Novel agents in the treatment of multiple myeloma: A review about the future

Journal of Hematology and Oncology

Volumn 9, Issue 1, 2016, Pages

  Naymagon, Leonard ^a   Abdul Hay, Maher ^a,b,c  

^a NEW YORK UNIVERSITY   (United States)

^b NEW YORK UNIVERSITY MEDICAL CENTER   (United States)

^c NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

AKT inhibitors; Alkylating agents; BTK inhibitors; CDK inhibitors; HDACIs; IL 6 inhibitors; Immunomodulators; Kinesin spindle protein inhibitors; Monoclonal antibodies; Multiple myeloma; Novel agents; PI3K inhibitors; Proteasome inhibitors

Indexed keywords

AFURESERTIB; BENDAMUSTINE; BORTEZOMIB; CARFILZOMIB; CYCLOPHOSPHAMIDE; DARATUMUMAB; DEXAMETHASONE; DINACICLIB; ELOTUZUMAB; FILANESIB; IBRUTINIB; INDATUXIMAB RAVTANSINE; ISATUXIMAB; IXAZOMIB; LENALIDOMIDE; MELPHALAN; OBATOCLAX; OPROZOMIB; PANOBINOSTAT; PLACEBO; POMALIDOMIDE; PREDNISONE; RICOLINOSTAT; SALINOSPORAMIDE A; SILTUXIMAB; THALIDOMIDE; VENETOCLAX; VORINOSTAT;

ABNORMAL LABORATORY RESULT; ACUTE KIDNEY FAILURE; ANEMIA; ANTINEOPLASTIC ACTIVITY; APNEA; APOPTOSIS; BACKACHE; BONE LESION; CANCER PROGNOSIS; CANCER STAGING; CANCER SURVIVAL; CELL EXPANSION; CELL MIGRATION; CELL PROLIFERATION; CELL SURVIVAL; CELL TRANSFORMATION; CLINICAL FEATURE; COUGHING; DIARRHEA; DIZZINESS; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG FATALITY; DRUG MEGADOSE; DRUG POTENTIATION; DRUG RESPONSE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSPEPSIA; ENZYME INHIBITION; FATIGUE; FEVER; FLUORESCENCE IN SITU HYBRIDIZATION; GASTROINTESTINAL SYMPTOM; HEADACHE; HEMATOLOGIC DISEASE; HUMAN; HYPERCALCEMIA; HYPERGLYCEMIA; HYPERTENSION; HYPOKALEMIA; HYPOPHOSPHATEMIA; IMMUNOMODULATION; INDUCTION CHEMOTHERAPY; INFECTION; INFUSION RELATED REACTION; KARYOTYPING; KIDNEY DISEASE; LEUKEMIA RELAPSE; LEUKOPENIA; LIVER DISEASE; LOW DRUG DOSE; LYMPHOCYTOPENIA; MALIGNANT TRANSFORMATION; MULTIPLE MYELOMA; NAUSEA; NEUROPATHY; NEUTROPENIA; OVERALL SURVIVAL; PANCYTOPENIA; PATHOPHYSIOLOGY; PERIPHERAL NEUROPATHY; PNEUMONIA; POLYNEUROPATHY; PROGRESSION FREE SURVIVAL; REVIEW; THROMBOCYTOPENIA; TRISOMY; TUMOR LYSIS SYNDROME; TUMOR VOLUME; UPPER RESPIRATORY TRACT INFECTION; VENOUS THROMBOEMBOLISM; VOMITING; MOLECULARLY TARGETED THERAPY; PROCEDURES; TRENDS;

HUMANS; MOLECULAR TARGETED THERAPY; MULTIPLE MYELOMA;

EID: 84976571365     PISSN: None     EISSN: 17568722     Source Type: Journal    
DOI: 10.1186/s13045-016-0282-1     Document Type: Review

References (117)

