Randomized Controlled Trials versus Single Cohort Studies in Relapse Refractory Multiple Myeloma

Main Article Content

John S. Sampalis, PhD, FACE, FAHA Khashayar Azimpour, MD, PhD Dimitrios Tomaras, MSc Christopher Zuraik, PhD Catherine Silotch, BSc Richard Lebrun Trachy, MSc Melissa Stutz, BSc

Abstract

Background:


The Randomized Controlled Trial (RCT) is considered the gold-standard for the evaluation of treatment efficacy. For rare or end stage cancers for which there are no effective treatments, or the number of patients is sparse, the use of RCTs for the assessment of efficacy and safety may be difficult. In these circumstances the single cohort study (SC) can be considered as an alternative to the RCT.


Purpose:


The purpose of this study was to compare the measures of efficacy as assessed with estimates of the Overall Response Rate (ORR) or Overall Survival (OS) obtained in RCT and SC studies that evaluate the same treatments for Relapse Refractory Multiple Myeloma (RRMM). The study also compared the estimates of ORR and OS ratios between treatments estimated in RCTs and extrapolated in SCs for the same treatments of RRMM.


Methods:


The study utilized data from 42 RCTs and 47 SCs assessing 18 different treatment protocols for RRMM that were identified through a MEDLINE search.


Results:


The results showed that there were no material differences in the demographics of patients enrolled in RCTs and SCs. The estimates of ORR and OS obtained in RCTs and SCs were comparable. Statistically significant Intra-Class Correlation Coefficient (ICC = 0.618, P = 0.027) was observed for ORR and for OS (ICC = 0.734; P = 0.014) indicating good agreement between RCTs and SCs.


Treatment effect size as measured by the ORR and OS ratios (new treatment / control) was ascertained directly from RCTs and extrapolated for SCs based on the control ORR and OS observed in RCTs. There was agreement between RCTs and SCs with respect to the magnitude and direction of the ORR ratios (91% of the studies) and the OS ratios (75% of the studies). With respect to the conclusion regarding the relative efficacy of the new treatment versus the control, there was agreement between RCTs and SCs for 8/11 treatments based on ORR ratios and for 6 / 8 based on OS ratios.


Conclusions:


The results of this study have shown that for RRMM single cohort studies can be used to assess the efficacy of new treatments, given that sufficient data are available on controls treatments used as standard of care. The results may have implications for the evaluation of treatments of rare and advanced cancers as well as other conditions.

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How to Cite
SAMPALIS, John S. et al. Randomized Controlled Trials versus Single Cohort Studies in Relapse Refractory Multiple Myeloma. Medical Research Archives, [S.l.], v. 9, n. 7, july 2021. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2452>. Date accessed: 19 may 2022. doi: https://doi.org/10.18103/mra.v9i7.2452.
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Research Articles

