proteasome inhibitor

Practical Aspects of the Use of Carfilzomib in Multiple Myeloma

NOVEL DRUGS , , , , ,

SV Semochkin1,2, GN Salogub3, SS Bessmeltsev4, KD Kaplanov5

1 NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

2 Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182

3 VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

4 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

5 Volgograd Regional Clinical Oncology Dispensary No. 1, 78 Zemlyachki str., Volgograd, Russian Federation, 400138

For correspondence: Prof. Sergei Vyacheslavovich Semochkin, MD, PhD, 3 Pekhotnaya str., Moscow, Russian Federation, 123182; Tel./fax: +7(495)369-00-36; e-mail: semochkin_sv@rsmu.ru

For citation: Semochkin SV, Salogub GN, Bessmeltsev SS, Kaplanov KD. Practical Aspects of the Use of Carfilzomib in Multiple Myeloma. Clinical oncohematology. 2019;12(1):21–31.

DOI: 10.21320/2500-2139-2019-12-1-21-31

ABSTRACT

Carfilzomib (Kyprolis®, Amgen), a second-generation proteasome inhibitor, is capable of covalent bonding and irreversible inhibition of the 20S proteasome chymotrypsin-like activity. In 2016 this drug was approved in Russia for monotherapy of relapsed refractory multiple myeloma (MM) and in combination with lenalidomide and dexamethasone (KRd) or only with dexamethasone (Kd) for treatment of patients with relapsed MM after at least one line of prior therapy. The present review outlines mechanism, clinical efficacy, and adverse effects of carfilzomib according to the data of a phase II (monotherapy) trial and two key randomized phase III (carfilzomib combined with other drugs) trials. The ASPIRE trial demonstrated that adding carfilzomib to the combination of lenalidomide and dexamethasone (KRd) significantly improves progression-free survival (PFS) compared with the Rd original regimen (median 26.3 vs. 17.6 months; hazard ratio [HR] 0.69; p = 0.0001). Median overall survival (OS) was 48.3 months (95% confidence interval [95% CI] 42.4–52.8 months) for KRd vs. 40.4 months (95% CI 33.6–44.4 months) for Rd (HR 0.79; p = 0.0045). The ENDEAVOR trial showed that as compared with combination of bortezomib and dexamethasone (Vd) the carfilzomib + dexamethasone (Kd) regimen significantly improves PFS (median 18.7 vs. 9.4 months; HR 0.53; p < 0.0001) and OS (47.6 vs. 40.0 months; HR 0.79; p = 0.010) as well. The present review also discusses how carfilzomib is to be used in special patient groups (with renal failure and high cytogenetic risk).

Keywords: carfilzomib, proteasome inhibitor, lenalidomide, bortezomib, multiple myeloma, renal failure, cytogenetic risk.

Received: May 12, 2018

Accepted: December 28, 2018

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REFERENCES

  1. Siegel D, 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.

  2. 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. doi: 10.3324/haematol.2013.089334.

  3. 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. doi: 10.1038/leu.2013.29.

  4. Wang TF, Ahluwalia R, Fiala MA, et al. The characteristics and outcomes of patients with multiple myeloma dual refractory or intolerant to bortezomib and lenalidomide in the era of carfilzomib and pomalidomide. Leuk Lymphoma. 2014;55(2):337–41. doi: 10.3109/10428194.2013.803547.

  5. Moreau P. How I treat myeloma with new agents. Blood. 2017;130(13):1507–13. doi: 10.1182/blood-2017-05-743203.

  6. 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.

  7. 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.

  8. Gea J, Agusti A, Roca J. Pathophysiology of muscle dysfunction in COPD. J Appl Physiol. 2013;114(9):1222–34. doi: 10.1152/japplphysiol.00981.2012.

  9. Ciehanover A, Hod Y, Hershko A. A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. Biochem Biophys Res Commun. 2012;425(3):565–70. doi: 10.1016/j.bbrc.2012.08.025.

  10. Nobel Prize in Chemistry 2004. Nobelprize.org. Nobel Media AB 2014. Available from: http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2004/ (accessed 10.01.2018).

  11. Vincenz L, Jager R, O’Dwyer M, Samali A. Endoplasmic reticulum stress and the unfolded protein response: targeting the Achilles heel of multiple myeloma. Mol Cancer Ther. 2013;12(6):831–43. doi: 10.1158/1535-7163.MCT-12-0782.

  12. Hasinoff BB. Progress curve analysis of the kinetics of slow-binding anticancer drug inhibitors of the 20S proteasome. Arch Biochem Biophys. 2018;639:52–8. doi: 10.1016/j.abb.2017.12.020.

  13. Kuhn DJ, Chen Q, Voorhees PM, 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):3281–90. doi: 10.1182/blood-2007-01-065888.

  14. Accardi F, Toscani D, Bolzoni M, et al. Mechanism of action of bortezomib and the new proteasome inhibitors on myeloma cells and the bone microenvironment: impact on myeloma-induced alterations of bone remodeling. Biomed Res Int. 2015;2015:1–13. doi: 10.1155/2015/172458.

