Risk and Response-Adapted Treatment in Multiple Myeloma

Myeloma therapeutic strategies have been adapted to patients' age and comorbidities for a long time. However, although cytogenetics and clinical presentations (plasmablastic cytology; extramedullary disease) are major prognostic factors, until recently, all patients received the same treatment whatever their initial risk. No strong evidence allows us to use a personalized treatment according to one cytogenetic abnormality in newly diagnosed myeloma. Retrospective studies showed a benefit of a double autologous transplant in high-risk cytogenetics according to the International Myeloma Working Group definition (t(4;14), t(14;16) or del(17p)). Moreover, this definition has to be updated since other independent abnormalities, namely gain 1q, del(1p32), and trisomies 5 or 21, as well as TP53 mutations, are also prognostic. Another very strong predictive tool is the response to treatment assessed by the evaluation of minimal residual disease (MRD). We are convinced that the time has come to use it to adapt the strategy to a dynamic risk. Many trials are ongoing to answer many questions: when and how should we adapt the therapy, its intensity and duration. Nevertheless, we also have to take into account the clinical outcome for one patient, especially adverse events affecting his or her quality of life and his or her preferences for continuous/fixed duration treatment

Tracking seabird migration in the tropical Indian Ocean reveals basin-scale conservation need

Summary Understanding marine predator distributions is an essential component of arresting their catastrophic declines.1,2,3,4 In temperate, polar, and upwelling seas, predictable oceanographic features can aggregate migratory predators, which benefit from site-based protection.5,6,7,8 In more oligotrophic tropical waters, however, it is unclear whether environmental conditions create similar multi-species hotspots. We track the non-breeding movements and habitat preferences of a tropical seabird assemblage (n = 348 individuals, 9 species, and 10 colonies in the western Indian Ocean), which supports globally important biodiversity.9,10,11,12 We mapped species richness from tracked populations and then predicted the same diversity measure for all known Indian Ocean colonies. Most species had large non-breeding ranges, low or variable residency patterns, and specific habitat preferences. This in turn revealed that maximum species richness covered >3.9 million km2, with no focused aggregations, in stark contrast to large-scale tracking studies in all other ocean basins.5,6,7,13,14 High species richness was captured by existing marine protected areas (MPAs) in the region; however, most occurred in the unprotected high seas beyond national jurisdictions. Seabirds experience cumulative anthropogenic impacts13 and high mortality15,16 during non-breeding. Therefore, our results suggest that seabird conservation in the tropical Indian Ocean requires an ocean-wide perspective, including high seas legislation.17 As restoration actions improve the outlook for tropical seabirds on land18,19,20,21,22 and environmental change reshapes the habitats that support them at sea,15,16 appropriate marine conservation will be crucial for their long-term recovery and whole ecosystem restoration

Toll-like receptor 4 selective inhibition in medullar microenvironment alters multiple myeloma cell growth.

peer reviewedBone marrow (BM) mesenchymal stromal cells (MSCs) are abnormal in multiple myeloma (MM) and play a critical role by promoting growth, survival, and drug resistance of MM cells. We observed higher Toll-like receptor 4 (TLR4) gene expression in MM MSCs than in MSCs from healthy donors. At the clinical level, we highlighted that TLR4 expression in MM MSCs evolves in parallel with the disease stage. Thus, we reasoned that the TLR4 axis is pivotal in MM by increasing the protumor activity of MSCs. Challenging primary MSCs with TLR4 agonists increased the expression of CD54 and interleukin-6 (IL-6), 2 factors directly implicated in MM MSC-MM cell crosstalk. Then, we evaluated the therapeutic efficacy of a TLR4 antagonist combined or not with conventional treatment in vitro with MSC-MM cell coculture and in vivo with the Vk*MYC mouse model. Selective inhibition of TLR4 specifically reduced the MM MSC ability to support the growth of MM cells in an IL-6-dependent manner and delayed the development of MM in the Vk*MYC mouse model by altering the early disease phase in vivo. For the first time, we demonstrate that specific targeting of the pathological BM microenvironment via TLR4 signaling could be an innovative approach to alter MM pathology development