References

1. Kabisch M, Ruckes C, Seibert-Grafe M, Blettner M. Randomized controlled trials: part 17 of a series on evaluation of scientific publications. Dtsch Arztebl Int 2011;108(39):663-8 doi: 10.3238/arztebl.2011.0663.
2. Rothwell PM. External validity of randomised controlled trials: "to whom do the results of this trial apply?". Lancet 2005;365(9453):82-93 doi: 10.1016/s0140-6736(04)17670-8.
3. Kaptchuk TJ. The double-blind, randomized, placebo-controlled trial: gold standard or golden calf? J Clin Epidemiol 2001;54(6):541-9 doi: 10.1016/s0895-4356(00)00347-4.
4. Black N. Why we need observational studies to evaluate the effectiveness of health care. Bmj 1996;312(7040):1215-8 doi: 10.1136/bmj.312.7040.1215.
5. Unger JM, Cook E, Tai E, Bleyer A. The Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies. Am Soc Clin Oncol Educ Book 2016;35:185-98 doi: 10.1200/edbk_156686.
6. Lai J, Forney L, Brinton DL, Simpson KN. Drivers of Start-Up Delays in Global Randomized Clinical Trials. Ther Innov Regul Sci 2021;55(1):212-27 doi: 10.1007/s43441-020-00207-2.
7. Phillippo DM, Ades AE, Dias S, Palmer S, Abrams KR, Welton NJ. Methods for Population-Adjusted Indirect Comparisons in Health Technology Appraisal. Med Decis Making 2018;38(2):200-11 doi: 10.1177/0272989x17725740.
8. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000;342(25):1878-86 doi: 10.1056/nejm200006223422506.
9. Kropff M, Baylon HG, Hillengass J, et al. Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma: results from OPTIMUM, a randomized trial. Haematologica 2012;97(5):784-91 doi: 10.3324/haematol.2011.044271.
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 doi: 10.1056/NEJMoa070596.
11. 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 doi: 10.1056/NEJMoa070594.
12. Miguel JS, 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 Oncol 2013;14(11):1055-66 doi: 10.1016/s1470-2045(13)70380-2.
13. Dimopoulos M, Siegel DS, 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):1129-40 doi: 10.1016/s1470-2045(13)70398-x.
14. Silverman SL. From randomized controlled trials to observational studies. Am J Med 2009;122(2):114-20 doi: 10.1016/j.amjmed.2008.09.030.
15. Yang W, Zilov A, Soewondo P, Bech OM, Sekkal F, Home PD. Observational studies: going beyond the boundaries of randomized controlled trials. Diabetes Res Clin Pract 2010;88 Suppl 1:S3-9 doi: 10.1016/s0168-8227(10)70002-4.
16. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342(25):1887-92 doi: 10.1056/nejm200006223422507.
17. Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized clinical trials good for us (in the short term)? Evidence for a "trial effect". J Clin Epidemiol 2001;54(3):217-24 doi: 10.1016/s0895-4356(00)00305-x.
18. Diehl LF, Perry DJ. A comparison of randomized concurrent control groups with matched historical control groups: are historical controls valid? J Clin Oncol 1986;4(7):1114-20 doi: 10.1200/jco.1986.4.7.1114.
19. Kunz R, Oxman AD. The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials. Bmj 1998;317(7167):1185-90 doi: 10.1136/bmj.317.7167.1185.
20. Shahar T, Nossek E, Steinberg DM, et al. The impact of enrollment in clinical trials on survival of patients with glioblastoma. J Clin Neurosci 2012;19(11):1530-4 doi: 10.1016/j.jocn.2012.04.005.
21. Gertz MA, Kalish LA, Kyle RA, Hahn RG, Tormey DC, Oken MM. Phase III study comparing vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD) chemotherapy with VAD plus recombinant interferon alfa-2 in refractory or relapsed multiple myeloma. An Eastern Cooperative Oncology Group study. Am J Clin Oncol 1995;18(6):475-80 doi: 10.1097/00000421-199512000-00003.
22. Young RI, Ranson M, Chang J, Lord B, Testa N, Scarffe JH. Phase II trial of rhIL-6 (interleukin-6) prior to and concurrently with VAD (vincristine, doxorubicin and dexamethasone) chemotherapy for patients with multiple myeloma. Eur J Cancer 1997;33(2):307-11 doi: 10.1016/s0959-8049(96)00383-8.
