{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:15:13Z","timestamp":1790388913605,"version":"4.1.0"},"reference-count":124,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T00:00:00Z","timestamp":1679875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Italian University and Research Ministry","doi-asserted-by":"publisher","award":["PRIN 20174TB8KW_002"],"award-info":[{"award-number":["PRIN 20174TB8KW_002"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"INNOLABS\u2013POR Puglia FESR-FSE 2014\u20132020 (Telemielolab)","award":["PRIN 20174TB8KW_002"],"award-info":[{"award-number":["PRIN 20174TB8KW_002"]}]},{"name":"Centro Interdipartimentale Ricerca Telemedicina (CITEL)\u2014University of Bari","award":["PRIN 20174TB8KW_002"],"award-info":[{"award-number":["PRIN 20174TB8KW_002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Angiogenesis represents a pivotal hallmark of multiple myeloma (MM) that correlates to patients\u2019 prognosis, overall survival, and drug resistance. Hence, several anti-angiogenic drugs that directly target angiogenic cytokines (i.e., monoclonal antibodies, recombinant molecules) or their cognate receptors (i.e., tyrosine kinase inhibitors) have been developed. Additionally, many standard antimyeloma drugs currently used in clinical practice (i.e., immunomodulatory drugs, bisphosphonates, proteasome inhibitors, alkylating agents, glucocorticoids) show anti-angiogenic effects further supporting the importance of inhibiting angiogenesis from potentiating the antimyeloma activity. Here, we review the most important anti-angiogenic therapies used for the management of MM patients with a particular focus on their pharmacological profile and on their anti-angiogenic effect in vitro and in vivo. Despite the promising perspective, the direct targeting of angiogenic cytokines\/receptors did not show a great efficacy in MM patients, suggesting the need to a deeper knowledge of the BM angiogenic niche for the design of novel multi-targeting anti-angiogenic therapies.<\/jats:p>","DOI":"10.3390\/cancers15071990","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T02:18:27Z","timestamp":1679883507000},"page":"1990","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Anti-Angiogenic Activity of Drugs in Multiple Myeloma"],"prefix":"10.3390","volume":"15","author":[{"given":"Ilaria","family":"Saltarella","sequence":"first","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7306-9621","authenticated-orcid":false,"given":"Concetta","family":"Altamura","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Campanale","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Laghetti","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4567-8216","authenticated-orcid":false,"given":"Angelo","family":"Vacca","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Antonia","family":"Frassanito","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, Section of Clinical Pathology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8816-9369","authenticated-orcid":false,"given":"Jean-Fran\u00e7ois","family":"Desaphy","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17046","DOI":"10.1038\/nrdp.2017.46","article-title":"Multiple myeloma","volume":"3","author":"Kumar","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-319-40320-5_1","article-title":"MGUS and Smoldering Multiple Myeloma: Diagnosis and Epidemiology","volume":"169","author":"Mateos","year":"2016","journal-title":"Cancer Treat. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"157496","DOI":"10.1155\/2012\/157496","article-title":"Bone marrow microenvironment in multiple myeloma progression","volume":"2012","author":"Manier","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"60698","DOI":"10.18632\/oncotarget.10849","article-title":"Microenvironment drug resistance in multiple myeloma: Emerging new players","volume":"7","author":"Desantis","year":"2016","journal-title":"Oncotarget"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1080\/10245330400018524","article-title":"Angiogenic switch in multiple myeloma","volume":"9","author":"Giuliani","year":"2004","journal-title":"Hematology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1111\/j.1365-2141.1994.tb08304.x","article-title":"Bone marrow angiogenesis and progression in multiple myeloma","volume":"87","author":"Vacca","year":"1994","journal-title":"Br. J. Haematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1182\/blood-2002-08-2441","article-title":"Prognostic value of angiogenesis in solitary bone plasmacytoma","volume":"10","author":"Kumar","year":"2003","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/sj.bmt.1704555","article-title":"Prognostic value of bone marrow angiogenesis in patients with multiple myeloma undergoing high-dose therapy","volume":"34","author":"Kumar","year":"2004","journal-title":"Bone Marrow Transplant."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13045-018-0691-4","article-title":"Prognostic or predictive value of circulating cytokines and angiogenic factors for initial treatment of multiple myeloma in the GIMEMA MM0305 randomized controlled trial","volume":"12","author":"Saltarella","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ribatti, D., and Vacca, A. (2018). New Insights in Anti-Angiogenesis in Multiple Myeloma. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19072031"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ria, R., Melaccio, A., Racanelli, V., and Vacca, A. (2020). Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients. J. Clin. Med., 9.","DOI":"10.3390\/jcm9061765"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7954580","DOI":"10.1155\/2016\/7954580","article-title":"Functional and Biological Role of Endothelial Precursor Cells in Tumour Progression: A New Potential Therapeutic Target in Haematological Malignancies","volume":"2016","author":"Reale","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3509","DOI":"10.1038\/s41375-021-01271-9","article-title":"JunB is a key regulator of multiple myeloma bone marrow angiogenesis","volume":"35","author":"Fan","year":"2021","journal-title":"Leukemia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1182\/blood-2008-10-184226","article-title":"Induction of angiogenesis by normal and malignant plasma cells","volume":"114","author":"Hose","year":"2009","journal-title":"Blood"},{"key":"ref_15","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_16","first-page":"176","article-title":"A paracrine loop in the vascular endothelial growth factor pathway triggers tumor angiogenesis and growth in multiple myeloma","volume":"88","author":"Vacca","year":"2003","journal-title":"Haematologica"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1160\/TH04-06-0334","article-title":"A VEGF-dependent autocrine loop mediates proliferation and capillarogenesis in bone marrow endothelial cells of patients with multiple myeloma","volume":"92","author":"Ria","year":"2004","journal-title":"Thromb. Haemost."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1038\/sj.leu.2402295","article-title":"Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: Therapeutic applications","volume":"15","author":"Gupta","year":"2001","journal-title":"Leukemia"},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"4371","DOI":"10.1158\/1078-0432.CCR-13-0039","article-title":"Novel targeting of phospho-cMET overcomes drug resistance and induces antitumor activity in multiple myeloma","volume":"19","author":"Moschetta","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1111\/bjh.12719","article-title":"MET dysregulation is a hallmark of aggressive disease in multiple myeloma patients","volume":"164","author":"Rocci","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1111\/j.1349-7006.2002.tb01278.x","article-title":"Elevated level of plasma basic fibroblast growth factor in multiple myeloma correlates with increased disease activity","volume":"93","author":"Sato","year":"2002","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1034\/j.1600-0609.2001.00348.x","article-title":"Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma","volume":"66","author":"Sezer","year":"2001","journal-title":"Eur. J. Haematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1182\/blood-2002-10-3257","article-title":"Proangiogenic properties of human myeloma cells: Production of angiopoietin-1 and its potential relationship to myeloma-induced angiogenesis","volume":"102","author":"Giuliani","year":"2003","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"48732","DOI":"10.18632\/oncotarget.8982","article-title":"The insulin-like growth factor system in multiple myeloma: Diagnostic and therapeutic potential","volume":"7","author":"Bieghs","year":"2016","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3064","DOI":"10.1182\/blood.V93.9.3064.409k07_3064_3073","article-title":"Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma","volume":"93","author":"Vacca","year":"1999","journal-title":"Blood"},{"key":"ref_27","first-page":"76","article-title":"Bone marrow angiogenesis and progression in multiple myeloma","volume":"1","author":"Ria","year":"2011","journal-title":"Am. J. Blood Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1158\/1078-0432.CCR-13-1950","article-title":"HIF-1\u03b1 of bone marrow endothelial cells implies relapse and drug resistance in patients with multiple myeloma and may act as a therapeutic target","volume":"20","author":"Ria","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/leu.2013.254","article-title":"Bone marrow fibroblasts parallel multiple myeloma progression in patients and mice: In vitro and in vivo studies","volume":"28","author":"Frassanito","year":"2014","journal-title":"Leukemia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"867576","DOI":"10.1155\/2011\/867576","article-title":"Angiogenesis-related cytokines, RANKL, and osteoprotegerin in multiple myeloma patients in relation to clinical features and response to treatment","volume":"2011","author":"Sfiridaki","year":"2011","journal-title":"Mediat. Inflamm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/978-3-0348-0837-8_14","article-title":"The role of inflammatory cells in angiogenesis in multiple myeloma","volume":"816","author":"Ribatti","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1089\/scd.2007.0132","article-title":"Mast cells contribute to vasculogenic mimicry in multiple myeloma","volume":"17","author":"Nico","year":"2008","journal-title":"Stem Cells Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/sj.onc.1210691","article-title":"Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma","volume":"27","author":"Scavelli","year":"2008","journal-title":"Oncogene"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Saltarella, I., Apollonio, B., Lamanuzzi, A., Desantis, V., Mariggi\u00f2, M.A., Desaphy, J.F., Vacca, A., and Frassanito, M.A. (2022). The Landscape of lncRNAs in Multiple Myeloma: Implications in the \u201cHallmarks of Cancer\u201d, Clinical Perspectives and Therapeutic Opportunities. Cancers, 14.","DOI":"10.3390\/cancers14081963"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3748","DOI":"10.1182\/blood-2014-05-576116","article-title":"Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1","volume":"124","author":"Umezu","year":"2014","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1093\/carcin\/bgs333","article-title":"miR-15a and miR-16 affect the angiogenesis of multiple myeloma by targeting VEGF","volume":"34","author":"Sun","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Saltarella, I., Lamanuzzi, A., Apollonio, B., Desantis, V., Bartoli, G., Vacca, A., and Frassanito, M.A. (2021). Role of Extracellular Vesicle-Based Cell-to-Cell Communication in Multiple Myeloma Progression. Cells, 10.","DOI":"10.3390\/cells10113185"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1634\/theoncologist.2009-0317","article-title":"Bevacizumab","volume":"15","author":"Beijnen","year":"2010","journal-title":"Oncologist"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1586\/era.12.13","article-title":"Bevacizumab: Overview of the literature","volume":"12","author":"Braghiroli","year":"2012","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1038\/labinvest.2011.162","article-title":"Bevacizumab attenuates major signaling cascades and eIF4E translation initiation factor in multiple myeloma cells","volume":"92","author":"Drucker","year":"2012","journal-title":"Lab. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kong, D.H., Kim, M.R., Jang, J.H., Na, H.J., and Lee, S. (2017). A Review of Anti-Angiogenic Targets for Monoclonal Antibody Cancer Therapy. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081786"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1111\/j.1365-2141.2011.08623.x","article-title":"Phase II randomized trial of bevacizumab versus bevacizumab and thalidomide for relapsed\/refractory multiple myeloma: A California Cancer Consortium trial","volume":"154","author":"Somlo","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1002\/cncr.27745","article-title":"Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma","volume":"119","author":"White","year":"2013","journal-title":"Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"20563","DOI":"10.18632\/oncotarget.25003","article-title":"Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma","volume":"9","author":"Lamanuzzi","year":"2018","journal-title":"Oncotarget"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.neo.2018.10.011","article-title":"Homotypic and Heterotypic Activation of the Notch Pathway in Multiple Myeloma-Enhanced Angiogenesis: A Novel Therapeutic Target?","volume":"21","author":"Saltarella","year":"2019","journal-title":"Neoplasia"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1097\/01.iae.0000242842.14624.e7","article-title":"Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration","volume":"26","author":"Ferrara","year":"2006","journal-title":"Retina"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s11912-010-0149-5","article-title":"Ramucirumab (IMC-1121B): Monoclonal antibody inhibition of vascular endothelial growth factor receptor-2","volume":"13","author":"Spratlin","year":"2011","journal-title":"Curr. Oncol. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kim, J., Choi, S.H., Ham, S.J., Cho, Y.C., Lee, S.I., Kang, J., Woo, D.C., Lee, W.S., Yoo, J.S., and Kim, K.W. (2018). Evaluation of drug mechanism and efficacy of a novel anti-angiogenic agent, TTAC-0001, using multi-modality bioimaging in a mouse breast cancer orthotopic model. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0187063"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1080\/19420862.2017.1305529","article-title":"Design and characterization of MP0250, a tri-specific anti-HGF\/anti-VEGF DARPin\u00ae drug candidate","volume":"9","author":"Binz","year":"2017","journal-title":"mAbs"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"13366","DOI":"10.18632\/oncotarget.24351","article-title":"Targeting angiogenesis in multiple myeloma by the VEGF and HGF blocking DARPin\u00ae protein MP0250: A preclinical study","volume":"9","author":"Rao","year":"2018","journal-title":"Oncotarget"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1182\/blood-2018-99-112859","article-title":"MP0250 Combined with Bortezomib and Dexamethasone in Multiple Myeloma Patients Previoulsy Exposed to Proteasome Inhibitors and Immunomodulatory Drugs","volume":"132","author":"Knop","year":"2018","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"112","DOI":"10.4103\/0974-620X.142591","article-title":"Vascular endothelial growth factor trap-eye and trap technology: Aflibercept from bench to bedside","volume":"7","year":"2014","journal-title":"Oman J. Ophthalmol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.critrevonc.2015.07.001","article-title":"Aflibercept a new target therapy in cancer treatment: A review","volume":"96","author":"Ricci","year":"2015","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"7099","DOI":"10.1158\/0008-5472.CAN-04-1443","article-title":"BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF\/MEK\/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis","volume":"64","author":"Wilhelm","year":"2004","journal-title":"Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1634\/theoncologist.12-4-426","article-title":"Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: A review of four phase I trials in patients with advanced refractory solid tumors","volume":"12","author":"Strumberg","year":"2007","journal-title":"Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5348","DOI":"10.1158\/0008-5472.CAN-12-0658","article-title":"Sorafenib has potent antitumor activity against multiple myeloma in vitro, ex vivo, and in vivo in the 5T33MM mouse model","volume":"72","author":"Kharaziha","year":"2012","journal-title":"Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1038\/onc.2009.403","article-title":"Sorafenib, a dual Raf kinase\/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs","volume":"29","author":"Ramakrishnan","year":"2010","journal-title":"Oncogene"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1002\/hon.2043","article-title":"Sorafenib in patients with refractory or recurrent multiple myeloma","volume":"31","author":"Yordanova","year":"2013","journal-title":"Hematol. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1038\/sj.bjc.6602603","article-title":"ZD6474--a novel inhibitor of VEGFR and EGFR tyrosine kinase activity","volume":"92","author":"Ryan","year":"2005","journal-title":"Br. J. Cancer."},{"key":"ref_60","first-page":"4645","article-title":"ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration","volume":"62","author":"Wedge","year":"2002","journal-title":"Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1634\/theoncologist.2008-0261","article-title":"Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: Current status and future directions","volume":"14","author":"Morabito","year":"2009","journal-title":"Oncologist"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s10637-006-9022-7","article-title":"A phase II study of ZD6474, Zactima, a selective inhibitor of VEGFR and EGFR tyrosine kinase in patients with relapsed multiple myeloma\u2014NCIC CTG IND.145","volume":"24","author":"Kovacs","year":"2006","journal-title":"Investig. New Drugs"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"19478","DOI":"10.1073\/pnas.0609329103","article-title":"The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma","volume":"103","author":"Podar","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4819","DOI":"10.1182\/blood-2009-02-207209","article-title":"Vascular endothelial growth factor inhibition is not an effective therapeutic strategy for relapsed or refractory multiple myeloma: A phase 2 study of pazopanib (GW786034)","volume":"113","author":"Prince","year":"2009","journal-title":"Blood"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1517\/14656566.2012.725722","article-title":"Dasatinib for the treatment of Philadelphia chromosome-positive leukemias","volume":"13","author":"Santos","year":"2012","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1182\/blood-2007-10-116590","article-title":"Validation of PDGFRbeta and c-Src tyrosine kinases as tumor\/vessel targets in patients with multiple myeloma: Preclinical efficacy of the novel, orally available inhibitor dasatinib","volume":"112","author":"Coluccia","year":"2008","journal-title":"Blood"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Asatsuma-Okumura, T., Ito, T., and Handa, H. (2020). Molecular Mechanisms of the Teratogenic Effects of Thalidomide. Pharmaceuticals, 13.","DOI":"10.3390\/ph13050095"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/2162-3619-1-27","article-title":"Thalidomide and its analogues in the treatment of Multiple Myeloma","volume":"1","author":"Latif","year":"2012","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_69","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":"2013","journal-title":"Leuk. Lymphoma"},{"key":"ref_70","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_71","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_72","doi-asserted-by":"crossref","first-page":"712147","DOI":"10.3389\/fphys.2021.712147","article-title":"Thalidomide Suppresses Angiogenesis Through the Signal Transducer and Activator of Transcription 3\/SP4 Signaling Pathway in the Peritoneal Membrane","volume":"12","author":"Zhu","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1182\/blood-2004-09-3679","article-title":"Thalidomide-induced antiangiogenic action is mediated by ceramide through depletion of VEGF receptors, and is antagonized by sphingosine-1-phosphate","volume":"106","author":"Yabu","year":"2005","journal-title":"Blood"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2958","DOI":"10.1007\/s10620-014-3257-5","article-title":"Inhibition of endothelial Slit2\/Robo1 signaling by thalidomide restrains angiogenesis by blocking the PI3K\/Akt pathway","volume":"59","author":"Li","year":"2014","journal-title":"Dig. Dis. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"677","DOI":"10.2174\/138920006778017777","article-title":"Thalidomide metabolism and hydrolysis: Mechanisms and implications","volume":"7","author":"Lepper","year":"2006","journal-title":"Curr. Drug Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s40265-017-0689-1","article-title":"Immunomodulatory Drugs in Multiple Myeloma: Mechanisms of Action and Clinical Experience","volume":"77","author":"Holstein","year":"2017","journal-title":"Drugs"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1097\/00007691-200202000-00017","article-title":"(5\u2032-OH-thalidomide, a metabolite of thalidomide, inhibits angiogenesis","volume":"24","author":"Price","year":"2002","journal-title":"Ther. Drug Monit."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1016\/j.thromres.2015.03.019","article-title":"Thalidomide and multiple myeloma serum synergistically induce a hemostatic imbalance in endothelial cells in vitro","volume":"135","author":"Gao","year":"2015","journal-title":"Thromb. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"573","DOI":"10.2174\/156800905774932806","article-title":"Novel therapeutic approaches targeting vascular endothelial growth factor and its receptors in haematological malignancies","volume":"5","author":"Ribatti","year":"2005","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5334","DOI":"10.1200\/JCO.2005.03.723","article-title":"Thalidomide downregulates angiogenic genes in bone marrow endothelial cells of patients with active multiple myeloma","volume":"23","author":"Vacca","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1158\/1078-0432.CCR-10-2381","article-title":"Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma","volume":"17","author":"Ferrucci","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1038\/sj.bjc.6600607","article-title":"Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects","volume":"87","author":"Dredge","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1038\/sj.leu.2403285","article-title":"Effect of thalidomide therapy on bone marrow angiogenesis in multiple myeloma","volume":"18","author":"Kumar","year":"2004","journal-title":"Leukemia"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1002\/hon.738","article-title":"The combination of intermediate doses of thalidomide and dexamethasone reduces bone marrow micro-vessel density but not serum levels of angiogenic cytokines in patients with refractory\/relapsed multiple myeloma","volume":"22","author":"Hatjiharissi","year":"2004","journal-title":"Hematol. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.htct.2019.04.006","article-title":"Effect of thalidomide on bone marrow angiogenesis in multiple myeloma patients","volume":"42","author":"Cury","year":"2020","journal-title":"Hematol. Transfus. Cell Ther."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.cyto.2007.11.017","article-title":"Bone marrow angiogenesis and angiogenic factors in multiple myeloma treated with novel agents","volume":"41","author":"Cibeira","year":"2008","journal-title":"Cytokine"},{"key":"ref_87","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_88","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s40262-018-0679-9","article-title":"Clinical Pharmacokinetics and Pharmacodynamics of Bortezomib","volume":"58","author":"Tan","year":"2019","journal-title":"Clin. Pharmacokinet."