Richard K. Kandasamy, Joel-Sean Hsu, Steve Eacker, Hayley Magelson, Zachary D. Stephens, Angela Dispenzieri, Esteban Braggio, P. Leif Bergsagel, Rafael Fonseca, S. Vincent Rajkumar, Shaji K. Kumar, Linda B. Baughn, Wilson I. Gonsalves, Akhilesh Pandey
<p>Multiple myeloma (MM) is a hematological malignancy with heterogeneous clinical courses despite morphological similarity, a phenomenon driven primarily by the genetic abnormalities seen in the disease. A plethora of primary genetic abnormalities, such as translocations involving immunoglobulin loci and trisomies, along with secondary chromosomal aberrations (mainly 17p, 1p, 13q deletions, 1q gains, and/or <i>MYC</i> translocations) are present in MM, with the latter underlying the serial progression of MGUS to MM [<span>1</span>]. Cytogenetic analysis with fluorescence in situ hybridization (FISH) is currently the gold-standard method for identifying these genetic abnormalities. However, owing to the poor proliferative capacity of plasma cells in frequently hemodiluted bone marrow aspirates, it is often difficult to get adequate yields of plasma cell metaphases, preventing karyotyping analysis and necessitating interphase FISH [<span>2</span>]. This limitation has largely been overcome by using a variety of FISH probes, which allowed detection of various genetic alterations including numerical amplifications or deletions, structural rearrangements, and translocations [<span>3</span>]. However, there are still several limitations of FISH-based analyses including detection sensitivity and inter-laboratory variation in analysis and scoring [<span>4</span>]. More importantly, genomic variations can also result in false positive/negative findings—for instance, 50% of MYC rearrangements are missed by the break apart probe due to variable MYC genomic rearrangements [<span>5</span>].</p> <p>The establishment of individualized and mutation-guided targeted therapies is of great importance to further improve clinical outcomes [<span>1</span>]. The Revised International Staging System (R-ISS) [<span>6</span>] and the Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART) [<span>7</span>] are the two most widely accepted prognostic classification systems that have adopted these methodologies. Overall, classifying the patients into high-risk or standard risk categories is mainly driven by the genetic abnormalities. Patients with del(17p), <i>t</i>(4;14), <i>t</i>(14;16), <i>t</i>(14;20), and specific chromosome 1 abnormalities are considered high-risk in whom survival remains poorer in spite of novel drugs and maintenance strategies. More recently, the International Myeloma Society (IMS) and the International Myeloma Working Group (IMWG) released the Consensus Genomic Staging (CGS) of high-risk MM (HRMM) to identify poor prognosis patients [<span>8</span>]. This CGS system for HRMM relies on the presence of one of these abnormalities derived from genomic methods: (1) Deletion of 17p (with a cancer clonal fraction of 20% or more) and/or the presence of a <i>TP53</i> mutation; (2) IGH translocations—including t(4;14), t(14;16), or t(14;20)—in combination with either 1q gain/amplification and/or deletion of 1p32; (3) Monoallelic deletion of 1p32 accompa
{"title":"Genomic Proximity Mapping for Identification of Chromosomal Aberrations in Multiple Myeloma","authors":"Richard K. Kandasamy, Joel-Sean Hsu, Steve Eacker, Hayley Magelson, Zachary D. Stephens, Angela Dispenzieri, Esteban Braggio, P. Leif Bergsagel, Rafael Fonseca, S. Vincent Rajkumar, Shaji K. Kumar, Linda B. Baughn, Wilson I. Gonsalves, Akhilesh Pandey","doi":"10.1002/ajh.70219","DOIUrl":"https://doi.org/10.1002/ajh.70219","url":null,"abstract":"<p>Multiple myeloma (MM) is a hematological malignancy with heterogeneous clinical courses despite morphological similarity, a phenomenon driven primarily by the genetic abnormalities seen in the disease. A plethora of primary genetic abnormalities, such as translocations involving immunoglobulin loci and trisomies, along with secondary chromosomal aberrations (mainly 17p, 1p, 13q deletions, 1q gains, and/or <i>MYC</i> translocations) are present in MM, with the latter underlying the serial