Relapsed and Refractory Multiple Myeloma: New Therapeutic Strategies

Hematology/Oncology Clinics of North America

Volumn 28, Issue 5, 2014, Pages 861-890

  Gentili, Silvia ^a   Lonial, Sagar ^b  

^a OSPEDALI RIUNITI   (Italy)

^b EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Complete remission; Emerging agents; Immunomodulatory drugs; Multiple myeloma; Prognostic factors; Proteasome inhibitors; Relapsed refractory

Indexed keywords

ANTINEOPLASTIC AGENT; BORTEZOMIB; CARFILZOMIB; CYCLOPHOSPHAMIDE; DEXAMETHASONE; DOXORUBICIN; HISTONE DEACETYLASE INHIBITOR; KINESIN INHIBITOR; KINESIN SPINDLE PROTEIN INHIBITOR; LENALIDOMIDE; MELPHALAN; MONOCLONAL ANTIBODY; POMALIDOMIDE; PREDNISONE; PROTEIN INHIBITOR; THALIDOMIDE; UNCLASSIFIED DRUG; OLIGOPEPTIDE;

CANCER COMBINATION CHEMOTHERAPY; CANCER IMMUNOTHERAPY; CANCER PATIENT; CANCER PROGNOSIS; CANCER RECURRENCE; CANCER REGRESSION; CHROMOSOME ABERRATION; FUTUROLOGY; HUMAN; MONOTHERAPY; MULTIPLE MYELOMA; PATIENT HISTORY OF THERAPY; RETREATMENT; REVIEW; TREATMENT RESPONSE; ANALOGS AND DERIVATIVES; DRUG EFFECTS; DRUG RESISTANCE; PATHOLOGY; REMISSION; TREATMENT OUTCOME; TUMOR RECURRENCE;

ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; DRUG RESISTANCE, NEOPLASM; HUMANS; MULTIPLE MYELOMA; NEOPLASM RECURRENCE, LOCAL; OLIGOPEPTIDES; REMISSION INDUCTION; THALIDOMIDE; TREATMENT OUTCOME;

EID: 84912535316     PISSN: 08898588     EISSN: 15581977     Source Type: Journal    
DOI: 10.1016/j.hoc.2014.06.008     Document Type: Review

References (134)