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

[Excerpt] Multiple myeloma (MM) is the third most common hematological malignancy, after Non-Hodgkin Lymphoma and Leukemia. MM is generally preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS) [1], and epidemiological studies have identified older age, male gender, family history, and MGUS as risk factors for developing MM [2]. The somatic mutational landscape of sporadic MM has been increasingly investigated, aiming to identify recurrent genetic events involved in myelomagenesis. Whole exome and whole genome sequencing studies have shown that MM is a genetically heterogeneous disease that evolves through accumulation of both clonal and subclonal driver mutations [3] and identified recurrently somatically mutated genes, including KRAS, NRAS, FAM46C, TP53, DIS3, BRAF, TRAF3, CYLD, RB1 and PRDM1 [3,4,5]. Despite the fact that family-based studies have provided data consistent with an inherited genetic susceptibility to MM compatible with Mendelian transmission [6], the molecular basis of inherited MM predisposition is only partly understood. Genome-Wide Association (GWAS) studies have identified and validated 23 loci significantly associated with an increased risk of developing MM that explain ~16% of heritability [7] and only a subset of familial cases are thought to have a polygenic background [8]. Recent studies have identified rare germline variants predisposing to MM in KDM1A [9], ARID1A and USP45 [10], and the implementation of next-generation sequencing technology will allow the characterization of more such rare variants. [...]French National Cancer Institute (INCA) and the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myélome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myélome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organizatio

Recent Advancements in Hematology: Knowledge, Methods and Dissemination, Part 2

Recent Advancements in Hematology: Knowledge, Methods and Dissemination is a series of commentary article which is published on a biannual basis by the editorial board of the journal Hemato [...

Caractérisation des cellules souches mésenchymateuses dans le myélome multiple

Le myélome multiple des os (MM) est une hémopathie maligne lymphocytaire B caractérisée par une prolifération clonale de plasmocytes conduisant à la destruction du tissu osseux. Les lésions osseuses sont le résultat d'une dérégulation de la balance des activités ostéoclastiques et ostéoblastiques. Si les mécanismes responsables de l'excès d'activité ostéoclastique sont maintenant en grande partie élucidés, la diminution de l'activité ostéoblastique est loin d'être comprise. La moelle osseuse contient deux types de cellules souches : les cellules souches hématopoïétiques et les cellules souches mésenchymateuses (CSM). Ces dernières sont à l'origine du microenvironnement médullaire, qui joue un rôle déterminant dans l'hématopoïèse. Les CSM sont caractérisées par leur capacité de différenciation vers les lignées cellulaires de type mésodermique, notamment les ostéoblastes. Nous avons voulu déterminer in vitro si les CSM isolées chez de patients atteints de MM présentent les mêmes caractéristiques quantitatives, phénotypiques et fonctionnelles que les CSM isolées chez des sujets sains. Aucune différence significative n'a été observée. Par des techniques de co-culture, nous avons également démontré que les lignées de plasmocytes de myélome ne prolifèrent pas d'avantage sur les CSM de myélome que sur les CSM normales. Enfin, par utilisation de puces à ADN, nous avons établi le profil d'expression génique des CSM isolées chez de patients atteints de MM et chez des sujets sains. 195 gènes ont été trouvés exprimés de façon différebtielle selon l'origine des CSM. Parmi ceux-ci, les gènes codant pour DKK-1, IL-1b et amphiréguline sont d'avantage exprimés dans les CSM de myélome, tandis que le gène codant pour SDF-1 est sous exprimé, par rapport aux CSM normales. Ces résultats ont été confirmés par RT-PCR et dosages ELISA dans les surnageants de culture...TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Précurseurs adipocytaires et adipocytes humains d origine médullaire et sous-cutanée (rôle dans l hématopoïèse)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Intérêt du myélogramme post-autogreffe dans la définition de la réponse au traitement chez 150 patients atteints de myélome multiple

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF