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We here describe the discovery, mechanism of action, and preclinical anti\u2010MM activity of engineered toxin body MT\u20100169, a next\u2010generation immunotoxin comprising a CD38\u2010specific antibody fragment linked to a de\u2010immunized Shiga\u2010like toxin A subunit (SLTA) payload. We show that specific binding of MT\u20100169 to CD38 on MM cell lines triggers rapid internalization of SLTA, causing cell death via irreversible ribosome inhibition, protein synthesis blockade, and caspase 3\/7 activation. In co\u2010culture experiments, bone marrow mesenchymal stromal cells did not induce drug resistance against MT\u20100169. In the preclinical setting, MT\u20100169 effectively lysed primary MM cells from newly diagnosed and heavily pretreated MM patients, including those refractory to daratumumab, with minimal toxicity against nonmalignant hematopoietic cells. MM cell lysis showed a significant correlation with their CD38 expression levels but not with cytogenetic risk, tumor load, or number of prior lines of therapy. Finally, MT\u20100169 showed efficient in vivo anti\u2010MM activity in various mouse xenograft models, including one in which MM cells are grown in a humanized bone marrow\u2010like niche. These findings support clinical investigation of MT\u20100169 in relapsed\/refractory MM patients, including those refractory to CD38\u2010targeting immunotherapies.<\/jats:p>","DOI":"10.1002\/hem3.70039","type":"journal-article","created":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T11:41:37Z","timestamp":1731584497000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Preclinical evaluation of the CD38\u2010targeting engineered toxin body MT\u20100169 against multiple myeloma"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4074-9257","authenticated-orcid":false,"given":"Wassilis S. 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