OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press34610.17650/1818-8346-2019-14-2-29-40HEMATOLOGIC MALIGNANCIES: TREATMENT, SUPPORTIVE CAREГЕМОБЛАСТОЗЫ: ЛЕЧЕНИЕ, СОПРОВОДИТЕЛЬНАЯ ТЕРАПИЯNew proteasome inhibitors in the management of multiple myelomaНовые ингибиторы протеасомы в терапии множественной миеломыhttps://orcid.org/0000-0002-8129-8114SemochkinS. V.СемочкинС. В.
Russian Federation

1 Ostrovityanova St., Moscow 117997, Russia;

 3 Pekhotnaya St., Moscow 123182, Russia

Россия, 117997 Москва, ул. Островитянова, 1

Россия, 123182 Москва, ул. Пехотная, 3

semochkin_sv@rsmu.ruN.I. Pirogov Russian National Research Medical University, Ministry of Health of RussiaФГБОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава РоссииCity Clinical Hospital No 52, Moscow Healthcare DepartmentГБУЗ г. Москвы «Городская клиническая больница № 52 Департамента здравоохранения г. Москвы»2607201914229402507201925072019https://oncohematology.abvpress.ru/ongm/article/view/346

The landscape of multiple myeloma treatment transformed at the last 15 years by the introduction of novel agents (bortezomib, lenalidomide) and wide application of autologous hematopoietic stem cell transplantation, which have prolonged the survival of multiple myeloma patients. Despite the fact that multiple myeloma remains an incurable disease due to the new options, the median overall survival of patients with multiple myeloma in Russia in 2006–2016 was about 55–68 months. Drug resistance and clonal evolution remain a problem. The novel proteasome inhibitors (carfilzomib, ixazomib) differ in chemical structure and pharmacological characteristics. Thereby the next-generation proteasome inhibitor (IPs)-based regimens (KRd (carfilzomib, lenalidomide, dexamethasone), IRd (ixazomib, lenalidomide, dexamethasone), and Kd (carfilzomib, dexamethasone)) are emerging as new standards for the treatment of patients with relapsed and/or refractory multiple myeloma. In a randomized trial phase 3 ENDEAVOR, carfilzomib demonstrated improved survival in direct comparison to bortezomib. The dose-dependent activity of carfilzomib demonstrated in the study of A.R.R.O.W. Аctivity of ixazomib is comparable to that of bortezomib, the oral method of administration and the absence of neurological toxicity, allow for long-term control of the disease. The new PIs are an important advance in relapsed and/or refractory multiple myeloma treatment, increasing survival, response rate and quality of life, even in subgroups of patients with poor prognosis. This review summarizes the main pharmacological properties, mechanisms of action and clinical outcomes of major clinical studies with these agents. A separate issue discusses the problem of overcoming new proteasome inhibitors of drug resistance to bortezomib.

Прогресс последних 15 лет в терапии множественной миеломы ассоциируется с применением новых препаратов (бортезомиб, леналидомид) и широким использованием аутологичной трансплантации гемопоэтических стволовых клеток. Несмотря на то что множественная миелома остается неизлечимым заболеванием, медиана общей выживаемости пациентов в России в 2006–2016 гг. достигла 55–68 мес. Ингибиторы протеасомы 2‑го поколения (карфилзомиб, иксазомиб) различаются по химической структуре и фармакологическим характеристикам. Схемы на их платформе (KRd (карфилзомиб, леналидомид, дексаметазон), IRd (иксазомиб, леналидомид, дексаметазон) и Kd (карфилзомиб, дексаметазон)) являются новым стандартом лечения рецидивирующей и / или рефрактерной множественной миеломы, демонстрирующим преимущества по выживаемости и частоте ответов даже у пациентов с неблагоприятным прогнозом. В исследовании III фазы ENDEAVOR применение карфилзомиба увеличивало выживаемость пациентов по сравнению с бортезомибом. Оптимальный дозовый режим использования карфилзомиба отработан в исследовании A.R.R.O.W. Активность иксазомиба сопоставима с таковой бортезомиба, однако оральный способ назначения и низкая неврологическая токсичность обеспечивают возможность проведения максимально длительной терапии. В настоящем обзоре представлены сведения по механизмам действия ингибиторов протеасомы и результатам основных клинических исследований. Отдельно обсуждается проблема преодоления новыми препаратами резистентности к бортезомибу.

