteasome inhibitors

Indexed keywords

BORONIC ACID DERIVATIVE; BORTEZOMIB; CARFILZOMIB; DELANZOMIB; IXAZOMIB; IXAZOMIB CITRATE; OPROZOMIB; PROTEASOME INHIBITOR; SALINOSPORAMIDE A; ANTINEOPLASTIC AGENT; PYRAZINE DERIVATIVE;

ADVANCED CANCER; ANEMIA; ANTINEOPLASTIC ACTIVITY; CANCER RECURRENCE; CANCER RESISTANCE; COGNITIVE DEFECT; DIARRHEA; DIZZINESS; DRUG EFFICACY; DRUG MECHANISM; DRUG SCREENING; DYSPNEA; FATIGUE; GASTROINTESTINAL SYMPTOM; HALLUCINATION; HEADACHE; HUMAN; HYPERGLYCEMIA; HYPERTENSION; HYPONATREMIA; HYPOPHOSPHATEMIA; INFECTION; KIDNEY FAILURE; LUNG EMBOLISM; LYMPHOCYTOPENIA; MULTIPLE MYELOMA; NAUSEA; NEUTROPENIA; PERIPHERAL NEUROPATHY; PHASE 2 CLINICAL TRIAL (TOPIC); PNEUMONIA; RASH; REVIEW; THROMBOCYTOPENIA; VOMITING; ANIMAL; CANCER STAGING; DRUG DESIGN; PATHOLOGY;

ANIMALS; ANTINEOPLASTIC AGENTS; BORONIC ACIDS; CLINICAL TRIALS, PHASE II AS TOPIC; DRUG DESIGN; HUMANS; MULTIPLE MYELOMA; NEOPLASM STAGING; PROTEASOME INHIBITORS; PYRAZINES;

EID: 84906053641     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2014.920821     Document Type: Review

References (107)

1. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364(11):1046-60
2. 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
3. Bladé J, Rosiñol L, Cibeira MT, et al. Hematopoietic stem cell transplantation for multiple myeloma beyond 2010. Blood 2010;115(18):3655-63
4. Ladetto M, Pagliano G, Ferrero S, et al. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol 2010;28(12):2077-84
5. Harousseau J-L, 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
6. 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). ASH Annual Meeting Abstracts 2010;116(21):40
7. 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
8. 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
9. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007;357(21):2123-32
10. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357(21):2133-42
11. Gentile M, Recchia AG, Mazzone C, et al. Perspectives in the treatment of multiple myeloma. Expert Opin Biol Ther 2013;13(Suppl 1):S1-22
12. McBride A, Ryan PY. Proteasome inhibitors in the treatment of multiple myeloma. Expert Rev Anticancer Ther 2013;13(3):339-58
13. Lois LM, Lima CD. Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1. EMBO J 2005;24(3):439-51
14. Orlowski RZ, Kuhn DJ. Proteasome inhibitors in cancer therapy: Lessons from the first decade. Clin Cancer Res 2008;14(6):1649-57
15. Glickman MH, Rubin DM, Coux O, et al. A subcomplex of the proteasome regulatory particle required for ubiquitinconjugate degradation and related to the COP9-signalosome and eIF3. Cell 1998;94(5):615-23
16. Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006;24(30):4867-74
17. Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-Agent carfilzomib: Experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica 2013;98(11):1753-61
18. Obaidat A, Weiss J, Wahlgren B, et al. Proteasome regulator marizomib (NPI-0052) exhibits prolonged inhibition, attenuated efflux, and greater cytotoxicity than its reversible analogs. J Pharmacol Exp Ther 2011;337(2):479-86
19. Adams J. The proteasome: A suitable antine oplastic target. Nat Rev Cancer 2004;4(5):349-60
20. Meiners S, Heyken D, Weller A, et al Inhibition of proteasome activity induces concerted expression of proteasome genes and De novo formation of Mammalian proteasomes. J Biol Chem 2003;278(24):21517-25
21. Dalton WS. The proteasome. Semin Oncol 2004;31(6 Suppl 16):3-9;discussion 33
22. Utecht KN, Kolesar J. Bortezomib: A novel chemotherapeutic agent for hematologic malignancies. Am J Health Syst Pharm 2008;65(13):1221-31
23. Chauhan D, Tian Z, Zhou B, et al. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res 2011;17(16):5311-21
24. Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001;7(3):683-94
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
26. 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
27. Potts BC, Albitar MX, Anderson KC, et al. Marizomib, a proteasome inhibitor for all seasons: Preclinical profile and a framework for clinical trials. Curr Cancer Drug Targets 2011;11(3):254-84
28. Kupperman E, Lee EC, Cao Y, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 2010;70(5):1970-80
29. Lee EC, Fitzgerald M, Bannerman B, et al. Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies. Clin Cancer Res 2011;17(23):7313-23
30. Gupta N, Saleh M, Venkatakrishnan K. Flat-dosing versus BSA-based dosing for MLN9708, an investigational proteasome inhibitor: Population pharmacokinetic (PK) analysis of pooled data from 4 phase-1 studies. ASH Annual Meeting Abstracts 2011;118(21):1433
31. Kumar S, Bensinger W, Reeder CB, et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory multiple myeloma (MM): A phase I study. J Clin Oncol 2012;30(Suppl):abstract 8034
32. Kumar S, Bensinger W, Zimmerman TM, et al. Weekly MLN9708, an investigational oral proteasome inhibitor (PI), in relapsed/refractory multiple myeloma (MM): Results from a phase I study after full enrollment. J Clin Oncol 2013;31(Suppl):abstract 8514
33. Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM). J Clin Oncol 2012;30(Suppl):abstract 8017
34. Kumar SK, Roy V, Reeder C, et al. Phase 2 trial of single agent MLN9708 in patients with relapsed multiple myeloma not refractory to bortezomib. Blood 2013;122(21):1944-4
35. Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). ASH Annual Meeting Abstracts 2012;120(21):332
36. Richardson PG, Hofmeister CC, Rosenbaum CA, et al. Twice-weekly oral MLN9708 (Ixazomib Citrate), an investigational proteasome inhibitor, in combination with lenalidomide (Len) and dexamethasone (Dex) in patients (Pts) with newly diagnosed multiple myeloma (MM): Final phase 1 results and phase 2 data. Blood 2013;122(21):535-5
37. Shah JJ, Baladandayuthapani V, Weber DM, et al. Phase II study of the combination of MLN 9708 with lenalidomide as maintenance therapy post autologous stem Cell transplant in patients with multiple myeloma. Blood 2013;122(21):1983-3
38. Sala F, Marangon E, Bagnati R, et al. Development and validation of a high-performance liquid chromatography-Tandem mass spectrometry method for the determination of the novel proteasome inhibitor CEP-18770 in human plasma and its application in a clinical pharmacokinetic study. J Mass Spectrom 2010;45(11):1299-305
39. Dorsey BD, Iqbal M, Chatterjee S, et al. Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer. J Med Chem 2008;51(4):1068-72
40. Sanchez E, Li M, Steinberg JA, et al. The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan. Br J Haematol 2010;148(4):569-81
41. Sanchez E, Li M, Li J, et al. CEP-18770 (delanzomib) in combination with dexamethasone and lenalidomide inhibits the growth of multiple myeloma. Leuk Res 2012;36(11):1422-7
