Bone marrow microenvironments that contribute to patient outcomes in newly diagnosed multiple myeloma: A cohort study of patients in the Total Therapy clinical trials

The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM ti...

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Veröffentlicht in:PLoS medicine 2020-11, Vol.17 (11), p.e1003323-e1003323
Hauptverfasser: Danziger, Samuel A, McConnell, Mark, Gockley, Jake, Young, Mary H, Rosenthal, Adam, Schmitz, Frank, Reiss, David J, Farmer, Phil, Alapat, Daisy V, Singh, Amrit, Ashby, Cody, Bauer, Michael, Ren, Yan, Smith, Kelsie, Couto, Suzana S, van Rhee, Frits, Davies, Faith, Zangari, Maurizio, Petty, Nathan, Orlowski, Robert Z, Dhodapkar, Madhav V, Copeland, Wilbert B, Fox, Brian, Hoering, Antje, Fitch, Alison, Newhall, Katie, Barlogie, Bart, Trotter, Matthew W B, Hershberg, Robert M, Walker, Brian A, Dervan, Andrew P, Ratushny, Alexander V, Morgan, Gareth J
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container_end_page e1003323
container_issue 11
container_start_page e1003323
container_title PLoS medicine
container_volume 17
creator Danziger, Samuel A
McConnell, Mark
Gockley, Jake
Young, Mary H
Rosenthal, Adam
Schmitz, Frank
Reiss, David J
Farmer, Phil
Alapat, Daisy V
Singh, Amrit
Ashby, Cody
Bauer, Michael
Ren, Yan
Smith, Kelsie
Couto, Suzana S
van Rhee, Frits
Davies, Faith
Zangari, Maurizio
Petty, Nathan
Orlowski, Robert Z
Dhodapkar, Madhav V
Copeland, Wilbert B
Fox, Brian
Hoering, Antje
Fitch, Alison
Newhall, Katie
Barlogie, Bart
Trotter, Matthew W B
Hershberg, Robert M
Walker, Brian A
Dervan, Andrew P
Ratushny, Alexander V
Morgan, Gareth J
description The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases. Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies. In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in p
doi_str_mv 10.1371/journal.pmed.1003323
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However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases. Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies. In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies.</description><identifier>ISSN: 1549-1676</identifier><identifier>ISSN: 1549-1277</identifier><identifier>EISSN: 1549-1676</identifier><identifier>DOI: 10.1371/journal.pmed.1003323</identifier><identifier>PMID: 33147277</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Algorithms ; Asymptomatic ; Biology and Life Sciences ; Biopsy ; Bone marrow ; Bone Marrow - pathology ; Cancer ; CD8 antigen ; Clinical outcomes ; Clinical trials ; Cohort analysis ; Cohort Studies ; Computer applications ; Development and progression ; Estimates ; Female ; Gene expression ; Genomes ; Granulocytes ; Health aspects ; Humans ; Immunohistochemistry ; Informed consent ; Leukocytes (granulocytic) ; Lymphocytes T ; Machine learning ; Male ; Medicine and Health Sciences ; Middle Aged ; Monocytes ; Multiple myeloma ; Multiple Myeloma - diagnosis ; Multiple Myeloma - drug therapy ; Multiple Myeloma - pathology ; Mutation ; Neutrophils ; Patients ; Physiological aspects ; Plasma ; Prognosis ; Review boards ; Thalidomide ; Transplants &amp; implants ; Tumor Burden ; Tumor Microenvironment ; Tumors</subject><ispartof>PLoS medicine, 2020-11, Vol.17 (11), p.e1003323-e1003323</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Danziger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Danziger et al 2020 Danziger