{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:42:25Z","timestamp":1790959345492,"version":"4.1.0"},"reference-count":109,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:00:00Z","timestamp":1619049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U01-CA-151837"],"award-info":[{"award-number":["U01-CA-151837"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA-154471"],"award-info":[{"award-number":["R01CA-154471"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R21-CA-164098"],"award-info":[{"award-number":["R21-CA-164098"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>SeverFigurel cellular elements of the bone marrow (BM) microenvironment in multiple myeloma (MM) patients contribute to the immune evasion, proliferation, and drug resistance of MM cells, including myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like, \u201calternatively activated\u201d macrophages, CD38+ regulatory B-cells (Bregs), and regulatory T-cells (Tregs). These immunosuppressive elements in bidirectional and multi-directional crosstalk with each other inhibit both memory and cytotoxic effector T-cell populations as well as natural killer (NK) cells. Immunomodulatory imide drugs (IMiDs), protease inhibitors (PI), monoclonal antibodies (MoAb), adoptive T-cell\/NK cell therapy, and inhibitors of anti-apoptotic signaling pathways have emerged as promising therapeutic platforms that can be employed in various combinations as part of a rationally designed immunomodulatory strategy against an immunosuppressive tumor microenvironment (TME) in MM. These platforms provide the foundation for a new therapeutic paradigm for achieving improved survival of high-risk newly diagnosed as well as relapsed\/refractory MM patients. Here we review the scientific rationale and clinical proof of concept for each of these platforms.<\/jats:p>","DOI":"10.3390\/cancers13092018","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T04:20:17Z","timestamp":1619065217000},"page":"2018","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9334-183X","authenticated-orcid":false,"given":"Fatih M.","family":"Uckun","sequence":"first","affiliation":[{"name":"Norris Comprehensive Cancer Center and Childrens Center for Cancer and Blood Diseases, University of Southern California Keck School of Medicine (USC KSOM), Los Angeles, CA 90027, USA"},{"name":"Department of Developmental Therapeutics, Immunology, and Integrative Medicine, Drug Discovery Institute, Ares Pharmaceuticals, St. Paul, MN 55110, USA"},{"name":"Reven Pharmaceuticals, Translational Oncology Program, Golden, CO 80401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,22]]},"reference":[{"key":"ref_1","first-page":"337","article-title":"A review on tumor heterogeneity and evolution in multiple myeloma: Pathological, radiological, molecular genetics, and clinical integration","volume":"476","author":"Rasche","year":"2019","journal-title":"Virchows Arch."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Holthof, L.C., and Mutis, T. (2020). Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance. Cancers, 12.","DOI":"10.3390\/cancers12040988"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4257","DOI":"10.1038\/sj.onc.1209456","article-title":"Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma","volume":"25","author":"Ribatti","year":"2006","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/imr.12233","article-title":"Targeting the bone marrow microenvironment in multiple myeloma","volume":"263","author":"Kawano","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3389\/fimmu.2020.00501","article-title":"Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions","volume":"11","author":"Caraccio","year":"2020","journal-title":"Front Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1016\/j.leukres.2009.08.012","article-title":"Interleukin-6 leads to interleukin-10 production in several human multiple myeloma cell lines. Does interleukin-10 enhance the proliferation of these cells?","volume":"34","author":"Kovacs","year":"2010","journal-title":"Leuk. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1111\/j.1365-2141.2000.02413.x","article-title":"Expression and production of interleukin 10 in human myeloma cell lines","volume":"111","author":"Otsuki","year":"2000","journal-title":"Br. J. Haematol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1080\/10428190290021579","article-title":"IL-10 in Myeloma Cells","volume":"43","author":"Otsumi","year":"2002","journal-title":"Leuk. Lymphoma"},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.semcancer.2012.01.011","article-title":"Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression","volume":"22","author":"Sinha","year":"2012","journal-title":"Semin. Cancer Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1182\/blood.V87.5.1928.1928","article-title":"Transforming growth factor-beta1: Differential effects on multiple myeloma versus normal B cells","volume":"87","author":"Urashima","year":"1996","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.ccell.2018.02.007","article-title":"Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment","volume":"33","author":"Nakamura","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8815","DOI":"10.3389\/fonc.2020.608815","article-title":"Exosomes in the Pathogenesis and Treatment of Multiple Myeloma in the Context of the Bone Marrow Microenvironment","volume":"10","author":"Chen","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"100595","DOI":"10.1016\/j.blre.2019.100595","article-title":"The emerging role of exosomes in multiple myeloma","volume":"38","author":"Moloudizargari","year":"2019","journal-title":"Blood Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6154","DOI":"10.7150\/jca.31752","article-title":"Potential Therapeutic Roles of Exosomes in Multiple Myeloma: A Systematic Review","volume":"10","author":"Li","year":"2019","journal-title":"J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Raimondo, S., Urz\u00ec, O., Conigliaro, A., Bosco, G.L., Parisi, S., Carlisi, M., Siragusa, S., Raimondi, L., de Luca, A., and Giavaresi, G. (2020). Extracellular Vesicle microRNAs Contribute to the Osteogenic Inhibition of Mesenchymal Stem Cells in Multiple Myeloma. Cancers, 12.","DOI":"10.3390\/cancers12020449"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Raimondi, L., de Luca, A., Fontana, S., Amodio, N., Costa, V., Carina, V., Bellavia, D., Raimondo, S., Siragusa, S., and Monteleone, F. (2020). Multiple Myeloma-Derived Extracellular Vesicles Induce Osteoclastogenesis through the Activation of the XBP1\/IRE1\u03b1 Axis. Cancers, 12.","DOI":"10.3390\/cancers12082167"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1002\/path.4712","article-title":"Multiple myeloma exosomes establish a favourable bone marrow microenvironment with enhanced angiogenesis and immunosuppression","volume":"239","author":"Wang","year":"2016","journal-title":"J. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Soekojo, C.Y., Ooi, M., De Mel, S., and Chng, W.J. (2020). Immunotherapy in Multiple Myeloma. Cells, 9.","DOI":"10.3390\/cells9030601"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e439","DOI":"10.1016\/S2352-3026(19)30149-8","article-title":"The future of checkpoint inhibition in multiple myeloma?","volume":"6","author":"Costello","year":"2019","journal-title":"Lancet Haematol."},{"key":"ref_22","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_23","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_24","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_25","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_26","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1038\/s41375-019-0620-8","article-title":"Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN","volume":"34","author":"Bjorklund","year":"2020","journal-title":"Leukemia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6648","DOI":"10.1021\/acs.jmedchem.9b01928","article-title":"Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma","volume":"63","author":"Hansen","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_28","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":"Gulla","year":"2020","journal-title":"Haematology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.5045\/br.2020.S008","article-title":"Treatment of relapsed and refractory multiple myeloma","volume":"55","author":"Lee","year":"2020","journal-title":"Blood Res."},{"key":"ref_30","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":"2019","journal-title":"EBioMedicine"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s10555-017-9707-8","article-title":"The proteasome and proteasome inhibitors in multiple myeloma","volume":"36","author":"Gandolfi","year":"2017","journal-title":"Cancer Metastasis Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"50","DOI":"10.3389\/fcell.2019.00050","article-title":"Immunogenic Cell Death and Immunotherapy of Multiple Myeloma","volume":"7","author":"Valle","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_33","first-page":"1","article-title":"Current status of autologous stem cell transplantation for multiple myeloma","volume":"9","author":"Bazarbachi","year":"2019","journal-title":"Blood Cancer J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1182\/blood-2017-06-740944","article-title":"CD38 antibodies in multiple myeloma: Back to the future","volume":"131","author":"Richardson","year":"2018","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Chong, L.L., Soon, Y.Y., Soekojo, C.Y., Ooi, M., Chng, W.J., and de Mel, S. (2021). Daratumumab-based induction therapy for multiple myeloma: A systematic review and meta-analysis. Crit. Rev. Oncol. Hematol., 103211.","DOI":"10.1016\/j.critrevonc.2020.103211"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1001\/jamaoncol.2020.4338","article-title":"Evaluation of Daratumumab for the Treatment of Multiple Myeloma in Patients with High-risk Cytogenetic Factors","volume":"6","author":"Giri","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e370","DOI":"10.1016\/S2352-3026(20)30070-3","article-title":"Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): A multicentre, open-label, non-inferiority, randomised, phase 3 trial","volume":"7","author":"Mateos","year":"2020","journal-title":"Lancet Haematol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1182\/blood.2020005288","article-title":"Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: The GRIFFIN trial","volume":"136","author":"Voorhees","year":"2020","journal-title":"Blood"},{"key":"ref_39","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_40","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/cyto.a.23693","article-title":"High-Parameter Mass Cytometry Evaluation of Relapsed\/Refractory Multiple Myeloma Patients Treated with Daratumumab Demonstrates Immune Modulation as a Novel Mechanism of Action","volume":"95","author":"Adams","year":"2019","journal-title":"Cytom. Part A"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.imlet.2018.04.005","article-title":"Immunomodulatory effects of CD38-targeting antibodies","volume":"199","year":"2018","journal-title":"Immunol. Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.3389\/fimmu.2018.02134","article-title":"CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance","volume":"9","author":"Usmani","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.3389\/fimmu.2018.02551","article-title":"Mechanisms of NK Cell Activation and Clinical Activity of the Therapeutic SLAMF7 Antibody, Elotuzumab in Multiple Myeloma","volume":"9","author":"Campbell","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4032","DOI":"10.1002\/cncr.31680","article-title":"Elotuzumab plus lenalidomide and dexamethasone in relapsed\/refractory multiple myeloma: Extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial","volume":"124","author":"Dimopoulos","year":"2018","journal-title":"Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1056\/NEJMoa1805762","article-title":"Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma","volume":"379","author":"Dimopoulos","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5813","DOI":"10.2147\/OTT.S174640","article-title":"Update on elotuzumab for the treatment of relapsed\/refractory multiple myeloma: Patients\u2019 selection and perspective","volume":"12","author":"Trudel","year":"2019","journal-title":"OncoTargets Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e1599636","DOI":"10.1080\/2162402X.2019.1599636","article-title":"Daratumumab in combination with urelumab to potentiate anti-myeloma activity in lymphocyte-deficient mice reconstituted with human NK cells","volume":"8","author":"Ochoa","year":"2019","journal-title":"OncoImmunology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e125932","DOI":"10.1172\/jci.insight.125932","article-title":"Chemotherapy followed by anti-CD137 mAb immunotherapy improves disease control in a mouse myeloma model","volume":"4","author":"Guillerey","year":"2019","journal-title":"JCI Insight"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.3389\/fimmu.2018.02431","article-title":"Update on PD-1\/PD-L1 Inhibitors in Multiple Myeloma","volume":"9","author":"Jelinek","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cellimm.2018.10.003","article-title":"The challenges of checkpoint inhibition in the treatment of multiple myeloma","volume":"334","author":"Paul","year":"2018","journal-title":"Cell. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Sponaas, A.M., Waage, A., Vandsemb, E.N., Misund, K., B\u00f8rset, M., Sundan, A., Sl\u00f8rdahl, T.S., and Standal, T. (2021). Bystander Memory T Cells and IMiD\/Checkpoint Therapy in Multiple Myeloma: A Dangerous Tango?. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.636375"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1111\/cas.12986","article-title":"Lymphocyte-activation gene-3, an important immune checkpoint in cancer","volume":"107","author":"He","year":"2016","journal-title":"Cancer Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1080\/19420862.2019.1629239","article-title":"Characterization of a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody for cancer immunotherapy","volume":"11","author":"Yu","year":"2019","journal-title":"mAbs"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1182\/blood-2020-139192","article-title":"REGN5458, a BCMA x CD3 Bispecific Monoclonal Antibody, Induces Deep and Durable Responses in Patients with Relapsed\/Refractory Multiple Myeloma (RRMM)","volume":"136","author":"Madduri","year":"2020","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1038\/s41375-020-0734-z","article-title":"B-cell maturation antigen (BCMA) in multiple myeloma: Rationale for targeting and current therapeutic approaches","volume":"34","author":"Shah","year":"2020","journal-title":"Leukemia"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1182\/blood-2018-99-109769","article-title":"Treatment with AMG 420, an Anti-B-Cell Maturation Antigen (BCMA) Bispecific T-Cell Engager (BiTE\u00ae) Antibody Construct, Induces Minimal Residual Disease (MRD) Negative Complete Responses in Relapsed and\/or Refractory (R\/R) Multiple Myeloma (MM) Patients: Results of a First-in-Human (FIH) Phase I Dose Escalation Study","volume":"132","author":"Topp","year":"2018","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1200\/JCO.19.02657","article-title":"Anti\u2013B-Cell Maturation Antigen BiTE Molecule AMG 420 Induces Responses in Multiple Myeloma","volume":"38","author":"Topp","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1080\/14737140.2019.1586539","article-title":"Anti-BCMA antibodies in the future management of multiple myeloma","volume":"19","author":"Gavriatopoulou","year":"2019","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"947","DOI":"10.3389\/fimmu.2018.00947","article-title":"NY-ESO-1 Based Immunotherapy of Cancer: Current Perspectives","volume":"9","author":"Thomas","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e12910","DOI":"10.1111\/sji.12910","article-title":"Overview of anti-BCMA CAR-T immunotherapy for multiple myeloma and relapsed\/refractory multiple myeloma","volume":"92","author":"Feng","year":"2020","journal-title":"Scand J. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1200\/JCO.2018.77.8084","article-title":"T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma","volume":"36","author":"Brudno","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.3389\/fonc.2020.01243","article-title":"CAR T-Cells in Multiple Myeloma: State of the Art and Future Directions","volume":"10","author":"Ganzetti","year":"2020","journal-title":"Front Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"25764","DOI":"10.18632\/oncotarget.25359","article-title":"Pre-clinical validation of B cell maturation antigen (BCMA) as a target for T cell immunotherapy of multiple myeloma","volume":"9","author":"Bu","year":"2018","journal-title":"Oncotarget"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1056\/NEJMoa1817226","article-title":"Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma","volume":"380","author":"Raje","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1182\/blood.2019000050","article-title":"\u03b3-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma","volume":"134","author":"Pont","year":"2019","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Fan, F., Zhao, W., Liu, J., He, A., Chen, Y., Cao, X., Yang, N., Wang, B., Zhang, P., and Zhang, Y. (2017, January 2\u20136). Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory\/relapsed multiple myeloma. Abstract LBA3001. Proceedings of the 2017 ASCO Annual Meeting, Chicago, IL, USA.","DOI":"10.1200\/JCO.2017.35.15_suppl.LBA3001"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"eaau7746","DOI":"10.1126\/scitranslmed.aau7746","article-title":"GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells","volume":"11","author":"Smith","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1084\/jem.136.6.1631","article-title":"Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor","volume":"136","author":"Brooks","year":"1972","journal-title":"J. Exp. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"211","DOI":"10.3171\/jns.1989.71.2.0211","article-title":"Inhibition of lymphocyte function by glioblastoma-derived transforming growth factor beta 2","volume":"71","author":"Kuppner","year":"1989","journal-title":"J. Neurosurg."