{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T07:05:50Z","timestamp":1778396750970,"version":"3.51.4"},"reference-count":264,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,2,10]],"date-time":"2020-02-10T00:00:00Z","timestamp":1581292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Multiple myeloma (MM) is the second most common blood cancer. Treatments for MM include corticosteroids, alkylating agents, anthracyclines, proteasome inhibitors, immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies. Survival outcomes have improved substantially due to the introduction of many of these drugs allied with their rational use. Nonetheless, MM patients successively relapse after one or more treatment regimens or become refractory, mostly due to drug resistance. This review focuses on the main drugs used in MM treatment and on causes of drug resistance, including cytogenetic, genetic and epigenetic alterations, abnormal drug transport and metabolism, dysregulation of apoptosis, autophagy activation and other intracellular signaling pathways, the presence of cancer stem cells, and the tumor microenvironment. Furthermore, we highlight the areas that need to be further clarified in an attempt to identify novel therapeutic targets to counteract drug resistance in MM patients.<\/jats:p>","DOI":"10.3390\/cancers12020407","type":"journal-article","created":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T11:45:30Z","timestamp":1581421530000},"page":"407","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":197,"title":["Multiple Myeloma: Available Therapies and Causes of Drug Resistance"],"prefix":"10.3390","volume":"12","author":[{"given":"Vanessa","family":"Pinto","sequence":"first","affiliation":[{"name":"i3S\u2013Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Cancer Drug Resistance Group, IPATIMUP\u2013Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal"},{"name":"FCTUC\u2013Faculty of Science and Technology of the University of Coimbra, 3030-790 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7811-9509","authenticated-orcid":false,"given":"Rui","family":"Bergantim","sequence":"additional","affiliation":[{"name":"i3S\u2013Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Cancer Drug Resistance Group, IPATIMUP\u2013Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal"},{"name":"Clinical Hematology, Hospital S\u00e3o Jo\u00e3o, 4200-319 Porto, Portugal"},{"name":"Clinical Hematology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7657-7410","authenticated-orcid":false,"given":"Hugo R.","family":"Caires","sequence":"additional","affiliation":[{"name":"i3S\u2013Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Cancer Drug Resistance Group, IPATIMUP\u2013Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3970-602X","authenticated-orcid":false,"given":"Hugo","family":"Seca","sequence":"additional","affiliation":[{"name":"i3S\u2013Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Cancer Drug Resistance Group, IPATIMUP\u2013Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal"}]},{"given":"Jos\u00e9 E.","family":"Guimar\u00e3es","sequence":"additional","affiliation":[{"name":"i3S\u2013Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Cancer Drug Resistance Group, IPATIMUP\u2013Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal"},{"name":"Clinical Hematology, Hospital S\u00e3o Jo\u00e3o, 4200-319 Porto, Portugal"},{"name":"Clinical Hematology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7801-4643","authenticated-orcid":false,"given":"M. Helena","family":"Vasconcelos","sequence":"additional","affiliation":[{"name":"i3S\u2013Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"Cancer Drug Resistance Group, IPATIMUP\u2013Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal"},{"name":"Department of Biological Sciences, FFUP-Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"nrdp201746","DOI":"10.1038\/nrdp.2017.46","article-title":"Multiple myeloma","volume":"3","author":"Kumar","year":"2017","journal-title":"Nat. Rev. Dis. Primers."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e328","DOI":"10.1016\/S1470-2045(16)30206-6","article-title":"International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma","volume":"17","author":"Kumar","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4065\/78.1.21","article-title":"Review of 1027 Patients with Newly Diagnosed Multiple Myeloma","volume":"78","author":"Kyle","year":"2003","journal-title":"Mayo Clin. Proc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1038\/leu.2014.34","article-title":"Racial disparities in the prevalence of monoclonal gammopathies: A population-based study of 12 482 persons from the National Health and Nutritional Examination Survey","volume":"28","author":"Landgren","year":"2014","journal-title":"Leukemia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/leu.2013.313","article-title":"Continued improvement in survival in multiple myeloma: Changes in early mortality and outcomes in older patients","volume":"28","author":"Kumar","year":"2014","journal-title":"Leukemia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1182\/bloodadvances.2016002493","article-title":"Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States","volume":"1","author":"Costa","year":"2017","journal-title":"Blood Adv."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/s41571-018-0018-y","article-title":"The multiple myelomas\u2014current concepts in cytogenetic classification and therapy","volume":"15","author":"Kumar","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1182\/blood-2007-10-116129","article-title":"Improved survival in multiple myeloma and the impact of novel therapies","volume":"111","author":"Kumar","year":"2008","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1002\/ajh.25117","article-title":"Multiple myeloma: 2018 update on diagnosis, risk-stratification, and management","volume":"93","author":"Rajkumar","year":"2018","journal-title":"Am. J. Hematol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1146\/annurev-pathol-011110-130249","article-title":"Pathogenesis of Myeloma","volume":"6","author":"Anderson","year":"2011","journal-title":"Annu. Rev. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/j.1749-6632.2003.tb06059.x","article-title":"Long-Lived Plasma Cells in Immunity and Inflammation","volume":"987","author":"Hauser","year":"2003","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1182\/blood-2014-11-568881","article-title":"Pathogenesis beyond the cancer clone(s) in multiple myeloma","volume":"125","author":"Bianchi","year":"2015","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.3389\/fimmu.2019.01121","article-title":"Cell of Origin and Genetic Alterations in the Pathogenesis of Multiple Myeloma","volume":"10","author":"Barwick","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_14","first-page":"JCO.2016.70.670","article-title":"Genomics of Multiple Myeloma","volume":"35","author":"Cleynen","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/864058","article-title":"The Genetic Architecture of Multiple Myeloma","volume":"2014","author":"Prideaux","year":"2014","journal-title":"Adv. Hematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nrc3257","article-title":"The genetic architecture of multiple myeloma","volume":"12","author":"Morgan","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3835","DOI":"10.1038\/s41467-019-11680-1","article-title":"Genomic landscape and chronological reconstruction of driver events in multiple myeloma","volume":"10","author":"Maura","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2604","DOI":"10.1038\/s41375-018-0037-9","article-title":"Analysis of the genomic landscape of multiple myeloma highlights novel prognostic markers and disease subgroups","volume":"32","author":"Bolli","year":"2018","journal-title":"Leukemia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1038\/ncomms3997","article-title":"Heterogeneity of genomic evolution and mutational profiles in multiple myeloma","volume":"5","author":"Bolli","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.semcancer.2017.09.007","article-title":"Epigenetics in multiple myeloma: From mechanisms to therapy","volume":"51","author":"Alzrigat","year":"2018","journal-title":"Semin. Cancer Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5412","DOI":"10.1182\/blood-2008-12-194241","article-title":"Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study","volume":"113","author":"Landgren","year":"2009","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5418","DOI":"10.1182\/blood-2008-12-195008","article-title":"A