et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c764t-15a8aba763005aadb5d3318b3546c854e2b50da1aec5a423859b9a3f55315a8f3</citedby><cites>FETCH-LOGICAL-c764t-15a8aba763005aadb5d3318b3546c854e2b50da1aec5a423859b9a3f55315a8f3</cites><orcidid>0000-0002-8615-6254 ; 0000-0002-5669-414X ; 0000-0003-0566-3607 ; 0000-0001-9959-1282 ; 0000-0003-1448-1346 ; 0000-0001-6116-1017 ; 0000-0002-1701-4084 ; 0000-0002-9616-6341 ; 0000-0003-4843-8645 ; 0000-0002-4709-3027 ; 0000-0003-0978-2291 ; 0000-0002-9361-0283 ; 0000-0002-4271-6360 ; 0000-0003-2921-6107 ; 0000-0001-7993-5308 ; 0000-0002-6482-8654 ; 0000-0002-9090-0277 ; 0000-0003-2498-7295</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641353/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641353/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33147277$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kawano, Yawara</contributor><creatorcontrib>Danziger, Samuel A</creatorcontrib><creatorcontrib>McConnell, Mark</creatorcontrib><creatorcontrib>Gockley, Jake</creatorcontrib><creatorcontrib>Young, Mary H</creatorcontrib><creatorcontrib>Rosenthal, Adam</creatorcontrib><creatorcontrib>Schmitz, Frank</creatorcontrib><creatorcontrib>Reiss, David J</creatorcontrib><creatorcontrib>Farmer, Phil</creatorcontrib><creatorcontrib>Alapat, Daisy V</creatorcontrib><creatorcontrib>Singh, Amrit</creatorcontrib><creatorcontrib>Ashby, Cody</creatorcontrib><creatorcontrib>Bauer, Michael</creatorcontrib><creatorcontrib>Ren, Yan</creatorcontrib><creatorcontrib>Smith, Kelsie</creatorcontrib><creatorcontrib>Couto, Suzana S</creatorcontrib><creatorcontrib>van Rhee, Frits</creatorcontrib><creatorcontrib>Davies, Faith</creatorcontrib><creatorcontrib>Zangari, Maurizio</creatorcontrib><creatorcontrib>Petty, Nathan</creatorcontrib><creatorcontrib>Orlowski, Robert Z</creatorcontrib><creatorcontrib>Dhodapkar, Madhav V</creatorcontrib><creatorcontrib>Copeland, Wilbert B</creatorcontrib><creatorcontrib>Fox, Brian</creatorcontrib><creatorcontrib>Hoering, Antje</creatorcontrib><creatorcontrib>Fitch, Alison</creatorcontrib><creatorcontrib>Newhall, Katie</creatorcontrib><creatorcontrib>Barlogie, Bart</creatorcontrib><creatorcontrib>Trotter, Matthew W B</creatorcontrib><creatorcontrib>Hershberg, Robert M</creatorcontrib><creatorcontrib>Walker, Brian A</creatorcontrib><creatorcontrib>Dervan, Andrew P</creatorcontrib><creatorcontrib>Ratushny, Alexander V</creatorcontrib><creatorcontrib>Morgan, Gareth J</creatorcontrib><title>Bone marrow microenvironments that contribute to patient outcomes in newly diagnosed multiple myeloma: A cohort study of patients in the Total Therapy clinical trials</title><title>PLoS medicine</title><addtitle>PLoS Med</addtitle><description>The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases. Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies. In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies.</description><subject>Adult</subject><subject>Algorithms</subject><subject>Asymptomatic</subject><subject>Biology and Life Sciences</subject><subject>Biopsy</subject><subject>Bone marrow</subject><subject>Bone Marrow - pathology</subject><subject>Cancer</subject><subject>CD8 antigen</subject><subject>Clinical outcomes</subject><subject>Clinical trials</subject><subject>Cohort analysis</subject><subject>Cohort Studies</subject><subject>Computer applications</subject><subject>Development and