progression of MGUS to MM [<span>1</span>]. Cytogenetic analysis with fluorescence in situ hybridization (FISH) is currently the gold-standard method for identifying these genetic abnormalities. However, owing to the poor proliferative capacity of plasma cells in frequently hemodiluted bone marrow aspirates, it is often difficult to get adequate yields of plasma cell metaphases, preventing karyotyping analysis and necessitating interphase FISH [<span>2</span>]. This limitation has largely been overcome by using a variety of FISH probes, which allowed detection of various genetic alterations including numerical amplifications or deletions, structural rearrangements, and translocations [<span>3</span>]. However, there are still several limitations of FISH-based analyses including detection sensitivity and inter-laboratory variation in analysis and scoring [<span>4</span>]. More importantly, genomic variations can also result in false positive/negative findings—for instance, 50% of MYC rearrangements are missed by the break apart probe due to variable MYC genomic rearrangements [<span>5</span>].</p>\u0000<p>The establishment of individualized and mutation-guided targeted therapies is of great importance to further improve clinical outcomes [<span>1</span>]. The Revised International Staging System (R-ISS) [<span>6</span>] and the Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART) [<span>7</span>] are the two most widely accepted prognostic classification systems that have adopted these methodologies. Overall, classifying the patients into high-risk or standard risk categories is mainly driven by the genetic abnormalities. Patients with del(17p), <i>t</i>(4;14), <i>t</i>(14;16), <i>t</i>(14;20), and specific chromosome 1 abnormalities are considered high-risk in whom survival remains poorer in spite of novel drugs and maintenance strategies. More recently, the International Myeloma Society (IMS) and the International Myeloma Working Group (IMWG) released the Consensus Genomic Staging (CGS) of high-risk MM (HRMM) to identify poor prognosis patients [<span>8</span>]. This CGS system for HRMM relies on the presence of one of these abnormalities derived from genomic methods: (1) Deletion of 17p (with a cancer clonal fraction of 20% or more) and/or the presence of a <i>TP53</i> mutation; (2) IGH translocations—including t(4;14), t(14;16), or t(14;20)—in combination with either 1q gain/amplification and/or deletion of 1p32; (3) Monoallelic deletion of 1p32 accompa","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"286 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146153576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Meletios A. Dimopoulos, Ioannis Ntanasis-Stathopoulos, Efstathios Kastritis
<p>We read with great interest the correspondence by Dr. Wang and colleagues entitled “Determinants of Ultra-Long-Term Survival in Multiple Myeloma: A Critical Appraisal of Foundational Assumptions and a Call for Biologically Driven Inquiry” regarding our recent publication, “Determinants of 15-Year Progression-Free Survival in Multiple Myeloma: Real-World Data from a Single Institution” [<span>1</span>]. We thank the authors for their thoughtful engagement and for emphasizing the importance of biologically driven research in this area.</p> <p>We acknowledge and we have already highlighted in the Discussion of our manuscript that the long observation window of our cohort encompasses substantial therapeutic evolution patterns in multiple myeloma. This temporal heterogeneity was anticipated and unavoidable since our study evaluated outcomes with a follow up of at least 15 years; this characteristic was explicitly addressed in the statistical analyses. The aim of our study was not to define predictors applicable solely to modern regimens, but to characterize the clinical phenotype of patients who achieved sustained remission including earlier therapeutic approaches. We believe that these data may serve as an important benchmark to be used as a comparator to novel treatment approaches including anti-CD38-based quadruplets and triplets in the first line of treatment [<span>2</span>].