1. Surveillance, Epidemiology, and End Results Program Turning Cancer Data Into Discovery. 2015 [cited 2015 October 22]; Myeloma. Surveillance, Epidemiology, and End Results Program. Available from: http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed 22 Oct 2015.
2. Bianchi G, Munshi NC. Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood. 2015;125(20):3049-58.
3. Rajkumar SV, Landgren O, Mateos MV. Smoldering multiple myeloma. Blood. 2015;125(20):3069-75.
4. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046-60.
5. Kuehl WM, Bergsagel PL. Molecular pathogenesis of multiple myeloma and its premalignant precursor. J Clin Invest. 2012;122(10):3456-63.
6. Mateos MV, Hernandez MT, Giraldo P, de la Rubia J, de Arriba F, Lopez Corral L, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369(5):438-47.
7. Smith D, Yong K. Multiple myeloma. BMJ. 2013;346:f3863.
8. Moreau P, Attal M, Facon T. Frontline therapy of multiple myeloma. Blood. 2015;125(20):3076-84.
9. Nooka AK, Kastritis E, Dimopoulos MA, Lonial S. Treatment options for relapsed and refractory multiple myeloma. Blood. 2015;125(20):3085-99.
10. Rollig C, Knop S, Bornhauser M. Multiple myeloma. Lancet. 2015;385(9983):2197-208.
11. Kurtin SE, Bilotti E. Novel agents for the treatment of multiple myeloma: proteasome inhibitors and immunomodulatory agents. J Adv Pract Oncol. 2013;4(5):307-21.
12. Gozzetti A, Candi V, Papini G, Bocchia M. Therapeutic advancements in multiple myeloma. Front Oncol. 2014;4:241.
13. Seifert M, Scholtysik R, Kuppers R. Origin and pathogenesis of B cell lymphomas. Methods Mol Biol. 2013;971:1-25.
14. Morgan GJ, Walker BA, Davies FE. The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012;12(5):335-48.
15. Shammas MA, Shmookler Reis RJ, Koley H, Batchu RB, Li C, Munshi NC. Dysfunctional homologous recombination mediates genomic instability and progression in myeloma. Blood. 2009;113(10):2290-7.
16. Lawasut P, Groen RW, Dhimolea E, Richardson PG, Anderson KC, Mitsiades CS. Decoding the pathophysiology and the genetics of multiple myeloma to identify new therapeutic targets. Semin Oncol. 2013;40(5):537-48.
17. Chauhan D, Uchiyama H, Urashima M, Yamamoto K, Anderson KC. Regulation of interleukin 6 in multiple myeloma and bone marrow stromal cells. Stem Cells. 1995;13 Suppl 2:35-9.
18. Xu FH, Sharma S, Gardner A, Tu Y, Raitano A, Sawyers C, et al. Interleukin-6-induced inhibition of multiple myeloma cell apoptosis: support for the hypothesis that protection is mediated via inhibition of the JNK/SAPK pathway. Blood. 1998;92(1):241-51.
19. Nilsson K, Jernberg H, Pettersson M. IL-6 as a growth factor for human multiple myeloma cells - a short overview. Curr Top Microbiol Immunol. 1990;166:3-12.
20. Uchiyama H, Barut BA, Mohrbacher AF, Chauhan D, Anderson KC. Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood. 1993;82(12):3712-20.
21. Puthier D, Derenne S, Barille S, Moreau P, Harousseau JL, Bataille R, et al. Mcl-1 and Bcl-xL are co-regulated by IL-6 in human myeloma cells. Br J Haematol. 1999;107(2):392-5.
22. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J, et al. International Staging System for multiple myeloma. J Clin Oncol. 2005;23(15):3412-20.
23. Dispenzieri A, Rajkumar SV, Gertz MA, Fonseca R, Lacy MQ, Bergsagel PL, et al. Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc. 2007;82(3):323-41.
24. Mateo G, Montalban MA, Vidriales MB, Lahuerta JJ, Mateos MV, Gutierrez N, et al. Prognostic value of immunophenotyping in multiple myeloma: a study by the PETHEMA/GEM cooperative study groups on patients uniformly treated with high-dose therapy. J Clin Oncol. 2008;26(16):2737-44.
25. Snozek CL, Katzmann JA, Kyle RA, Dispenzieri A, Larson DR, Therneau TM, et al. Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the International Staging System. Leukemia. 2008;22(10):1933-7.
26. Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, 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.
27. Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116(5):679-86.
28. Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Blade J, et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood. 2011;117(23):6063-73.
29. Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10):906-17.
30. Fonseca R. Strategies for risk-adapted therapy in myeloma. Hematology Am Soc Hematol Educ Program. 2007: 304-10.
31. Holstein SA, Richardson PG, Laubach JP, McCarthy PL. Management of relapsed multiple myeloma after autologous stem cell transplant. Biol Blood Marrow Transplant. 2015;21(5):793-8.
32. Kumar SK, Therneau TM, Gertz MA, Lacy MQ, Dispenzieri A, Rajkumar SV, et al. Clinical course of patients with relapsed multiple myeloma. Mayo Clin Proc. 2004;79(7):867-74.
33. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516-20.
34. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357(21):2133-42.
35. Monge J et al. Cyclophosphamide, b., and dexamethasone (CYBORD) treatment for relapsed/refractory multiple myeloma. J Clin Oncol. 2014;32(suppl; abstr 8586):5s.
36. Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27(30):5008-14.
37. Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24(11):1934-9.
38. Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, et al. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myelome 2009-02. Blood. 2013;121(11):1968-75.
39. San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(11):1055-66.
40. Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123(12):1826-32.
41. Forsberg PA, Mark TM. Pomalidomide in the treatment of relapsed multiple myeloma. Future Oncol. 2013;9(7):939-48.
42. Dimopoulos MA, Leleu X, Palumbo A, Moreau P, Delforge M, Cavo M, et al. Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. Leukemia. 2014;28(8):1573-85.
43. Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, 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.
44. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem. 2002;277(19):16639-47.
45. Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142-52.
46. Perel G, Bliss J, Thomas CM. Carfilzomib (Kyprolis): a novel proteasome inhibitor for relapsed and/or refractory multiple myeloma. PT. 2016;41(5):303-7.
47. Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hajek R, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17(1):27-38.
48. Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, et al. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014;124(1):63-9.
49. Mikhael JR, Reeder CB, Libby EN, Costa LJ, Bergsagel PL, Buadi F, et al. Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma. Br J Haematol. 2015;169(2):219-27.
50. Moreau P, Kolb B, Attal M, Caillot D, Benboubker L, Tiab M, et al. Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma. Blood. 2015;125(20):3100-4.
51. Kumar SK, Bensinger WI, Zimmerman TM, Reeder CB, Berenson JR, Berg D, et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014;124(7):1047-55.
52. Richardson PG, Baz R, Wang M, Jakubowiak AJ, Laubach JP, Harvey RD, et al. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014;124(7):1038-46.
53. Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014;15(13):1503-12.
54. Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374(17):1621-34.
55. Dou QP, Zonder JA. Overview of proteasome inhibitor-based anti-cancer therapies: perspective on bortezomib and second generation proteasome inhibitors versus future generation inhibitors of ubiquitin-proteasome system. Curr Cancer Drug Targets. 2014;14(6):517-36.
56. Allegra A, Alonci A, Gerace D, Russo S, Innao V, Calabro L, et al. New orally active proteasome inhibitors in multiple myeloma. Leuk Res. 2014;38(1):1-9.
57. Ghobrial I, Kaufman J, Siegel D, 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 [abstract]. Ash Annual Meeting 2013. New Orleans, LA: American Society of Hematology; 2013. Abstract 3184.
58. Tsakiri E, Kastritis E, et al. The novel proteasome inhibitors carfilzomib and oprozomib induce milder degenerative effects compared to bortezomib when administered via oral feeding in an in vivo drosophila experimental model: a biological platform to evaluate safety/efficacy of proteasome inhibitors [abstract]. ASH Annual Meeting 2013. New Orleans, LA: American Society of Hematology; 2013. Abstract 1930.
59. Parameswaran H, Shain K, Voorhees P, et al. Oprozomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma: initial results from the dose escalation portion of a phase 1b/2, multicenter, open-label study [abstract]. ASH Annual Meeting 2014. San Francisco, CA: American Society of Hematology; 2014. Abstract 3453.
60. Vij R, Savona M, Siegel D, et al. Clinical profile of single-agent oprozomib in Patients (Pts) with Multiple Myeloma (MM): updated results from a multicenter, open-label, dose escalation phase 1b/2 study [abstract]. ASH Annual Meeting 2014. San Francisco, Ca: American Society of Hematology; 2014. Abstract 34.
61. Khagi Y, Mark TM. Potential role of daratumumab in the treatment of multiple myeloma. Onco Targets Ther. 2014;7:1095-100.
62. Overdijk MB, Verploegen S, Bogels M, van Egmond M, Lammerts van Bueren JJ, Mutis T, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7(2):311-21.
63. Plesner T, Arkenau H, Lokhorst H, et al. Safety and efficacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma [abstract]. ASH Annual Meeting 2014. San Francisco, CA: American Society of Hematology. 2014. Abstract 84.
64. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373(13):1207-19.
65. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387(10027):1551-60.
66. Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood, 2016. [Epub ahead of print].
67. Rajkumar SV. Daratumumab in multiple myeloma. Lancet. 2016;387(10027):1490-2.
68. Liu YC, Szmania S, van Rhee F. Profile of elotuzumab and its potential in the treatment of multiple myeloma. Blood Lymphat Cancer. 2014;2014(4):15-27.
69. Jakubowiak A, Offidani M, Pegourie B, De La Rubia J, Garderet L, Laribi K, et al. Randomized phase 2 study of elotuzumab plus bortezomib/dexamethasone (Bd) versus Bd for relapsed/refractory multiple myeloma. Blood. 2016. [Epub ahead of print].
70. Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621-31.
71. Robak T, Robak E. Current phase II antibody-drug conjugates for the treatment of lymphoid malignancies. Expert Opin Investig Drugs. 2014;23(7):911-24.
72. Kelly K, Chanan-Khan A, Somlo G, et al. Indatuximab Ravtansine (BT062) in combination with lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma: clinical activity in len/dex-refractory patients [abstract] ASH Annual Meeting 2013. New Orleans, LA: American Society of Hematology. 2013. Abstract 758.
73. Martin TG, Baz R, Benson D, et al. A phase Ib dose escalation trial of SAR650984 (Anti-CD-38 MAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma [abstract]. ASH Annual Meeting 2014. San, Francisco, CA: American Society of Hematology. 2014. Abstract 83.
74. Martin TG, Hsu K, Stickland SA, et al. A phase I trial of SAR650984, a CD38 monoclonal antibody, in relapsed or refractory multiple myeloma. J Clin Oncol. 2014(suppl; abstr 8532):32:5s.
75. Mithraprabhu S, Khong T, Jones SS, Spencer A. Histone deacetylase (HDAC) inhibitors as single agents induce multiple myeloma cell death principally through the inhibition of class I HDAC. Br J Haematol. 2013;162(4):559-62.
76. Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE, Gasparetto C, et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013;122(14):2331-7.
77. Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, et al. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016;127(6):713-21.
78. Richardson PG, Harvey RD, Laubach JP, Moreau P, Lonial S, San-Miguel JF. Panobinostat for the treatment of relapsed or relapsed/refractory multiple myeloma: pharmacology and clinical outcomes. Expert Rev Clin Pharmacol. 2016;9(1):35-48.
79. Mishima Y, Santo L, Eda H, Cirstea D, Nemani N, Yee AJ, et al. Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death. Br J Haematol. 2015;169(3):423-34.
80. Santo L, Hideshima T, Kung AL, Tseng JC, Tamang D, Yang M, et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood. 2012;119(11):2579-89.
81. Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013;14(11):1129-40.
82. Sborov DW, Benson DM, Williams N, Huang Y, Bowers MA, Humphries K, et al. Lenalidomide and vorinostat maintenance after autologous transplant in multiple myeloma. Br J Haematol. 2015;171(1):74-83.
83. Siegel DS, Richardson P, Dimopoulos M, Moreau P, Mitsiades C, Weber D, et al. Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood Cancer J. 2014;4:e202.
84. Vesole DH, Bilotti E, Richter JR, McNeill A, McBride L, Raucci L, et al. Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma. Br J Haematol. 2015;171(1):52-9.
85. Siegel DS, Dimopoulos M, Yoon S, et al. Vantage 095: Vorinostat in combination with bortezomib in salvage multiple myeloma patients: final study results of a global phase 2b trial [abstract]. ASH Annual Meeting 2011. San Diego, Ca: American Society of Hematology. 2011. Abstract 480.
86. Siegel DS. Relapsed/refractory multiple myeloma: defining refractory disease and identifying strategies to overcome resistance. Semin Hematol. 2012;49 Suppl 1:S3-15.
87. Afifi S, Michael A, Azimi M, Rodriguez M, Lendvai N, Landgren O. Role of histone deacetylase inhibitors in relapsed refractory multiple myeloma: a focus on vorinostat and panobinostat. Pharmacotherapy. 2015;35(12):1173-88.
88. Gentile M, Vigna E, Recchia AG, Morabito L, Mendicino F, Giagnuolo G, et al. Bendamustine in multiple myeloma. Eur J Haematol. 2015;95(5):377-88.
89. Palumbo A, Offidani M, Patriarca F, Petrucci MT, Cavo M. Bendamustine for the treatment of multiple myeloma in first-line and relapsed-refractory settings: a review of clinical trial data. Leuk Lymphoma. 2015;56(3):559-67.
90. Lentzsch S, O'Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL, et al. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012;119(20):4608-13.
91. Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, et al. Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood. 2014;123(7):985-91.
92. Rodon P, Hulin C, Pegourie B, Tiab M, Anglaret B, Benboubker L, et al. Phase II study of bendamustine, bortezomib and dexamethasone as second-line treatment for elderly patients with multiple myeloma: the Intergroupe Francophone du Myelome 2009-01 trial. Haematologica. 2015;100(2):e56-9.
93. Lau IJ, Smith D, Aitchison R, Blesing N, Roberts P, Peniket A, et al. Bendamustine in combination with thalidomide and dexamethasone is a viable salvage option in myeloma relapsed and/or refractory to bortezomib and lenalidomide. Ann Hematol. 2015;94(4):643-9.
94. Keane NA, Glavey SV, Krawczyk J, O'Dwyer M. AKT as a therapeutic target in multiple myeloma. Expert Opin Ther Targets. 2014;18(8):897-915.
95. Spencer A, Yoon SS, Harrison SJ, Morris SR, Smith DA, Brigandi RA, et al. The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood. 2014;124(14):2190-5.
96. Voorhees P, Spencer A, Sutherland H, et al. Novel AKT inhibitor afuresertib in combination with bortezomib and dexamethasone demonstrates favorable safety profile and significant clinical activity in patients with relapsed/refractory multiple myeloma [abstract]. ASH Annual Meeting 2013. New Orleans, LA: American Society of Hematology; 2013. Abstract 283.
97. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435(7042):677-81.
98. Touzeau C, Dousset C, Le Gouill S, Sampath D, Leverson JD, Souers AJ, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28(1):210-2.