progression</subject><subject>Estimates</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genomes</subject><subject>Granulocytes</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Informed consent</subject><subject>Leukocytes (granulocytic)</subject><subject>Lymphocytes T</subject><subject>Machine learning</subject><subject>Male</subject><subject>Medicine and Health Sciences</subject><subject>Middle Aged</subject><subject>Monocytes</subject><subject>Multiple myeloma</subject><subject>Multiple Myeloma - diagnosis</subject><subject>Multiple Myeloma - drug therapy</subject><subject>Multiple Myeloma - pathology</subject><subject>Mutation</subject><subject>Neutrophils</subject><subject>Patients</subject><subject>Physiological aspects</subject><subject>Plasma</subject><subject>Prognosis</subject><subject>Review boards</subject><subject>Thalidomide</subject><subject>Transplants &amp; implants</subject><subject>Tumor Burden</subject><subject>Tumor Microenvironment</subject><subject>Tumors</subject><issn>1549-1676</issn><issn>1549-1277</issn><issn>1549-1676</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqVk9tu1DAQhiMEoqXwBggsISG42MWO7Ry4QCoVh0oVlaBwa00SZ-PKsRfbadkX4jmZbbdVF-0FKBeOxt_84zll2VNG54yX7M25n4IDO1-OupszSjnP-b1sn0lRz1hRFvfv_O9lj2I8pzSvaU0fZnucM1HmZbmf_X7vnSYjhOAvyWja4LW7MMG7UbsUSRogkda7FEwzJU2SJ0tIBu-In1LrRx2JccTpS7sinYGF81F3ZJxsMkuLwitt_QhvySGqDD4kEtPUrYjvb3Su_NOgyZlPYMnZoAMsV6S1xpkWDRgZbHycPejx0E8250H2_eOHs6PPs5PTT8dHhyeztixEmjEJFTRQFpxSCdA1ssNUq4ZLUbSVFDpvJO2AgW4liJxXsm5q4L2UfO3a84Ps-bXu0vqoNiWOKi_qgla0ZAUSx9dE5-FcLYPB2q2UB6OuDD4sFIRkWquVqEDWXdXnfVOIBqBuSlHKPBey7nsNNWq920SbGuxii-UIYLdEt2-cGdTCXyhMlnHJUeDVRiD4n5OOSY0mttpacNpP-G4hy7qkOBmIvvgL3Z3dhloAJmBc7zFuuxZVh4WkFRNFmSM120EttMPeWZyn3qB5i5_v4PHrNI7cTofXWw7rCdS_0gKmGNXxt6__wX75d_b0xzb78g47aLBpiN5OyXgXt0FxDeLyxBh0f9tARtV6VW8qrdarqjarim7P7jb_1ulmN_kf9yk7cA</recordid><startdate>20201104</startdate><enddate>20201104</enddate><creator>Danziger, Samuel A</creator><creator>McConnell, Mark</creator><creator>Gockley, Jake</creator><creator>Young, Mary H</creator><creator>Rosenthal, Adam</creator><creator>Schmitz, Frank</creator><creator>Reiss, David J</creator><creator>Farmer, Phil</creator><creator>Alapat, Daisy V</creator><creator>Singh, Amrit</creator><creator>Ashby, Cody</creator><creator>Bauer, Michael</creator><creator>Ren, Yan</creator><creator>Smith, Kelsie</creator><creator>Couto, Suzana S</creator><creator>van Rhee, Frits</creator><creator>Davies, Faith</creator><creator>Zangari, Maurizio</creator><creator>Petty, Nathan</creator><creator>Orlowski, Robert Z</creator><creator>Dhodapkar, Madhav V</creator><creator>Copeland, Wilbert B</creator><creator>Fox, Brian</creator><creator>Hoering, Antje</creator><creator>Fitch, Alison</creator><creator>Newhall, Katie</creator><creator>Barlogie, Bart</creator><creator>Trotter, Matthew W B</creator><creator>Hershberg, Robert M</creator><creator>Walker, Brian A</creator><creator>Dervan, Andrew P</creator><creator>Ratushny, Alexander V</creator><creator>Morgan, Gareth