</p> <p>Regarding the concept of complete response (CR), we agree that the definition has evolved with the advent of minimal residual disease (MRD) testing. MRD negativity has indeed emerged as a robust prognostic marker in modern clinical research. While MRD data were unavailable for the earlier years of our cohort, all surviving patients with evaluable bone marrow samples at 15 years who were MRD-negative by modern assays remain progression-free at last follow-up. These findings suggest that a subset of historical CRs likely corresponded biologically to MRD-negative states by current standards.</p> <p>The correspondents also raised the issue of the observed association between female sex and longer survival. Actually, sex was not significantly associated with survival outcomes in the multivariable analysis. In any case, such observations should be viewed as exploratory and they may reflect unmeasured social, behavioral, or treatment-tolerance factors rather than inherent biological differences.</p> <p>Finally, we share the authors' view that the next frontier lies in biologically grounded, multi-omics research. Our group is actively pursuing integrative multi-omics studies combining genomic, immune, and MRD profiling of long-term survivors to better define the molecular underpinnings of sustained remission and potential “functional cure.”</p> <p>We thank Dr. Wang and colleagues for their insightful comments. As already stated in our manuscript, we regard our findings not as conclusive but as a foundation upon which molecularly informed investigation can build to inform c
{"title":"Response to “Determinants of Ultra-Long-Term Survival in Multiple Myeloma: A Critical Appraisal of Foundational Assumptions and a Call for Biologically Driven Inquiry”","authors":"Meletios A. Dimopoulos, Ioannis Ntanasis-Stathopoulos, Efstathios Kastritis","doi":"10.1002/ajh.70232","DOIUrl":"https://doi.org/10.1002/ajh.70232","url":null,"abstract":"<p>We read with great interest the correspondence by Dr. Wang and colleagues entitled “Determinants of Ultra-Long-Term Survival in Multiple Myeloma: A Critical Appraisal of Foundational Assumptions and a Call for Biologically Driven Inquiry” regarding our recent publication, “Determinants of 15-Year Progression-Free Survival in Multiple Myeloma: Real-World Data from a Single Institution” [<span>1</span>]. We thank the authors for their thoughtful engagement and for emphasizing the importance of biologically driven research in this area.</p>\u0000<p>We acknowledge and we have already highlighted in the Discussion of our manuscript that the long observation window of our cohort encompasses substantial therapeutic evolution patterns in multiple myeloma. This temporal heterogeneity was anticipated and unavoidable since our study evaluated outcomes with a follow up of at least 15 years; this characteristic was explicitly addressed in the statistical analyses. The aim of our study was not to define predictors applicable solely to modern regimens, but to characterize the clinical phenotype of patients who achieved sustained remission including earlier therapeutic approaches. We believe that these data may serve as an important benchmark to be used as a comparator to novel treatment approaches including anti-CD38-based quadruplets and triplets in the first line of treatment [<span>2</span>].</p>\u0000<p>Regarding the concept of complete response (CR), we agree that the definition has evolved with the advent of minimal residual disease (MRD) testing. MRD negativity has indeed emerged as a robust prognostic marker in modern clinical research. While MRD data were unavailable for the earlier years of our cohort, all surviving patients with evaluable bone marrow samples at 15 years who were MRD-negative by modern assays remain progression-free at last follow-up. These findings suggest that a subset of historical CRs likely corresponded biologically to MRD-negative states by current standards.</p>\u0000<p>The correspondents also raised the issue of the observed association between female sex and longer survival. Actually, sex was not significantly associated with survival outcomes in the multivariable analysis. In any case, such observations should be viewed as exploratory and they may reflect unmeasured social, behavioral, or treatment-tolerance factors rather than inherent biological differences.