99. Matulis S, Sharp C, Nooka A. Efficacy Of ABT-199 in multiple myeloma [abstract]. ASH Annual Meeting 2013. New Orleans, LA: American Society of Hematology; 2013. Abstract 4453.
100. Anderson MA, Huang D, Roberts A. Targeting BCL2 for the treatment of lymphoid malignancies. Semin Hematol. 2014;51(3):219-27.
101. Liu Y, Dong Y, Jiang QL, Zhang B, Hu AM. Bruton's tyrosine kinase: potential target in human multiple myeloma. Leuk Lymphoma. 2014;55(1):177-81.
102. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-16.
103. Rushworth SA, Bowles KM, Barrera LN, Murray MY, Zaitseva L, MacEwan DJ. BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-kappaB. Cell Signal. 2013;25(1):106-12.
104. Vij R, Huff C, Bensinger W, et al. Ibrutinib, single agent or in combination with dexamethasone, in patients with relapsed or relapsed/refractory multiple myeloma (MM): preliminary phase 2 results [abstract]. ASH Annual Meeting 2014. San Francisco, Ca: American Society of Hematology; 2014. Abstract 31.
105. Kumar SK, LaPlant B, Chng WJ, Zonder J, Callander N, Fonseca R, et al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015;125(3):443-8.
106. Gado K, Domjan G, Hegyesi H, Falus A. Role of INTERLEUKIN-6 in the pathogenesis of multiple myeloma. Cell Biol Int. 2000;24(4):195-209.
107. Orlowski RZ, Gercheva L, Williams C, Sutherland H, Robak T, Masszi T, et al. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol. 2015;90(1):42-9.
108. San-Miguel J, Blade J, Shpilberg O, Grosicki S, Maloisel F, Min CK, et al. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood. 2014;123(26):4136-42.
109. LoRusso PM, Goncalves PH, Casetta L, Carter JA, Litwiler K, Roseberry D, et al. First-in-human phase 1 study of filanesib (ARRY-520), a kinesin spindle protein inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2015;33(2):440-9.
110. Chari A, Myo H, Zonder J, et al. A phase 1 study of ARRY-520 (filanesib) with bortezomib (BTZ) and dexamethasone (dex) in relapsed or refractory multiple myeloma (RRMM) [abstract]. ASH Annual Meeting 2013. New Orleans, LA: American Society of Hematology; 2013. Abstract 1938.
111. Shah J, Lei F, Thomas S, et al. Phase 1 study of the novel kinesin spindle protein inhibitor ARRY-520 (filanesib) + carfilzomib (Car) in patients with relapsed and/or refractory multiple myeloma (RRMM) [abstract]. ASH Annual Meeting 2013. New Orleans, LA: American Society of Hematology; 2013. Abstract 1982.
112. Shah J, Zonder J, Cohen A, et al. The novel KSP inhibitor ARRY-520 is active both with and without low-dose dexamethasone in patients with multiple myeloma refractory to bortezomib and lenalidomide: results from a phase 2 study [abstract]. ASH Annual Meeting 2012. Atlanta, GA: American Society of Hematology; 2012. Abstract 449.
113. Lonial S, Shah J, Zonder J, et al. Prolonged survival and improved response rates with ARRY-520 (filanesib) in relapsed/refractory multiple myeloma (RRMM) patients with low α-1 acid glycoprotein (AAG) levels: results from a phase 2 study [abstract]. ASH Annual Meeting 2013. New Orleans, LA. American Society of Hematology. 9 Dec 2013. Abstract 285.
114. Zhu J, Wang M, Yu Y, Qi H, Han K, Tang J, et al. A novel PI3K inhibitor PIK-C98 displays potent preclinical activity against multiple myeloma. Oncotarget. 2015;6(1):185-95.
115. Glauer J, Pletz N, Schon M, Schneider P, Liu N, Ziegelbauer K, et al. A novel selective small-molecule PI3K inhibitor is effective against human multiple myeloma in vitro and in vivo. Blood Cancer J. 2013;3:e141.
116. Munugalavadla V, Mariathasan S, Slaga D, Du C, Berry L, Del Rosario G, et al. The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma. Oncogene. 2014;33(3):316-25.
117. Martin SK, Gan ZY, Fitter S, To LB, Zannettino AC. The effect of the PI3K inhibitor BKM120 on tumour growth and osteolytic bone disease in multiple myeloma. Leuk Res. 2015;39(3):380-7.