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Nevertheless, responses in relapsed and refractory (r\/r) multiple myeloma (MM) are heterogenous, emphasizing the need for optimized patient selection before RPT. Current approaches mostly rely on qualitative assessments, confirming relevant CXCR4-expression by CXCR4-directed PET in vital myeloma burden, the latter usually being determined by additional [\n                      <jats:sup>18<\/jats:sup>\n                      F]FDG-PET.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>To evaluate whether quantitative imaging biomarkers derived from dual-tracer PET\/CT can enhance patient stratification and predict therapeutic response and survival following CXCR4-RPT.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>22 patients with r\/r MM who underwent CXCR4-directed [\u2076\u2078Ga]Ga-PentixaFor-PET\/CT and [\u00b9\u2078F]FDG-PET\/CT imaging prior to CXCR4-RPT were retrospectively analyzed. A fully automated pipeline performed deep-learning\u2013based lesion segmentation and dual-tracer fusion; batch quality control and correction ensured segmentation accuracy and concordant-lesion adjudication (&gt;\u200910% volumetric overlap) prior to lesion-level feature extraction. Features included demographics, laboratory\/genetic variables, and imaging metrics from FDG- and CXCR4-PET, stratified by anatomic site (medullary vs. extramedullary) and concordance (concordant vs. discordant as defined by comparing FDG- and CXCR4-positive myeloma lesions). Surface-standardized maximum inter-lesion distances (sDmax) were additionally computed. Endpoints were therapy response (responder vs. non-responder as defined by serological response assessment based on IMWG-criteria or PET\/MRI based response assessment) and overall survival (OS). Group comparisons were performed using Welch\u2019s t-test\/Chi-square; survival analysis was conducted applying Kaplan\u2013Meier estimates and log-rank tests. Decision-tree models were interpreted with SHapley Additive exPlanations (SHAP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Responders to RPT showed lower [\n                      <jats:sup>18<\/jats:sup>\n                      F]FDG-SUV\n                      <jats:sub>mean<\/jats:sub>\n                      in medullary and extramedullary concordant lesions (Welch\u2019s\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.03). In the response classifier, these metrics ranked among the top predictors by SHAP, alongside selected extramedullary CXCR4-dominant discordant features and high-risk cytogenetics. Shorter OS was associated with higher TLG[FDG medullary concordant], greater sDmax[FDG], and higher CXCR4-positive medullary burden (MTV\/TLC) (log-rank\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). SHAP directionality agreed with univariate trends. BMI showed a modest inverse association with early mortality in the 6-month survival model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In our exploratory analysis, [\u00b9\u2078F]FDG-uptake within medullary concordant lesions was linked to both response and survival, while CXCR4-expressing medullary volume and sDmax added survival information. Concordance-aware, lesion-level quantification from dual-tracer PET\/CT might present as a promising approach to aid risk stratification for CXCR4-directed RPT. However, initial findings of our hypothesis generating analysis warrant prospective validation in larger cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00259-026-07814-5","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T09:11:59Z","timestamp":1771405919000},"page":"4560-4571","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Lesion-level dual-tracer PET biomarkers predict prognosis in multiple myeloma treated with CXCR4-directed radiopharmaceutical therapy"],"prefix":"10.1007","volume":"53","author":[{"given":"Song","family":"Xue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Kraus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna S.","family":"Enke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Michalski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Hacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann","family":"Einsele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas K.","family":"Buck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantin","family":"Lapa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0016-6233","authenticated-orcid":false,"given":"Xiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Dreher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"7814_CR1","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/S0140-6736(21)00237-3","volume":"397","author":"MS Hofman","year":"2021","unstructured":"Hofman MS, Emmett L, Sandhu S, Iravani A, Joshua AM, Goh JC, et al. 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Blood. 2025;145:1780\u20137.","journal-title":"Blood"}],"container-title":["European Journal of Nuclear Medicine and Molecular Imaging"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00259-026-07814-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00259-026-07814-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00259-026-07814-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T04:10:14Z","timestamp":1779423014000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00259-026-07814-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,18]]},"references-count":36,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["7814"],"URL":"https:\/\/doi.org\/10.1007\/s00259-026-07814-5","relation":{},"ISSN":["1619-7070","1619-7089"],"issn-type":[{"value":"1619-7070","type":"print"},{"value":"1619-7089","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,18]]},"assertion":[{"value":"12 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. CXCR4-directed RPT was conducted on an individual basis according to the German Pharmaceutical Act (\u00a7\u00a013.2b). The need for an approval for this analysis was waived by the local ethics committee due to the retrospective nature of this study (# 20220103 01).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All authors have read this manuscript and would like to have it considered exclusively for publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"AKB: involved in [68Ga]Ga-Pentixafor PET imaging in marginal zone lymphoma (LYMFOR) and has previously received speakers honoraria from PentixaPharm. AKB is a member of the advisory board of PentixaPharm. M.H. is an editor of EJNMMI.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}