Myeloma Precursors Erode Durable Immunity: Results of the IMPACT study

Myeloma Precursors Erode Durable Immunity: Results of the IMPACT study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Myeloma Precursors Erode Durable Immunity: Results of the IMPACT study Irene Ghobrial, Noe Perron, Michelle Aranha, Ting Wu, Lorena Pantano Rubino, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9226435/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Multiple myeloma (MM) is a plasma cell malignancy marked by profound immune dysfunction and substantial infection-related mortality. MM is preceded by the asymptomatic precursor states monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), yet whether these patients can mount effective immune responses remains unknown. In this prospective observational study of 731 individuals recruited nationwide through Dana-Farber Cancer Institute, we used SARS-CoV-2 vaccination as a standardized immunological challenge alongside childhood vaccine serology. We show that precursor myeloma is associated with broad dysfunction across innate and adaptive immunity, including accelerated antibody waning, erosion of childhood vaccine titers, impaired antigen-specific T cell expansion, and blunted innate activation. Mechanistically, we link these defects to tumor burden-dependent APRIL depletion and downregulation of APRIL-responsive pathways in normal plasma cells, validated in an independent cohort. These findings have direct implications for cancer vaccine development, immunotherapy, and infection management in early-stage hematologic malignancies. Health sciences/Oncology/Cancer/Cancer microenvironment Biological sciences/Cancer/Cancer therapy/Tumour vaccines Biological sciences/Cancer/Haematological cancer Health sciences/Oncology/Cancer/Tumour immunology Health sciences/Medical research/Biomarkers/Diagnostic markers Full Text Additional Declarations Yes there is potential Competing Interest. N.P., M.P.A, L.P.R., T.W., H.Y., E.D.L., R.S., M.R., M.T., D.H.M., S.V., M.P.A., S.B., R.P.N., J.P., E.H., N.K.S., and L.T., have no conflicts to disclose. Y.K. receives research funds from Regeneron. E.S.F. is a founder, member of the scientific advisory board (SAB), and equity holder of Civetta Therapeutics, Jengu Therapeutics, Proximity Therapeutics, and Neomorph Inc, SAB member and equity holder in Avilar Therapeutics and Photys Therapeutics, and a consultant to Astellas, Sanofi, Novartis, Deerfield and EcoR1 capital. The Fischer laboratory receives or has received research funding from Novartis, Deerfield, Ajax, Interline, and Astellas. M.H., D.A., and H.J.C. are or have been employees of the Multiple Myeloma Research Foundation. G.G. is a consultant, a current equity holder, and a co-founder for Scorpion Therapeutics and Predicta Biosciences, is receiving research funds from IBM and Pharmacyclics, and is a holder of patents and royalties for SignatureAnalyzer-GPU, MSMuTect, MSMutSig, MSIDetect, and POLYSOLVER. R.S.P. is a co-founder, equity holder and consultant for PreDICTA Biosciences. I.M.G. has consulted for AbbVie, Adaptive, Amgen, Aptitude Health, Arcellx, AstraZeneca, BioSkryb Genomics, Bristol-Myers Squibb, Civala, Inc., Clinical Care Options, Clinical, Education Alliance, ENGAGE, Feromics Inc., Genentech, GlaxoSmithKline, Janssen, Kite Pharma, Menarini, ONK Therapeutics, Pfizer, Regeneron, Sanofi, Silicon Biosystems, Takeda, TG Therapeutics. Window Therapeutics. She has received honoraria or speaker fees from Amgen, Curio Science, Janssen, MD Education, MJH Life Sciences, Physicians’ Education Resource, Regeneron, Standard Biotools, Takeda, Thermo Fischer / Binding Site, Veeva, Vor Biopharma. She is a founder and executive board member of and holds private equity in Predicta Biosciences. Her spouse is the chief medical officer of and holds private equity in Disc Medicine. Supplementary Files SupplementaryTable1ELISAcohort.csv Supplementary Table 1 SupplementaryTable3APRILresponsivegenes.csv Supplementary Table 3 SupplementaryTable4AntigenspecificTCR.csv Supplementary Table 4 SupplementaryTable2scRNAseqsamplelist.csv Supplementary Table 2 SupFig4SpikeClonotypesShippedVsNonShipped.png Supplementary Figure 4 SupFig1scRNAseqAnnotation.png Supplementary Figure 1 SupFig3APRILgenesviolins.png Supplementary Figure 3 SupFig2APRILsignaturevalidation.png Supplementary Figure 2 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9226435","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":616730498,"identity":"bddab310-c4fa-4062-9b56-807c78d7a3e5","order_by":0,"name":"Irene 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have no conflicts to disclose. Y.K. receives research funds from Regeneron. E.S.F. is a founder, member of the scientific advisory board (SAB), and equity holder of Civetta Therapeutics, Jengu Therapeutics, Proximity Therapeutics, and Neomorph Inc, SAB member and equity holder in Avilar Therapeutics and Photys Therapeutics, and a consultant to Astellas, Sanofi, Novartis, Deerfield and EcoR1 capital. The Fischer laboratory receives or has received research funding from Novartis, Deerfield, Ajax, Interline, and Astellas. M.H., D.A., and H.J.C. are or have been employees of the Multiple Myeloma Research Foundation. G.G. is a consultant, a current equity holder, and a co-founder for Scorpion Therapeutics and Predicta Biosciences, is receiving research funds from IBM and Pharmacyclics, and is a holder of patents and royalties for SignatureAnalyzer-GPU, MSMuTect, MSMutSig, MSIDetect, and POLYSOLVER. R.S.P. is a co-founder, equity holder and consultant for PreDICTA Biosciences. I.M.G. has consulted for AbbVie, Adaptive, Amgen, Aptitude Health, Arcellx, AstraZeneca, BioSkryb Genomics, Bristol-Myers Squibb, Civala, Inc., Clinical Care Options, Clinical, Education Alliance, ENGAGE, Feromics Inc., Genentech, GlaxoSmithKline, Janssen, Kite Pharma, Menarini, ONK Therapeutics, Pfizer, Regeneron, Sanofi, Silicon Biosystems, Takeda, TG Therapeutics. Window Therapeutics. She has received honoraria or speaker fees from Amgen, Curio Science, Janssen, MD Education, MJH Life Sciences, Physicians’ Education Resource, Regeneron, Standard Biotools, Takeda, Thermo Fischer / Binding Site, Veeva, Vor Biopharma. She is a founder and executive board member of and holds private equity in Predicta Biosciences. Her spouse is the chief medical officer of and holds private equity in Disc Medicine.","formattedTitle":"Myeloma Precursors Erode Durable Immunity: Results of the IMPACT study","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9226435/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9226435/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Multiple myeloma (MM) is a plasma cell malignancy marked by profound immune dysfunction and substantial infection-related mortality. MM is preceded by the asymptomatic precursor states monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), yet whether these patients can mount effective immune responses remains unknown. In this prospective observational study of 731 individuals recruited nationwide through Dana-Farber Cancer Institute, we used SARS-CoV-2 vaccination as a standardized immunological challenge alongside childhood vaccine serology. We show that precursor myeloma is associated with broad dysfunction across innate and adaptive immunity, including accelerated antibody waning, erosion of childhood vaccine titers, impaired antigen-specific T cell expansion, and blunted innate activation. Mechanistically, we link these defects to tumor burden-dependent APRIL depletion and downregulation of APRIL-responsive pathways in normal plasma cells, validated in an independent cohort. These findings have direct implications for cancer vaccine development, immunotherapy, and infection management in early-stage hematologic malignancies.","manuscriptTitle":"Myeloma Precursors Erode Durable Immunity: Results of the IMPACT study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-14 10:16:55","doi":"10.21203/rs.3.rs-9226435/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"492796da-c44a-4a2f-b53d-c8ef7a3cb525","owner":[],"postedDate":"April 14th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":65630148,"name":"Health sciences/Oncology/Cancer/Cancer microenvironment"},{"id":65630149,"name":"Biological sciences/Cancer/Cancer therapy/Tumour vaccines"},{"id":65630150,"name":"Biological sciences/Cancer/Haematological cancer"},{"id":65630151,"name":"Health sciences/Oncology/Cancer/Tumour immunology"},{"id":65630152,"name":"Health sciences/Medical research/Biomarkers/Diagnostic markers"}],"tags":[],"updatedAt":"2026-04-14T10:16:55+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-14 10:16:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9226435","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9226435","identity":"rs-9226435","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}