multiple myelomaproteasome inhibitorbortezomibixazomibcarfilzomibмножественная миеломаингибитор протеасомыбортезомибиксазомибкарфилзомибMoreau P., San Miguel J., Sonneveld P. et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(suppl_4): 52–61. DOI: 10.1093/annonc/mdx096.Luchinin A.S., Semochkin S.V., Minaeva N.V. et al. Epidemiology of multiple myeloma according to the Kirov region population registers. Oncohematology 2017;12(3):50–6. (In Russ.). DOI: 10.17650/1818-8346-2017-12-3-50-56.Лучинин А.С., Семочкин С.В., Минаев Н.В. и др. Эпидемиология множественной миеломы по данным анализа популяционного регистра Кировской области. Онкогематология 2017;12(3): 50–6. DOI: 10.17650/1818-8346-2017-12-3-50-56.Skvortsova N.V., Pospelova T.I., Kovynev I.B. et al. Epidemiology of multiple myeloma in Novosibirsk (Siberian Federal District). Clinichtskaya Onkogematologiya = Clinical Oncohematology 2019;12(1):86–94. (In Russ.). DOI: 10.21320/2500-2139-2019-12-1-86-94.Скворцова Н.В., Поспелова Т.И., Ковынев И.Б. и др. Эпидемиология множественной миеломы в Новосибирске (Сибирский федеральный округ). Клиническая онкогематология 2019;12(1):86–94. DOI: 10.21320/2500-2139-2019-12-1-86-94.Dimopoulos M.A., 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.Vincenz L., Jäger 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.Vincenz L., Jäger 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.Hershko A., Heller H., Elias S., Ciechanover A. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem 1983;258(13):8206–14.Hershko A., Heller H., Elias S., Ciechanover A. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem 1983;258(13):8206–14.Clague M.J, Urbé S. Ubiquitin: same molecule, different degradation pathways. Cell 2010;143(5):682–5. DOI: 10.1016/j.cell.2010.11.012.Hershko A., Heller H., Elias S., Ciechanover A. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem 1983;258(13):8206–14.Roos-Mattjus P., Sistonen L. The ubiquitin-proteasome pathway. Ann Med 2004;36(4):285–95.Clague M.J, Urbé S. Ubiquitin: same molecule, different degradation pathways. Cell 2010;143(5):682–5. DOI: 10.1016/j.cell.2010.11.012.Scheffner M., Nuber U., Huibregtse J.M. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature. 1995;373(6509):81–3. DOI: 10.1038/373081a0.Clague M.J, Urbé S. Ubiquitin: same molecule, different degradation pathways. Cell 2010;143(5):682–5. DOI: 10.1016/j.cell.2010.11.012.Zhuang J., Shirazi F., Singh R.K. et al. Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma. Blood 2019;133(14):1572–84. DOI: 10.1182/blood-2018-06-859686.Roos-Mattjus P., Sistonen L. The ubiquitin-proteasome pathway. Ann Med 2004;36(4):285–95.Kimura H., Caturegli P., Takahashi M., Suzuki K. New Insights into the Function of the Immunoproteasome in Immune and Nonimmune Cells. J Immunol Res 2015;2015:541984. DOI: 10.1155/2015/541984.Roos-Mattjus P., Sistonen L. The ubiquitin-proteasome pathway. Ann Med 2004;36(4):285–95.Fabre C., Mimura N., Bobb K. et al. Dual inhibition of canonical and noncanonical NF-κB pathways demonstrates significant antitumor activities in multiple myeloma. Clin Cancer Res 2012;18(17):4669–81. DOI: 10.1158/1078-0432.CCR-12-0779.Scheffner M., Nuber U., Huibregtse J.M. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature. 1995;373(6509):81–3. DOI: 10.1038/373081a0.Richardson P.G., Sonneveld P., Schuster M.W. et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352(24):2487–98. DOI: 10.1056/NEJMoa043445.Scheffner M., Nuber U., Huibregtse J.M. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature. 1995;373(6509):81–3. DOI: 10.1038/373081a0.San Miguel J.F., Schlag R., Khuageva N.K. et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359(9):906–17. DOI: 10.1056/NEJMoa0801479.Zhuang J., Shirazi F., Singh R.K. et al. Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma. Blood 2019;133(14):1572–84. DOI: 10.1182/blood-2018-06-859686.Spencer A., Lentzsch S., Weisel K. et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018;103(12):2079–87. DOI: 10.3324/haematol.2018.194118.Zhuang J., Shirazi F., Singh R.K. et al. Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma. Blood 2019;133(14):1572–84. DOI: 10.1182/blood-2018-06-859686.Richardson P.G., Oriol A., Beksac M. et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol 2019;S1470–2045(19):30152–4. DOI: 10.1016/S1470-2045(19)30152-4.Kimura H., Caturegli P., Takahashi M., Suzuki K. New Insights into the Function of the Immunoproteasome in Immune and Nonimmune Cells. J Immunol Res 2015;2015:541984. DOI: 10.1155/2015/541984.Mu S.D., Ai L.S., Qin Y., Hu Y. Subcutaneous versus intravenous bortezomib administration for multiple myeloma patients: a meta-analysis. Curr Med Sci 2018;38(1):43–50. DOI: 10.1007/s11596-018-1844-y.Kimura H., Caturegli P., Takahashi M., Suzuki K. New Insights into the Function of the Immunoproteasome in Immune and Nonimmune Cells. J Immunol Res 2015;2015:541984. DOI: 10.1155/2015/541984.Tan C.R.C., Abdul-Majeed S., Cael B., Barta S.K. Clinical pharmacokinetics and pharmacodynamics of bortezomib. Clin Pharmacokinet 2019;58(2):157–68. DOI: 10.1007/s40262-018-0679-9.Fabre C., Mimura N., Bobb K. et al. Dual inhibition of canonical and noncanonical NF-κB pathways demonstrates significant antitumor activities in multiple myeloma. Clin Cancer Res 2012;18(17):4669–81. DOI: 10.1158/1078-0432.CCR-12-0779.Gupta N., Hanley M.J., Xia C. et al. Clinical pharmacology of ixazomib: the first oral proteasome inhibitor. Clin Pharmacokinet 2019;58(4):431–49. DOI: 10.1007/s40262-018-0702-1.Fabre C., Mimura N., Bobb K. et al. Dual inhibition of canonical and noncanonical NF-κB pathways demonstrates significant antitumor activities in multiple myeloma. Clin Cancer Res 2012;18(17):4669–81. DOI: 10.1158/1078-0432.CCR-12-0779.Khan M.L., Stewart A.K. Carfilzomib: a novel second-generation proteasome inhibitor. Future Oncol 2011;7(5):607–12. DOI: 10.2217/fon.11.42.Richardson P.G., Sonneveld P., Schuster M.W. et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352(24):2487–98. DOI: 10.1056/NEJMoa043445.Wang Z., Yang J., Kirk C. et al. Clinical pharmacokinetics, metabolism, and drugdrug interaction of carfilzomib. Drug Metab Dispos 2013;41(1):230–7. DOI: 10.1124/dmd.112.047662.Richardson P.G., Sonneveld P., Schuster M.W. et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352(24):2487–98. DOI: 10.1056/NEJMoa043445.Siegel D.S., 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.San Miguel J.F., Schlag R., Khuageva N.K. et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359(9):906–17. DOI: 10.1056/NEJMoa0801479.Hajek R., Masszi T., Petrucci M.T. 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.San Miguel J.F., Schlag R., Khuageva N.K. et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359(9):906–17. DOI: 10.1056/NEJMoa0801479.Moreau P., Mateos M.V., Berenson J.R. et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol 2018;19(7):953–64. DOI: 10.1016/S1470-2045(18)30354-1.Spencer A., Lentzsch S., Weisel K. et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018;103(12):2079–87. DOI: 10.3324/haematol.2018.194118.Stewart A.K., Rajkumar S.V., Dimopoulos M.A. et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372(2): 142–52. DOI: 10.1056/NEJMoa1411321.Spencer A., Lentzsch S., Weisel K. et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018;103(12):2079–87. DOI: 10.3324/haematol.2018.194118.Siegel D.S., Dimopoulos M.A., Ludwig H. et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol 2018;36(8):728–34. DOI: 10.1200/JCO.2017.76.5032.Richardson P.G., Oriol A., Beksac M. et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol 2019;S1470–2045(19):30152–4. DOI: 