  15. Wang Z, Yang J, Kirk C, et al. Clinical pharmacokinetics, metabolism, and drug-drug interaction of carfilzomib. Drug Metab Dispos. 2013;41(1):230–7. doi: 10.1124/dmd.112.047662.

  16. Alsina M, Trudel S, Furman RR, et al. A phase 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):4830–40. doi: 10.1158/1078-0432.ccr-11-3007.

  17. Squifflet P, Michiels S, Siegel D, et al. Relationship between carfilzomib dose and efficacy outcomes in patients with relapsed and/or refractory multiple myeloma. Clin Lymph Myel Leuk. 2015;15(11):680–6. doi: 10.1016/j.clml.2015.09.005.

  18. Papadopoulos KP, Siegel DS, Vesole DH, et al. Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. 2015;33(7):732–9. doi: 10.1200/JCO.2013.52.3522.

  19. Hajek 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.

  20. Dimopoulos MA, Stewart AK, Masszi T, et al. Carfilzomib-lenalidomide-dexamethasone vs lenalidomide-dexamethasone in relapsed multiple myeloma by previous treatment. Blood Cancer J. 2017;7(4):e554. doi: 10.1038/bcj.2017.31.

  21. Stewart KA, Siegel D, Ludwig H, et al. Overall Survival (OS) of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Versus Lenalidomide and Dexamethasone (Rd): Final Analysis from the Randomized Phase 3 Aspire Trial. Blood (ASH Annual Meeting Abstracts). 2017;130(Suppl 1): Abstract 743.

  22. Stewart AK, Dimopoulos MA, Masszi T, et al. Health-Related Quality of Life Results From the Open-Label, Randomized, Phase III ASPIRE Trial Evaluating Carfilzomib, Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone in Patients With Relapsed Multiple Myeloma. J Clin Oncol. 2016;34(32):3921–30. doi: 10.1200/JCO.2016.66.9648.

  23. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(10):1327–37. doi: 10.1016/S1470-2045(17)30578-8.

  24. Gavriatopoulou M, Terpos E, Kastritis E, Dimopoulos MA. Current treatments for renal failure due to multiple myeloma. Expert Opin Pharmacother. 2016;17(16):2165–77. doi: 10.1080/14656566.2016.1236915.

  25. Yadav P, Cook M, Cockwell P. Current Trends of Renal Impairment in Multiple Myeloma. Kidney Dis. 2016;1(4):241–57. doi: 10.1159/000442511.

  26. Рехтина И.Г., Менделеева Л.П., Бирюкова Л.С. Диализзависимая почечная недостаточность у больных множественной миеломой: факторы обратимости. Терапевтический архив. 2015;87(7):72–6. doi: 10.17116/terarkh201587772-76.

    [Rekhtina IG, Mendeleeva LP, Biryukova LS. Dialysis-dependent renal failure in patients with multiple myeloma: Reversibility factors. Terapevticheskii arkhiv. 2015;87(7):72–6. doi: 10.17116/terarkh201587772-76. (In Russ)]

  27. Dimopoulos MA, Sonneveld P, Leung N, et al. International Myeloma Working Group Recommendations for the Diagnosis and Management of Myeloma-Related Renal Impairment. J Clin Oncol. 2016;34(13):1544–57. doi: 10.1200/JCO.2015.65.0044.

  28. Stansfield LC, Gonsalves WI, Buadi FK. The use of novel agents in multiple myeloma patients with hepatic impairment. Fut Oncol. 2015;11(3):501–10. doi: 10.2217/fon.14.270.

  29. Kumar SK, Lee JH, Lahuerta JJ, 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(1):149–57. doi: 10.1038/leu.2011.196.

  30. Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955–62. doi: 10.1182/blood-2016-01-631200.

  31. Jakubowiak AJ, Siegel DS, Martin T, et al. Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study. Leukemia. 2013;27(12):2351–6. doi: 10.1038/leu.2013.152.

  32. Avet-Loiseau H, Fonseca R, Siegel D, et al. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016;128(9):1174–80. doi: 10.1182/blood-2016-03-707596.

  33. Stessman HA, Baughn LB, Sarver A, et al. Profiling bortezomib resistance identifies secondary therapies in a mouse myeloma model. Mol Cancer Ther. 2013;12(6):1140–50. doi: 10.1158/1535-7163.MCT-12-1151.

  34. Berenson JR, Hilger JD, Yellin O, et al. Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy. Leukemia. 2014;28(7):1529–36. doi: 10.1038/leu.2014.27.

  35. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(8):754–66. doi: 10.1056/NEJMoa1606038.

  36. Moreau Ph, Oriol A, Kaufman JL, et al. Daratumumab, Lenalidomide, and Dexamethasone (DRd) Versus Lenalidomide and Dexamethasone (Rd) in Relapsed or Refractory Multiple Myeloma (RRMM) Based on Prior Treatment History, Renal Function, and Cytogenetic Risk: Subgroup Analyses of Pollux. Blood (ASH Annual Meeting Abstracts). 2017;130(Suppl 1): Abstract 1883.