monoclonal gammopathy precedes multiple myeloma in most patients","volume":"113","author":"Weiss","year":"2009","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1056\/NEJMoa1709974","article-title":"Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance","volume":"378","author":"Kyle","year":"2018","journal-title":"New Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3069","DOI":"10.1182\/blood-2014-09-568899","article-title":"Smoldering multiple myeloma","volume":"125","author":"Rajkumar","year":"2015","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/ejh.12533","article-title":"Plasma cell leukemia: from biology to treatment","volume":"95","author":"Jelinek","year":"2015","journal-title":"Eur. J. Haematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/s41408-018-0140-1","article-title":"Revised diagnostic criteria for plasma cell leukemia: results of a Mayo Clinic study with comparison of outcomes to multiple myeloma","volume":"8","author":"Ravi","year":"2018","journal-title":"Blood Cancer J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1080\/17474086.2017.1317589","article-title":"Which therapies will move to the front line for multiple myeloma?","volume":"10","author":"Cejalvo","year":"2017","journal-title":"Expert Rev. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1002\/hon.2586","article-title":"Multiple myeloma: Every year a new standard?","volume":"37","author":"Rajkumar","year":"2019","journal-title":"Hematol. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"278","DOI":"10.3816\/CLM.2009.n.056","article-title":"Treatment of Multiple Myeloma: A Comprehensive Review","volume":"9","author":"Kyle","year":"2009","journal-title":"Clin. Lymphoma Myeloma"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1056\/NEJMct0805626","article-title":"Autologous Hematopoietic Stem-Cell Transplantation for Multiple Myeloma","volume":"360","author":"Harousseau","year":"2009","journal-title":"New Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Mina, R., Bringhen, S., Wildes, T.M., Zweegman, S., and Rosko, A.E. (2019). Approach to the Older Adult With Multiple Myeloma. Am. Soc. Clin. Oncol. Educ. Book, 500\u2013518.","DOI":"10.1200\/EDBK_239067"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/nrclinonc.2011.63","article-title":"Treatment of multiple myeloma","volume":"8","author":"Rajkumar","year":"2011","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/leu.2011.196","article-title":"Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study","volume":"26","author":"Kumar","year":"2012","journal-title":"Leukemia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/leu.2017.329","article-title":"Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond","volume":"32","author":"Chim","year":"2017","journal-title":"Leukemia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1080\/17474086.2019.1624158","article-title":"Novel targets for the treatment of relapsing multiple myeloma","volume":"12","author":"Giuliani","year":"2019","journal-title":"Expert Rev. Hematol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3076","DOI":"10.1182\/blood-2014-09-568915","article-title":"Frontline therapy of multiple myeloma","volume":"125","author":"Moreau","year":"2015","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1182\/blood-2018-08-825349","article-title":"Pros and cons of frontline autologous transplant in multiple myeloma: the debate over timing","volume":"133","author":"Kumar","year":"2019","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4519","DOI":"10.1182\/blood-2011-06-358812","article-title":"Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN)","volume":"118","author":"Palumbo","year":"2011","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s00277-018-3528-x","article-title":"Real-life data on safety and efficacy of autologous stem cell transplantation in elderly patients with multiple myeloma","volume":"98","author":"Marini","year":"2019","journal-title":"Ann. Hematol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/leu.2013.247","article-title":"IMWG consensus on risk stratification in multiple myeloma","volume":"28","author":"Chng","year":"2014","journal-title":"Leukemia"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1200\/JCO.2015.61.2267","article-title":"Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group","volume":"33","author":"Palumbo","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1182\/blood-2015-06-653261","article-title":"How I treat high-risk myeloma","volume":"126","author":"Lonial","year":"2015","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Nooka, A.K., and Lonial, S. (2016). New Targets and New Agents in High-Risk Multiple Myeloma. Am. Soc. Clin. Oncol. Educ. Book, e431\u2013e441.","DOI":"10.14694\/EDBK_159516"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"JCO.18.02096","DOI":"10.1200\/JCO.18.02096","article-title":"Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline","volume":"37","author":"Mikhael","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"iv52","DOI":"10.1093\/annonc\/mdx096","article-title":"Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"28","author":"Moreau","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"x334","DOI":"10.1093\/annonc\/mds311","article-title":"How to select among available options for the treatment of multiple myeloma","volume":"23","author":"Harousseau","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1182\/blood-2014-10-551531","article-title":"How I treat relapsed myeloma","volume":"125","year":"2015","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"396","DOI":"10.3324\/haematol.2015.129189","article-title":"Treatment of relapsed and refractory multiple myeloma","volume":"101","author":"Sonneveld","year":"2016","journal-title":"Haematologica"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1182\/blood-2019-04-901157","article-title":"Facing lenalidomide-refractory myeloma","volume":"134","author":"Cavo","year":"2019","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2920","DOI":"10.1002\/cncr.32177","article-title":"Recycling therapies for myeloma: The need for prospective trials","volume":"125","author":"Kumar","year":"2019","journal-title":"Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1056\/NEJMoa043445","article-title":"Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma","volume":"352","author":"Richardson","year":"2005","journal-title":"New Engl. J. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2174\/156800911794519752","article-title":"Bortezomib as the first proteasome inhibitor anticancer drug: Current status and future perspectives","volume":"11","author":"Chen","year":"2011","journal-title":"Curr. Cancer Drug Tar."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1056\/NEJMoa030288","article-title":"A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma","volume":"348","author":"Richardson","year":"2003","journal-title":"New Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1002\/cncr.28481","article-title":"The effects of bortezomib on bone disease in patients with multiple myeloma","volume":"120","author":"Mohty","year":"2014","journal-title":"Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.1182\/blood-2007-01-065888","article-title":"Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma","volume":"110","author":"Kuhn","year":"2007","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1182\/blood-2012-05-425934","article-title":"A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma","volume":"120","author":"Siegel","year":"2012","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5661","DOI":"10.1182\/blood-2012-03-414359","article-title":"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","volume":"119","author":"Vij","year":"2012","journal-title":"Blood"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1056\/NEJMoa1411321","article-title":"Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma","volume":"372","author":"Stewart","year":"2015","journal-title":"New Engl. J. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S1470-2045(15)00464-7","article-title":"Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): A randomised, phase 3, open-label, multicentre study","volume":"17","author":"Dimopoulos","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1182\/blood-2012-04-422683","article-title":"A phase 1\/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma","volume":"120","author":"Jakubowiak","year":"2012","journal-title":"Blood"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1111\/jcmm.12279","article-title":"Proteasome inhibitors \u2013 molecular basis and current perspectives in multiple myeloma","volume":"18","author":"Kubiczkova","year":"2014","journal-title":"J. Cell Mol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1056\/NEJMoa1516282","article-title":"Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma","volume":"374","author":"Moreau","year":"2016","journal-title":"New Engl. J. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1016\/S1470-2045(14)71125-8","article-title":"Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: An open-label phase 1\/2 study","volume":"15","author":"Kumar","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/1756-8722-2-36","article-title":"Mechanism of action of lenalidomide in hematological malignancies","volume":"2","author":"Kotla","year":"2009","journal-title":"J. Hematol. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1053\/j.seminhematol.2005.10.001","article-title":"Lenalidomide and Thalidomide: Mechanisms of Action\u2014Similarities and Differences","volume":"42","author":"Anderson","year":"2005","journal-title":"Semin. Hematol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1182\/blood.V96.9.2943","article-title":"Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy","volume":"96","author":"Hideshima","year":"2000","journal-title":"Blood"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1182\/blood-2008-12-196238","article-title":"Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma","volume":"114","author":"Richardson","year":"2009","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1126\/science.1177319","article-title":"Identification of a Primary Target of Thalidomide Teratogenicity","volume":"327","author":"Ito","year":"2010","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1126\/science.1244917","article-title":"The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins","volume":"343","author":"Lu","year":"2014","journal-title":"Science"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1182\/blood-2014-02-557819","article-title":"Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma","volume":"124","author":"Zhu","year":"2014","journal-title":"Blood"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1126\/science.1244851","article-title":"Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells","volume":"343","author":"Udeshi","year":"2014","journal-title":"Science"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4771","DOI":"10.1182\/blood-2011-05-356063","article-title":"Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide","volume":"118","author":"Zhu","year":"2011","journal-title":"Blood"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1182\/blood-2015-01-625004","article-title":"Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds","volume":"126","author":"Lagrue","year":"2015","journal-title":"Blood"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"683","DOI":"10.3109\/10428194.2012.728597","article-title":"Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma","volume":"54","author":"Zhu","year":"2012","journal-title":"Leukemia Lymphoma"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5008","DOI":"10.1200\/JCO.2009.23.6802","article-title":"Pomalidomide (CC4047) Plus Low-Dose Dexamethasone As Therapy for Relapsed Multiple Myeloma","volume":"27","author":"Lacy","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/S1470-2045(13)70380-2","article-title":"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","volume":"14","author":"Miguel","year":"2013","journal-title":"Lancet Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1182\/blood-2013-11-538835","article-title":"Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: A randomized phase 2 study","volume":"123","author":"Richardson","year":"2014","journal-title":"Blood"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1182\/blood-2015-10-646810","article-title":"Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma","volume":"127","author":"Moreau","year":"2016","journal-title":"Blood"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1182\/blood-2015-12-687749","article-title":"Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma","volume":"128","author":"Krejcik","year":"2016","journal-title":"Blood"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/cpt.550","article-title":"Daratumumab, Elotuzumab, and the Development of Therapeutic Monoclonal Antibodies in Multiple Myeloma","volume":"101","author":"Laubach","year":"2017","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.4049\/jimmunol.1003032","article-title":"Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors","volume":"186","author":"Tai","year":"2011","journal-title":"J. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1056\/NEJMoa1506348","article-title":"Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma","volume":"373","author":"Lokhorst","year":"2015","journal-title":"New Engl. J. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/leu.2015.223","article-title":"Monoclonal antibodies in the treatment of multiple myeloma: Current status and future perspectives","volume":"30","author":"Lonial","year":"2016","journal-title":"Leukemia"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"S71","DOI":"10.1016\/j.clml.2014.06.016","article-title":"Novel Drug Combinations for the Management of Relapsed\/Refractory Multiple Myeloma","volume":"14","author":"Usmani","year":"2014","journal-title":"Clin. Lymphoma Myeloma Leukemia"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1056\/NEJMoa1607751","article-title":"Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma","volume":"375","author":"Dimopoulos","year":"2016","journal-title":"New Engl. J. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1056\/NEJMoa1606038","article-title":"Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma","volume":"375","author":"Palumbo","year":"2016","journal-title":"New Engl. J. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1182\/blood-2017-05-785246","article-title":"Daratumumab plus pomalidomide and dexamethasone in relapsed and\/or refractory multiple myeloma","volume":"130","author":"Chari","year":"2017","journal-title":"Blood"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1056\/NEJMoa1714678","article-title":"Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma","volume":"378","author":"Mateos","year":"2018","journal-title":"New Engl. J. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0140-6736(19)31240-1","article-title":"Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase 3 study","volume":"394","author":"Moreau","year":"2019","journal-title":"Lancet"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1056\/NEJMoa1817249","article-title":"Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma","volume":"380","author":"Facon","year":"2019","journal-title":"New Engl. J. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"4574","DOI":"10.1158\/1078-0432.CCR-14-0695","article-title":"SAR650984, A Novel Humanized CD38-Targeting Antibody, Demonstrates Potent Antitumor Activity in Models of Multiple Myeloma and Other CD38+ Hematologic Malignancies","volume":"20","author":"Deckert","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/leu.2015.240","article-title":"SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide","volume":"30","author":"Jiang","year":"2016","journal-title":"Leukemia"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.2217\/fon-2017-0616","article-title":"Isatuximab plus pomalidomide\/dexamethasone versus pomalidomide\/dexamethasone in relapsed\/refractory multiple myeloma: ICARIA Phase III study design","volume":"14","author":"Richardson","year":"2018","journal-title":"Futur. Oncol. Lond. Engl."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"TPS8055","DOI":"10.1200\/JCO.2018.36.15_suppl.TPS8055","article-title":"Phase III (IMROZ) study design: Isatuximab plus bortezomib (V), lenalidomide (R), and dexamethasone (d) vs VRd in transplant-ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM)","volume":"36","author":"Orlowski","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1158\/1078-0432.CCR-07-4246","article-title":"CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma","volume":"14","author":"Hsi","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1007\/s00262-013-1493-8","article-title":"Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC","volume":"62","author":"Collins","year":"2013","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1182\/blood-2011-06-360552","article-title":"A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma","volume":"120","author":"Zonder","year":"2012","journal-title":"Blood"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e516","DOI":"10.1016\/S2352-3026(15)00197-0","article-title":"Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: Final phase 2 results from the randomised, open-label, phase 1b\u20132 dose-escalation study","volume":"2","author":"Richardson","year":"2015","journal-title":"Lancet Haematol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1056\/NEJMoa1505654","article-title":"Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma","volume":"373","author":"Lonial","year":"2015","journal-title":"New Engl. J. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"4767","DOI":"10.1158\/1078-0432.CCR-15-0530","article-title":"Panobinostat for the Treatment of Multiple Myeloma","volume":"21","author":"Laubach","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_101","first-page":"516","article-title":"Panobinostat and Multiple Myeloma in 2018","volume":"23","author":"Yee","year":"2018","journal-title":"Oncology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1002\/phar.1671","article-title":"Role of Histone Deacetylase Inhibitors in Relapsed Refractory Multiple Myeloma: A Focus on Vorinostat and Panobinostat","volume":"35","author":"Afifi","year":"2015","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/S1470-2045(14)70440-1","article-title":"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","volume":"15","author":"Hungria","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1182\/blood-2015-09-665018","article-title":"Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment","volume":"127","author":"Richardson","year":"2016","journal-title":"Blood"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.clml.2018.03.002","article-title":"An Expanded Treatment Protocol of Panobinostat Plus Bortezomib and Dexamethasone in Patients With Previously Treated Myeloma","volume":"18","author":"Hansen","year":"2018","journal-title":"Clin. Lymphoma Myeloma Leukemia"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"5250","DOI":"10.1158\/1078-0432.CCR-08-2850","article-title":"Phase I Study of Vorinostat in Combination with Bortezomib for Relapsed and Refractory Multiple Myeloma","volume":"15","author":"Badros","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/S1470-2045(13)70398-X","article-title":"Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): A multicentre, randomised, double-blind study","volume":"14","author":"Dimopoulos","year":"2013","journal-title":"Lancet Oncol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e182","DOI":"10.1038\/bcj.2014.1","article-title":"Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma","volume":"4","author":"Siegel","year":"2014","journal-title":"Blood Cancer J."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJMoa1903455","article-title":"Oral Selinexor\u2013Dexamethasone for Triple-Class Refractory Multiple Myeloma","volume":"381","author":"Chari","year":"2019","journal-title":"New Engl. J. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1182\/blood-2017-08-797886","article-title":"Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia","volume":"131","author":"Chen","year":"2018","journal-title":"Blood"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1007\/s40265-019-01188-9","article-title":"Selinexor: First Global Approval","volume":"79","author":"Syed","year":"2019","journal-title":"Drugs"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/s41571-019-0275-4","article-title":"Responses to selinexor in multiple myeloma","volume":"16","author":"Romero","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/nrclinonc.2014.200","article-title":"Current treatment landscape for relapsed and\/or refractory multiple myeloma","volume":"12","author":"Dimopoulos","year":"2015","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_114","first-page":"1","article-title":"Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma","volume":"2015","author":"Yang","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.18632\/oncotarget.1497","article-title":"Drug resistance in multiple myeloma: Latest findings and new concepts on molecular mechanisms","volume":"4","author":"Abdi","year":"2013","journal-title":"Oncotarget"},{"key":"ref_116","first-page":"01","article-title":"Drug Resistance in Multiple Myeloma: How to Cross the Border","volume":"2","author":"Pandey","year":"2015","journal-title":"Ann. Hematol. Oncol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3109\/10428194.2014.907890","article-title":"The role of P-glycoprotein in drug resistance in multiple myeloma","volume":"56","author":"Abraham","year":"2014","journal-title":"Leukemia Lymphoma"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"40496","DOI":"10.18632\/oncotarget.5800","article-title":"Cancer stem cells are the cause of drug resistance in multiple myeloma: Fact or fiction?","volume":"6","author":"Wendlandt","year":"2015","journal-title":"Oncotarget"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/S0140-6736(04)15736-X","article-title":"Multiple myeloma","volume":"363","author":"Sirohi","year":"2004","journal-title":"Lancet"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"nrc2189","DOI":"10.1038\/nrc2189","article-title":"Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets","volume":"7","author":"Hideshima","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"226","DOI":"10.2174\/1568009616666151113120705","article-title":"Understanding Cancer Drug Resistance by Developing and Studying Resistant Cell Line Models","volume":"16","author":"Xavier","year":"2016","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"4630","DOI":"10.1200\/JCO.2010.28.3945","article-title":"Bortezomib Plus Dexamethasone Induction Improves Outcome of Patients With t(4;14) Myeloma but Not Outcome of Patients With del(17p)","volume":"28","author":"Leleu","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.bbmt.2009.11.025","article-title":"Gain of 1q21 Is an Unfavorable Genetic Prognostic Factor for Multiple Myeloma Patients Treated with High-Dose Chemotherapy","volume":"16","author":"Nemec","year":"2010","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1111\/j.1365-2141.2008.07454.x","article-title":"The prognostic significance of 8p21 deletion in multiple myeloma","volume":"144","author":"Sutlu","year":"2009","journal-title":"Brit. J. Haematol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1007\/s12185-014-1514-1","article-title":"The impact of C-Myc gene-related aberrations in newly diagnosed myeloma with bortezomib\/dexamethasone therapy","volume":"99","author":"Sekiguchi","year":"2014","journal-title":"Int. J. Hematol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/1756-8722-4-37","article-title":"Suppressing miRNA-15a\/-16 expression by interleukin-6 enhances drug-resistance in myeloma cells","volume":"4","author":"Hao","year":"2011","journal-title":"J. Hematol. Oncol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"3958","DOI":"10.1182\/blood-2012-01-401794","article-title":"Investigational agent MLN9708\/2238 targets tumor-suppressor miR33b in MM cells","volume":"120","author":"Tian","year":"2012","journal-title":"Blood"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1002\/ajh.23387","article-title":"Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1","volume":"88","author":"Hawley","year":"2013","journal-title":"Am. J. Hematol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/leu.2017.212","article-title":"Carfilzomib resistance due to ABCB1\/MDR1 overexpression is overcome by nelfinavir and lopinavir in multiple myeloma","volume":"32","author":"Besse","year":"2018","journal-title":"Leukemia"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.4161\/cc.3.10.1196","article-title":"Mcl-1 Regulation and Its Role in Multiple Myeloma","volume":"3","author":"Gouill","year":"2004","journal-title":"Cell Cycle"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1182\/blood.V99.6.1885","article-title":"Myeloid cell factor\u20131 is a critical survival factor for multiple myeloma","volume":"99","author":"Zhang","year":"2002","journal-title":"Blood"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/sj.leu.2403784","article-title":"Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival","volume":"19","author":"Robillard","year":"2005","journal-title":"Leukemia"},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Qu, X., Du, J., Zhang, C., Fu, W., Xi, H., Zou, J., and Hou, J. (2012). Arsenic trioxide exerts antimyeloma effects by inhibiting activity in the cytoplasmic substrates of histone deacetylase 6. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032215"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1136\/jclinpath-2015-203414","article-title":"Molecular mechanisms in multiple myeloma drug resistance","volume":"69","author":"Nikesitch","year":"2016","journal-title":"J. Clin. Pathol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.3324\/haematol.2013.090142","article-title":"High XBP1 expression is a marker of better outcome in multiple myeloma patients treated with bortezomib","volume":"99","author":"Gambella","year":"2014","journal-title":"Haematologica"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"4415","DOI":"10.1158\/0008-5472.CAN-08-2839","article-title":"The Role of ATF4 Stabilization and Autophagy in Resistance of Breast Cancer Cells Treated with Bortezomib","volume":"69","author":"Milani","year":"2009","journal-title":"Cancer Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1182\/blood-2006-05-024372","article-title":"STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90\u03b1 and \u03b2 in multiple myeloma cells, which critically contribute to tumor-cell survival","volume":"109","author":"Chatterjee","year":"2007","journal-title":"Blood"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1158\/1535-7163.MCT-11-0174","article-title":"Targeting HSP 90 Induces Apoptosis and Inhibits Critical Survival and Proliferation Pathways in Multiple Myeloma","volume":"10","author":"Khong","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1111\/j.1365-2141.2010.08360.x","article-title":"Inhibition of heat shock protein 90 (HSP90) as a therapeutic strategy for the treatment of myeloma and other cancers","volume":"152","author":"Richardson","year":"2011","journal-title":"Brit. J. Haematol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.3324\/haematol.2012.066175","article-title":"The PI3K\/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma","volume":"98","author":"Chatterjee","year":"2013","journal-title":"Haematologica"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"e68","DOI":"10.1038\/bcj.2012.13","article-title":"Anti-tumor activity against multiple myeloma by combination of KW-2478, an Hsp90 inhibitor, with bortezomib","volume":"2","author":"Ishii","year":"2012","journal-title":"Blood Cancer J."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1182\/blood-2005-03-1158","article-title":"Antimyeloma activity of heat shock protein-90 inhibition","volume":"107","author":"Mitsiades","year":"2006","journal-title":"Blood"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"84","DOI":"10.4252\/wjsc.v7.i1.84","article-title":"Identify multiple myeloma stem cells: Utopia?","volume":"7","author":"Saltarella","year":"2015","journal-title":"World J. Stem Cells"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1182\/blood-2013-02-482919","article-title":"RAR\u03b12 expression confers myeloma stem cell features","volume":"122","author":"Yang","year":"2013","journal-title":"Blood"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1172\/JCI66517","article-title":"BM mesenchymal stromal cell\u2013derived exosomes facilitate multiple myeloma progression","volume":"123","author":"Roccaro","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.ctrv.2012.04.007","article-title":"Interleukin-6 signaling pathway in targeted therapy for cancer","volume":"38","author":"Guo","year":"2012","journal-title":"Cancer Treat. Rev."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1","DOI":"10.13055\/ojhmt_3_S1_04.120221","article-title":"Cell Trafficking in Multiple Myeloma","volume":"3","author":"Bianchi","year":"2012","journal-title":"Open J. Hematol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/leu.2014.255","article-title":"Targeting phospho-MARCKS overcomes drug-resistance and induces antitumor activity in preclinical models of multiple myeloma","volume":"29","author":"Yang","year":"2015","journal-title":"Leukemia"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1124\/jpet.111.187542","article-title":"Inactivating PSMB5 Mutations and P-Glycoprotein (Multidrug Resistance-Associated Protein\/ATP-Binding Cassette B1) Mediate Resistance to Proteasome Inhibitors: Ex Vivo Efficacy of (Immuno)Proteasome Inhibitors in Mononuclear Blood Cells from Patients with Rheumatoid Arthritis","volume":"341","author":"Verbrugge","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1182\/blood-2007-08-104950","article-title":"Molecular basis of bortezomib resistance: proteasome subunit \u03b25 (PSMB5) gene mutation and overexpression of PSMB5 protein","volume":"112","author":"Oerlemans","year":"2008","journal-title":"Blood"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1182\/blood-2016-02-698092","article-title":"Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes","volume":"128","author":"Mai","year":"2016","journal-title":"Blood"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"6122","DOI":"10.1073\/pnas.0305855101","article-title":"Illegitimate WNT signaling promotes proliferation of multiple myeloma cells","volume":"101","author":"Derksen","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1182\/blood-2016-03-703439","article-title":"CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma","volume":"128","author":"Nijhof","year":"2016","journal-title":"Blood"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1038\/leu.2015.123","article-title":"Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab","volume":"29","author":"Nijhof","year":"2015","journal-title":"Leukemia"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1182\/blood-2005-04-1411","article-title":"Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy","volume":"106","author":"Gertz","year":"2005","journal-title":"Blood"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1177\/205873920601900107","article-title":"c-MYC deregulation is involved in melphalan resistance of multiple myeloma: role of PDGF-BB","volume":"19","author":"Greco","year":"2006","journal-title":"Int. J. Immunopath. Pharmacol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/ejh.12124","article-title":"Aberrant microRNA expression in multiple myeloma","volume":"91","author":"Dimopoulos","year":"2013","journal-title":"Eur. J. Haematol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"3881","DOI":"10.1182\/blood-2005-10-009084","article-title":"ABCG2 expression, function, and promoter methylation in human multiple myeloma","volume":"108","author":"Turner","year":"2006","journal-title":"Blood"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1182\/blood.V93.5.1658","article-title":"Cell adhesion mediated drug resistance (CAM-DR): Role of integrins and resistance to apoptosis in human myeloma cell lines","volume":"93","author":"Damiano","year":"1999","journal-title":"Blood"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.ctrv.2018.09.001","article-title":"Drug resistance in multiple myeloma","volume":"70","author":"Robak","year":"2018","journal-title":"Cancer Treat. Rev."},{"key":"ref_161","first-page":"87","article-title":"Drug targets and resistance mechanisms in multiple myeloma","volume":"1","author":"Nass","year":"2018","journal-title":"Cancer Drug Resist."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1158\/0008-5472.CAN-03-2876","article-title":"Genetics and Cytogenetics of Multiple Myeloma A Workshop Report","volume":"64","author":"Fonseca","year":"2004","journal-title":"Cancer Res."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"e365","DOI":"10.1038\/bcj.2015.92","article-title":"Interpretation of cytogenetic results in multiple myeloma for clinical practice","volume":"5","author":"Rajan","year":"2015","journal-title":"Blood Cancer J."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"6333","DOI":"10.1200\/JCO.2005.05.021","article-title":"Molecular Pathogenesis and a Consequent Classification of Multiple Myeloma","volume":"23","author":"Bergsagel","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bmb\/ldu041","article-title":"Genetics in myeloma: genetic technologies and their application to screening approaches in myeloma","volume":"113","author":"Talley","year":"2015","journal-title":"Brit. Med. Bull."