</p>\u0000<p>Finally, we share the authors' view that the next frontier lies in biologically grounded, multi-omics research. Our group is actively pursuing integrative multi-omics studies combining genomic, immune, and MRD profiling of long-term survivors to better define the molecular underpinnings of sustained remission and potential “functional cure.”</p>\u0000<p>We thank Dr. Wang and colleagues for their insightful comments. As already stated in our manuscript, we regard our findings not as conclusive but as a foundation upon which molecularly informed investigation can build to inform c","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"45 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Carmina Fatigati, Silvia Costantini, Immacolata Andolfo, Maria Rosaria Storino, Marco Laccetti, Tiziana Di Matola, Anna Spasiano, Michela Grosso, Alessandra Perrotta, Roberta Russo, Paolo Ricchi
{"title":"A Rare Combination of High‐Affinity Hemoglobin, Non‐Transfusion‐Dependent Thalassemia (Αlpha‐Triplication and Codon 39 Mutation), and Hereditary Stomatocytosis","authors":"Carmina Fatigati, Silvia Costantini, Immacolata Andolfo, Maria Rosaria Storino, Marco Laccetti, Tiziana Di Matola, Anna Spasiano, Michela Grosso, Alessandra Perrotta, Roberta Russo, Paolo Ricchi","doi":"10.1002/ajh.70223","DOIUrl":"https://doi.org/10.1002/ajh.70223","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"302 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pregnancy and Bariatric Surgery: Very Different and Very Similar","authors":"Maureen Okam Achebe, Michael Auerbach","doi":"10.1002/ajh.70227","DOIUrl":"https://doi.org/10.1002/ajh.70227","url":null,"abstract":"<h2> Conflicts of Interest</h2>\u0000<p>The authors declare no conflicts of interest.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"56 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Silvia Escribano-Serrat,Ofrat Beyar-Katz,Roni Shouval,Parastoo B Dahi,Sigrun Einarsdottir,Shamir Geller,Marina Gomez-Llobel,Andre Goy,Steven M Horwitz,Cecilia Lezcano,Efrat Luttwak,Andrea Moy,Jae H Park,Miguel-Angel Perales,Melissa Pulitzer,Kai Rejeski,Jason Romancik,Amethyst Saldia,Gilles Salles,Craig Sauter,Michael Scordo,Gunjan Shah,Cesar A Virgen,M Lia Palomba,Andrew Ip,Robert Stuver
{"title":"CD19 CAR T-Cell Therapy in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type.","authors":"Silvia Escribano-Serrat,Ofrat Beyar-Katz,Roni Shouval,Parastoo B Dahi,Sigrun Einarsdottir,Shamir Geller,Marina Gomez-Llobel,Andre Goy,Steven M Horwitz,Cecilia Lezcano,Efrat Luttwak,Andrea Moy,Jae H Park,Miguel-Angel Perales,Melissa Pulitzer,Kai Rejeski,Jason Romancik,Amethyst Saldia,Gilles Salles,Craig Sauter,Michael Scordo,Gunjan Shah,Cesar A Virgen,M Lia Palomba,Andrew Ip,Robert Stuver","doi":"10.1002/ajh.70218","DOIUrl":"https://doi.org/10.1002/ajh.70218","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"6 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146072987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dunia Hatabah,Noor Alzraikat,Zayir M Malik,Sarah G Lazarus,Rawan Korman,Nitya Bakshi,Chris A Rees,Robert Hagbom,Claudia R Morris
{"title":"Clinician Assessment for Acute Chest Syndrome in Febrile Children With Sickle Cell Disease Revisited.","authors":"Dunia Hatabah,Noor Alzraikat,Zayir M Malik,Sarah G Lazarus,Rawan Korman,Nitya Bakshi,Chris A Rees,Robert Hagbom,Claudia R Morris","doi":"10.1002/ajh.70213","DOIUrl":"https://doi.org/10.1002/ajh.70213","url":null,"abstract":"","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"73 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Weiqiang Liu, Christian Kassasseya, Lazaros Papamanolis, Kim-Anh Nguyen-Peyre, Morgane Garreau, Saskia Eckert, Gonzalo De Luna, Thomas d'Humières, Vincent de Pierrefeu, Cecile Arnaud, Nour Bekeziz, Marie Pierre Gobin Metteil, Corentin Provost, Jean-Frédéric Gerbeau, Suzanne Verlhac, Pablo Bartolucci, Irene Vignon-Clementel