23. Friedenberg WR, Rue M, Blood EA, et al. Phase III study of PSC-833 (valspodar) in combination with vincristine, doxorubicin, and dexamethasone (valspodar/VAD) versus VAD alone in patients with recurring or refractory multiple myeloma (E1A95): a trial of the Eastern Cooperative Oncology Group. Cancer 2006;106(4):830-8 doi: 10.1002/cncr.21666.
24. Browman GP, Belch A, Skillings J, et al. Modified adriamycin-vincristine-dexamethasone (m-VAD) in primary refractory and relapsed plasma cell myeloma: an NCI (Canada) pilot study. The National Cancer Institute of Canada Clinical Trials Group. Br J Haematol 1992;82(3):555-9 doi: 10.1111/j.1365-2141.1992.tb06466.x.
25. Sonneveld P, Suciu S, Weijermans P, et al. Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). Br J Haematol 2001;115(4):895-902 doi: 10.1046/j.1365-2141.2001.03171.x.
26. Mineur P, Ménard JF, Le Loët X, et al. VAD or VMBCP in multiple myeloma refractory to or relapsing after cyclophosphamide-prednisone therapy (protocol MY 85). Br J Haematol 1998;103(2):512-7 doi: 10.1046/j.1365-2141.1998.00997.x.
27. Phillips JK, Sherlaw-Johnson C, Pearce R, et al. A randomized study of MOD versus VAD in the treatment of relapsed and resistant multiple myeloma. Leuk Lymphoma 1995;17(5-6):465-72 doi: 10.3109/10428199509056859.
28. Dalton WS, Crowley JJ, Salmon SS, et al. A phase III randomized study of oral verapamil as a chemosensitizer to reverse drug resistance in patients with refractory myeloma. A Southwest Oncology Group study. Cancer 1995;75(3):815-20 doi: 10.1002/1097-0142(19950201)75:3<815::aid-cncr2820750311>3.0.co;2-r.
29. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372(2):142-52 doi: 10.1056/NEJMoa1411321.
30. 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 doi: 10.1182/blood-2013-07-511170.
31. Niesvizky R, Martin TG, 3rd, 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 doi: 10.1158/1078-0432.Ccr-12-3352.
32. Sharma M, Khan H, Thall PF, et al. A randomized phase 2 trial of a preparative regimen of bortezomib, high-dose melphalan, arsenic trioxide, and ascorbic acid. Cancer 2012;118(9):2507-15 doi: 10.1002/cncr.26517.
33. Berenson JR, Boccia R, Siegel D, et al. Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single-arm study. Br J Haematol 2006;135(2):174-83 doi: 10.1111/j.1365-2141.2006.06280.x.
34. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med 2015;373(7):621-31 doi: 10.1056/NEJMoa1505654.
35. Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol 2012;30(16):1953-9 doi: 10.1200/jco.2011.37.2649.
36. Richardson PG, Jagannath S, Moreau P, et al. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol 2015;2(12):e516-27 doi: 10.1016/s2352-3026(15)00197-0.
37. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014;15(11):1195-206 doi: 10.1016/s1470-2045(14)70440-1.
38. San-Miguel JF, Richardson PG, Günther A, et al. Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol 2013;31(29):3696-703 doi: 10.1200/jco.2012.46.7068.
39. Richardson PG, Schlossman RL, 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):2331-7 doi: 10.1182/blood-2013-01-481325.
40. 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. J Clin Oncol 2012;30(20):2475-82 doi: 10.1200/jco.2011.37.4918.
41. 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(7):1419-27 doi: 10.1038/leu.2008.99.
42. 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 doi: 10.1111/j.1365-2141.2004.05188.x.
43. Ozaki S, Hata H, Abe M, et al. Reduced frequency treatment with bortezomib plus dexamethasone for elderly patients with relapsed and/or refractory multiple myeloma: a phase 2 study of the Japanese Myeloma Study Group (JMSG-0902). Ann Hematol 2016;95(6):921-9 doi: 10.1007/s00277-016-2661-7.
44. Hjorth M, Hjertner Ø, Knudsen LM, et al. Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol 2012;88(6):485-96 doi: 10.1111/j.1600-0609.2012.01775.x.
45. Bao L, Lu XJ, Zhang XH, Huang XJ. [Effects of bortezomib at different doses in combination with dexamethasone in treatment of relapsed or refractory multiple myeloma: a comparative study]. Zhonghua Yi Xue Za Zhi 2008;88(26):1829-31