J</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><scope>CZK</scope><orcidid>https://orcid.org/0000-0002-8615-6254</orcidid><orcidid>https://orcid.org/0000-0002-5669-414X</orcidid><orcidid>https://orcid.org/0000-0003-0566-3607</orcidid><orcidid>https://orcid.org/0000-0001-9959-1282</orcidid><orcidid>https://orcid.org/0000-0003-1448-1346</orcidid><orcidid>https://orcid.org/0000-0001-6116-1017</orcidid><orcidid>https://orcid.org/0000-0002-1701-4084</orcidid><orcidid>https://orcid.org/0000-0002-9616-6341</orcidid><orcidid>https://orcid.org/0000-0003-4843-8645</orcidid><orcidid>https://orcid.org/0000-0002-4709-3027</orcidid><orcidid>https://orcid.org/0000-0003-0978-2291</orcidid><orcidid>https://orcid.org/0000-0002-9361-0283</orcidid><orcidid>https://orcid.org/0000-0002-4271-6360</orcidid><orcidid>https://orcid.org/0000-0003-2921-6107</orcidid><orcidid>https://orcid.org/0000-0001-7993-5308</orcidid><orcidid>https://orcid.org/0000-0002-6482-8654</orcidid><orcidid>https://orcid.org/0000-0002-9090-0277</orcidid><orcidid>https://orcid.org/0000-0003-2498-7295</orcidid></search><sort><creationdate>20201104</creationdate><title>Bone marrow microenvironments that contribute to patient outcomes in newly diagnosed multiple myeloma: A cohort study of patients in the Total Therapy clinical trials</title><author>Danziger, Samuel A ; McConnell, Mark ; Gockley, Jake ; Young, Mary H ; Rosenthal, Adam ; Schmitz, Frank ; Reiss, David J ; Farmer, Phil ; Alapat, Daisy V ; Singh, Amrit ; Ashby, Cody ; Bauer, Michael ; Ren, Yan ; Smith, Kelsie ; Couto, Suzana S ; van Rhee, Frits ; Davies, Faith ; Zangari, Maurizio ; Petty, Nathan ; Orlowski, Robert Z ; Dhodapkar, Madhav V ; Copeland, Wilbert B ; Fox, Brian ; Hoering, Antje ; Fitch, Alison ; Newhall, Katie ; Barlogie, Bart ; Trotter, Matthew W B ; Hershberg, Robert M ; Walker, Brian A ; Dervan, Andrew P ; Ratushny, Alexander V ; Morgan, Gareth J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c764t-15a8aba763005aadb5d3318b3546c854e2b50da1aec5a423859b9a3f55315a8f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adult</topic><topic>Algorithms</topic><topic>Asymptomatic</topic><topic>Biology and Life Sciences</topic><topic>Biopsy</topic><topic>Bone marrow</topic><topic>Bone Marrow - pathology</topic><topic>Cancer</topic><topic>CD8 antigen</topic><topic>Clinical outcomes</topic><topic>Clinical trials</topic><topic>Cohort analysis</topic><topic>Cohort Studies</topic><topic>Computer applications</topic><topic>Development and progression</topic><topic>Estimates</topic><topic>Female</topic><topic>Gene expression</topic><topic>Genomes</topic><topic>Granulocytes</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Informed consent</topic><topic>Leukocytes (granulocytic)</topic><topic>Lymphocytes T</topic><topic>Machine learning</topic><topic>Male</topic><topic>Medicine and Health Sciences</topic><topic>Middle Aged</topic><topic>Monocytes</topic><topic>Multiple myeloma</topic><topic>Multiple Myeloma - diagnosis</topic><topic>Multiple Myeloma - drug therapy</topic><topic>Multiple Myeloma - pathology</topic><topic>Mutation</topic><topic>Neutrophils</topic><topic>Patients</topic><topic>Physiological aspects</topic><topic>Plasma</topic><topic>Prognosis</topic><topic>Review boards</topic><topic>Thalidomide</topic><topic>Transplants &amp; implants</topic><topic>Tumor Burden</topic><topic>Tumor Microenvironment</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Danziger, Samuel A</creatorcontrib><creatorcontrib>McConnell, Mark</creatorcontrib><creatorcontrib>Gockley, Jake</creatorcontrib><creatorcontrib>Young, Mary H</creatorcontrib><creatorcontrib>Rosenthal, Adam</creatorcontrib><creatorcontrib>Schmitz, Frank</creatorcontrib><creatorcontrib>Reiss, David J</creatorcontrib><creatorcontrib>Farmer, Phil</creatorcontrib><creatorcontrib>Alapat, Daisy