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/S1470-2045(03)01195-1","article-title":"New insights into the pathophysiology of multiple myeloma","volume":"4","author":"Seidl","year":"2003","journal-title":"Lancet Oncol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.ccr.2004.10.020","article-title":"Focus on multiple myeloma","volume":"6","author":"Mitsiades","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1182\/blood-2012-05-432203","article-title":"Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma","volume":"121","author":"Bergsagel","year":"2013","journal-title":"Blood"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"e89","DOI":"10.1038\/bcj.2012.37","article-title":"The t(4;14) translocation and FGFR3 overexpression in multiple myeloma: Prognostic implications and current clinical strategies","volume":"2","author":"Kalff","year":"2012","journal-title":"Blood Cancer J."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"4457","DOI":"10.1182\/blood.V91.12.4457.412k48_4457_4463","article-title":"Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma","volume":"91","author":"Chesi","year":"1998","journal-title":"Blood"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"78","DOI":"10.3324\/haematol.13426","article-title":"MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells","volume":"94","author":"Brito","year":"2009","journal-title":"Haematologica"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1182\/blood.V97.3.729","article-title":"Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma","volume":"97","author":"Chesi","year":"2001","journal-title":"Blood"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.3324\/haematol.2009.016329","article-title":"The t(14;20) is a poor prognostic factor in myeloma but is associated with long-term stable disease in monoclonal gammopathies of undetermined significance","volume":"95","author":"Ross","year":"2010","journal-title":"Haematologica"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1111\/j.1365-2141.2004.05050.x","article-title":"The recurrent translocation t(14;20)(q32;q12) in multiple myeloma results in aberrant expression of MAFB: A molecular and genetic analysis of the chromosomal breakpoint","volume":"126","author":"Kuipers","year":"2004","journal-title":"Brit. J. Haematol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1111\/j.1349-7006.2001.tb01142.x","article-title":"Ectopic Expression of MAFB Gene in Human Myeloma Cells Carrying (14;20)(q32;q11) Chromosomal Translocations","volume":"92","author":"Hanamura","year":"2001","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S1535-6108(04)00019-4","article-title":"Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma","volume":"5","author":"Hurt","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.3109\/10428194.2010.496014","article-title":"Monitoring bortezomib therapy in multiple myeloma: Screening of cyclin D1, D2, and D3 via reliable real-time polymerase chain reaction and association with clinico-pathological features and outcome","volume":"51","author":"Ngo","year":"2010","journal-title":"Leukemia Lymphoma"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.clml.2013.07.008","article-title":"Cyclin D1 Amplification in Multiple Myeloma Is Associated With Multidrug Resistance Expression","volume":"14","author":"Sewify","year":"2014","journal-title":"Clin. Lymphoma Myeloma Leukemia."},{"key":"ref_179","first-page":"529","article-title":"Gene abnormalities in multiple myeloma; the relevance of TP53, MDM2, and CDKN2A","volume":"88","author":"Elnenaei","year":"2003","journal-title":"Haematologica"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.3324\/haematol.2010.023697","article-title":"Mutations in TP53 are exclusively associated with del(17p) in multiple myeloma","volume":"95","author":"Eveillard","year":"2010","journal-title":"Haematologica"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1182\/blood-2008-12-193458","article-title":"Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: Adverse effect of deletion 17p13","volume":"114","author":"Reece","year":"2009","journal-title":"Blood"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1002\/gcc.20899","article-title":"The clinical impact and molecular biology of del(17p) in multiple myeloma treated with conventional or thalidomide-based therapy","volume":"50","author":"Boyd","year":"2011","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1038\/leu.2010.175","article-title":"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","volume":"24","author":"Dimopoulos","year":"2010","journal-title":"Leukemia"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1182\/blood.V99.6.2185","article-title":"Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation","volume":"99","author":"Facon","year":"2002","journal-title":"Blood"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/sj.leu.2404459","article-title":"Bortezomib in relapsed multiple myeloma: Response rates and duration of response are independent of a chromosome 13q-deletion","volume":"21","author":"Sagaster","year":"2007","journal-title":"Leukemia"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.bbmt.2007.05.014","article-title":"Deletion of the Short Arm of Chromosome 1 (del 1p) is a Strong Predictor of Poor Outcome in Myeloma Patients Undergoing an Autotransplant","volume":"13","author":"Qazilbash","year":"2007","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"7776","DOI":"10.1158\/1078-0432.CCR-11-1791","article-title":"Mapping of Chromosome 1p Deletions in Myeloma Identifies FAM46C at 1p12 and CDKN2C at 1p32.3 as Being Genes in Regions Associated with Adverse Survival","volume":"17","author":"Boyd","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.clml.2014.02.004","article-title":"Patterns of Relapse or Progression After Bortezomib-Based Salvage Therapy in Patients With Relapsed\/Refractory Multiple Myeloma","volume":"14","author":"Ahn","year":"2014","journal-title":"Clin. Lymphoma Myeloma Leukemia"},{"key":"ref_189","doi-asserted-by":"crossref","unstructured":"Duru, A., Sutlu, T., Wallblom, A., Uttervall, K., Lund, J., Stellan, B., Gahrton, G., Nahi, H., and Alici, E. (2015). Deletion of Chromosomal Region 8p21 Confers Resistance to Bortezomib and Is Associated with Upregulated Decoy TRAIL Receptor Expression in Patients with Multiple Myeloma. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0138248"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"e191","DOI":"10.1038\/bcj.2014.13","article-title":"Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients","volume":"4","author":"Walker","year":"2014","journal-title":"Blood Cancer J."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1038\/leu.2008.142","article-title":"Clinical and biological significance of RAS mutations in multiple myeloma","volume":"22","author":"Chng","year":"2008","journal-title":"Leukemia"},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"3911","DOI":"10.1200\/JCO.2014.59.1503","article-title":"Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma","volume":"33","author":"Walker","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3389\/fgene.2011.00022","article-title":"MicroRNAs: New Players in Multiple Myeloma","volume":"2","author":"Pichiorri","year":"2011","journal-title":"Front. Genet."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1586\/14737159.2014.946906","article-title":"The potential of miRNAs as biomarkers for multiple myeloma","volume":"14","author":"Rocci","year":"2014","journal-title":"Expert Rev. Mol. Diagn."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1111\/bjh.13506","article-title":"Global hypomethylation in myeloma is associated with poor prognosis","volume":"172","author":"Sive","year":"2016","journal-title":"Brit. J. Haematol."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"521586","DOI":"10.1155\/2014\/521586","article-title":"MicroRNA: Important Player in the Pathobiology of Multiple Myeloma","volume":"2014","author":"Bi","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"12885","DOI":"10.1073\/pnas.0806202105","article-title":"MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis","volume":"105","author":"Pichiorri","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"6669","DOI":"10.1182\/blood-2009-01-198408","article-title":"MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma","volume":"113","author":"Roccaro","year":"2009","journal-title":"Blood"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.3109\/10428194.2011.591004","article-title":"Myeloma cell adhesion to bone marrow stromal cells confers drug resistance by microRNA-21 up-regulation","volume":"52","author":"Wang","year":"2011","journal-title":"Leukemia Lymphoma"},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1182\/blood-2007-03-081133","article-title":"Interleukin-6\u2013dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer","volume":"110","author":"Pfeifer","year":"2007","journal-title":"Blood"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1158\/1078-0432.CCR-12-3325","article-title":"Targeting miR-21 Inhibits In Vitro and In Vivo Multiple Myeloma Cell Growth","volume":"19","author":"Leone","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1159\/000302889","article-title":"MicroRNA Profiles of Drug-Resistant Myeloma Cell Lines","volume":"123","author":"Munker","year":"2010","journal-title":"Acta Haematol."