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Uckun, F.M., Qazi, S., Hwang, L., and Trieu, V.N. (2019). Recurrent or Refractory High-Grade Gliomas Treated by Convection-Enhanced Delivery of a TGF\u03b22-Targeting RNA Therapeutic: A Post-Hoc Analysis with Long-Term Follow-Up. Cancers, 11.","DOI":"10.3390\/cancers11121892"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.immuni.2018.03.037","article-title":"TGF-\u03b2 Inhibition and Immunotherapy: Checkmate","volume":"48","author":"Ganesh","year":"2018","journal-title":"Immunity"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/nature25501","article-title":"TGF\u03b2 attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells","volume":"554","author":"Mariathasan","year":"2018","journal-title":"Nature"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.ccr.2005.10.012","article-title":"TGF-\u03b2 directly targets cytotoxic T cell functions during tumor evasion of immune surveillance","volume":"8","author":"Thomas","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/nature25492","article-title":"TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis","volume":"554","author":"Tauriello","year":"2018","journal-title":"Nature"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Teramachi, J., Tenshin, H., Hiasa, M., Oda, A., Bat-Erdene, A., Harada, T., Nakamura, S., Ashtar, M., Shimizu, S., and Iwasa, M. (2020). TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma. Haematologica.","DOI":"10.3324\/haematol.2019.234476"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4321","DOI":"10.3389\/fphar.2020.594321","article-title":"Rejuveinix Shows a Favorable Clinical Safety Profile in Human Subjects and Exhibits Potent Preclinical Protective Activity in the Lipopolysaccharide-Galactosamine Mouse Model of Acute Respiratory Distress Syndrome and Multi-Organ Failure","volume":"11","author":"Uckun","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Trieu, V., Saund, S., Rahate, P.V., Barge, V.B., Nalk, S., Windlass, H., and Uckun, F.M. (2021). Targeting TGF-\u03b2 pathway with COVID-19 Drug Candidate ARTIVeda\/PulmoHeal Accelerates Recovery from Mild-Moderate COVID-19. MedRxiv.","DOI":"10.1101\/2021.01.24.21250418"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"649532","DOI":"10.3389\/fphar.2021.649532","article-title":"Repurposing Anti-Malaria Phytomedicine Artemisinin as a COVID-19 Drug","volume":"12","author":"Uckun","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/leu.2017.193","article-title":"Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma","volume":"32","author":"Wang","year":"2018","journal-title":"Leukemia"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.tranon.2019.04.023","article-title":"IL-17A Increases Multiple Myeloma Cell Viability by Positively Regulating Syk Expression","volume":"12","author":"Wang","year":"2019","journal-title":"Transl. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"23785","DOI":"10.1002\/jcp.28947","article-title":"Identification of key candidate genes and pathways in multiple myeloma by integrated bioinformatics analysis","volume":"234","author":"Yan","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/s41375-019-0486-9","article-title":"The WNT receptor ROR2 drives the interaction of multiple myeloma cells with the microenvironment through AKT activation","volume":"34","author":"Frenquelli","year":"2019","journal-title":"Leukemia"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1111\/bjh.13825","article-title":"From CLL to Multiple Myeloma\u2014Spleen Tyrosine Kinase (SYK) influences multiple myeloma cell survival and migration","volume":"174","author":"Lorenz","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s40164-015-0016-z","article-title":"Analysis of the anti-proliferative and the pro-apoptotic efficacy of Syk inhibition in multiple myeloma","volume":"4","author":"Koerber","year":"2015","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4348","DOI":"10.1182\/blood-2012-11-470633","article-title":"Nanoscale liposomal formulation of a SYK P-site inhibitor against B-precursor leukemia","volume":"121","author":"Uckun","year":"2013","journal-title":"Blood"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.3109\/10428194.2013.778409","article-title":"Macrophages in multiple myeloma: Emerging concepts and therapeutic implications","volume":"54","author":"Asimakopoulos","year":"2013","journal-title":"Leuk. Lymphoma"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Van Dalen, F.J., van Stevendaal, M.H.M.E., Fennemann, F.L., Verdoes, M., and Ilina, O. (2019). Molecular repolarisation of tumour-associated macrophages. Molecules, 24.","DOI":"10.3390\/molecules24010009"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Tamura, H., Ishibashi, M., Sunakawa, M., and Inokuchi, K. (2019). Immunotherapy for Multiple Myeloma. Cancers, 11.","DOI":"10.3390\/cancers11122009"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1111\/bjh.14686","article-title":"A novel multi-epitope vaccine from MMSA-1 and DKK1 for multiple myeloma immunotherapy","volume":"178","author":"Lu","year":"2017","journal-title":"Br. J. Haematol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3310","DOI":"10.1038\/s41375-020-0828-7","article-title":"Oncolytic measles virus therapy enhances tumor antigen-specific T-cell responses in patients with multiple myeloma","volume":"34","author":"Packiriswamy","year":"2020","journal-title":"Leukemia"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.3389\/fonc.2020.591342","article-title":"Metabolic Reprogramming Induces Immune Cell Dysfunction in the Tumor Microenvironment of Multiple Myeloma","volume":"10","author":"Wu","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.cmet.2018.03.008","article-title":"The Science and Translation of Lactate Shuttle Theory","volume":"27","author":"Brooks","year":"2018","journal-title":"Cell Metab."