42. Gallerani E, Zucchetti M, Brunelli D, et al. A first in human phase I study of the proteasome inhibitor CEP-18770 in patients with advanced solid tumours and multiple myeloma. Eur J Cancer 2013; 49(2):290-6
43. Ocio EM, Mateos M-V, San-Miguel JF. Novel agents derived from the currently approved treatments for MM: Novel proteasome inhibitors and novel IMIDs. Expert Opin Investig Drugs 2012;21(8):1075-87
44. Hanada M, Sugawara K, Kaneta K, et al. Epoxomicin, a new antitumor agent of microbial origin. J Antibiot (Tokyo) 1992;45(11):1746-52
45. Meng L, Mohan R, Kwok BH, et al. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proc Natl Acad Sci USA 1999;96(18):10403-8
46. 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
47. 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
48. OConnor 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
49. Badros AZ, Vij R, Martin T, et al. Phase II study of carfilzomib in patients with relapsed/refractory multiple myeloma and renal insufficiency. J Clin Oncol 2010;28:15s(Suppl):abstract 8128
50. Badros AZ, Vij R, Martin T, et al. Phase I study of carfilzomib in patients (Pts) with relapsed and refractory multiple myeloma (MM) and varying degrees of renal insufficiency. ASH Annual Meeting Abstracts 2009;114(22):3877
51. Alsina M, Trudel S, Furman RR, et al. A phase I single-Agent study of twiceweekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res 2012;18(17):4830-40
52. Jagannath S, Vij R, Stewart AK, et al. An open-label single-Arm pilot phase II study (PX-171-003-A0) of low-dose, single-Agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk 2012;12(5):310-18
53. 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
54. Vij R, Wang M, Kaufman JL, et al. An open-label, single-Arm, phase 2 (PX-171-004) study of single-Agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood 2012;119(24):5661-70
55. Squifflet P, Michiels S, Siegel DS, et al. Multivariate modelling reveals evidence of a dose-response relationship in phase 2 studies of single-Agent carfilzomib. ASH Annual Meeting Abstracts 2011;118(21):1877
56. Vij R, Siegel DS, Jagannath S, et al. An open-label, single-Arm, phase 2 study of single-Agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol 2012;158(6):739-48
57. Jakubowiak AJ, Siegel DS, Singhal S, et al. Unfavorable cytogenetic characteristics do not adversely impact response rates in patients with relapsed and/or refractory multiple myeloma treated with single-Agent carfilzomib on the 003 (A1) study. ASH Annual Meeting Abstracts 2011;118(21):1875
58. 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
59. Singhal S, Siegel DS, Martin T, et al. Integrated safety from phase 2 studies of monotherapy carfilzomib in patients with relapsed and refractory multiple myeloma (MM): An updated analysis. ASH Annual Meeting Abstracts 2011;118(21):1876
60. Badros AZ, Papadopoulos KP, Zojwalla N, et al. 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. ASH Annual Meeting Abstracts 2012;120(21):4036
61. Berenson JR, Klein L, Rifkin RM, et al. A phase 1, dose-escalation study (CHAMPION-1) investigating weekly carfilzomib in combination with dexamethasone for Patients with relapsed or refractory multiple myeloma. Blood 2013;122(21):1934-4
62. 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
63. 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
64. Sonneveld P, Asselberg-Hacker E, Zweegman S, et al. Dose escalation phase 2 trial of carfilzomib combined with thalidomide and low-dose dexamethason in newly diagnosed, transplant eligible patients with multiple myeloma. A trial of the European myeloma network. Blood 2013;122(21):688-8
65. Mikhael JR, 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: Final results of MTD expansion cohort. Blood 2013;122(21):3179-9
66. Bringhen S, Cerrato C, Petrucci MT, et al. A phase II study with carfilzomib, cyclophosphamide and dexamethasone (CCd) for newly diagnosed multiple myeloma. Blood 2013;122(21):685-5
67. Moreau P, Kolb B, Hulin C, et al. Carfilzomib plus melphalan and prednisone (CMP) is a promising combination therapy for the treatment of elderly patients with newly diagnosed multiple myeloma: Results of a phase I/II trial in 68 cases. Blood 2013;122(21):1933-3
68. 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). J Clin Oncol 2011;29(Suppl):abstract TPS225
69. Zhou H-J, Aujay MA, Bennett MK, et al. Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J Med Chem 2009;52(9):3028-38
70. Papadopoulos KP, Mendelson DS, Tolcher AW, et al. A phase I, open-label, dose-escalation study of the novel oral proteasome inhibitor (PI) ONX 0912 in patients with advanced refractory or recurrent solid tumors. J Clin Oncol 2011;29(Suppl):abstract 3075
71. Ghobrial IM, Kaufman JL, Siegel DS, et al. Clinical profile of single-Agent modified-release oprozomib tablets in patients (Pts) with hematologic malignancies: Updated results from a multicenter, open-label, dose escalation phase 1b/2 study. Blood 2013;122(21):3184-4
72. Feling RH, Buchanan GO, Mincer TJ, et al. Salinosporamide A: A highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed Engl 2003;42(3):355-7
73. Groll M, Huber R, Potts BCM. Crystal structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in complex with the 20S proteasome reveal important consequences of beta-lactone ring opening and a mechanism for irreversible binding. J Am Chem Soc 2006;128(15):5136-41
74. Manam RR, McArthur KA, Chao T-H, et al. Leaving groups prolong the duration of 20S proteasome inhibition and enhance the potency of salinosporamides. J Med Chem 2008;51(21):6711-24
75. Miller CP, Manton CA, Hale R, et al. Specific and prolonged proteasome inhibition dictates apoptosis induction by marizomib and its analogs. Chem Biol Interact 2011;194(1):58-68
76. Lawasut P, Chauhan D, Laubach J, et al. New proteasome inhibitors in myeloma. Curr Hematol Malig Rep 2012;7(4):258-66
77. Bross PF, Kane R, Farrell AT, et al. Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res 2004;10(12 Pt 1):3954-64
78. 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
79. 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(3):1654-64
80. Roccaro AM, Leleu X, Sacco A, et al. Dual targeting of the proteasome regulates survival and homing in waldenstrom macroglobulinemia. Blood 2008;111(9):4752-63
81. Sloss CM, Wang F, Liu R, et al. Proteasome inhibition activates epidermal growth factor receptor (EGFR) and EGFR-independent mitogenic kinase signaling pathways in pancreatic cancer cells. Clin Cancer Res 2008;14(16):5116-23
82. Baritaki S, Suzuki E, Umezawa K, et al. Inhibition of Yin Yang 1-dependent repressor activity of DR5 transcription and expression by the novel proteasome inhibitor NPI-0052 contributes to its TRAIL-enhanced apoptosis in cancer cells. J Immunol 2008;180(9):6199-210
83. Chauhan D, Singh AV, Ciccarelli B, et al. Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. Blood 2010;115(4):834-45
84. Marques AJ, Palanimurugan R, Matias AC, et al. Catalytic mechanism and assembly of the proteasome. Chem Rev 2009;109(4):1509-36
85. Aghajanian C, Younes A, Hong DS, et al. First-in-human phase I study of the novel structure proteasome inhibitor NPI-0052. J Clin Oncol 2009;27(15S):abstract 3516
86. Ling T, Potts BC, Macherla VR. Concise formal synthesis of (-)-salinosporamide A (marizomib) using a regio-And stereoselective epoxidation and reductive oxirane ring-opening strategy. J Org Chem 2010;75(11):3882-5
87. Nguyen H, Ma G, Romo D. A(1,3)-strain enabled retention of chirality during bis-cyclization of beta-ketoamides: Total synthesis of (-)-salinosporamide A and (-)-homosalinosporamide A. Chem Commun (Camb) 2010;46(26):4803-5
88. Richardson PG, Spencer A, Cannell P, et al. Phase 1 clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma (MM). ASH Annual Meeting Abstracts 2011;118(21):302
89. Moreau P, Coiteux V, Hulin C, et al. Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma. Haematologica 2008;93(12):1908-11
90. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: A randomised, phase 3, non-inferiority study. Lancet Oncol 2011;12(5):431-40
91. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 2012;366(19):1759-69
92. Facon T, Dimopoulos MA, Dispenzieri A, et al. Initial phase 3 results of the first (Frontline Investigation of Lenalidomide + Dexamethasone versus Standard Thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma (NDMM) patients (Pts) ineligible for stem cell transplantation (SCT). Blood 2013;122(21):2
93. Palumbo A, Bringhen S, Larocca A, et al. Bortezomib-melphalan- prednisonethalidomide followed by maintenance with bortezomib-Thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: Updated follow-up and improved survival. J Clin Oncol 2014;32(7):634-40
94. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366(19):1770-81
95. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366(19):1782-91
96. Miska EA. How microRNAs control cell division, differentiation and death. Curr Opin Genet Dev 2005;15(5):563-8
97. Tassone P, Neri P, Burger R, et al. Mouse models as a translational platform for the development of new therapeutic agents in multiple myeloma. Curr Cancer Drug Targets 2012;12(7):814-22
98. Di Martino MT, Leone E, Amodio N, et al. Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: In vitro and in vivo evidence. Clin Cancer Res 2012;18(22):6260-70
99. Di Martino MT, Campani V, Misso G, et al. In vivo activity of miR-34a mimics delivered by stable nucleic acid lipid particles (SNALPs) against multiple myeloma. PLoS One 2014;9(2):e90005
100. Amodio N, Di Martino MT, Foresta U, et al. miR-29b sensitizes multiple myeloma cells to bortezomib-induced apoptosis through the activation of a feedback loop with the transcription factor Sp1. Cell Death Dis 2012;3:e436
101. Misso G, Zappavigna S, Castellano M, et al. Emerging pathways as individualized therapeutic target of multiple myeloma. Expert Opin Biol Ther 2013;13(Suppl 1):S95-109
102. 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 20/56mg/m2 expansion cohort of PX-171-007. ASH Annual Meeting Abstracts 2011;118(21):2930
103. Shah JJ, Feng L, Thomas SK, et al. phase 1 study of the novel kinesin spindle protein inhibitor ARRY-520 + carfilzomib (car) in patients with relapsed and/or refractory multiple myeloma (RRMM). Blood 2013;122(21):1982
104. Shah JJ, Stadtmauer EA, Abonour R, et al. Phase I/II dose expansion of a multi-center trial Of carfilzomib and pomalidomide with dexamethasone (car-pom-d) in patients with relapsed/refractory multiple myeloma. Blood 2013;122(21):690
105. Berdeja J, Savona M, Mace JR, et al. A single-Arm, open-label, multi-center phase I/II study of the combination of panobinostat and carfilzomib in patients (pts) with relapsed or relapse/refractory multiple myeloma (MM). Blood 2013;122(21):1937
106. Mark TM, Allan JN, Marano G, et al. Car-bird [carfilzomib, clarithromycin (biaxin(R)), lenalidomide/(revlimid(R)), dexamethasone) for newly-diagnosed multiple myeloma. Blood 2013;122(21):3216
107. Korde N, Zingone A, Kwok ML, et al. Phase II clinical and correlative study Of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide extended dosing (CRD-R) induces high rates of MRD negativity in newly diagnosed multiple myeloma (MM) patients. Blood 2013;122(21):538.