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.bbrc.2011.09.063","article-title":"Overexpression of microRNA-29b induces apoptosis of multiple myeloma cells through down regulating Mcl-1","volume":"414","author":"Zhang","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"e436","DOI":"10.1038\/cddis.2012.175","article-title":"miR-29b sensitizes multiple myeloma cells to bortezomib-induced apoptosis through the activation of a feedback loop with the transcription factor Sp1","volume":"3","author":"Amodio","year":"2012","journal-title":"Cell Death Dis."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1146\/annurev.med.53.082901.103929","article-title":"MECHANISMS OF CANCER DRUG RESISTANCE","volume":"53","author":"Gottesman","year":"2002","journal-title":"Medicine"},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1042\/bse0500209","article-title":"The controversial role of ABC transporters in clinical oncology","volume":"50","author":"Tamaki","year":"2011","journal-title":"Essays Biochem."},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1038\/sj.leu.2400724","article-title":"Detection of multidrug resistance gene expression in multiple myeloma","volume":"11","author":"Dalton","year":"1997","journal-title":"Leukemia"},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/S0344-0338(96)80099-9","article-title":"Molecular Mechanisms of Multidrug Resistance in Cancer Chemotherapy","volume":"192","author":"Nooter","year":"1996","journal-title":"Pathol. Res. Pract."},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1182\/blood.V81.2.490.490","article-title":"P-glycoprotein expression in human plasma cell myeloma: Correlation with prior chemotherapy","volume":"81","author":"Grogan","year":"1993","journal-title":"Blood"},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1007\/s00280-014-2438-4","article-title":"No clinically significant drug interactions between lenalidomide and P-glycoprotein substrates and inhibitors: Results from controlled phase I studies in healthy volunteers","volume":"73","author":"Chen","year":"2014","journal-title":"Cancer Chemoth. Pharm."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1007\/s00280-013-2136-7","article-title":"The interaction of bortezomib with multidrug transporters: Implications for therapeutic applications in advanced multiple myeloma and other neoplasias","volume":"71","author":"Ooi","year":"2013","journal-title":"Cancer Chemoth. Pharm."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"178","DOI":"10.3322\/canjclin.55.3.178","article-title":"Targeting Apoptosis Pathways in Cancer Therapy","volume":"55","author":"Ghobrial","year":"2005","journal-title":"Cancer J. Clin."},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.1200\/JCO.2003.06.001","article-title":"Overcoming Drug Resistance in Multiple Myeloma: The Emergence of Therapeutic Approaches to Induce Apoptosis","volume":"21","author":"Yang","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1038\/sj.leu.2403486","article-title":"PI3-K\/AKT\/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells","volume":"18","author":"Lentzsch","year":"2004","journal-title":"Leukemia"},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1182\/blood.V96.8.2856","article-title":"Insulin-like growth factor I is a dual effector of multiple myeloma cell growth","volume":"96","author":"Ge","year":"2000","journal-title":"Blood"},{"key":"ref_216","first-page":"6763","article-title":"The phosphatidylinositol 3-kinase\/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses","volume":"60","author":"Tu","year":"2000","journal-title":"Cancer Res."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1182\/blood.V98.3.795","article-title":"TRAIL\/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: Therapeutic applications","volume":"98","author":"Mitsiades","year":"2001","journal-title":"Blood"},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.bcp.2008.11.024","article-title":"Cooperation between Apo2L\/TRAIL and bortezomib in multiple myeloma apoptosis","volume":"77","author":"Balsas","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"2950","DOI":"10.1038\/sj.onc.1206423","article-title":"A major role for Mcl-1 antiapoptotic protein in the IL-6-induced survival of human myeloma cells","volume":"22","author":"Jourdan","year":"2003","journal-title":"Oncogene"},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"3945","DOI":"10.1002\/(SICI)1521-4141(199912)29:12<3945::AID-IMMU3945>3.0.CO;2-O","article-title":"IL-6 up-regulates Mcl-1 in human myeloma cells through JAK\u2009\/\u2009STAT rather than Ras\u2009\/\u2009MAP kinase pathway","volume":"29","author":"Puthier","year":"1999","journal-title":"Eur. J. Immunol."},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"2886","DOI":"10.1182\/blood-2004-05-1760","article-title":"VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis","volume":"104","author":"Gouill","year":"2004","journal-title":"Blood"},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1034\/j.1600-0609.2002.01549.x","article-title":"Expression of the bcl-2 family of pro- and anti-apoptotic genes in multiple myeloma and normal plasma cells","volume":"69","author":"Spets","year":"2002","journal-title":"Eur. J. Haematol."},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"16639","DOI":"10.1074\/jbc.M200360200","article-title":"NF-\u03baB as a therapeutic target in multiple myeloma","volume":"277","author":"Hideshima","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_224","first-page":"286","article-title":"Integration of autophagy, proteasomal degradation, unfolded protein response and apoptosis","volume":"34","author":"Benbrook","year":"2012","journal-title":"Exp. Oncol."},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"4907","DOI":"10.1182\/blood-2005-08-3531","article-title":"Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells","volume":"107","author":"Obeng","year":"2006","journal-title":"Blood"},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1158\/1535-7163.MCT-12-0782","article-title":"Endoplasmic Reticulum Stress and the Unfolded Protein Response: Targeting the Achilles Heel of Multiple Myeloma","volume":"12","author":"Vincenz","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.4161\/auto.29264","article-title":"Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed\/refractory myeloma","volume":"10","author":"Vogl","year":"2014","journal-title":"Autophagy"},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"5775","DOI":"10.1182\/blood.V124.21.5775.5775","article-title":"A Phase II Trial of Chloroquine in Combination with Bortezomib and Cyclophosphamide in Patients with Relapsed and Refractory Multiple Myeloma","volume":"124","author":"Montanari","year":"2014","journal-title":"Blood"},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"70845","DOI":"10.18632\/oncotarget.12226","article-title":"Hydroxychloroquine potentiates carfilzomib toxicity towards myeloma cells","volume":"7","author":"Baranowska","year":"2016","journal-title":"Oncotarget"},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2016.08.019","article-title":"Inhibition of autophagy with chloroquine potentiates carfilzomib-induced apoptosis in myeloma cells in vitro and in vivo","volume":"382","author":"Jarauta","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1158\/1078-0432.CCR-07-1299","article-title":"Targeting Akt and Heat Shock Protein 90 Produces Synergistic Multiple Myeloma Cell Cytotoxicity in the Bone Marrow Microenvironment","volume":"14","author":"Huston","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"100645","DOI":"10.1016\/j.drup.2019.100645","article-title":"The multi-factorial nature of clinical multidrug resistance in cancer","volume":"46","author":"Assaraf","year":"2019","journal-title":"Drugs Resist. Updat."},{"key":"ref_233","first-page":"411","article-title":"Mouse myeloma tumor stem cells: a primary cell culture assay","volume":"46","author":"Park","year":"1971","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1158\/0008-5472.CAN-07-3096","article-title":"Clonogenic Multiple Myeloma Progenitors, Stem Cell Properties, and Drug Resistance","volume":"68","author":"Matsui","year":"2008","journal-title":"Cancer Res."