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.devcel.2020.06.018","article-title":"Cancer Cells Don\u2019t Live Alone: Metabolic Communication within Tumor Microenvironments","volume":"54","author":"Li","year":"2020","journal-title":"Dev. Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.1172\/JCI69741","article-title":"Targeting lactate metabolism for cancer therapeutics","volume":"123","author":"Doherty","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.18632\/oncotarget.1736","article-title":"Hypoxia inducible factor-1 alpha as a therapeutic target in multiple myeloma","volume":"5","author":"Borsi","year":"2014","journal-title":"Oncotarget"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Nagao, A., Kobayashi, M., Koyasu, S., Chow, C.C.T., and Harada, H. (2019). HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20020238"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1172\/JCI126397","article-title":"B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma","volume":"129","author":"Cohen","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2019.04.006","article-title":"A review of bispecific antibodies and antibody constructs in oncology and clinical challenges","volume":"201","author":"Suurs","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/S0140-6736(19)32956-3","article-title":"Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): A randomised, open-label, phase 3 trial","volume":"395","author":"Mateos","year":"2020","journal-title":"Lancet"},{"key":"ref_100","first-page":"e528","article-title":"Multiple Myeloma: EHA-ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up","volume":"5","author":"Dimopoulos","year":"2021","journal-title":"Hemasphere"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/S1470-2045(18)30354-1","article-title":"Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): Interim analysis results of a randomised, phase 3 study","volume":"19","author":"Moreau","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.clml.2019.05.017","article-title":"Oprozomib, pomalidomide, and Dexamethasone in Patients with Relapsed and\/or Refractory Multiple Myeloma","volume":"19","author":"Shah","year":"2019","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1111\/bjh.15679","article-title":"Phase 2 study of all-oral ixazomib, cyclophosphamide and low-dose dexamethasone for relapsed\/refractory multiple myeloma","volume":"184","author":"Kumar","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_104","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":"N. Engl. J. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"5609","DOI":"10.3389\/fimmu.2020.575609","article-title":"Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy","volume":"11","author":"Alfarra","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Pinto, V., Bergantim, R., Caires, H.R., Seca, H., Guimar\u00e3es, J.E., and Vasconcelos, M.H. (2020). Multiple Myeloma: Available Therapies and Causes of Drug Resistance. Cancers, 12.","DOI":"10.3390\/cancers12020407"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Grywalska, E., Sosnowska-Pasiarska, B., Smok-Kalwat, J., Pasiarski, M., Nied\u017awiedzka-Rystwej, P., and Roli\u0144ski, J. (2020). Paving the Way toward Successful Multiple Myeloma Treatment: Chimeric Antigen Receptor T-Cell Therapy. Cells, 9.","DOI":"10.3390\/cells9040983"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.3389\/fimmu.2018.02743","article-title":"Enhancing the Activation and Releasing the Brakes: A Double Hit Strategy to Improve NK Cell Cytotoxicity Against Multiple Myeloma","volume":"9","author":"Tognarelli","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1158\/2326-6066.CIR-19-0148","article-title":"Lessons Learned from Checkpoint Blockade Targeting PD-1 in Multiple Myeloma","volume":"7","author":"Lesokhin","year":"2019","journal-title":"Cancer Immunol. Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/9\/2018\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:51:09Z","timestamp":1760161869000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/9\/2018"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,22]]},"references-count":109,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["cancers13092018"],"URL":"https:\/\/doi.org\/10.3390\/cancers13092018","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,22]]}}}