1. Palumbo A., Anderson K. Multiple myeloma. NEngl J Med 2011, 364(11):1046-1060.
2. Durie B.G., Harousseau J.L., Miguel J.S., et al. International uniform response criteria for multiple myeloma. Leukemia 2006, 20:1467-1473.
3. Kyle R.A., Rajkumar S.V. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia 2009, 23:3-9.
4. Anderson K.C., Kyle R.A., Rajkumar S.V., et al. Clinically relevant end points and new drug approvals for myeloma. Leukemia 2008, 22:231-239.
5. Keats J.J., Chesi M., Egan J.B., et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012, 120(5):1067-1076.
6. Egan J.B., Shi C.X., Tembe W., et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood 2012, 120(5):1060-1066.
7. Magrangeas F., Avet-Loiseau H., Gouraud W., et al. Minor clone provides a reservoir for relapse in multiple myeloma. Leukemia 2013, 27(2):473-481.
8. Lonial S., Anderson K.C. Association of response endpoints with survival outcomes in multiple myeloma. JClin Oncol 2014, 28(2):258-268.
9. Niesvizky R., Richardson P.G., Rajkumar S.V., et al. The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma. Br J Haematol 2008, 143:46-53.
10. Palumbo A., Gay F., Bringhen S., et al. Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma. Ann Oncol 2008, 19(6):1160-1165.
11. Offidani M., Corvatta L., Polloni C., et al. Thalidomide, dexamethasone, Doxil and Velcade (ThaDD-V) followed by consolidation/maintenance therapy in patients with relapsed-refractory multiple myeloma. Ann Hematol 2011, 90:1449-1456.
12. Harousseau J.L., Dimopoulos M.A., Wang M., et al. The quality of response to lenalidomide plus dexamethasone is associated with improved clinical outcomes in patients with relapsed or refractory multiple myeloma. Haematologica 2010, 95(10):1738-1744.
13. Siegel D.S., Martin T., Wang M., et al. Aphase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012, 120(14):2817-2825.
14. Richardson P.G., Siegel D.S., Vij R., et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood 2014, 123:1826-1832.
15. San Miguel J., Weisel K., Moreau P., 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 2013, 14(11):1055-1066.
16. Chang H., Trieu Y., Qi X., et al. Impact of cytogenetics in patients with relapsed or refractory multiple myeloma treated with bortezomib: adverse effect of 1q21 gains. Leuk Res 2011, 35(1):95-98.
17. Chen C., Reece D.E., Siegel D., et al. Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma. Br J Haematol 2009, 146(2):164-170.
18. Avet-Loiseau H., Soulier J., Fermand J.P., et al. Impact of high-risk cytogenetics and prior therapy on outcomes in patients with advanced relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone. Leukemia 2010, 24(3):623-628.
19. Knop S., Gerecke C., Liebisch P., et al. Lenalidomide, adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: a report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom). Blood 2009, 113(18):4137-4143.
20. Reece D., Song K., Fu T., et al. Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13. Blood 2009, 114(3):522-525.
21. Dimopoulos M.A., Kastritis E., Christoulas D., et al. Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies. Leukemia 2010, 24(10):1769-1778.
22. Jakubowiak A.J., Siegel D.S., 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, 27(12):2351-2356.
23. Dimopoulos M.A., Weisel K., Song K.W., et al. Final analysis, cytogenetics, long-term treatment, and long-term survival in MM-003, a phase 3 study comparing pomalidomide+ low-dose dexamethasone (POM+ LoDEX) vs high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM). ASH Annual Meeting Abstract 2013, 122(21):408.
24. Kumar S.V., Therneau T.M., Gertz M.A., et al. Clinical course of patients with relapsed multiple myeloma. Mayo Clin Proc 2004, 79(7):867-874.
25. Krejci M., Gregora E., Straub J., et al. Similar efficacy of thalidomide- and bortezomib-based regimens for first relapse of multiple myeloma. Ann Hematol 2011, 90(12):1441-1447.
26. San Miguel J.F., Weisel K., Song K.W., et al. Patient outcomes by prior therapies and depth of response: analysis of MM-003, a phase 3 study comparing pomalidomide+ low-dose dexamethasone (POM+ LoDEX) vs high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM). ASH Annual Meeting Abstract 2013, 122(21):686.
27. Olin R.L., Vogl D.T., Porter D.L., et al. Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma. Bone Marrow Transplant 2009, 43(5):417-422.
28. Gonsalves W.I., Gertz M.A., Lacy M.Q., et al. Second auto-SCT for treatment of relapsed multiple myeloma. Bone Marrow Transplant 2013, 48(4):568-573.