46. Dimopoulos MA, Moreau P, Palumbo A, 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 doi: 10.1016/s1470-2045(15)00464-7.
47. Jakubowiak A, Offidani M, Pégourie B, et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood 2016;127(23):2833-40 doi: 10.1182/blood-2016-01-694604.
48. Siegel DS, Dimopoulos M, Jagannath S, et al. VANTAGE 095: An International, Multicenter, Open-Label Study of Vorinostat (MK-0683) in Combination With Bortezomib in Patients With Relapsed and Refractory Multiple Myeloma. Clin Lymphoma Myeloma Leuk 2016;16(6):329-34.e1 doi: 10.1016/j.clml.2016.02.042.
49. 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 doi: 10.1200/jco.2006.10.5460.
50. Orlowski RZ, Voorhees PM, Garcia RA, et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 2005;105(8):3058-65 doi: 10.1182/blood-2004-07-2911.
51. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol 2009;27(30):5008-14 doi: 10.1200/jco.2009.23.6802.
52. Richardson PG, Siegel DS, 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(12):1826-32 doi: 10.1182/blood-2013-11-538835.
53. Ichinohe T, Kuroda Y, Okamoto S, et al. A multicenter phase 2 study of pomalidomide plus dexamethasone in patients with relapsed and refractory multiple myeloma: the Japanese MM-011 trial. Exp Hematol Oncol 2015;5:11 doi: 10.1186/s40164-016-0040-7.
54. Dimopoulos MA, Weisel KC, Song KW, et al. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica 2015;100(10):1327-33 doi: 10.3324/haematol.2014.117077.
55. Sehgal K, Das R, Zhang L, et al. Clinical and pharmacodynamic analysis of pomalidomide dosing strategies in myeloma: impact of immune activation and cereblon targets. Blood 2015;125(26):4042-51 doi: 10.1182/blood-2014-11-611426.
56. 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 Myélome 2009-02. Blood 2013;121(11):1968-75 doi: 10.1182/blood-2012-09-452375.
57. Lacy MQ, Allred JB, Gertz MA, 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):2970-5 doi: 10.1182/blood-2011-04-348896.
58. Hou J, Du X, Jin J, et al. A multicenter, open-label, phase 2 study of lenalidomide plus low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma: the MM-021 trial. J Hematol Oncol 2013;6:41 doi: 10.1186/1756-8722-6-41.
59. Alegre A, Oriol-Rocafiguera A, Garcia-Larana J, et al. Efficacy, safety and quality-of-life associated with lenalidomide plus dexamethasone for the treatment of relapsed or refractory multiple myeloma: the Spanish experience. Leuk Lymphoma 2012;53(9):1714-21 doi: 10.3109/10428194.2012.662643.
60. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016;375(14):1319-31 doi: 10.1056/NEJMoa1607751.
61. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006;108(10):3458-64 doi: 10.1182/blood-2006-04-015909.
62. Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016;374(17):1621-34 doi: 10.1056/NEJMoa1516282.
63. Berenson JR, Cartmell A, Bessudo A, et al. CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood 2016;127(26):3360-8 doi: 10.1182/blood-2015-11-683854.
64. Lendvai N, Hilden P, Devlin S, et al. A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma. Blood 2014;124(6):899-906 doi: 10.1182/blood-2014-02-556308.
65. Murakami H, Handa H, Abe M, et al. Low-dose thalidomide plus low-dose dexamethasone therapy in patients with refractory multiple myeloma. Eur J Haematol 2007;79(3):234-9 doi: 10.1111/j.1600-0609.2007.00908.x.
66. Offidani M, Bringhen S, Corvatta L, et al. Thalidomide-dexamethasone plus pegylated liposomal doxorubicin vs. thalidomide-dexamethasone: a case-matched study in advanced multiple myeloma. Eur J Haematol 2007;78(4):297-302 doi: 10.1111/j.1600-0609.2007.00823.x.
67. Chiou TJ, Wang TH, Chao TY, et al. Randomized Phase II trial of thalidomide alone versus thalidomide plus interferon alpha in patients with refractory multiple myeloma. Cancer Invest 2007;25(3):140-7 doi: 10.1080/07357900701208808.
68. Mileshkin L, Biagi JJ, Mitchell P, et al. Multicenter phase 2 trial of thalidomide in relapsed/refractory multiple myeloma: adverse prognostic impact of advanced age. Blood 2003;102(1):69-77 doi: 10.1182/blood-2002-09-2846.
69. 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 doi: 10.1056/NEJMoa043445.
70. Petrucci MT, Giraldo P, Corradini P, et al. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol 2013;160(5):649-59 doi: 10.1111/bjh.12198.
71. Orlowski RZ, Gercheva L, Williams C, 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 doi: 10.1002/ajh.23868.
72. Hainsworth JD, Spigel DR, Barton J, et al. Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network. Cancer 2008;113(4):765-71 doi: 10.1002/cncr.23606.
73. Hellmann A, Rule S, Walewski J, et al. Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or non-Hodgkin's lymphoma. Clin Pharmacokinet 2011;50(12):781-91 doi: 10.2165/11594410-000000000-00000.
74. Richardson PG, Barlogie B, Berenson J, et al. Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma:: final time-to-event results from the SUMMIT trial. Cancer 2006;106(6):1316-9 doi: 10.1002/cncr.21740.
75. 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 doi: 10.1111/j.1365-2141.2008.07409.x.
76. White D, Kassim A, Bhaskar B, Yi J, Wamstad K, Paton VE. Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma. Cancer 2013;119(2):339-47 doi: 10.1002/cncr.27745.
77. Jagannath S, Barlogie B, Berenson JR, 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):537-40 doi: 10.1111/j.1365-2141.2008.07359.x.
78. Hájek R, Masszi T, Petrucci MT, et al. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia 2017;31(1):107-14 doi: 10.1038/leu.2016.176.
79. Herndon TM, Deisseroth A, Kaminskas E, et al. U.s. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma. Clin Cancer Res 2013;19(17):4559-63 doi: 10.1158/1078-0432.Ccr-13-0755.
80. 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):310-8 doi: 10.1016/j.clml.2012.08.003.
81. 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 doi: 10.1182/blood-2012-05-425934.
82. 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 doi: 10.1111/j.1365-2141.2012.09232.x.
83. 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 doi: 10.1182/blood-2012-03-414359.
84. Watanabe T, Tobinai K, Matsumoto M, et al. A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma. Br J Haematol 2016;172(5):745-56 doi: 10.1111/bjh.13900.
85. Neben K, Moehler T, Benner A, et al. Dose-dependent effect of thalidomide on overall survival in relapsed multiple myeloma. Clin Cancer Res 2002;8(11):3377-82
86. Uppal G, Raina V, Sharma A, et al. Use of simple hematological, biochemical and clinical parameters to monitor response of multiple myeloma patients on high dose thalidomide therapy. Indian J Cancer 2005;42(1):46-50 doi: 10.4103/0019-509x.15100.
87. Decaux O, Renault A, Sébille V, et al. Predictive factors of survival after thalidomide therapy in advanced multiple myeloma: long-term follow-up of a prospective multicenter nonrandomized phase II study in 120 patients. Clin Lymphoma Myeloma Leuk 2012;12(6):418-22 doi: 10.1016/j.clml.2012.06.003.
88. Murakami H, Shimizu K, Sawamura M, et al. Phase II and pharmacokinetic study of thalidomide in Japanese patients with relapsed/refractory multiple myeloma. Int J Hematol 2009;89(5):636-41 doi: 10.1007/s12185-009-0314-5.
89. Hattori Y, Okamoto S, Shimada N, et al. Single-institute phase 2 study of thalidomide treatment for refractory or relapsed multiple myeloma: prognostic factors and unique toxicity profile. Cancer Sci 2008;99(6):1243-50 doi: 10.1111/j.1349-7006.2008.00792.x.
90. Yakoub-Agha I, Mary JY, Hulin C, et al. Low-dose vs. high-dose thalidomide for advanced multiple myeloma: a prospective trial from the Intergroupe Francophone du Myélome. Eur J Haematol 2012;88(3):249-59 doi: 10.1111/j.1600-0609.2011.01729.x.
91. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341(21):1565-71 doi: 10.1056/nejm199911183412102.