{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:58:05Z","timestamp":1790927885692,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T00:00:00Z","timestamp":1782518400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T00:00:00Z","timestamp":1782518400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:p>Despite promising outcomes in CAR T\u2010cell therapy for relapsed\/refractory multiple myeloma (RRMM), nearly all patients eventually relapse. Resistance and relapse may be driven by CAR T\u2010cell and tumor\u2010intrinsic factors. Here, we developed a mechanistic quantitative systems pharmacology (QSP) model of multiple myeloma growth and CAR T\u2010cell therapy using measurable biomarkers to predict and identify factors associated with response and relapse. The model incorporates key components to explore disease dynamics and CAR T\u2010cell expansion. Our model reproduced published pharmacokinetics and biomarker response data from anti\u2010BCMA and anti\u2010GPRC5D CAR T\u2010cell therapies. We then validated the model using clinical biomarker data from a total of 29 real\u2010world RRMM patients treated with commercial anti\u2010BCMA CAR T. Virtual trial simulations, exploring the impact of variable baseline disease and CAR T characteristics on response, predicted that factors associated with worse outcomes are intrinsic to tumor cells (disease burden, low\u2010antigen expression) and CAR T cells (low CAR T\u2010induced killing rate). Interestingly, simulations suggested that a lower baseline percentage of normal plasma cells is associated with higher overall response. The developed model was also used to predict the outcome of BCMA\u2010targeted and GPRC5D\u2010targeted combination CAR T\u2010cell treatment. Sequential combination therapy simulations predicted a better response in scenarios starting with anti\u2010GPRC5D CAR T infusion, followed by anti\u2010BCMA CAR T infusion. Our model can serve as a framework to investigate response mechanisms as well as multi\u2010antigen targeting, and to optimize clinical trial design and dosing regimens.<\/jats:p>","DOI":"10.1002\/cpt.70378","type":"journal-article","created":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T02:35:13Z","timestamp":1782614113000},"page":"991-1003","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Patient\u2010Specific Determinants of Response to\n                    <scp>BCMA<\/scp>\n                    \u2010 and\n                    <scp>GPRC5D<\/scp>\n                    \u2010Targeted\n                    <scp>CAR<\/scp>\n                    T\u2010Cell Therapy in Multiple Myeloma: A\n                    <scp>QSP<\/scp>\n                    Analysis of Clinical Trial and Real\u2010World Data"],"prefix":"10.1002","volume":"120","author":[{"given":"Vasiliki","family":"Kostiou","sequence":"first","affiliation":[{"name":"Certara, Applied Biosimulation  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijayalakshmi","family":"Chelliah","sequence":"additional","affiliation":[{"name":"Certara, Applied Biosimulation  Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piet H.","family":"van der Graaf","sequence":"additional","affiliation":[{"name":"Certara, Applied Biosimulation  Sheffield UK"},{"name":"Leiden Academic Centre for Drug Research  Leiden The Netherlands"},{"name":"Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej M.","family":"Kierzek","sequence":"additional","affiliation":[{"name":"Certara, Applied Biosimulation  Sheffield UK"},{"name":"School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey  Guildford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tasmin","family":"Farzana","sequence":"additional","affiliation":[{"name":"Cellular Therapy Service, Division of Hematologic Malignancies, Department of Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2815-9561","authenticated-orcid":false,"given":"Sham","family":"Mailankody","sequence":"additional","affiliation":[{"name":"Myeloma and Cellular Therapy Service, Division of Hematologic Malignancies, Department of Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Jurgens","sequence":"additional","affiliation":[{"name":"Cellular Therapy Service, Division of Hematologic Malignancies, Department of Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"},{"name":"Adult Bone Marrow Transplantation Service, Division of Hematologic Malignancies, Department of Medicine Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,27]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12020407"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-024-01191-8"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023012354"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/hematology.2020000111"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/2643-3230.BCD-20-0020"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2631"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2040"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2019.1688616"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11538-021-00869-5"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-025-10008-5"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12636"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13009"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12598"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13259"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1012908"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13421"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-025-01531-2"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.70075"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12922"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-14726-5"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-024-00821-1"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2025016712"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02496-0"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1819745116"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1817226"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2209900"},{"key":"e_1_2_9_27_1","unstructured":"Rohatgi A.WebPlotDigitizer<https:\/\/automeris.io> (2024). Accessed 2024."},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12972"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejh.70025"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO-24-01730"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.991092"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2024026212"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.27225"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02491-5"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aau7746"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3057"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21177-5"},{"key":"e_1_2_9_38_1","unstructured":"Phase I trial of concurrent administration of GPRC5D\u2010targeted CAR T Cell MCARH109 and BCMA\u2010targeted CAR T cell MCARH125 in patients with relapsed or refractory multiple myeloma(2022)."},{"key":"e_1_2_9_39_1","unstructured":"An open\u2010label dose finding study to investigate the safety pharmacokinetics and preliminary efficacy of BMCA and GPRC5D dual target CAR\u2010T cells therapy in patients with relapsed or refractory multiple myeloma(2022)."},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-025-02232-7"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00933-8"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/2643-3230.BCD-22-0018"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.757"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminhematol.2025.12.004"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-023-00966-9"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-023-03559-4"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(25)00048-1"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2025029773"},{"key":"e_1_2_9_49_1","article-title":"Sequencing BCMA\u2010 and GPRC5D\u2010targeting immunotherapies in multiple myeloma: practical guidance from the European myeloma network","volume":"9","author":"Donk N.","year":"2025","journal-title":"Hema"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70378","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70378","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70378","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:50:48Z","timestamp":1790927448000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70378"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,27]]},"references-count":49,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/cpt.70378"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70378","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,27]]},"assertion":[{"value":"2026-02-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}