{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T13:37:21Z","timestamp":1762522641159,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T00:00:00Z","timestamp":1633392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["18K07277, 19K08825"],"award-info":[{"award-number":["18K07277, 19K08825"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The prognosis of multiple myeloma (MM) has drastically improved owing to the development of new drugs, such as proteasome inhibitors and immunomodulatory drugs. Nevertheless, MM is an extremely challenging disease, and many patients are still refractory to the existing therapies, thus requiring new treatment alternatives. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 that shows efficacy in MM not only as a single agent but also in combination therapy, especially for MM patients with translocation t(11;14). However, many patients are refractory to this drug. Here, we treated the MM cell lines KMS12PE and KMS27 with a combination treatment of venetoclax targeting BCL-2 and daratumumab targeting CD38 to evaluate the synergistic cytotoxicity of these drugs in vitro. MM cell lines were co-cultured with natural killer (NK) cells at an effector:target ratio of 0.3:1 in the presence of serial concentrations of daratumumab and venetoclax, and the resulting apoptotic MM cells were detected by flow cytometry using annexin V. These results indicated that the antibody-dependent cell-mediated NK cytotoxicity was enhanced in KMS12PE and KMS27 cells harboring t(11;14) with a high BCL-2 expression, suggesting that the combination treatment of venetoclax and daratumumab should be especially effective in patients with these characteristics.<\/jats:p>","DOI":"10.3390\/ijms221910761","type":"journal-article","created":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T16:23:58Z","timestamp":1633623838000},"page":"10761","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Synergistic Effects of Venetoclax and Daratumumab on Antibody-Dependent Cell-Mediated Natural Killer Cytotoxicity in Multiple Myeloma"],"prefix":"10.3390","volume":"22","author":[{"given":"Ayano","family":"Nakamura","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susumu","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Research Creation Support Center, Aichi Medical University, Nagakute 480-1195, Japan"},{"name":"Department of Tumor Immunology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jo","family":"Kanasugi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Ejiri","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University Hospital, Aichi Medical University, Nagakute 480-1195, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6681-8927","authenticated-orcid":false,"given":"Ichiro","family":"Hanamura","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuzo","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Tumor Immunology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masao","family":"Seto","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1822-9976","authenticated-orcid":false,"given":"Akiyoshi","family":"Takami","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1002\/ajh.25791","article-title":"Multiple myeloma: 2020 update on diagnosis, risk-stratification and management","volume":"95","author":"Rajkumar","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1038\/s41375-018-0223-9","article-title":"Targeting Bcl-2 for the treatment of multiple myeloma","volume":"32","author":"Touzeau","year":"2018","journal-title":"Leukemia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/leu.2013.216","article-title":"The Bcl-2 specific BH3 mimetic ABT-199: A promising targeted therapy for t(11;14) multiple myeloma","volume":"28","author":"Touzeau","year":"2013","journal-title":"Leukemia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1182\/blood-2018-02-791350","article-title":"The rise of apoptosis: Targeting apoptosis in hematologic malignancies","volume":"132","author":"Valentin","year":"2018","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1182\/blood-2017-06-788786","article-title":"Efficacy of venetoclax as targeted therapy for relapsed\/refractory t(11;14) multiple myeloma","volume":"130","author":"Kumar","year":"2017","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1182\/blood-2017-06-788323","article-title":"Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed\/refractory MM","volume":"130","author":"Moreau","year":"2017","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5418","DOI":"10.1158\/0008-5472.CAN-06-4322","article-title":"Noxa Up-regulation and Mcl-1 Cleavage Are Associated to Apoptosis Induction by Bortezomib in Multiple Myeloma","volume":"67","author":"Trichet","year":"2007","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1158\/1535-7163.MCT-15-0730","article-title":"Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models","volume":"15","author":"Punnoose","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1038\/leu.2015.350","article-title":"Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax","volume":"30","author":"Matulis","year":"2015","journal-title":"Leukemia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1007\/BF02623725","article-title":"Establishment of five human myeloma cell lines","volume":"25","author":"Namba","year":"1989","journal-title":"In Vitro Cell. Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2026","DOI":"10.1080\/10428194.2017.1283032","article-title":"Pathways and mechanisms of venetoclax resistance","volume":"58","author":"Bose","year":"2017","journal-title":"Leuk. Lymphoma"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Offidani, M., Corvatta, L., Mor\u00e8, S., Nappi, D., Martinelli, G., Olivieri, A., and Cerchione, C. (2021). Daratumumab for the Management of Newly Diagnosed and Relapsed\/Refractory Multiple Myeloma: Current and Emerging Treatments. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.624661"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"D\u2019Agostino, M., Innorcia, S., Boccadoro, M., and Bringhen, S. (2020). Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218192"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Roccatello, D., Fenoglio, R., Sciascia, S., Naretto, C., Rossi, D., Ferro, M., Barreca, A., Malavasi, F., and Baldovino, S. (2020). CD38 and Anti-CD38 Monoclonal Antibodies in AL Amyloidosis: Targeting Plasma Cells and beyond. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21114129"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1080\/1042819031000099652","article-title":"Effects of All-transRetinoic Acid (ATRA) on Human Myeloma Cells","volume":"44","author":"Otsuki","year":"2003","journal-title":"Leuk. Lymphoma"},{"key":"ref_16","first-page":"1840","article-title":"Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors","volume":"186","author":"Tai","year":"2010","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1158\/2159-8290.CD-13-0609","article-title":"Selective BCL-2 Inhibition by ABT-199 Causes On-Target Cell Death in Acute Myeloid Leukemia","volume":"4","author":"Pan","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/35069004","article-title":"Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death","volume":"410","author":"Joza","year":"2001","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Di Martino, L., Tosello, V., Peroni, E., and Piovan, E. (2021). Insights on Metabolic Reprogramming and Its Therapeutic Potential in Acute Leukemia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168738"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5047","DOI":"10.1158\/1078-0432.CCR-15-0685","article-title":"How Do Cytotoxic Lymphocytes Kill Cancer Cells?","volume":"21","author":"Anel","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Golay, J., and Taylor, R. (2020). The Role of Complement in the Mechanism of Action of Therapeutic Anti-Cancer mAbs. Antibodies, 9.","DOI":"10.3390\/antib9040058"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5008","DOI":"10.1158\/0008-5472.CAN-15-1330","article-title":"Antibody-Dependent Phagocytosis of Tumor Cells by Macrophages: A Potent Effector Mechanism of Monoclonal Antibody Therapy of Cancer","volume":"75","year":"2015","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5430","DOI":"10.1073\/pnas.81.17.5430","article-title":"The increase in intracellular free calcium associated with IgG gamma 2b\/gamma 1 Fc receptor-ligand interactions: Role in phagocytosis","volume":"81","author":"Young","year":"1984","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.it.2009.04.002","article-title":"Is complement good or bad for cancer patients? A new perspective on an old dilemma","volume":"30","author":"Markiewski","year":"2009","journal-title":"Trends Immunol."},{"key":"ref_25","first-page":"E34","article-title":"The combination of venetoclax, daratumumab and dexamethasone for the treatment of refractory primary plasma cell leukemia","volume":"95","author":"Nalghranyan","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1182\/blood-2019-124407","article-title":"First Analysis from a Phase 1\/2 Study of Venetoclax in Combination with Daratumumab and Dexamethasone, +\/- Bortezomib, in Patients with Relapsed\/Refractory Multiple Myeloma","volume":"134","author":"Bahlis","year":"2019","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.clml.2020.03.017","article-title":"Clinical Updates Regarding Multiple Myeloma from the 2019 American Society of Hematology Annual Meeting","volume":"20","author":"Terpos","year":"2020","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1038\/leu.2015.123","article-title":"Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab","volume":"29","author":"Nijhof","year":"2015","journal-title":"Leukemia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1182\/bloodadvances.2017006866","article-title":"Effects of daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma","volume":"1","author":"Casneuf","year":"2017","journal-title":"Blood Adv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4006","DOI":"10.1158\/1078-0432.CCR-17-3117","article-title":"Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by Ex Vivo\u2013Expanded Autologous NK Cells","volume":"24","author":"Wang","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7498","DOI":"10.1158\/1078-0432.CCR-17-2027","article-title":"Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab","volume":"23","author":"Krejcik","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.ccr.2006.03.027","article-title":"Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members","volume":"9","author":"Certo","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"458","DOI":"10.3389\/fimmu.2017.00458","article-title":"Shaping of Natural Killer Cell Antitumor Activity by Ex Vivo Cultivation","volume":"8","author":"Granzin","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_34","first-page":"477","article-title":"Established immunoglobulin producing myeloma (IgE) and lymphoblastoid (IgG) cell lines from an IgE myeloma patient","volume":"7","author":"Nilsson","year":"1970","journal-title":"Clin. Exp. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1111\/j.1349-7006.2001.tb01142.x","article-title":"Ectopic expression of MAFB gene in human myeloma cells carrying (14;20)(q32;q11) chromosomal translocations","volume":"92","author":"Hanamura","year":"2001","journal-title":"Jpn. J. Cancer Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10761\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:09:35Z","timestamp":1760166575000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10761"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,5]]},"references-count":35,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms221910761"],"URL":"https:\/\/doi.org\/10.3390\/ijms221910761","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,10,5]]}}}