29. Vogl D.T., Stadtmauer E.A., Richardson P.G., et al. Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma. Br J Haematol 2009, 147(4):531-534.
30. Sonneveld P., Hajek R., Nagler A., et al. Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy. Cancer 2008, 112(7):1529-1537.
31. Wang M., Dimopoulos M.A., Chen C., et al. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood 2008, 112(12):4445-4451.
32. Pineda-Roman M., Zangari M., van Rhee F., et al. VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma. Leukemia 2008, 22:1419-1427.
33. 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):330-337.
34. Klein U., Neben K., Hielscher T., et al. Lenalidomide in combination with dexamethasone: effective regimen in patients with relapsed or refractory multiple myeloma complicated by renal impairment. Ann Hematol 2011, 90(4):429-439.
35. Chang H., Jiang A., Connie Q., et al. Impact of genomic aberrations including chromosome 1 abnormalities on the outcome of patients with relapsed or refractory multiple myeloma treated with lenalidomide and dexamethasone. Leuk Lymphoma 2010, 51(11):2084-2091.
36. Mateos M.V., Richardson P.G., 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. JClin Oncol 2010, 28(13):2259-2266.
37. Vij R., Wang M., Kaufman J.L., 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):5661-5670.
38. Vij R., Siegel D.S., 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):739-748.
39. Hrusovsky I., Emmerich B., Von Rohr A., et al. Bortezomib retreatment in relapsed multiple myeloma - results from a retrospective multicenter survey in Germany and Switzerland. Oncology 2010, 79(3-4):247-254.
40. Petrucci M.T., Giraldo P., Corradini P., et al. Aprospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol 2013, 160:649-659.
41. Glasmacher A., Hahn C., Hoffmann F., et al. Asystematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma. Br J Haematol 2006, 132(5):584-593.
42. Palumbo A., Facon T., Sonneveld P., et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood 2008, 111(8):3968-3977.
43. von Lilienfeld-Toal M., Hahn-Ast C., Furkert K., et al. Asystematic review of phase II trials of thalidomide/dexamethasone combination therapy in patients with relapsed or refractory multiple myeloma. Eur J Haematol 2008, 81(4):247-252.
44. Garcia-Sanz R., Gonzalez-Porras J.R., Hernandez J.M., et al. The oral combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is effective in relapsed/refractory multiple myeloma. Leukemia 2004, 18(4):856-863.
45. Kyriakou C., Thomson K., D'Sa S., et al. Low-dose thalidomide in combination with oral weekly cyclophosphamide and pulsed dexamethasone is a well tolerated and effective regimen in patients with relapsed and refractory multiple myeloma. Br J Haematol 2005, 129(6):763-770.
46. Kropff M.H., Lang N., Bisping G., et al. Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (hyperCDT) in primary refractory or relapsed multiple myeloma. Br J Haematol 2003, 122(4):607-616.
47. Dimopoulos M.A., Hamilos G., Zomas A., et al. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma. Hematol J 2004, 5(2):112-117.
48. Sidra G., Williams C.D., Russell N.H., et al. Combination chemotherapy with cyclophosphamide, thalidomide and dexamethasone for patients with refractory, newly diagnosed or relapsed myeloma. Haematologica 2006, 91(6):862-863.
49. Hovenga S., Daenen S.M., de Wolf J.T., et al. Combined thalidomide and cyclophosphamide treatment for refractory or relapsed multiple myeloma patients: a prospective phase II study. Ann Hematol 2005, 84(5):311-316.
50. Offidani M., Marconi M., Corvatta L., et al. Thalidomide plus oral melphalan for advanced multiple myeloma: a phase II study. Haematologica 2003, 88(12):1432-1433.
51. Palumbo A., Avonto I., Bruno B., et al. Intravenous melphalan, thalidomide and prednisone in refractory and relapsed multiple myeloma. Eur J Haematol 2006, 76(4):273-277.
52. Srkalovic G., Elson P., Trebisky B., et al. Use of melphalan, thalidomide, and dexamethasone in treatment of refractory and relapsed multiple myeloma. Med Oncol 2002, 19(4):219-226.
53. Offidani M., Corvatta L., Marconi M., et al. Low dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/refractory multiple myeloma: a prospective, multicenter, phase II study. Haematologica 2006, 91(1):133-136.
54. Hussein M.A., Baz R., Srkalovic G., et al. Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma. Mayo Clin Proc 2006, 81(7):889-895.
