{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T07:11:26Z","timestamp":1781421086387,"version":"3.54.1"},"reference-count":32,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,2,16]],"date-time":"2025-02-16T00:00:00Z","timestamp":1739664000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:p>Cytokine release syndrome (CRS) is a common, acute adverse event associated with T\u2010cell redirecting therapies such as bispecific antibodies (BsAbs). The nature of CRS events data makes it challenging to capture an unbiased exposure\u2013response relationship with commonly used models. For example, simple logistic regression models cannot handle traditional time\u2010varying exposure, and static exposure metrics chosen at early time points and with lower priming doses may underestimate the incidence of CRS. Therefore, more advanced modeling techniques are needed to adequately describe the time course of BsAb\u2010induced CRS. Herein, we present a two\u2010part mixture model that describes the population incidence and time course of CRS following various dose\u2010priming regimens of elranatamab, a humanized BsAb that targets the B\u2010cell maturation antigen on myeloma cells and CD3 on T cells, where the conditional time\u2010evolution of CRS was described with a two\u2010state (i.e., CRS\u2010yes or no) Markov model. In the first part, increasing elranatamab exposure (maximum elranatamab concentration at first CRS event time (<jats:italic>C<\/jats:italic><jats:sub>max,event<\/jats:sub>)) was associated with an increased CRS incidence probability. Similarly, in the second part, increased early elranatamab exposure (<jats:italic>C<\/jats:italic><jats:sub>max,D1<\/jats:sub>) increased the predicted probability of CRS over time, whereas premedication including corticosteroids and IL\u20106 pathway inhibitors use demonstrated the opposite effect. This is the first reported application of a Markov model to describe the probability of CRS following BsAb therapy, and it successfully explained differences between different dose\u2010priming regimens via clinically relevant covariates. This approach may be useful for the future clinical development of BsAbs.<\/jats:p>","DOI":"10.1002\/cpt.3533","type":"journal-article","created":{"date-parts":[[2025,2,16]],"date-time":"2025-02-16T17:05:46Z","timestamp":1739725546000},"page":"1687-1695","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Novel Two\u2010Part Mixture Model for the Incidence and Time Course of Cytokine Release Syndrome After Elranatamab Dosing in Multiple Myeloma Patients"],"prefix":"10.1002","volume":"117","author":[{"given":"Donald","family":"Irby","sequence":"first","affiliation":[{"name":"Pfizer Research and Development, Pfizer, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Hibma","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development, Pfizer, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9825-5890","authenticated-orcid":false,"given":"Mohamed","family":"Elmeliegy","sequence":"additional","affiliation":[{"name":"Oncology Research and Development, Pfizer, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Wang","sequence":"additional","affiliation":[{"name":"Oncology Research and Development, Pfizer, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Vandendries","sequence":"additional","affiliation":[{"name":"Oncology Research and Development, Pfizer, Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamrine","family":"Poels","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development, Pfizer, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blerta","family":"Shtylla","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development, Pfizer, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason H.","family":"Williams","sequence":"additional","affiliation":[{"name":"Pfizer Research and Development, Pfizer, Inc.  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Mesa H. Chatel K.&Vermeulen A.Mixture models and model mixtures with MONOLIX. Population Approach Group Europe 19th Annual Conference<www.page\u2010meeting.org\/?abstract=1853> (2010)."},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.71"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2022-169971"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12487"},{"key":"e_1_2_11_15_1","unstructured":"Hibma J.E.E.M. King L.E. McCush F. Wang D.&Williams J.H.Population pharmacokinetic analysis of elranatamab in patients with multiple myeloma. 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