Sickle cell disease (SCD) is the leading cause of stroke in children and young adults, primarily due to cerebral vasculopathy (CV) occurring within the first decade of life. The main risk factor for CV is elevated blood velocity in intracranial arteries, contributing to stenosis formation in very young children. This study addresses three key questions: (i) the relationship between hemoglobin levels and intracranial blood velocities in SCD patients, (ii) additional factors contributing to elevated velocity beyond anemia, and (iii) the presence of flow anomalies. To investigate these aspects, biological and transcranial Doppler data from pediatric and adult SCD patients were analyzed. An image-based in silico modeling approach was also developed to simulate blood flow in the internal carotid, anterior cerebral, and middle cerebral arteries of SCD patients, of different age classes, and prior to any possible stenosis. Analysis revealed that while anemia is a recognized CV risk factor, it does not fully explain elevated velocities, as no significant correlation was found in children under five. In in silico simulations, young patients reached pathological arterial intracranial velocities at physiological flow rates, whereas adults remained below risk thresholds even at high flow rates. Pathological velocities were primarily observed in distal internal carotid arteries, where stenoses often develop. High flow rates, small arterial diameters, and pronounced curvatures led to extreme velocities and complex flow, likely causing endothelial damage and promoting CV progression. These findings enhance understanding of hemodynamic mechanisms underlying SCD-related stroke risk, paving the way for improved predictive models and early interventions.
{"title":"Vascular Geometry Drives Stroke Risk in Sickle Cell Disease","authors":"Weiqiang Liu, Christian Kassasseya, Lazaros Papamanolis, Kim-Anh Nguyen-Peyre, Morgane Garreau, Saskia Eckert, Gonzalo De Luna, Thomas d'Humières, Vincent de Pierrefeu, Cecile Arnaud, Nour Bekeziz, Marie Pierre Gobin Metteil, Corentin Provost, Jean-Frédéric Gerbeau, Suzanne Verlhac, Pablo Bartolucci, Irene Vignon-Clementel","doi":"10.1002/ajh.70184","DOIUrl":"10.1002/ajh.70184","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Sickle cell disease (SCD) is the leading cause of stroke in children and young adults, primarily due to cerebral vasculopathy (CV) occurring within the first decade of life. The main risk factor for CV is elevated blood velocity in intracranial arteries, contributing to stenosis formation in very young children. This study addresses three key questions: (i) the relationship between hemoglobin levels and intracranial blood velocities in SCD patients, (ii) additional factors contributing to elevated velocity beyond anemia, and (iii) the presence of flow anomalies. To investigate these aspects, biological and transcranial Doppler data from pediatric and adult SCD patients were analyzed. An image-based in silico modeling approach was also developed to simulate blood flow in the internal carotid, anterior cerebral, and middle cerebral arteries of SCD patients, of different age classes, and prior to any possible stenosis. Analysis revealed that while anemia is a recognized CV risk factor, it does not fully explain elevated velocities, as no significant correlation was found in children under five. In in silico simulations, young patients reached pathological arterial intracranial velocities at physiological flow rates, whereas adults remained below risk thresholds even at high flow rates. Pathological velocities were primarily observed in distal internal carotid arteries, where stenoses often develop. High flow rates, small arterial diameters, and pronounced curvatures led to extreme velocities and complex flow, likely causing endothelial damage and promoting CV progression. These findings enhance understanding of hemodynamic mechanisms underlying SCD-related stroke risk, paving the way for improved predictive models and early interventions.</p>\u0000 \u0000 <p>\u0000 <b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT05199766.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"101 3","pages":"477-486"},"PeriodicalIF":9.9,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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