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Ito, S. (2020). Proteasome Inhibitors for the Treatment of Multiple Myeloma. Cancers, 12.","DOI":"10.3390\/cancers12020265"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1111\/j.1349-7006.2010.01544.x","article-title":"Bortezomib potentially inhibits cellular growth of vascular endothelial cells through suppression of G2\/M transition","volume":"101","author":"Tamura","year":"2010","journal-title":"Cancer Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.yexcr.2009.11.005","article-title":"Bortezomib induces autophagic death in proliferating human endothelial cells","volume":"316","author":"Belloni","year":"2010","journal-title":"Exp. Cell Res."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Di Lernia, G., Leone, P., Solimando, A.G., Buonavoglia, A., Saltarella, I., Ria, R., Ditonno, P., Silvestris, N., Crudele, L., and Vacca, A. (2020). Bortezomib Treatment Modulates Autophagy in Multiple Myeloma. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020552"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1182\/blood-2006-06-032664","article-title":"Hypoxia-inducible transcription factor-1 alpha determines sensitivity of endothelial cells to the proteosome inhibitor bortezomib","volume":"109","author":"Veschini","year":"2007","journal-title":"Blood"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1158\/0008-5472.CAN-05-1195","article-title":"Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells","volume":"66","author":"Roccaro","year":"2006","journal-title":"Cancer Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4912","DOI":"10.1182\/blood.V104.11.4912.4912","article-title":"Anti-angiogenic effect of bortezomib in patients with multiple myeloma","volume":"104","author":"Politou","year":"2005","journal-title":"Blood"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1182\/blood-2018-11-852459","article-title":"Myeloma bone disease: From biology findings to treatment approaches","volume":"133","author":"Terpos","year":"2019","journal-title":"Blood"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.4065\/83.9.1032","article-title":"Bisphosphonates: Mechanism of action and role in clinical practice","volume":"83","author":"Drake","year":"2008","journal-title":"Mayo Clin. Proc."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"305","DOI":"10.18433\/J3RK5J","article-title":"Long term bisphosphonate use in osteoporotic patients; a step forward, two steps back","volume":"15","author":"Salari","year":"2012","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/sj.leu.2401770","article-title":"Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines","volume":"14","author":"Tassone","year":"2000","journal-title":"Leukemia"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/BF02983818","article-title":"The bisphosphonate zoledronic acid induces cytotoxicity in human myeloma cell lines with enhancing effects of dexamethasone and thalidomide","volume":"78","author":"Ural","year":"2003","journal-title":"Int. J. Hematol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"3256","DOI":"10.1158\/1535-7163.MCT-07-0311","article-title":"Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma","volume":"6","author":"Scavelli","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1359\/jbmr.2003.18.3.482","article-title":"Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: Evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival","volume":"18","author":"Croucher","year":"2003","journal-title":"J. Bone Miner. Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.ejca.2009.10.019","article-title":"Bortezomib and zoledronic acid on angiogenic and vasculogenic activities of bone marrow macrophages in patients with multiple myeloma","volume":"46","author":"Moschetta","year":"2010","journal-title":"Eur. J. Cancer"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1586\/14737140.7.7.945","article-title":"Melphalan and its role in the management of patients with multiple myeloma","volume":"7","author":"Falco","year":"2007","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.ejmech.2018.04.001","article-title":"Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives","volume":"151","author":"Singh","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Poczta, A., Rogalska, A., and Marczak, A. (2021). Treatment of Multiple Myeloma and the Role of Melphalan in the Era of Modern Therapies-Current Research and Clinical Approaches. J. Clin. Med., 10.","DOI":"10.3390\/jcm10091841"},{"key":"ref_107","first-page":"353","article-title":"Evidence for active transport of melphalan by two amino acid carriers in