55. Pönisch W., Rozanski M., Goldschmidt H., et al. Combined bendamustine, prednisolone and thalidomide for refractory or relapsed multiple myeloma after autologous stem-cell transplantation or conventional chemotherapy: results of a phase I clinical trial. Br J Haematol 2008, 143(2):191-200.
56. Lee C.K., Barlogie B., Munshi N., et al. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. JClin Oncol 2003, 21(14):2732-2739.
57. Palumbo A., Rajkumar S.V., Dimopoulos M.A., et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia 2008, 22(2):414-423.
58. Richardson P.G., Sonneveld P., Schuster M.W., Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. NEngl J Med 2005, 352(24):2487-2498.
59. Richardson P.G., Sonneveld P., Schuster M., et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood 2007, 110(10):3557-3560.
60. Jagannath S., Barlogie B., Berenson J.R., et al. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol 2008, 143(4):537-540.
61. Mikhael J.R., Belch A.R., Prince H.M., 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):169-175.
62. Kropff M.H., Bisping G., Wenning D., et al. Bortezomib in combination with dexamethasone for relapsed multiple myeloma. Leuk Res 2005, 29:587-590.
63. Orlowski R.Z., Voorhees P.M., Garcia R.A., et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 2005, 105(8):3058-3065.
64. Orlowski R.Z., 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. JClin Oncol 2007, 25(25):3892-3901.
65. Berenson J.R., Yang H.H., Sadler K., et al. Phase I/II trial assessing bortezomib andmelphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. JClin Oncol 2006, 24(6):937-944.
66. Popat R., Oakervee H., Williams C., et al. Bortezomib, low-dose intravenous melphalan, and dexamethasone for patients with relapsed multiple myeloma. Br J Haematol 2009, 144(6):887-894.
67. 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):330-337.
68. Reece D.E., Rodriguez G.P., Chen C., et al. Phase I-II trial of bortezomib plus oral cyclophosphamide and prednisone in relapsed and refractory multiple myeloma. JClin Oncol 2008, 26(29):4777-4783.
69. Ludwig H., Kasparu H., Leitgeb C., et al. Bendamustine-bortezomib-dexamethasone is an active and well tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood 2014, 123:985-991.
70. Offidani M., Corvatta L., Maracci L., et al. Efficacy and tolerability of bendamustine, bortezomib and dexamethasone in patients with relapsed-refractory multiple myeloma: a phase II study. Blood Cancer J 2013, 3(11):162.
71. Richardson P.G., Briemberg H., Jagannath S., et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. JClin Oncol 2006, 124(19):3113-3120.
72. Bringhen S., Larocca A., Rossi D., et al. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 2010, 116(23):4745-4753.
73. Moreau P., Pylypenko H., Grosicki S., et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: arandomised, phase 3, non-inferiority study. Lancet Oncol 2011, 12(5):431-440.
74. Chanan-Khan A., Sonneveld P., Schuster M.W., et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. JClin Oncol 2008, 26:4784-4790.
75. Kumar S., Bensinger W., Zimmerman T.M., 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. ASCO Meeting Abstracts 2013, 31(15):8514.
76. Richardson P.G., Schlossman R.L., Weller E., et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002, 100(9):3063-3067.
77. Richardson P.G., Blood E., Mitsiades C.S., et al. Arandomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006, 108(10):3458-3464.
78. Richardson P., Jagannath S., Hussein M., et al. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood 2009, 114(4):772-778.
79. Dimopoulos M., Spencer A., Attal M., et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. NEngl J Med 2007, 357(21):2123-2132.
80. Weber D.M., Chen C., Niesvizky R., et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. NEngl J Med 2007, 357(21):2133-2142.
81. Dimopoulos M.A., Chen C., Spencer A., et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia 2009, 23(11):2147-2152.
82. Baz R., Walker E., Karam M.A., et al. Lenalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Ann Oncol 2006, 17(12):1766-1771.
83. van de Donk N.W., Wittebol S., Minnema M.C., et al. Lenalidomide (Revlimid) combined with continuous oral cyclophosphamide (endoxan) and prednisone (REP) is effective in lenalidomide/dexamethasone-refractory myeloma. Br J Haematol 2010, 148(2):335-337.
84. Reece D.E., Masih-Khan E., Khan A., et al. Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide (Revlimid) (CPR) for the treatment of patients with relapsed and refractory multiple myeloma. ASH Annual Meeting Abstract 2010, 116(21):3055.
85. Morgan G.J., Schey S.A., Wu P., et al. Lenalidomide (Revlimid), in combination with cyclophosphamide and dexamethasone (RCD), is an effective and tolerated regimen for myeloma patients. Br J Haematol 2007, 137(3):268-269.
86. Schey S., Morgan G.J., Ramasamy K., et al. The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study. Br J Haematol 2010, 150(3):326-333.
87. Lentzsch S., O'Sullivan A., Kennedy R.C., 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):4608-4613.
88. Pönisch W., Heyn S., Beck J., et al. Lenalidomide, bendamustine and prednisolone exhibits a favourable safety and efficacy profile in relapsed or refractory multiple myeloma: final results of a phase 1 clinical trial OSHO - #077. Br J Haematol 2013, 162(2):202-209.
89. Wang Z., Yang J., Kirk C., et al. Clinical pharmacokinetics, metabolism, and drug-drug interaction of carfilzomib. Drug Metab Dispos 2013, 41(1):230-237.
90. Kuhn D.J., Chen Q., Voorhees P.M., et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 2007, 110(9):3281-3290.
91. O'Connor O.A., Stewart A.K., Vallone M., et al. Aphase 1 dose escalation study of the safety and pharmaco-kinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res 2009, 15(22):7085-7091.
92. Alsina M., Trudel S., Furman R.R., et al. Aphase I single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res 2012, 18(17):4830-4840.
93. 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):1753-1761.
94. 2 plus 40 mg weekly dexamethasone in patients with relapsed and/or refractory (R/R) multiple myeloma. ASH Annual Meeting Abstract 2012, 120(21):4036.
95. Kaufman J.L., Siegel D., Ghobrial I.M., et al. Clinical profile of once-daily, modified-release oprozomib tablets in patients with hematologic malignancies: results of a phase IB/2 trial. EHA Annual Meeting Abstracts 2013, P233.
96. Schey S.A., Fields P., Bartlett J.B., et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. JClin Oncol 2004, 22(16):3269-3276.
97. Streetly M.J., Gyertson K., Daniel Y., et al. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of invivo immunomodulation. Br J Haematol 2008, 141(1):41-51.
98. Richardson P.G., Siegel D., Baz R., et al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood 2013, 121(11):1961-1967.
99. Lacy M.Q., Hayman S.R., Gertz M.A., et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. JClin Oncol 2009, 27(30):5008-5014.
100. Lacy M.Q., Hayman S.R., Gertz M.A., 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):1934-1939.
101. Lacy M.Q., Allred J.B., Gertz M.A., et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood 2011, 118(11):2970-2975.
102. Leleu X., Attal M., Arnulf B., 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):1968-1975.
103. Larocca A., Montefusco V., Bringhen S., et al. Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label study. Blood 2013, 122(16):2799-2806.
104. Mark T.M., Boyer A., Rossi A.C., et al. ClaPD (clarithromycin, pomalidomide, dexamethasone) therapy in relapsed or refractory multiple myeloma. ASH Annual Meeting Abstract 2013, 122(21):1955.
105. Lonial S., Mitsiades C., Richardson P.G. Treatment options for relapsed and refractory multiple myeloma. Clin Cancer Res 2011, 17(6):1264-1277.
106. Garderet L., Iacobelli S., Moreau P., et al. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone 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. JClin Oncol 2012, 30(20):2475-2482.
107. Kim Y.K., Sohn S.K., Lee J.H., et al. Clinical efficacy of a bortezomib, cyclophosphamide, thalidomide, and dexamethasone (Vel-CTD) regimen in patients with relapsed or refractory multiple myeloma: a phase II study. Ann Hematol 2010, 89:475-482.
108. Terpos E., Kastritis E., Roussou M., et al. The combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide is an effective regimen for relapsed/refractory myeloma and is associated with improvement of abnormal bone metabolism and angiogenesis. Leukemia 2008, 22(12):2247-2256.
109. Palumbo A., Ambrosini M.T., Benevolo G., et al. Bortezomib, melphalan, prednisone and thalidomide for relapsed multiple myeloma. Blood 2007, 109(7):2767-2772.
110. Palumbo A., Larocca A., Falco P., et al. Lenalidomide, melphalan, prednisone and thalidomide (RMPT) for relapsed/refractory multiple myeloma. Leukemia 2010, 24(5):1037-1042.
