{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:22:57Z","timestamp":1790634177601,"version":"4.1.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2016,4,2]],"date-time":"2016-04-02T00:00:00Z","timestamp":1459555200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,4,2]],"date-time":"2016-04-02T00:00:00Z","timestamp":1459555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Invest New Drugs"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p><jats:italic>Background<\/jats:italic> Ixazomib is the first oral, small molecule proteasome inhibitor to reach phase 3 trials. The current analysis characterized the exposure-safety and exposure-efficacy relationships of ixazomib in patients with relapsed\/refractory multiple myeloma (MM) with a purpose of recommending an approach to ixazomib dosing for maintenance therapy. <jats:italic>Methods<\/jats:italic> Logistic regression was used to investigate relationships between ixazomib plasma exposure (area under the curve\/day; derived from individual apparent clearance values from a published population pharmacokinetic analysis) and safety\/efficacy outcomes (hematologic [grade\u00a0\u2265\u00a03 vs \u2264\u20092] or non-hematologic [grade\u00a0\u2265\u00a02 vs \u2264\u20091] adverse events [AEs], and clinical benefit [\u2265stable disease vs progressive disease]) using phase 1 data in relapsed\/refractory MM (NCT00963820; <jats:italic>N<\/jats:italic>\u00a0=\u00a044). <jats:italic>Results<\/jats:italic> Significant relationships to ixazomib exposure were observed for five AEs (neutropenia, thrombocytopenia, rash, fatigue, and diarrhea) and clinical benefit (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.05). Dose\u2013response relationships indicated a favorable benefit\/risk ratio at 3\u00a0mg and 4\u00a0mg weekly, which are below the maximum tolerated dose of 5.5\u00a0mg. At 3\u00a0mg, the model predicted that: 37\u00a0% of patients will achieve clinical benefit; incidence of grade\u00a0\u2265\u00a03 neutropenia and thrombocytopenia will be 10\u00a0% and 23\u00a0%, respectively; and incidence of grade\u00a0\u2265\u00a02 rash, fatigue, and diarrhea will be 8\u00a0%, 19\u00a0%, and 19\u00a0%, respectively. <jats:italic>Conclusions<\/jats:italic> Based on the findings, patients in the phase 3 maintenance trial will initiate ixazomib at a once-weekly dose of 3\u00a0mg, increasing to 4\u00a0mg if acceptable tolerability after 4\u00a0cycles, to provide maximum clinical benefit balanced with adequate tolerability.<\/jats:p>","DOI":"10.1007\/s10637-016-0346-7","type":"journal-article","created":{"date-parts":[[2016,4,2]],"date-time":"2016-04-02T02:55:35Z","timestamp":1459565735000},"page":"338-346","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Exposure\u2013safety\u2013efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed\/refractory multiple myeloma: dose selection for a phase 3 maintenance study"],"prefix":"10.1007","volume":"34","author":[{"given":"Neeraj","family":"Gupta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Labotka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai-Min","family":"Hui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik","family":"Venkatakrishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,4,2]]},"reference":[{"key":"346_CR1","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.2147\/OTT.S49187","volume":"7","author":"M Offidani","year":"2014","unstructured":"Offidani M, Corvatta L, Caraffa P, Gentili S, Maracci L, Leoni P (2014) An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma. 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All other authors are employees of Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Written informed consent was obtained from all individual participants included in the clinical studies from which the data for these analyses were derived.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"All procedures performed in the clinical studies were approved by institutional review boards\/ethics committees at each center and were in accordance with the ethical standards of the 1964 Helsinki declaration and its later amendments, the International Conference on Harmonization, and Guidelines for Good Clinical Practice.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"This work was funded by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}}]}}