L5178Y lymphoblasts in vitro","volume":"39","author":"Begleiter","year":"1979","journal-title":"Cancer Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1111\/j.1365-2125.2010.03638.x","article-title":"Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy","volume":"69","author":"Nath","year":"2010","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Winter, U., Mena, H.A., Negrotto, S., Arana, E., Pascual-Pasto, G., Laurent, V., Su\u00f1ol, M., Chantada, G.L., Carcaboso, A.M., and Schaiquevich, P. (2016). Schedule-Dependent Antiangiogenic and Cytotoxic Effects of Chemotherapy on Vascular Endothelial and Retinoblastoma Cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160094"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"6709","DOI":"10.1007\/s13277-015-4444-5","article-title":"In search of underlying mechanisms and potential drugs of melphalan-induced vascular toxicity through retinal endothelial cells using bioinformatics approach","volume":"37","author":"Yang","year":"2016","journal-title":"Tumor Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1080\/17512433.2022.2075847","article-title":"Melflufen for the treatment of multiple myeloma","volume":"15","author":"Ocio","year":"2022","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Miettinen, J.J., Kumari, R., Traustadottir, G.A., Huppunen, M.E., Sergeev, P., Majumder, M.M., Schepsky, A., Gudjonsson, T., Lievonen, J., and Bazou, D. (2021). Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen. Cancers, 13.","DOI":"10.3390\/cancers13071527"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"3019","DOI":"10.1158\/1078-0432.CCR-12-3752","article-title":"In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells","volume":"19","author":"Chauhan","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Gebraad, A., Ohlsbom, R., Miettinen, J.J., Emeh, P., Pakarinen, T.K., Manninen, M., Eskelinen, A., Kuismanen, K., Slipicevic, A., and Lehmann, F. (2022). Growth Response and Differentiation of Bone Marrow-Derived Mesenchymal Stem\/Stromal Cells in the Presence of Novel Multiple Myeloma Drug Melflufen. Cells, 11.","DOI":"10.3390\/cells11091574"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s00277-018-3465-8","article-title":"Glucocorticoids in multiple myeloma: Past, present, and future","volume":"98","author":"Burwick","year":"2019","journal-title":"Ann. Hematol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/978-1-4939-2895-8_14","article-title":"Glucocorticoids and Cancer","volume":"872","author":"Pufall","year":"2015","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1188\/17.CJON.240-249","article-title":"Steroid-Associated Side Effects: A Symptom Management Update on Multiple Myeloma Treatment","volume":"21","author":"King","year":"2017","journal-title":"Clin. J. Oncol. Nurs."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"24453","DOI":"10.1074\/jbc.C100074200","article-title":"Apaf-1\/cytochrome c-independent and Smac-dependent induction of apoptosis in multiple myeloma (MM) cells","volume":"276","author":"Chauhan","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1038\/sj.onc.1205205","article-title":"Identification of genes regulated by dexamethasone in multiple myeloma cells using oligonucleotide arrays","volume":"21","author":"Chauhan","year":"2002","journal-title":"Oncogene"},{"key":"ref_120","first-page":"42","article-title":"The Effect of Glucocorticoids on Angiogenesis in the Treatment of Solid Tumors","volume":"1","author":"Liu","year":"2020","journal-title":"J. Cell Signal"},{"key":"ref_121","first-page":"1699","article-title":"Prednisolone and chlormethine inhibit multiple myeloma through inhibition of Notch\/NF-kappa B-mediated angiogenesis","volume":"11","author":"Guo","year":"2018","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.3389\/fimmu.2018.02722","article-title":"CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma","volume":"9","author":"Morandi","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_123","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":"N. Engl. J. Med."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/ijc.32125","article-title":"Effect of induction therapy with lenalidomide, doxorubicin and dexamethasone on bone remodeling and angiogenesis in newly diagnosed multiple myeloma","volume":"145","author":"Terpos","year":"2019","journal-title":"Int. J. Cancer"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/7\/1990\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:03:42Z","timestamp":1760123022000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/7\/1990"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,27]]},"references-count":124,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["cancers15071990"],"URL":"https:\/\/doi.org\/10.3390\/cancers15071990","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,27]]}}}