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

Analyse de la prise en charge thérapeutique des patients atteints de leucémie lymphoïde chronique B diagnostiquée au Centre hospitalier de Grenoble entre le 1e janvier 1996 et le 31 décembre 2001

La prise en charge thérapeutique de 117 patients porteurs de LLC B diagnostiquée au centre hospitalier de Grenoble entre le 1e janvier 1996 et le 31 décembre 2001 a été analysée. Les patients en stade I à IV selon Rai au diagnostic ou après évolution d'un stade 0 ont été traités par Chloraminophène discontinu à forte dose. La survie globale des 60 patients traités par Chloraminophène est de 70 % à 5 ans avec une médiane de survie de 88 mois. La survie sans événement est de 30 % à 3 ans.38 patients (64.4 %) sont reclassés en stade 0 après Chloraminophène (répondeurs). Parmi eux, 18 resteront en stade 0 après une ligne de Chloraminophène, soit 30.5 %de la population traitée, avec un recul moyen de 49 mois. La reprise du Chloraminophène chez des patients antérieurement répondeurs permet d'obtenir un retour en stade 0 dans 58.3 % des cas. Par ailleurs, 6 patients ont été retraités par Chloraminophène après splénectomie et 5 (83.3%) ont pu être remis en stade 0. Parmi les 60 patients traités, 36 (60 %) sont en stade 0 à la date des dernières nouvelles, après une ou plusieurs lignes thérapeutiques, avec un recul moyen de 59 mois.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Recommandations de l’IFM (Intergroupe francophone du myélome) pour l’harmonisation de l’analyse des électrophorèses des protéines sériques et urinaires dans le diagnostic et le suivi du myélome multiple [IFM (Intergroupe francophone du myelome) recommendations for uniform interpretation of serum and urine protein electrophoresis in multiple myeloma diagnosis and follow-up]

National audienceSerum and urine proteins electrophoresis take a major place in multiple myeloma management, at time of diagnosis, during follow-up for treatment response evaluation and also in detection of relapse. The Intergroupe francophone du myelome (IFM) suggests recommendations to clinicians and biologists, to perform and interpret these biochemical analysis, with the objective of harmonizing practices between laboratories and improving patients' follow-up

Twice Weekly Induction with Ixazomib-Lenalidomide-Dexamethasone (IRd) Combination Followed By Extended IRD Consolidation and Lenalidomide Maintenance in Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM): A Phase 2 Study from the Intergroupe Francophone Du Myelome (IFM 2014-03)

61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Orlando, FL, DEC 07-10, 2019International audienc

Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results.

International audienceThe combination of pomalidomide and low-dose dexamethasone (Pom-Dex) can be safely administered to patients with end-stage relapsed/refractory multiple myeloma (RRMM). However, we observed a shorter median progression-free survival (PFS) and overall survival (OS) in these patients when characterized with adverse cytogenetics (deletion 17p and translocation [4;14]) in the Intergroupe Francophone Myélome (IFM) 2009-02 trial. We then sought to determine whether MM with adverse cytogenetics would benefit more from Pom-Dex if exposed earlier in the multicenter IFM 2010-02 trial. The intention-to-treat population included 50 patients, with a median age of 63 years (38% were ≥65 years). Interestingly, there was a striking difference in time to progression (TTP), duration of response, and overall response rate (ORR) according to the presence of del(17p) compared with t(4;14) (TTP, 7.3 vs 2.8 months; duration of response, 8.3 vs 2.4 months; and ORR, 32% vs 15%). OS was prolonged after Pom-Dex, particularly in t(4;14), given the short TTP, suggesting that patients were rescued at relapse with further lines of therapy. Pom-Dex, a doublet immunomodulatory drug-based regimen, is active and well tolerated in adverse cytogenetic patients with early RRMM, particularly in those with del(17p), who are characterized by a high and rapid development of a refractoriness state and known for their poor prognosis. Future studies will determine the underlying mechanisms of Pom-Dex activity in del(17p). This trial is registered at www.clinicaltrials.gov as #NCT01745640

Heavy + light chain analysis to assign myeloma response is analogous to the IMWG response criteria

IF 2.755International audienceAutomated serum heavy + light chain (HLC) immunoassays can measure the intact immunoglobulins of each light chain type separately. We though to compare HLC assays with electrophoretic techniques in determining International Myeloma Working Group (IMWG) response criteria. 114 myeloma patients from 2 trials were included. HLC measurements were made utilizing archived sera and response assessments compared with those based on electrophoretic analysis at the time of the trials. Assessments at ∼90 days and maximal response were compared as was the power of the 2 techniques for predicting later responses, overall survival, and progression. The kappa statistic indicated good agreement between the 2 methods for determining IMWG response criteria, although HLC measurements might give better predictions of subsequent responses and frequently gave an earlier indication of change. HLC measurements could represent an alternative to electrophoretic techniques in determining IMWG response. Validation with a greater range of patient responses is needed for confirmation