10.1016/S1470-2045(19)30152-4.Facon T., Lee J.H., Moreau P. et al. Randomized phase 3 study of carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible, NDMM patients. Blood 2019. DOL: 10.1182/blood-2018-09-874396.Richardson P.G., Oriol A., Beksac M. et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol 2019;S1470–2045(19):30152–4. DOI: 10.1016/S1470-2045(19)30152-4.Zimmerman T., Raje N.S., Vij R. et al. Final results of a phase 2 trial of extended treatment (tx) with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (KRd) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM). ASH 2016. Blood 2016;128:675.Mu S.D., Ai L.S., Qin Y., Hu Y. Subcutaneous versus intravenous bortezomib administration for multiple myeloma patients: a meta-analysis. Curr Med Sci 2018;38(1):43–50. DOI: 10.1007/s11596-018-1844-y.Gay F.M., Cerrato Ch., Scalabrini D.R. et al. Carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous transplant (ASCT)-Krd consolidation vs KRd 12 cycles vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation: analysis of the randomized forte trial in newly diagnosed multiple myeloma (NDMM). ASH 2018. Blood 2018;132:121. DOI: https://doi.org/10.1182/blood-2018-99-112093.Mu S.D., Ai L.S., Qin Y., Hu Y. Subcutaneous versus intravenous bortezomib administration for multiple myeloma patients: a meta-analysis. Curr Med Sci 2018;38(1):43–50. DOI: 10.1007/s11596-018-1844-y.Gay F.M., Scalabrini D.R., Belotti A. et al. Carfilzomib-lenalidomide-dexamethasone (KRd) vs carfilzomib-cyclophosphamidedexamethasone (KCd) induction: planned interim analysis of the randomized FORTE trial in newly diagnosed multiple myeloma (NDMM). ASCO 2017. J Clin Oncol 2017;35(15_suppl):8003. DOI: 10.1200/JCO.2017.35.15_suppl.8003.Tan C.R.C., Abdul-Majeed S., Cael B., Barta S.K. Clinical pharmacokinetics and pharmacodynamics of bortezomib. Clin Pharmacokinet 2019;58(2):157–68. DOI: 10.1007/s40262-018-0679-9.Zhao F., Yang B., Wang J. et al. Incidence and risk of cardiac toxicities in patients with relapsed and refractory multiple myeloma treated with carfilzomib. Drug Des Devel Ther 2018;12:1525–31. DOI: 10.2147/DDDT.S159818.Tan C.R.C., Abdul-Majeed S., Cael B., Barta S.K. Clinical pharmacokinetics and pharmacodynamics of bortezomib. Clin Pharmacokinet 2019;58(2):157–68. DOI: 10.1007/s40262-018-0679-9.Bringhen S., Milan A., D'Agostino M. et al. Prevention, monitoring and treatment of cardiovascular adverse events in myeloma patients receiving carfilzomib A consensus paper by the European Myeloma Network and the Italian Society of Arterial Hypertension. J Intern Med 2019. DOI: 10.1111/joim.12882.Gupta N., Hanley M.J., Xia C. et al. Clinical pharmacology of ixazomib: the first oral proteasome inhibitor. Clin Pharmacokinet 2019;58(4):431–49. DOI: 10.1007/s40262-018-0702-1.Richardson P.G., Zweegman S., O’Donnell E.K. et al. Ixazomib for the treatment of multiple myeloma. Expert Opin Pharmacother 2018;19(17):1949–68. DOI: 10.1080/14656566.2018.1528229.Gupta N., Hanley M.J., Xia C. et al. Clinical pharmacology of ixazomib: the first oral proteasome inhibitor. Clin Pharmacokinet 2019;58(4):431–49. DOI: 10.1007/s40262-018-0702-1.Kupperman E., Lee E.C., Cao Y. et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 2010;70(5):1970–80. DOI: 10.1158/0008-5472.CAN-09-2766.Khan M.L., Stewart A.K. Carfilzomib: a novel second-generation proteasome inhibitor. Future Oncol 2011;7(5):607–12. DOI: 10.2217/fon.11.42.Richardson P.G., Avet-Loiseau H., Antonio Palumbo A. et al. Efficacy and safety of ixazomib plus lenalidomide-dexamethasone (IRd) vs placebo-Rd in patients (pts) with relapsed/refractory multiple myeloma (RRMM) by cytogenetic risk status in the global phase III TOURMALINE-MM1 study. ASCO 2016. J Clin Oncol 2016;34(15_suppl):8018–8. DOI: 10.1200/JCO.2016.34.15_suppl.8018.Khan M.L., Stewart A.K. Carfilzomib: a novel second-generation proteasome inhibitor. Future Oncol 2011;7(5):607–12. DOI: 10.2217/fon.11.42.