  37. Dimopoulos MA, Lonial S, White D, et al. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017;178(6):896–905. doi: 10.1111/bjh.14787.

  38. Grandin EW, Ky B, Cornell RF, et al. Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma. J Card Fail. 2015;21(2):138–44. doi: 10.1016/j.cardfail.2014.11.008.

  39. Бессмельцев С.С., Карягина Е.В., Стельмашенко Л.В. и др. Частота, характеристика и методы лечения периферической нейропатии у больных множественной миеломой, получающих бортезомиб (велкейд). Онкогематология. 2008;3(3):52–62.

    [Bessmeltsev SS, Karyagina EV, Stelmashenko LV, et al. Incidence, characteristics, and treatments of peripheral neuropathy in multiple myeloma patients receiving bortezomib (velcade). Onkogematologiya. 2008;3(3):52–62. (In Russ)]

  40. Скворцова Н.В., Поспелова Т.И., Нечунаева И.Н. и др. Эффективность повторной терапии бортезомибом у пациентов с рефрактерными и рецидивирующими формами множественной миеломы. Сибирский научный медицинский журнал. 2013;33(1):76–81.

    [Skvortsova NV, Pospelova TI, Nechunaeva IN, et al. Antitumor activity of bortezomib retreatment in relapsed or refractory multiple myeloma patients. Sibirskii nauchnyi meditsinskii zhurnal. 2013;33(1):76–81. (In Russ)]

  41. Rosenthal A, Luthi J, Belohlavek M, et al. Carfilzomib and the cardiorenal system in myeloma: an endothelial effect? Blood Cancer J. 2016;6(1):e384. doi: 10.1038/bcj.2015.112.

  42. Atrash S, Tullos A, Panozzo S, et al. Cardiac complications in relapsed and refractory multiple myeloma patients treated with carfilzomib. Blood Cancer J. 2015;5(1):e272. doi: 10.1038/bcj.2014.93.

  43. Danhof S, Schreder M, Rasche L, et al. ‘Real-life’ experience of preapproval carfilzomib-based therapy in myeloma – analysis of cardiac toxicity and predisposing factors. Eur J Haematol. 2016;97(1):25–32. doi: 10.1111/ejh.12677.

  44. 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.

  45. Chari A, Hajje D. Case series discussion of cardiac and vascular events following carfilzomib treatment: possible mechanism, screening, and monitoring. BMC Cancer. 2014;14(1):915. doi: 10.1186/1471-2407-14-915.

  46. Sullivan MR, Danilov AV, Lansigan F, Dunbar NM. Carfilzomib associated thrombotic microangiopathy initially treated with therapeutic plasma exchange. J Clin Apher. 2015;30(5):308–10. doi: 10.1002/jca.21371.

  47. Yui JC, Van Keer J, Weiss BM, et al. Proteasome inhibitor associated thrombotic microangiopathy. Am J Hematol. 2016;91(9):E348–52. doi: 10.1002/ajh.24447.

  48. Григорьева В.Н., Стамо А.П., Авдонина Ю.Д., Беляков К.М. Особенности поражения периферической нервной системы при множественной миеломе. Неврологический журнал. 2013;18(2):4–10.

    [Grigor’eva VN, Stamo AP, Avdonina YuD, Belyakov KM. Characteristics of lesions in the peripheral nervous system in multiple myeloma. Nevrologicheskii zhurnal. 2013;18(2):4–10. (In Russ)]

  49. Менделеева Л.П., Вотякова О.М., Покровская О.С. и др. Национальные клинические рекомендации по диагностике и лечению множественной миеломы. Гематология и трансфузиология. 2016;61(1, прил. 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2).

    [Mendeleeva LP, Votyakova OM, Pokrovskaya OS, et al. National clinical guidelines on diagnosis and treatment of multiple myeloma. Gematologiya i transfuziologiya. 2016;61(1, Suppl. 2):1–24. doi: 10.18821/0234-5730-2016-61-1(Прил.2). (In Russ)]

  50. Lataifeh AR, Nusair A. Fatal pulmonary toxicity due to carfilzomib (Kyprolis). J Oncol Pharm Pract. 2016;22(5):720–4. doi: 10.1177/1078155215588630.

  51. Cai X, Bhattacharyya S, Plitt A, et al. Management of posterior reversible encephalopathy syndrome induced by carfilzomib in a patient with multiple myeloma. J Clin Oncol. 2016;34(2):e1–5. doi: 10.1200/JCO.2013.49.6166.

  52. Скворцова В.И., Губский Л.В., Мельникова Е.А. Синдром задней обратимой энцефалопатии. Журнал неврологии и психиатрии им. C.C. Корсакова. 2010;110(5):104–9.

    [Skvortsova VI, Gubskii LV, Mel’nikova EA. Posterior reversible encephalopathy syndrome. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2010;110(5):104–9. (In Russ)]