{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:57:56Z","timestamp":1787313476333,"version":"build-2736575974"},"reference-count":136,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Relapsed and refractory multiple myeloma remains the principal cause of myeloma-related mortality despite major advances in therapeutic options, including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and T-cell-based immunotherapies. Conventional resistance models based on linear genetic clonal evolution inadequately explain reversible drug resistance, heterogeneous responses, and relapse after deep remissions. Emerging data from longitudinal genomics, single-cell analyses, and functional studies support a paradigm in which relapsed and refractory multiple myeloma is driven by adaptive plasticity rather than irreversible genetic change alone. Myeloma cells undergo reversible cell state transitions through transcriptional, epigenetic, metabolic, and proteostatic reprogramming, shaped by bone marrow microenvironmental cues and immune pressure. This narrative review integrates current evidence supporting adaptive plasticity as a central driver of therapeutic failure in relapsed and refractory multiple myeloma and discusses clinical and translational implications, highlighting adaptive treatment strategies and approaches targeting phenotypic flexibility to improve durability of response.<\/jats:p>","DOI":"10.3390\/cancers18121873","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T16:25:16Z","timestamp":1780935916000},"page":"1873","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Shape-Shifting Myeloma: Adaptive Plasticity as a Hallmark of Relapse and Refractoriness"],"prefix":"10.3390","volume":"18","author":[{"given":"Maria Elisa","family":"Nasso","sequence":"first","affiliation":[{"name":"Hematology Unit, Department of Human Pathology in Adulthood and Childhood \u201cGaetano Barresi\u201d, University of Messina, Via Consolare Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adele","family":"Bottaro","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Human Pathology in Adulthood and Childhood \u201cGaetano Barresi\u201d, University of Messina, Via Consolare Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demetrio","family":"Gerace","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Human Pathology in Adulthood and Childhood \u201cGaetano Barresi\u201d, University of Messina, Via Consolare Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Russo","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Human Pathology in Adulthood and Childhood \u201cGaetano Barresi\u201d, University of Messina, Via Consolare Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8665-1258","authenticated-orcid":false,"given":"Donato","family":"Mannina","sequence":"additional","affiliation":[{"name":"Hematology Unit, Oncology-Hematology Department, Azienda Ospedaliera Papardo, 98158 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6156-8239","authenticated-orcid":false,"given":"Alessandro","family":"Allegra","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Human Pathology in Adulthood and Childhood \u201cGaetano Barresi\u201d, University of Messina, Via Consolare Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41572-024-00529-7","article-title":"Multiple myeloma","volume":"10","author":"Malard","year":"2024","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.3390\/curroncol30020179","article-title":"Relapsed\/Refractory Multiple Myeloma: A Review of Available Therapies and Clinical Scenarios Encountered in Myeloma Relapse","volume":"30","author":"Bhatt","year":"2023","journal-title":"Curr. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"341430","DOI":"10.1155\/2015\/341430","article-title":"Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma","volume":"2015","author":"Yang","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4517","DOI":"10.1038\/s41467-022-32145-y","article-title":"The spatio-temporal evolution of multiple myeloma from baseline to relapse-refractory states","volume":"13","author":"Rasche","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_5","unstructured":"Renatino Canevarolo, R., Sudalagunta, P.R., Meads, M.B., Silva, M., Zhao, X., Magaletti, D., Alugubelli, R.R., DeAvila, G., Persi, E., and Maura, F. (2025). Epigenetic Plasticity Drives Carcinogenesis and Multi-Therapy Resistance in Multiple Myeloma. Res. Sq."