},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1182\/blood-2003-09-3064","article-title":"Characterization of clonogenic multiple myeloma cells","volume":"103","author":"Matsui","year":"2004","journal-title":"Blood"},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2008.08.005","article-title":"Cancer stem cells in multiple myeloma","volume":"277","author":"Ghosh","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"2530","DOI":"10.1038\/leu.2012.140","article-title":"CD19-CD45 low\/-CD38 high\/CD138+ plasma cells enrich for human tumorigenic myeloma cells","volume":"26","author":"Kim","year":"2012","journal-title":"Leukemia"},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"35466","DOI":"10.18632\/oncotarget.8154","article-title":"Multiple myeloma cancer stem cells","volume":"7","author":"Gao","year":"2016","journal-title":"Oncotarget"},{"key":"ref_239","first-page":"djz159","article-title":"Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma","volume":"112","author":"Gao","year":"2019","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_240","doi-asserted-by":"crossref","first-page":"4048","DOI":"10.1073\/pnas.0611682104","article-title":"Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma","volume":"104","author":"Peacock","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_241","doi-asserted-by":"crossref","first-page":"3511","DOI":"10.1182\/blood-2003-07-2254","article-title":"Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells","volume":"103","author":"Jundt","year":"2004","journal-title":"Blood"},{"key":"ref_242","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/1756-8722-6-91","article-title":"Fact or fiction - identifying the elusive multiple myeloma stem cell","volume":"6","author":"Kellner","year":"2013","journal-title":"J. Hematol. Oncol."},{"key":"ref_243","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/nrc2714","article-title":"Environment-mediated drug resistance: A major contributor to minimal residual disease","volume":"9","author":"Meads","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S1074-7613(00)80011-4","article-title":"Constitutive Activation of Stat3 Signaling Confers Resistance to Apoptosis in Human U266 Myeloma Cells","volume":"10","author":"Landowski","year":"1999","journal-title":"Immunity"},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1158\/1535-7163.MCT-08-0149","article-title":"Janus kinase inhibitor INCB20 has antiproliferative and apoptotic effects on human myeloma cells in vitro and in vivo","volume":"8","author":"Burger","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"ref_246","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1593\/neo.91192","article-title":"INCB16562, a JAK1\/2 Selective Inhibitor, Is Efficacious against Multiple Myeloma Cells and Reverses the Protective Effects of Cytokine and Stromal Cell Support","volume":"12","author":"Li","year":"2010","journal-title":"Neoplasia"},{"key":"ref_247","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1111\/j.1365-2141.2010.08533.x","article-title":"Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma","volume":"152","author":"Hunsucker","year":"2011","journal-title":"Brit. J. Haematol."},{"key":"ref_248","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1038\/leu.2011.175","article-title":"The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells","volume":"25","author":"Monaghan","year":"2011","journal-title":"Leukemia"},{"key":"ref_249","doi-asserted-by":"crossref","first-page":"6469","DOI":"10.1158\/1078-0432.CCR-07-1293","article-title":"Inhibition of Interleukin-6 Signaling with CNTO 328 Enhances the Activity of Bortezomib in Preclinical Models of Multiple Myeloma","volume":"13","author":"Voorhees","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_250","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1002\/ijc.26152","article-title":"A small molecule, LLL12 inhibits constitutive STAT3 and IL-6-induced STAT3 signaling and exhibits potent growth suppressive activity in human multiple myeloma cells","volume":"130","author":"Lin","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_251","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1182\/blood.V87.3.1104.bloodjournal8731104","article-title":"Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B","volume":"87","author":"Chauhan","year":"1996","journal-title":"Blood"},{"key":"ref_252","first-page":"3071","article-title":"The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells","volume":"61","author":"Hideshima","year":"2001","journal-title":"Cancer Res."},{"key":"ref_253","doi-asserted-by":"crossref","first-page":"22382","DOI":"10.1074\/jbc.M100938200","article-title":"Inhibition of NF-\u03baB Activity by Thalidomide through Suppression of I\u03baB Kinase Activity","volume":"276","author":"Keifer","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_254","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1182\/blood-2014-03-559963","article-title":"The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma","volume":"124","author":"Spencer","year":"2014","journal-title":"Blood"},{"key":"ref_255","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1182\/blood.V98.2.428","article-title":"Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration","volume":"98","author":"Podar","year":"2001","journal-title":"Blood"},{"key":"ref_256","first-page":"5019","article-title":"The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787\/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment","volume":"62","author":"Lin","year":"2002","journal-title":"Cancer Res."},{"key":"ref_257","doi-asserted-by":"crossref","first-page":"5796","DOI":"10.1158\/1078-0432.CCR-14-0847","article-title":"A HGF\/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target","volume":"20","author":"Ferrucci","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_258","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1182\/blood-2014-03-562439","article-title":"Bone marrow stromal cell\u2013derived exosomes as communicators in drug resistance in multiple myeloma cells","volume":"124","author":"Wang","year":"2014","journal-title":"Blood"},{"key":"ref_259","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1080\/14737159.2019.1583103","article-title":"An update on extracellular vesicles in multiple myeloma: A focus on their role in cell-to-cell crosstalk and as potential liquid biopsy biomarkers","volume":"19","author":"Laurenzana","year":"2019","journal-title":"Expert Rev. Mol. Diagn."},{"key":"ref_260","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1158\/1078-0432.CCR-18-2363","article-title":"Exosome-Transmitted PSMA3 and PSMA3-AS1 Promote Proteasome Inhibitor Resistance in Multiple Myeloma","volume":"25","author":"Xu","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_261","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1083\/jcb.201211138","article-title":"Extracellular vesicles: Exosomes, microvesicles, and friends","volume":"200","author":"Raposo","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_262","doi-asserted-by":"crossref","first-page":"1000647","DOI":"10.1016\/j.drup.2019.100647","article-title":"Extracellular vesicles as a novel source of biomarkers in liquid biopsies for monitoring cancer progression and drug resistance","volume":"47","author":"Vasconcelos","year":"2019","journal-title":"Drugs Resist. Updat."},{"key":"ref_263","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.molmed.2015.08.002","article-title":"Intercellular Transfer of Cancer Drug Resistance Traits by Extracellular Vesicles","volume":"21","author":"Sousa","year":"2015","journal-title":"Trends Mol. Med."},{"key":"ref_264","first-page":"1023","article-title":"Multidrug resistant tumour cells shed more microvesicle-like EVs and less exosomes than their drug-sensitive counterpart cells","volume":"6","author":"Luca","year":"2019","journal-title":"Biochim. Biophys. Acta"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/2\/407\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:56:30Z","timestamp":1760172990000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/2\/407"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,10]]},"references-count":264,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["cancers12020407"],"URL":"https:\/\/doi.org\/10.3390\/cancers12020407","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,10]]}}}