{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:06:40Z","timestamp":1792789600001,"version":"4.5.0"},"reference-count":72,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T00:00:00Z","timestamp":1686268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ares Pharmaceuticals"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The main goal of the present study was to examine if the RNA-sequencing (RNAseq)-based ERBB2\/HER2 expression level in malignant plasma cells from multiple myeloma (MM) patients has clinical significance for treatment outcomes and survival. We examined the relationship between the RNAseq-based ERBB2 messenger ribonucleic acid (mRNA) levels in malignant plasma cells and survival outcomes in 787 MM patients treated on contemporary standard regimens. ERBB2 was expressed at significantly higher levels than ERBB1 as well as ERBB3 across all three stages of the disease. Upregulated expression of ERBB2 mRNA in MM cells was correlated with amplified expression of mRNAs for transcription factors (TF) that recognize the ERBB2 gene promoter sites. Patients with higher levels of ERBB2 mRNA in their malignant plasma cells experienced significantly increased cancer mortality, shorter progression-free survival, and worse overall survival than other patients. The adverse impact of high ERBB2 expression on patient survival outcomes remained significant in multivariate Cox proportional hazards models that accounted for the effects of other prognostic factors. To the best of our knowledge, this is the first demonstration of an adverse prognostic impact of high-level ERBB2 expression in MM patients. Our results encourage further evaluation of the prognostic significance of high-level ERBB2 mRNA expression and the clinical potential of ERBB2-targeting therapeutics as personalized medicines to overcome cancer drug resistance in high-risk as well as relapsed\/refractory MM.<\/jats:p>","DOI":"10.3390\/ijms24129943","type":"journal-article","created":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T09:54:32Z","timestamp":1686304472000},"page":"9943","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Upregulated Expression of ERBB2\/HER2 in Multiple Myeloma as a Predictor of Poor Survival Outcomes"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9334-183X","authenticated-orcid":false,"given":"Fatih M.","family":"Uckun","sequence":"first","affiliation":[{"name":"Immuno-Oncology Program, Ares Pharmaceuticals, St. Paul, MN 55110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjive","family":"Qazi","sequence":"additional","affiliation":[{"name":"Immuno-Oncology Program, Ares Pharmaceuticals, St. Paul, MN 55110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3159","DOI":"10.1093\/emboj\/19.13.3159","article-title":"The ErbB signaling network: Receptor heterodimerization in development and cancer","volume":"19","author":"Olayioye","year":"2000","journal-title":"EMBO J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0014-5793(99)00283-5","article-title":"Binding specificities and affinities of egf domains for ErbB receptors","volume":"447","author":"Jones","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/978-3-031-12974-2_3","article-title":"ERBB Signaling Pathway in Cancer Stem Cells","volume":"1393","author":"Hassan","year":"2022","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e00708","DOI":"10.7554\/eLife.00708","article-title":"Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family","volume":"2","author":"Arkhipov","year":"2013","journal-title":"eLife"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S1357-2725(99)00015-1","article-title":"EGF receptor","volume":"31","author":"Wells","year":"1999","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"815","DOI":"10.2174\/1568026620666200303123102","article-title":"Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors","volume":"20","author":"Sabbah","year":"2020","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-4939-7219-7_1","article-title":"ErbB Receptors and Cancer","volume":"1652","author":"Wang","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"120082","DOI":"10.1016\/j.ijpharm.2020.120082","article-title":"EGFR targeting for cancer therapy: Pharmacology and immunoconjugates with drugs and nanoparticles","volume":"592","author":"Santos","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nrc1609","article-title":"ERBB receptors and cancer: The complexity of targeted inhibitors","volume":"5","author":"Hynes","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1517\/13543780903066772","article-title":"EGFR-directed therapies to treat non-small-cell lung cancer","volume":"18","author":"Ho","year":"2009","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1056\/NEJMra0707704","article-title":"EGFR Antagonists in Cancer Treatment","volume":"358","author":"Ciardiello","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.2217\/fon.15.183","article-title":"Afatinib: A second-generation EGF receptor and ErbB tyrosine kinase inhibitor for the treatment of advanced non-small-cell lung cancer","volume":"11","author":"Popat","year":"2015","journal-title":"Futur. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.2174\/1389557516666160321114917","article-title":"Review on EGFR Inhibitors: Critical Updates","volume":"16","author":"Singh","year":"2016","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.3389\/fonc.2020.01249","article-title":"The Latest Battles Between EGFR Monoclonal Antibodies and Resistant Tumor Cells","volume":"10","author":"Cai","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41568-020-00322-0","article-title":"Antitumour immunity regulated by aberrant ERBB family signalling","volume":"21","author":"Kumagai","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.immuni.2012.09.023","article-title":"Amphiregulin Enhances Regulatory T Cell-Suppressive Function via the Epidermal Growth Factor Receptor","volume":"38","author":"Zaiss","year":"2013","journal-title":"Immunity"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.immuni.2017.09.013","article-title":"Epidermal Growth Factor Receptor Expression Licenses Type-2 Helper T Cells to Function in a T Cell Receptor-Independent Fashion","volume":"47","author":"Minutti","year":"2017","journal-title":"Immunity"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.jacc.2017.10.084","article-title":"Selective EGF-Receptor Inhibition in CD4+ T Cells Induces Anergy and Limits Atherosclerosis","volume":"71","author":"Zeboudj","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"45917","DOI":"10.1038\/srep45917","article-title":"Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress","volume":"8","author":"Wang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"483","DOI":"10.4161\/cc.4.3.1533","article-title":"Activated EGFR Promotes the Survival of B-Lineage Acute Leukemia in the Absence of Stromal Cells","volume":"4","author":"Spengeman","year":"2005","journal-title":"Cell Cycle"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3512","DOI":"10.1038\/sj.onc.1208536","article-title":"Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells","volume":"24","author":"Mahtouk","year":"2005","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5269","DOI":"10.1182\/bloodadvances.2021004695","article-title":"ALCAM-EGFR interaction regulates myelomagenesis","volume":"5","author":"Luo","year":"2021","journal-title":"Blood Adv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9925","DOI":"10.1038\/srep09925","article-title":"Multiple myeloma acquires resistance to EGFR inhibitor via induction of pentose phosphate pathway","volume":"5","author":"Chen","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13045-018-0689-y","article-title":"Multiple myeloma-derived exosomes are enriched of amphiregulin (AREG) and activate the epidermal growth factor pathway in the bone microenvironment leading to osteoclastogenesis","volume":"12","author":"Raimondo","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"282","DOI":"10.3390\/onco2040016","article-title":"ERBB1\/EGFR and JAK3 Tyrosine Kinases as Potential Therapeutic Targets in High-Risk Multiple Myeloma","volume":"2","author":"Uckun","year":"2022","journal-title":"Onco"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3286","DOI":"10.1128\/MCB.01520-09","article-title":"PHF8 Targets Histone Methylation and RNA Polymerase II To Activate Transcription","volume":"30","author":"Fortschegger","year":"2010","journal-title":"Mol. Cell. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Cruz, R.G.B., Madden, S.F., Brennan, K., and Hopkins, A.M. (2022). A Transcriptional Link between HER2, JAM-A and FOXA1 in Breast Cancer. Cells, 11.","DOI":"10.3390\/cells11040735"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1042\/bj20030388","article-title":"Characterization of the human activator protein-2gamma (AP-2gamma) gene: Control of expression by Sp1\/Sp3 in breast tumour cells","volume":"373","author":"Hasleton","year":"2003","journal-title":"Biochem. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"102612","DOI":"10.1016\/j.ebiom.2019.102612","article-title":"Contribution of synergism between PHF8 and HER2 signalling to breast cancer development and drug resistance","volume":"51","author":"Liu","year":"2020","journal-title":"Ebiomedicine"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1042\/bj20021238","article-title":"Identification of HTF (HER2 transcription factor) as an AP-2 (activator protein-2) transcription factor and contribution of the HTF binding site to ERBB2 gene overexpression","volume":"370","author":"Vernimmen","year":"2003","journal-title":"Biochem. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"R83","DOI":"10.1186\/bcr2450","article-title":"Ku proteins interact with activator protein-2 transcription factors and contribute to ERBB2overexpression in breast cancer cell lines","volume":"11","author":"Nolens","year":"2009","journal-title":"Breast Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"24428","DOI":"10.1074\/jbc.M503790200","article-title":"Yin Yang 1 Cooperates with Activator Protein 2 to Stimulate ERBB2 Gene Expression in Mammary Cancer Cells","volume":"280","author":"Begon","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1186\/bcr329","article-title":"Update on HER-2 as a target for cancer therapy: The ERBB2 promoter and its exploitation for cancer treatment","volume":"3","author":"Hurst","year":"2001","journal-title":"Breast Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4374","DOI":"10.1073\/pnas.84.13.4374","article-title":"Characterization of the promoter region of the human c-erbB-2 protooncogene","volume":"84","author":"Ishii","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Das, S., Juliana, N., Abu Yazit, N.A., Azmani, S., and Abu, I.F. (2022). Multiple Myeloma: Challenges Encountered and Future Options for Better Treatment. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031649"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1020011","DOI":"10.3389\/fonc.2022.1020011","article-title":"Advances in the molecular characterization of multiple myeloma and mechanism of therapeutic resistance","volume":"12","author":"Saldarriaga","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.ebiom.2018.12.004","article-title":"Contemporary patient-tailored treatment strategies against high risk and relapsed or refractory multiple myeloma","volume":"39","author":"Uckun","year":"2018","journal-title":"Ebiomedicine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2358","DOI":"10.3324\/haematol.2020.247015","article-title":"Multiple myeloma: The (r)evolution of current therapy and a glance into future","volume":"105","author":"Anderson","year":"2020","journal-title":"Haematologica"},{"key":"ref_39","first-page":"271","article-title":"Cancer drug resistance in multiple myeloma","volume":"5","author":"Uckun","year":"2022","journal-title":"Cancer Drug Resist."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S1470-2045(20)30756-7","article-title":"Treatment of relapsed and refractory multiple myeloma: Recommendations from the International Myeloma Working Group","volume":"22","author":"Moreau","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1080\/17474086.2018.1437345","article-title":"The multiple myeloma treatment landscape: International guide-line recommendations and clinical practice in Europe","volume":"11","author":"Cavo","year":"2018","journal-title":"Expert Rev. Hematol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13045-022-01234-2","article-title":"Deciphering mechanisms of immune escape to inform immunotherapeutic strategies in multiple myeloma","volume":"15","author":"Swamydas","year":"2022","journal-title":"J. Hematol. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"760382","DOI":"10.3389\/fonc.2021.760382","article-title":"Dual Targeting of Multiple Myeloma Stem Cells and Myeloid-Derived Suppressor Cells for Treatment of Chemotherapy-Resistant Multiple Myeloma","volume":"11","author":"Uckun","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/CCO.0000000000000615","article-title":"The microenvironment in myeloma","volume":"32","author":"Lomas","year":"2020","journal-title":"Curr. Opin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"941437","DOI":"10.3389\/fonc.2022.941437","article-title":"Molecular Impact of the Tumor Microenvironment on Multiple Myeloma Dissemination and Extramedullary Disease","volume":"12","author":"Forster","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Neumeister, P., Schulz, E., Pansy, K., Szmyra, M., and Deutsch, A.J. (2022). Targeting the Microenvironment for Treating Multiple Myeloma. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147627"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Ortiz, A., Rodr\u00edguez-Garc\u00eda, Y., Encinas, J., Maroto-Mart\u00edn, E., Castellano, E., Teixid\u00f3, J., and Mart\u00ednez-L\u00f3pez, J. (2021). The Role of Tumor Microenvironment in Multiple Myeloma Development and Progression. Cancers, 13.","DOI":"10.3390\/cancers13020217"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1102471","DOI":"10.3389\/fimmu.2022.1102471","article-title":"The immune suppressive tumor microenvironment in multiple myeloma: The contribution of myeloid-derived suppressor cells","volume":"13","author":"Giannotta","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Uckun, F.M. (2021). Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma. Cancers, 13.","DOI":"10.3390\/cancers13092018"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"94591","DOI":"10.18632\/oncotarget.21813","article-title":"C-C motif chemokine receptor 1 (CCR1) is a target of the EGF-AKT-mTOR-STAT3 signaling axis in breast cancer cells","volume":"8","author":"Shin","year":"2017","journal-title":"Oncotarget"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1007\/BF02850052","article-title":"Clinical significance of hepatocyte growth factor, platelet-derived growth factor-AB, and transforming growth factor-\u03b1 in bone marrow and peripheral blood of patients with multiple myeloma","volume":"23","author":"Kara","year":"2006","journal-title":"Adv. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2017\/1852517","article-title":"Inflammatory and Anti-Inflammatory Equilibrium, Proliferative and Antiproliferative Balance: The Role of Cytokines in Multiple Myeloma","volume":"2017","author":"Musolino","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Akhtar, S., Ali, T.A., Faiyaz, A., Khan, O.S., Raza, S.S., Kulinski, M., El Omri, H., Bhat, A.A., and Uddin, S. (2020). Cytokine-Mediated Dysregulation of Signaling Pathways in the Pathogenesis of Multiple Myeloma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21145002"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Melaccio, A., Reale, A., Saltarella, I., Desantis, V., Lamanuzzi, A., Cicco, S., Frassanito, M.A., Vacca, A., and Ria, R. (2022). Pathways of Angiogenic and Inflammatory Cytokines in Multiple Myeloma: Role in Plasma Cell Clonal Expansion and Drug Resistance. J. Clin. Med., 11.","DOI":"10.3390\/jcm11216491"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1016\/j.immuni.2014.10.016","article-title":"Interleukin-10-Producing Plasmablasts Exert Regulatory Function in Autoimmune Inflammation","volume":"41","author":"Matsumoto","year":"2014","journal-title":"Immunity"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1158\/1078-0432.CCR-17-2003","article-title":"Platelets Enhance Multiple Myeloma Progression via IL-1\u03b2 Upregulation","volume":"24","author":"Takagi","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4478","DOI":"10.1158\/1078-0432.CCR-20-4557","article-title":"FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer","volume":"27","author":"Narayan","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4278","DOI":"10.1002\/cncr.33102","article-title":"Novel HER2\u2013targeted therapies for HER2\u2013positive metastatic breast cancer","volume":"126","author":"Kunte","year":"2020","journal-title":"Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12032-022-01849-y","article-title":"Therapeutic landscape of advanced HER2-positive breast cancer in 2022","volume":"39","author":"Gupta","year":"2022","journal-title":"Med. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Hideshima, T., and Anderson, K.C. (2021). Signaling Pathway Mediating Myeloma Cell Growth and Survival. Cancers, 13.","DOI":"10.3390\/cancers13020216"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Zhou, J., and Chng, W.-J. (2022). Biological Hallmarks and Emerging Strategies to Target STAT3 Signaling in Multiple Myeloma. Cells, 11.","DOI":"10.3390\/cells11060941"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1059715","DOI":"10.3389\/fcell.2022.1059715","article-title":"Targeting TGF-\u03b2 signaling in the multiple myeloma microenvironment: Steering CARs and T cells in the right direction","volume":"10","author":"Rana","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"846310","DOI":"10.3389\/fendo.2022.846310","article-title":"Targeting Chemokine Receptor CCR1 as a Potential Therapeutic Approach for Multiple Myeloma","volume":"13","author":"Gilchrist","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Minakata, D., Fujiwara, S., Yokoyama, D., Noguchi, A., Aoe, S., Oyama, T., Koyama, S., Murahashi, R., Nakashima, H., and Hyodo, K. (Br. J. Haematol., 2023). Relapsed and refractory multiple myeloma: A systematic review and network meta-analysis of the efficacy of novel therapies, Br. J. Haematol., ahead of print.","DOI":"10.1111\/bjh.18654"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Coira, I.F., Rinc\u00f3n, R., and Cuendet, M. (2022). The Multiple Myeloma Landscape: Epigenetics and Non-Coding RNAs. Cancers, 14.","DOI":"10.3390\/cancers14102348"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Barreto, I.V., Machado, C.B., Almeida, D.B., Pessoa, F.M.C.D.P., Gadelha, R.B., Pantoja, L.D.C., Oliveira, D.D.S., Ribeiro, R.M., Lopes, G.S., and Filho, M.O.D.M. (2022). Kinase Inhibition in Multiple Myeloma: Current Scenario and Clinical Perspectives. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14091784"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"973836","DOI":"10.3389\/fonc.2022.973836","article-title":"Drug resistance in multiple myeloma: Soldiers and weapons in the bone marrow niche","volume":"12","author":"Solimando","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6368","DOI":"10.3389\/fonc.2020.606368","article-title":"Harnessing the Immune System Against Multiple Myeloma: Challenges and Opportunities","volume":"10","author":"Yamamoto","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1172\/JCI129205","article-title":"Immunotherapy of multiple myeloma","volume":"130","author":"Minnie","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_71","first-page":"D433","article-title":"STRING: Known and predicted protein-protein associations, integrated and transferred across organisms","volume":"33","author":"Jensen","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"S96","DOI":"10.1093\/bioinformatics\/18.suppl_1.S96","article-title":"Variance stabilization applied to microarray data calibration and to the quantification of differential expression","volume":"18","author":"Huber","year":"2002","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/9943\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:51:28Z","timestamp":1760125888000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/9943"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,9]]},"references-count":72,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms24129943"],"URL":"https:\/\/doi.org\/10.3390\/ijms24129943","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,9]]}}}