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Alipoor, S.D., Shrestha, M., Liu, A., and Chang, H. (2026). Deciphering epigenetic crosstalk in multiple myeloma pathogenesis and treatment. Clin. Epigenet.","DOI":"10.1186\/s13148-026-02109-w"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Medina-Herrera, A., Sarasquete, M.E., Jim\u00e9nez, C., Puig, N., and Garc\u00eda-Sanz, R. (2023). Minimal Residual Disease in Multiple Myeloma: Past, Present, and Future. Cancers, 15.","DOI":"10.3390\/cancers15143687"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.1158\/0008-5472.CAN-25-0999","article-title":"Epigenetic Heritability of Cell Plasticity Drives Cancer Drug Resistance through a One-to-Many Genotype-to-Phenotype Paradigm","volume":"85","author":"Oliveira","year":"2025","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/s41408-022-00695-5","article-title":"Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee","volume":"12","author":"Kumar","year":"2022","journal-title":"Blood Cancer J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.hoc.2023.12.012","article-title":"Impact of Clonal Heterogeneity in Multiple Myeloma","volume":"38","author":"Schinke","year":"2024","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_11","first-page":"5659","article-title":"Branching clonal evolution patterns predominate mutational landscape in multiple myeloma","volume":"11","author":"Farswan","year":"2021","journal-title":"Am. J. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/s41467-017-00296-y","article-title":"Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing","volume":"8","author":"Rasche","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.1038\/s41467-022-31430-0","article-title":"The genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma","volume":"13","author":"Vo","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1038\/s41586-024-07690-9","article-title":"Cellular adaptation to cancer therapy along a resistance continuum","volume":"631","author":"Baron","year":"2024","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s12943-025-02323-9","article-title":"Drug-induced tolerant persisters in tumor: Mechanism, vulnerability and perspective implication for clinical treatment","volume":"24","author":"Liu","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1182\/blood-2012-06-436220","article-title":"Clinical drug resistance linked to interconvertible phenotypic and functional states of tumor-propagating cells in multiple myeloma","volume":"121","author":"Chaidos","year":"2013","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1038\/ncomms3997","article-title":"Heterogeneity of genomic evolution and mutational profiles in multiple myeloma","volume":"5","author":"Bolli","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.ccell.2020.03.007","article-title":"Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance","volume":"37","author":"Marusyk","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nrclinonc.2016.122","article-title":"Genomic complexity of multiple myeloma and its clinical implications","volume":"14","author":"Manier","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1182\/blood.2023019758","article-title":"Resolving therapy resistance mechanisms in multiple myeloma by multiomics subclone analysis","volume":"142","author":"Poos","year":"2023","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.cell.2010.02.027","article-title":"A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations","volume":"141","author":"Sharma","year":"2010","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/s41416-020-01191-y","article-title":"Modulating proteasome inhibitor tolerance in multiple myeloma: An alternative strategy to reverse inevitable resistance","volume":"124","author":"Ge","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s12079-017-0435-1","article-title":"Tumor cell-intrinsic phenotypic plasticity facilitates adaptive cellular reprogramming driving acquired drug resistance","volume":"12","author":"Hammerlindl","year":"2018","journal-title":"J. Cell Commun. Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1182\/blood-2014-11-568907","article-title":"New criteria for response assessment: Role of minimal residual disease in multiple myeloma","volume":"125","author":"Paiva","year":"2015","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4894","DOI":"10.1158\/0008-5472.CAN-08-3658","article-title":"Adaptive therapy","volume":"69","author":"Gatenby","year":"2009","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1038\/bjc.2015.146","article-title":"Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse: \u2018What does not kill me strengthens me\u2019","volume":"112","author":"Pisco","year":"2015","journal-title":"Br. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s43018-020-0053-3","article-title":"Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma","volume":"1","author":"Zavidij","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nrclinonc.2017.197","article-title":"The bone-marrow niche in MDS and MGUS: Implications for AML and MM","volume":"15","author":"Ghobrial","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/nature12624","article-title":"Tumour heterogeneity and cancer cell plasticity","volume":"501","author":"Meacham","year":"2013","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/s41568-020-00302-4","article-title":"Non-genetic mechanisms of therapeutic resistance in cancer","volume":"20","author":"Marine","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1038\/s41556-021-00766-y","article-title":"Dynamic transcriptional reprogramming leads to immunotherapeutic vulnerabilities in myeloma","volume":"23","author":"Frede","year":"2021","journal-title":"Nat. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Adomako, A., Calvo, V., Biran, N., Osman, K., Chari, A., Paton, J.C., Paton, A.W., Moore, K., Schewe, D.M., and Aguirre-Ghiso, J.A. (2015). Identification of markers that functionally define a quiescent multiple myeloma cell sub-population surviving bortezomib treatment. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1460-1"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1083\/jcb.201709072","article-title":"Pathways of cellular proteostasis in aging and disease","volume":"217","author":"Klaips","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_34","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_35","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1038\/s41591-018-0269-2","article-title":"Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma","volume":"24","author":"Ledergor","year":"2018","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.stem.2014.02.006","article-title":"Evolution of the cancer stem cell model","volume":"14","author":"Kreso","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/nature10762","article-title":"Clonal evolution in cancer","volume":"481","author":"Greaves","year":"2012","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1158\/1078-0432.CCR-07-2223","article-title":"The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance","volume":"14","author":"Meads","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1182\/blood-2017-03-774422","article-title":"Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma","volume":"130","author":"Rasche","year":"2017","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/s41573-019-0044-1","article-title":"The great escape: Tumour cell plasticity in resistance to targeted therapy","volume":"19","author":"Boumahdi","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1182\/blood-2005-03-1158","article-title":"Antimyeloma activity of heat shock protein-90 inhibition","volume":"107","author":"Mitsiades","year":"2006","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3040","DOI":"10.1182\/blood-2008-08-172734","article-title":"The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition","volume":"113","author":"Bianchi","year":"2009","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1182\/blood-2015-03-575365","article-title":"Promising therapies in multiple myeloma","volume":"126","author":"Bianchi","year":"2015","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1158\/0008-5472.CAN-14-3400","article-title":"Metabolic signature identifies novel targets for drug resistance in multiple myeloma","volume":"75","author":"Maiso","year":"2015","journal-title":"Cancer Res."},{"key":"ref_45","first-page":"26","article-title":"Metabolic alterations and the potential for targeting metabolic pathways in the treatment of multiple myeloma","volume":"5","author":"Rizzieri","year":"2019","journal-title":"J. Cancer Metastasis Treat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"111213","DOI":"10.18632\/oncotarget.22740","article-title":"Alteration of mitochondrial biogenesis promotes disease progression in multiple myeloma","volume":"8","author":"Zhan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1126\/science.1206727","article-title":"Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy","volume":"334","author":"Sarosiek","year":"2011","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/cdd.2017.183","article-title":"Why do BCL-2 inhibitors work and where should we use them in the clinic?","volume":"25","author":"Montero","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1038\/sj.emboj.7601009","article-title":"Progressively impaired proteasomal capacity during terminal plasma cell differentiation","volume":"25","author":"Cenci","year":"2006","journal-title":"EMBO J."},{"key":"ref_50","first-page":"1028","article-title":"Overcoming drug resistance by targeting protein homeostasis in multiple myeloma","volume":"4","author":"Moscvin","year":"2021","journal-title":"Cancer Drug Resist."},{"key":"ref_51","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_52","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/s41419-022-04629-8","article-title":"NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma","volume":"13","author":"Huang","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.15252\/embj.201796697","article-title":"Molecular definitions of autophagy and related processes","volume":"36","author":"Galluzzi","year":"2017","journal-title":"EMBO J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1126\/science.1193497","article-title":"Autophagy and metabolism","volume":"330","author":"Rabinowitz","year":"2010","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Pelon, M., Krzeminski, P., Tracz-Gaszewska, Z., and Misiewicz-Krzeminska, I. (2024). Factors determining the sensitivity to proteasome inhibitors of multiple myeloma cells. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1351565"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Weir, P., Donaldson, D., McMullin, M.F., and Crawford, L. (2023). Metabolic Alterations in Multiple Myeloma: From Oncogenesis to Proteasome Inhibitor Resistance. Cancers, 15.","DOI":"10.3390\/cancers15061682"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Schwestermann, J., Besse, A., Driessen, C., and Besse, L. (2022). Contribution of the Tumor Microenvironment to Metabolic Changes Triggering Resistance of Multiple Myeloma to Proteasome Inhibitors. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.899272"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1182\/blood.V93.5.1658","article-title":"Cell adhesion mediated drug resistance (CAM-DR): Role of integrins and resistance to apoptosis in human myeloma cell lines","volume":"93","author":"Damiano","year":"1999","journal-title":"Blood"},{"key":"ref_59","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_60","first-page":"218","article-title":"Evidence for cell adhesion-mediated drug resistance of multiple myeloma cells in vivo","volume":"21","author":"Schmidmaier","year":"2006","journal-title":"Int. J. Biol. Markers"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Allegra, A., Innao, V., Allegra, A.G., Pugliese, M., Di Salvo, E., Ventura-Spagnolo, E., Musolino, C., and Gangemi, S. (2019). Lymphocyte Subsets and Inflammatory Cytokines of Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112822"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1852517","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_63","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1182\/blood.V85.4.863.bloodjournal854863","article-title":"Interleukin-6 in human multiple myeloma","volume":"85","author":"Klein","year":"1995","journal-title":"Blood"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1182\/blood.V87.3.1104.bloodjournal8731104","article-title":"Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B","volume":"87","author":"Chauhan","year":"1996","journal-title":"Blood"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1182\/blood.V96.8.2856","article-title":"Insulin-like growth factor I is a dual effector of multiple myeloma cell growth","volume":"96","author":"Ge","year":"2000","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2708","DOI":"10.1182\/blood-2006-07-035857","article-title":"Mechanisms of regulation of CXCR4\/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma","volume":"109","author":"Alsayed","year":"2007","journal-title":"Blood"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1182\/blood-2010-02-269126","article-title":"Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug","volume":"116","author":"Hu","year":"2010","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5782","DOI":"10.1182\/blood-2011-09-380410","article-title":"Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features","volume":"119","author":"Azab","year":"2012","journal-title":"Blood"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3363","DOI":"10.1038\/s41467-018-05058-y","article-title":"Genomic patterns of progression in smoldering multiple myeloma","volume":"9","author":"Bolli","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Bottaro, A., Nasso, M.E., Stagno, F., Fazio, M., and Allegra, A. (2025). Modeling the Bone Marrow Niche in Multiple Myeloma: From 2D Cultures to 3D Systems. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26136229"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Allegra, A., Casciaro, M., Lo Presti, E., Musolino, C., and Gangemi, S. (2022). Harnessing Unconventional T Cells and Innate Lymphoid Cells to Prevent and Treat Hematological Malignancies: Prospects for New Immunotherapy. Biomolecules, 12.","DOI":"10.3390\/biom12060754"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Lopes, R., Caetano, J., Ferreira, B., Barahona, F., Carneiro, E.A., and Jo\u00e3o, C. (2021). The Immune Microenvironment in Multiple Myeloma: Friend or Foe?. Cancers, 13.","DOI":"10.3390\/cancers13040625"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"647","DOI":"10.20517\/cdr.2022.23","article-title":"Therapeutics to harness the immune microenvironment in multiple myeloma","volume":"5","author":"Driscoll","year":"2022","journal-title":"Cancer Drug Resist."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/nrc2714","article-title":"Environment-mediated drug resistance: A major contributor to minimal residual disease","volume":"9","author":"Meads","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1182\/bloodadvances.2021005822","article-title":"Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma","volume":"6","author":"Mohan","year":"2022","journal-title":"Blood Adv."