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.Wang Z., Yang J., Kirk C. et al. Clinical pharmacokinetics, metabolism, and drugdrug interaction of carfilzomib. Drug Metab Dispos 2013;41(1):230–7. DOI: 10.1124/dmd.112.047662.Dimopoulos M.A., Gay F., Schjesvold F. et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet 2019;393(10168):253–64. DOI: 10.1016/S0140-6736(18)33003-4.Wang Z., Yang J., Kirk C. et al. Clinical pharmacokinetics, metabolism, and drugdrug interaction of carfilzomib. Drug Metab Dispos 2013;41(1):230–7. DOI: 10.1124/dmd.112.047662.Harrison S.J., Mainwaring P., Price T. et al. Phase I clinical trial of marizomib (NPI-0052) in patients with advanced malignancies including multiple myeloma: study NPI-0052-102 final results. Clin Cancer Res 2016;22(18):4559–66. DOI: 10.1158/1078-0432.CCR-15-2616.Siegel D.S., 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.Spencer A., Harrison S., Zonder J. et al. A phase I clinical trial evaluating marizomib, pomalidomide and low-dose dexamethasone in relapsed and refractory multiple myeloma (NPI-0052-107): final study results. Br J Haematol 2018;180(1):41–51. DOI: 10.1111/bjh.14987.Siegel D.S., 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.Sanchez E., Li M., Wang C.S. et al. Antiangiogenic and anti-multiple myeloma effects of oprozomib (OPZ) alone and in combination with pomalidomide (Pom) and/or dexamethasone (Dex). Leuk Res 2017;57:45–54. DOI: 10.1016/j.leukres.2017.03.002.Hajek R., Masszi T., Petrucci M.T. 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.Berkers C.R., Leestemaker Y., Schuurman K.G. et al. Probing the specificity and activity profiles of the proteasome inhibitors bortezomib and delanzomib. Mol Pharm 2012;9(5):1126–35. DOI: 10.1021/mp2004143.Hajek R., Masszi T., Petrucci M.T. 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.Vogl D.T., Martin T.G., Vij R. et al. Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma. Leuk Lymphoma 2017;58(8):1872–9. DOI: 10.1080/10428194.2016.1263842.Moreau P., Mateos M.V., Berenson J.R. et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol 2018;19(7):953–64. DOI: 10.1016/S1470-2045(18)30354-1.Chauhan D., Tian Z., Zhou B. et al. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res 2011;17(16):5311–21. DOI: 10.1158/1078-0432.CCR-11-0476.Moreau P., Mateos M.V., Berenson J.R. et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol 2018;19(7):953–64. DOI: 10.1016/S1470-2045(18)30354-1.Besse A., Besse L., Kraus M. et al. Proteasome inhibition in multiple myeloma: head-to-head comparison of currently available proteasome inhibitors. Cell Chem Biol 2019;26(3):340–51. DOI: 10.1016/j.chembiol.2018.11.007.Stewart A.K., Rajkumar S.V., Dimopoulos M.A. et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372(2): 142–52. DOI: 10.1056/NEJMoa1411321.Stewart A.K., Rajkumar S.V., Dimopoulos M.A. et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372(2): 142–52. DOI: 10.1056/NEJMoa1411321.Siegel D.S., Dimopoulos M.A., Ludwig H. et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol 2018;36(8):728–34. DOI: 10.1200/JCO.2017.76.5032.Siegel D.S., Dimopoulos M.A., Ludwig H. et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol 2018;36(8):728–34. DOI: 10.1200/JCO.2017.76.5032.Facon T., Lee J.H., Moreau P. et al. Randomized phase 3 study of carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible, NDMM patients. Blood 2019. DOL: 10.1182/blood-2018-09-874396.Facon T., Lee J.H., Moreau P. et al. Randomized phase 3 study of carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible, NDMM patients. Blood 2019. DOL: 10.1182/blood-2018-09-874396.Zimmerman T., Raje N.S., Vij R. et al. Final results of a phase 2 trial of extended treatment (tx) with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (KRd) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM). ASH 2016. Blood 2016;128:675.Zimmerman T., Raje N.S., Vij R. et al. Final results of a phase 2 trial of extended treatment (tx) with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (KRd) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM). ASH 2016. Blood 2016;128:675.Gay F.M., Cerrato Ch., Scalabrini D.R. et al. Carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous transplant (ASCT)-Krd consolidation vs KRd 12 cycles vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation: analysis of the randomized forte trial in newly diagnosed multiple myeloma (NDMM). ASH 2018. Blood 2018;132:121. DOI: https://doi.org/10.1182/blood-2018-99-112093.Gay F.M., Cerrato Ch., Scalabrini D.R. et al. Carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous transplant (ASCT)-Krd consolidation vs KRd 12 cycles vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation: analysis of the randomized forte trial in newly diagnosed multiple myeloma (NDMM). ASH 2018. Blood 2018;132:121. DOI: https://doi.org/10.1182/blood-2018-99-112093.Gay F.M., Scalabrini D.R., Belotti A. et al. Carfilzomib-lenalidomide-dexamethasone (KRd) vs carfilzomib-cyclophosphamidedexamethasone (KCd) induction: planned interim analysis of the randomized FORTE trial in newly diagnosed multiple myeloma (NDMM). ASCO 2017. J Clin Oncol 2017;35(15_suppl):8003. DOI: 10.1200/JCO.2017.35.15_suppl.8003.Gay F.M., Scalabrini D.R., Belotti A. et al. Carfilzomib-lenalidomide-dexamethasone (KRd) vs carfilzomib-cyclophosphamidedexamethasone (KCd) induction: planned interim analysis of the randomized FORTE trial in newly diagnosed multiple myeloma (NDMM). ASCO 2017. J Clin Oncol 2017;35(15_suppl):8003. DOI: 10.1200/JCO.2017.35.15_suppl.8003.Zhao F., Yang B., Wang J. et al. Incidence and risk of cardiac toxicities in patients with relapsed and refractory multiple myeloma treated with carfilzomib. Drug Des Devel Ther 2018;12:1525–31. DOI: 10.2147/DDDT.S159818.Zhao F., Yang B., Wang J. et al. Incidence and risk of cardiac toxicities in patients with relapsed and refractory multiple myeloma treated with carfilzomib. Drug Des Devel Ther 2018;12:1525–31. DOI: 10.2147/DDDT.S159818.Bringhen S., Milan A., D'Agostino M. et al. Prevention, monitoring and treatment of cardiovascular adverse events in myeloma patients receiving carfilzomib A consensus paper by the European Myeloma Network and the Italian Society of Arterial Hypertension. J Intern Med 2019. DOI: 10.1111/joim.12882.Bringhen S., Milan A., D'Agostino M. et al. Prevention, monitoring and treatment of cardiovascular adverse events in myeloma patients receiving carfilzomib A consensus paper by the European Myeloma Network and the Italian Society of Arterial Hypertension. J Intern Med 2019. DOI: 10.1111/joim.12882.Richardson P.G., Zweegman S., O’Donnell E.K. et al. Ixazomib for the treatment of multiple myeloma. Expert Opin Pharmacother 2018;19(17):1949–68. DOI: 10.1080/14656566.2018.1528229.Richardson P.G., Zweegman S., O’Donnell E.K. et al. Ixazomib for the treatment of multiple myeloma. Expert Opin Pharmacother 2018;19(17):1949–68. DOI: 10.1080/14656566.2018.1528229.Kupperman E., Lee E.C., Cao Y. et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 2010;70(5):1970–80. DOI: 10.1158/0008-5472.CAN-09-2766.Kupperman E., Lee E.C., Cao Y. et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 2010;70(5):1970–80. DOI: 10.1158/0008-5472.CAN-09-2766.Richardson P.G., Avet-Loiseau H., Antonio Palumbo A. et al. Efficacy and safety of ixazomib plus lenalidomide-dexamethasone (IRd) vs placebo-Rd in patients (pts) with relapsed/refractory multiple myeloma (RRMM) by cytogenetic risk status in the global phase III TOURMALINE-MM1 study. ASCO 2016. J Clin Oncol 2016;34(15_suppl):8018–8. DOI: 10.1200/JCO.2016.34.15_suppl.8018.Richardson P.G., Avet-Loiseau H., Antonio Palumbo A. et al. Efficacy and safety of ixazomib plus lenalidomide-dexamethasone (IRd) vs placebo-Rd in patients (pts) with relapsed/refractory multiple myeloma (RRMM) by cytogenetic risk status in the global phase III TOURMALINE-MM1 study. ASCO 2016. J Clin Oncol 2016;34(15_suppl):8018–8. DOI: 10.1200/JCO.2016.34.15_suppl.8018.