V</creatorcontrib><creatorcontrib>Singh, Amrit</creatorcontrib><creatorcontrib>Ashby, Cody</creatorcontrib><creatorcontrib>Bauer, Michael</creatorcontrib><creatorcontrib>Ren, Yan</creatorcontrib><creatorcontrib>Smith, Kelsie</creatorcontrib><creatorcontrib>Couto, Suzana S</creatorcontrib><creatorcontrib>van Rhee, Frits</creatorcontrib><creatorcontrib>Davies, Faith</creatorcontrib><creatorcontrib>Zangari, Maurizio</creatorcontrib><creatorcontrib>Petty, Nathan</creatorcontrib><creatorcontrib>Orlowski, Robert Z</creatorcontrib><creatorcontrib>Dhodapkar, Madhav V</creatorcontrib><creatorcontrib>Copeland, Wilbert B</creatorcontrib><creatorcontrib>Fox, Brian</creatorcontrib><creatorcontrib>Hoering, Antje</creatorcontrib><creatorcontrib>Fitch, Alison</creatorcontrib><creatorcontrib>Newhall, Katie</creatorcontrib><creatorcontrib>Barlogie, Bart</creatorcontrib><creatorcontrib>Trotter, Matthew W B</creatorcontrib><creatorcontrib>Hershberg, Robert M</creatorcontrib><creatorcontrib>Walker, Brian A</creatorcontrib><creatorcontrib>Dervan, Andrew P</creatorcontrib><creatorcontrib>Ratushny, Alexander V</creatorcontrib><creatorcontrib>Morgan, Gareth J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health &amp; 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However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases. Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies. In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>33147277</pmid><doi>10.1371/journal.pmed.1003323</doi><orcidid>https://orcid.org/0000-0002-8615-6254</orcidid><orcidid>https://orcid.org/0000-0002-5669-414X</orcidid><orcidid>https://orcid.org/0000-0003-0566-3607</orcidid><orcidid>https://orcid.org/0000-0001-9959-1282</orcidid><orcidid>https://orcid.org/0000-0003-1448-1346</orcidid><orcidid>https://orcid.org/0000-0001-6116-1017</orcidid><orcidid>https://orcid.org/0000-0002-1701-4084</orcidid><orcidid>https://orcid.org/0000-0002-9616-6341</orcidid><orcidid>https://orcid.org/0000-0003-4843-8645</orcidid><orcidid>https://orcid.org/0000-0002-4709-3027</orcidid><orcidid>https://orcid.org/0000-0003-0978-2291</orcidid><orcidid>https://orcid.org/0000-0002-9361-0283</orcidid><orcidid>https://orcid.org/0000-0002-4271-6360</orcidid><orcidid>https://orcid.org/0000-0003-2921-6107</orcidid><orcidid>https://orcid.org/0000-0001-7993-5308</orcidid><orcidid>https://orcid.org/0000-0002-6482-8654</orcidid><orcidid>https://orcid.org/0000-0002-9090-0277</orcidid><orcidid>https://orcid.org/0000-0003-2498-7295</orcidid><oa>free_for_read</oa></addata></record>
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subjects Adult
Algorithms
Asymptomatic
Biology and Life Sciences
Biopsy
Bone marrow
Bone Marrow - pathology
Cancer
CD8 antigen
Clinical outcomes
Clinical trials
Cohort analysis
Cohort Studies
Computer applications
Development and progression
Estimates
Female
Gene expression
Genomes
Granulocytes
Health aspects
Humans
Immunohistochemistry
Informed consent
Leukocytes (granulocytic)
Lymphocytes T
Machine learning
Male
Medicine and Health Sciences
Middle Aged
Monocytes
Multiple myeloma
Multiple Myeloma - diagnosis
Multiple Myeloma - drug therapy
Multiple Myeloma - pathology
Mutation
Neutrophils
Patients
Physiological aspects
Plasma
Prognosis
Review boards
Thalidomide
Transplants & implants
Tumor Burden
Tumor Microenvironment
Tumors
title Bone marrow microenvironments that contribute to patient outcomes in newly diagnosed multiple myeloma: A cohort study of patients in the Total Therapy clinical trials
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