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/s41590-021-00931-3","article-title":"The multiple myeloma microenvironment is defined by an inflammatory stromal cell landscape","volume":"22","author":"Kellermayer","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1182\/blood-2004-01-0037","article-title":"Advances in biology of multiple myeloma: Clinical applications","volume":"104","author":"Hideshima","year":"2004","journal-title":"Blood"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1182\/blood-2014-11-568881","article-title":"Pathogenesis beyond the cancer clone(s) in multiple myeloma","volume":"125","author":"Bianchi","year":"2015","journal-title":"Blood"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1053\/j.seminhematol.2004.02.001","article-title":"Targeting the bone marrow microenvironment in hematologic malignancies","volume":"41","author":"Dalton","year":"2004","journal-title":"Semin. Hematol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1182\/blood.2023022499","article-title":"BCMA- or GPRC5D-targeting bispecific antibodies in multiple myeloma: Efficacy, safety, and resistance mechanisms","volume":"143","author":"Lee","year":"2024","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/s41408-020-00350-x","article-title":"Immune-based therapies in the management of multiple myeloma","volume":"10","author":"Zanwar","year":"2020","journal-title":"Blood Cancer J."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1182\/blood.2023023557","article-title":"Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma","volume":"144","author":"Firestone","year":"2024","journal-title":"Blood"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1053\/j.seminhematol.2025.12.004","article-title":"BCMA biology and therapeutic targeting in multiple myeloma: From ligand signaling to antigen escape","volume":"62","author":"Sezer","year":"2025","journal-title":"Semin. Hematol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"6430","DOI":"10.1182\/bloodadvances.2023010162","article-title":"CD38 antibody re-treatment in daratumumab-refractory multiple myeloma after time on other therapies","volume":"7","author":"Reiman","year":"2023","journal-title":"Blood Adv."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Tedder, B., and Bhutani, M. (2025). Resistance Mechanisms to BCMA Targeting Bispecific Antibodies and CAR T-Cell Therapies in Multiple Myeloma. Cells, 14.","DOI":"10.3390\/cells14141077"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41392-025-02280-1","article-title":"Immune evasion in cancer: Mechanisms and cutting-edge therapeutic approaches","volume":"10","author":"Tufail","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1038\/leu.2015.79","article-title":"PD-L1\/PD-1 presence in the tumor microenvironment and activity of PD-1 blockade in multiple myeloma","volume":"29","author":"Paiva","year":"2015","journal-title":"Leukemia"},{"key":"ref_88","first-page":"17","article-title":"Dissecting molecular mechanisms of immune microenvironment dysfunction in multiple myeloma and precursor conditions","volume":"9","author":"Moscvin","year":"2023","journal-title":"J. Cancer Metastasis Treat."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/s41577-024-01026-4","article-title":"Cancer cell metabolism and antitumour immunity","volume":"24","author":"Rathmell","year":"2024","journal-title":"Nat. Rev. Immunol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/j.it.2021.09.002","article-title":"Metabolic regulation of the cancer-immunity cycle","volume":"42","author":"Vardhana","year":"2021","journal-title":"Trends Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Wang, C., Wang, W., Wang, M., Deng, J., Sun, C., Hu, Y., and Luo, S. (2024). Different evasion strategies in multiple myeloma. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1346211"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1111\/bjh.19486","article-title":"The role of proliferating stem-like plasma cells in relapsed or refractory multiple myeloma: Insights from single-cell RNA sequencing and proteomic analysis","volume":"205","author":"Xu","year":"2024","journal-title":"Br. J. Haematol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/s41419-021-04116-6","article-title":"The metabolic flexibility of quiescent CSC: Implications for chemotherapy resistance","volume":"12","author":"Chen","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1158\/2643-3230.BCD-23-0212","article-title":"Understanding Mechanisms of Response to CAR T-cell Therapy through Single-Cell Sequencing: Insights and Challenges","volume":"5","author":"Haradhvala","year":"2024","journal-title":"Blood Cancer Discov."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Franssen, L.E., Stege, C.A.M., Zweegman, S., van de Donk, N.W.C.J., and Nijhof, I.S. (2020). Resistance Mechanisms Towards CD38-Directed Antibody Therapy in Multiple Myeloma. J. Clin. Med., 9.","DOI":"10.3390\/jcm9041195"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1182\/blood.2024028107","article-title":"Biallelic antigen escape is a mechanism of resistance to anti-CD38 antibodies in multiple myeloma","volume":"146","author":"Diamond","year":"2025","journal-title":"Blood"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s40164-023-00402-5","article-title":"Identification of potential resistance mechanisms and therapeutic targets for the relapse of BCMA CAR-T therapy in relapsed\/refractory multiple myeloma through single-cell sequencing","volume":"12","author":"Li","year":"2023","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/s41420-024-02006-2","article-title":"Immunometabolism in cancer: Basic mechanisms and new targeting strategy","volume":"10","author":"Su","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.chembiol.2024.02.001","article-title":"Metabolic rewiring and communication in cancer immunity","volume":"31","author":"Chapman","year":"2024","journal-title":"Cell Chem. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1002\/ijc.35426","article-title":"Epigenetic reprogramming in multiple myeloma\u2014Challenges and opportunities","volume":"158","author":"Kumar","year":"2026","journal-title":"Int. J. Cancer"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1038\/s41375-024-02419-z","article-title":"PVR (CD155) epigenetic status mediates immunotherapy response in multiple myeloma","volume":"38","author":"Veselinova","year":"2024","journal-title":"Leukemia"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Fraschilla, I., Amatullah, H., and Jeffrey, K.L. (2022). One genome, many cell states: Epigenetic control of innate immunity. Curr. Opin. Immunol., 75.","DOI":"10.1016\/j.coi.2022.102173"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.trecan.2024.06.002","article-title":"Targeting cancer stem cells in multiple myeloma","volume":"10","author":"Gunes","year":"2024","journal-title":"Trends Cancer"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Radhakrishnan, V., Golla, U., and Kudva, A.K. (2024). Role of Immune Cells and Immunotherapy in Multiple Myeloma. Life, 14.","DOI":"10.3390\/life14040461"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Wang, H., and Chen, J. (2025). Immunoparesis in multiple myeloma: A current overview. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1628144"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e693","DOI":"10.1016\/S2352-3026(24)00186-8","article-title":"Mechanisms of resistance against T-cell engaging bispecific antibodies in multiple myeloma: Implications for novel treatment strategies","volume":"11","author":"Chari","year":"2024","journal-title":"Lancet Haematol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1038\/s43018-024-00763-8","article-title":"Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma","volume":"5","author":"Rade","year":"2024","journal-title":"Nat. Cancer"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/s13148-021-01100-x","article-title":"Leveraging epigenetics to enhance the efficacy of immunotherapy","volume":"13","author":"Licht","year":"2021","journal-title":"Clin. Epigenet."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1182\/bloodadvances.2023012354","article-title":"Mechanisms of resistance to bispecific T-cell engagers in multiple myeloma and their clinical implications","volume":"8","author":"Moreau","year":"2024","journal-title":"Blood Adv."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1038\/s43018-023-00625-9","article-title":"Acquired resistance to a GPRC5D-directed T-cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation","volume":"4","author":"Derrien","year":"2023","journal-title":"Nat. Cancer"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/s41467-019-08679-z","article-title":"Long non-coding RNAs discriminate the stages and gene regulatory states of human humoral immune response","volume":"10","author":"Agirre","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Allegra, A., Ettari, R., Innao, V., and Bitto, A. (2021). Potential Role of microRNAs in inducing Drug Resistance in Patients with Multiple Myeloma. Cells, 10.","DOI":"10.3390\/cells10020448"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/nrc2734","article-title":"STATs in cancer inflammation and immunity: A leading role for STAT3","volume":"9","author":"Yu","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1126\/science.aaf4405","article-title":"Hypoxic control of metastasis","volume":"352","author":"Rankin","year":"2016","journal-title":"Science"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.cell.2017.01.017","article-title":"Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy","volume":"168","author":"Sharma","year":"2017","journal-title":"Cell"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1158\/2643-3230.BCD-20-0227","article-title":"Determinants of response and mechanisms of resistance of CAR T-cell therapy in multiple myeloma","volume":"2","author":"Themeli","year":"2021","journal-title":"Blood Cancer Discov."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s43556-025-00373-5","article-title":"Epigenetic drugs in cancer therapy: Mechanisms, immune modulation, and therapeutic applications","volume":"6","author":"Ma","year":"2025","journal-title":"Mol. Biomed."