111. Richardson P.G., Xie W., Jagannath S., et al. Aphase II trial of lenalidomide, bortezomib and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood 2014, 123:1461-1469.
112. 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):3122-3128.
113. Richardson P.G., Hofmeister C.G., Siegel D., et al. MM-005: a phase 1 trial of pomalidomide, bortezomib, and low-dose dexamethasone (PVD) in relapsed and/or refractory multiple myeloma (RRMM). ASH Annual Meeting Abstract 2013, 122(21):1969.
114. Shah J.J., Stadtmauer E.A., 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. ASH Annual Meeting Abstract 2013, 122(21):690.
115. Kumar S.K., Lee J.H., Lahuerta J.J., et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 2012, 26:149-157.
116. San-Miguel J.F., Richardson P.G., Günther A., et al. Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma. JClin Oncol 2013, 31(29):3696-3703.
117. Badros A., Burger A.M., Philip S., et al. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 2009, 15(16):5250-5257.
118. Richardson P.G., Schlossman R.L., Alsina M., et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood 2013, 122(14):2331-2337.
119. Richardson P.G., Schlossman R.L., Alsina M., et al. Time to event analyses in PANORAMA 2: a phase 2 study of panobinostat, bortezomib, and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma. ASH Annual Meeting Abstract 2013, 122(21):1970.
120. Siegel D.S., Dimopoulos M.A., Yoon S.S., et al. Vantage 095: vorinostat in combination with bortezomib in salvage multiple myeloma patients: final study results of a global phase 2b trial. ASH Annual Meeting Abstracts 2011, 118(21):480.
121. Dimopoulos M., Siegel D.S., Lonial S., 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):1129-1140.
122. San-Miguel J.F., Moreau P., Yoon S.S., et al. Phase III study of panobinostat with bortezomib and dexamethasone in patients with relapsed multiple myeloma (PANORAMA 1). ASCO Meeting Abstracts 2012, 30(15 Suppl):18572.
123. Raje N., Vogl D.T., Hari P.N., et al. ACY-1215, a selective histone deacetylase (HDAC) 6 inhibitor: interim results of combination therapy with bortezomib in patients with multiple myeloma (MM). ASH Annual Meeting Abstracts 2011, 118(21):759.
124. Zonder J.A., Mohrbacher A.F., Singhal S., et al. Aphase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 2012, 120(3):552-559.
125. Lonial S., Vij R., Harousseau J.L., et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. JClin Oncol 2012, 30(16):1953-1959.
126. Richardson P.G., Jagannath S., Moreau P., et al. Aphase 2 study of elotuzumab (Elo) in combination with lenalidomide and low-dose dexamethasone (Ld) in patients (pts) with relapsed/refractory multiple myeloma (R/R MM): updated results. ASH Annual Meeting Abstracts 2012, 120(21):202.
127. Jakubowiak A.J., Benson D.M., Bensinger W., et al. Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma. JClin Oncol 2012, 30(16):1960-1965.
128. Lokhorst H.M., Plesner T., Gimsing P., et al. Phase I/II dose-escalation study of daratumumab in patients with relapsed or refractory multiple myeloma. ASCO Meeting Abstracts 2013, 31(15 Suppl):8512.
129. Nijhof I.S., Noort W.A., van Bueren J.L., et al. CD38-targeted immunochemotherapy of multiple myeloma: preclinical evidence for its combinatorial use in lenalidomide and bortezomib refractory/intolerant MM patients. ASH Annual Meeting Abstract 2013, 122(21):277.
130. Plesner T., Arkenau T., Lokhorst H., et al. Preliminary safety and efficacy data of daratumumab in combination with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. ASH Annual Meeting Abstract 2013, 122(21):1986.
131. Martin T.G., Strickland S.A., Glenn M., et al. SAR650984, a CD38 monoclonal antibody in patients with selected CD38+ hematological malignancies- data from a dose-escalation phase I study. ASH Annual Meeting Abstract 2013, 122(21):284.
132. Lonial S., Shah J.J., Zonder J., et al. Prolonged survival and improved response rates with ARRY-520 in relapsed/refractory multiple myeloma (RRMM) patients with low α-1 acid glycoprotein (AAG) levels: results from a phase 2 study. ASH Annual Meeting Abstract 2013, 122(21):285.
133. Shah J.J., Feng L., Thomas S.K., 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). ASH Annual Meeting Abstract 2013, 122(21):1982.
134. Chari A., Htut M., Zonder J., et al. Aphase 1 study of ARRY-520 with bortezomib (BTZ) and dexamethasone (dex) in relapsed or refractory multiple myeloma (RRMM). ASH Annual Meeting Abstract 2013, 122(21):1938.