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.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.Dimopoulos M.A., Gay F., Schjesvold F. et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet 2019;393(10168):253–64. DOI: 10.1016/S0140-6736(18)33003-4.Dimopoulos M.A., Gay F., Schjesvold F. et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet 2019;393(10168):253–64. DOI: 10.1016/S0140-6736(18)33003-4.Harrison S.J., Mainwaring P., Price T. et al. Phase I clinical trial of marizomib (NPI-0052) in patients with advanced malignancies including multiple myeloma: study NPI-0052-102 final results. Clin Cancer Res 2016;22(18):4559–66. DOI: 10.1158/1078-0432.CCR-15-2616.Harrison S.J., Mainwaring P., Price T. et al. Phase I clinical trial of marizomib (NPI-0052) in patients with advanced malignancies including multiple myeloma: study NPI-0052-102 final results. Clin Cancer Res 2016;22(18):4559–66. DOI: 10.1158/1078-0432.CCR-15-2616.Spencer A., Harrison S., Zonder J. et al. A phase I clinical trial evaluating marizomib, pomalidomide and low-dose dexamethasone in relapsed and refractory multiple myeloma (NPI-0052-107): final study results. Br J Haematol 2018;180(1):41–51. DOI: 10.1111/bjh.14987.Spencer A., Harrison S., Zonder J. et al. A phase I clinical trial evaluating marizomib, pomalidomide and low-dose dexamethasone in relapsed and refractory multiple myeloma (NPI-0052-107): final study results. Br J Haematol 2018;180(1):41–51. DOI: 10.1111/bjh.14987.Sanchez E., Li M., Wang C.S. et al. Antiangiogenic and anti-multiple myeloma effects of oprozomib (OPZ) alone and in combination with pomalidomide (Pom) and/or dexamethasone (Dex). Leuk Res 2017;57:45–54. DOI: 10.1016/j.leukres.2017.03.002.Sanchez E., Li M., Wang C.S. et al. Antiangiogenic and anti-multiple myeloma effects of oprozomib (OPZ) alone and in combination with pomalidomide (Pom) and/or dexamethasone (Dex). Leuk Res 2017;57:45–54. DOI: 10.1016/j.leukres.2017.03.002.Berkers C.R., Leestemaker Y., Schuurman K.G. et al. Probing the specificity and activity profiles of the proteasome inhibitors bortezomib and delanzomib. Mol Pharm 2012;9(5):1126–35. DOI: 10.1021/mp2004143.Berkers C.R., Leestemaker Y., Schuurman K.G. et al. Probing the specificity and activity profiles of the proteasome inhibitors bortezomib and delanzomib. Mol Pharm 2012;9(5):1126–35. DOI: 10.1021/mp2004143.Vogl D.T., Martin T.G., Vij R. et al. Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma. Leuk Lymphoma 2017;58(8):1872–9. DOI: 10.1080/10428194.2016.1263842.Vogl D.T., Martin T.G., Vij R. et al. Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma. Leuk Lymphoma 2017;58(8):1872–9. DOI: 10.1080/10428194.2016.1263842.Chauhan D., Tian Z., Zhou B. et al. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res 2011;17(16):5311–21. DOI: 10.1158/1078-0432.CCR-11-0476.Chauhan D., Tian Z., Zhou B. et al. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res 2011;17(16):5311–21. DOI: 10.1158/1078-0432.CCR-11-0476.Besse A., Besse L., Kraus M. et al. Proteasome inhibition in multiple myeloma: head-to-head comparison of currently available proteasome inhibitors. Cell Chem Biol 2019;26(3):340–51. DOI: 10.1016/j.chembiol.2018.11.007.Besse A., Besse L., Kraus M. et al. Proteasome inhibition in multiple myeloma: head-to-head comparison of currently available proteasome inhibitors. Cell Chem Biol 2019;26(3):340–51. DOI: 10.1016/j.chembiol.2018.11.007.