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1158\/0008-5472.CAN-23-2244","article-title":"Chromatin Remodelers Are Regulators of the Tumor Immune Microenvironment","volume":"84","author":"Chaudhri","year":"2024","journal-title":"Cancer Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1038\/s41375-018-0153-6","article-title":"Multiple myeloma clonal evolution in homogeneously treated patients","volume":"32","author":"Corre","year":"2018","journal-title":"Leukemia"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"oyag105","DOI":"10.1093\/oncolo\/oyag105","article-title":"Dynamic Cytogenetic Evolution in Multiple Myeloma: Prognostic Implications from Diagnosis to First Relapse","volume":"31","author":"Chen","year":"2026","journal-title":"Oncologist"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Li, S., Liu, J., Peyton, M., Lazaro, O., McCabe, S.D., Huang, X., Liu, Y., Shi, Z., Zhang, Z., and Walker, B.A. (2025). Multiple Myeloma Insights from Single-Cell Analysis: Clonal Evolution, the Microenvironment, Therapy Evasion, and Clinical Implications. Cancers, 17.","DOI":"10.20944\/preprints202501.1092.v1"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1038\/s41375-022-01597-y","article-title":"Clonal evolution after treatment pressure in multiple myeloma: Heterogenous genomic aberrations and transcriptomic convergence","volume":"36","author":"Misund","year":"2022","journal-title":"Leukemia"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"e502","DOI":"10.1097\/HS9.0000000000000502","article-title":"A Journey Through Myeloma Evolution: From the Normal Plasma Cell to Disease Complexity","volume":"4","author":"Ziccheddu","year":"2020","journal-title":"Hemasphere"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Matamala Montoya, M., van Slobbe, G.J.J., Chang, J.C., Zaal, E.A., and Berkers, C.R. (2023). Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1155621"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s12935-026-04188-4","article-title":"Mechanisms and intervention strategies of microenvironment-mediated drug resistance in multiple myeloma","volume":"26","author":"Xiaoling","year":"2026","journal-title":"Cancer Cell Int."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/s41568-024-00737-z","article-title":"Cancer drug-tolerant persister cells: From biological questions to clinical opportunities","volume":"24","author":"Russo","year":"2024","journal-title":"Nat. Rev. Cancer"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1158\/2643-3230.BCD-25-0005","article-title":"Timing Genomic Antigen Loss in Multiple Myeloma Treated with T Cell-Redirecting Immunotherapies","volume":"6","author":"Papadimitriou","year":"2025","journal-title":"Blood Cancer Discov."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/s41591-025-04175-8","article-title":"Multimodal antigenic escape to GPRC5D-targeted T cell engagers in multiple myeloma","volume":"32","author":"Lee","year":"2026","journal-title":"Nat. Med."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"e10816","DOI":"10.1002\/advs.202510816","article-title":"Type I Interferon Pathway Activation Disrupts Monocyte Maturation and Enhances Immune Evasion in Multiple Myeloma","volume":"13","author":"Cui","year":"2026","journal-title":"Adv. Sci."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1007\/s11899-023-00704-9","article-title":"Response-Adapted Therapy for Newly Diagnosed Multiple Myeloma","volume":"18","author":"Teo","year":"2023","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"ref_131","first-page":"101074","article-title":"Hematologic malignancies and an overview of emerging therapies for hematologic malignancies: A systematic review","volume":"46","author":"Ghaffari","year":"2026","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"110699","DOI":"10.1016\/j.isci.2024.110699","article-title":"Modeling tumors as complex ecosystems","volume":"27","author":"Anderson","year":"2024","journal-title":"iScience"},{"key":"ref_133","unstructured":"Ahmed, A., and Killeen, R.B. (2026). Relapsed and Refractory Multiple Myeloma. StatPearls [Internet], StatPearls Publishing."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1007\/s10585-024-10305-2","article-title":"Multiple myeloma: Clinical characteristics, current therapies and emerging innovative treatments targeting ribosome biogenesis dynamics","volume":"41","author":"Elbahoty","year":"2024","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1182\/blood-2012-01-405985","article-title":"Clonal competition with alternating dominance in multiple myeloma","volume":"120","author":"Keats","year":"2012","journal-title":"Blood"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"e313","DOI":"10.3324\/haematol.2017.165217","article-title":"The prognostic value of the depth of response in multiple myeloma depends on the time of assessment, risk status and molecular subtype","volume":"102","author":"Schinke","year":"2017","journal-title":"Haematologica"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/12\/1873\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T16:33:57Z","timestamp":1780936437000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/12\/1873"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,8]]},"references-count":136,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cancers18121873"],"URL":"https:\/\/doi.org\/10.3390\/cancers18121873","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,8]]}}}