Prise en charge des syndromes de Fanconi secondaires à une immunoglobuline monoclonale

Adult-acquired Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. It is characterized by urinary leak of phosphorus, uric acid and glucose. We retrospectively reviewed 21 patients diagnosed with adult-acquired FS between 1988 and 2012 in seven French centers.At diagnosis most patients had smoldering multiple myeloma (47%) or monoclonal gammopathy of undetermined significance (28%). They were usually referred for osteomalacia (30%) or chronic renal failure (55%). Every patient had tubular dysfunction and median creatinine level was 141 μmol/L (range 94-298). 19/21 patients had a renal biopsy performed, 40% showing characteristic crystal inclusions.18 patients received chemotherapy. The main indication for treatment was renal preservation. High dose melphalan followed by autologous stem cell transplantation was administrated in nine cases, without major complications. Six patients received bortezomib based therapy, with frequent grade III neuropathy. Imids were usually second line treatment, with acceptable safety and efficiency. Hematological response to treatment was satisfying. Six patients (33%) had an improvement of tubular disorder; every patient had a stabilization of creatinine level until free light chain (FLC) elevation.In conclusion, chemotherapy treatment may be proposed to patients with Fanconi syndrome if they are fit with a prolonged life expectancy. Benefice on renal function is probably better in case of early treatment.Le syndrome de Fanconi est une complication rare des gammapathies monoclonales, caractérisée par une dysfonction tubulaire proximale généralisée. Nous avons revu 21 patients suivis entre 1988 et 2012 dans 7 centres français. Au diagnostic la plupart des patients présente un myélome multiple de faible masse tumorale (47%) ou une gammapathie monoclonale de signification indéterminée (28%). Ils consultent pour ostéomalacie (30%) ou insuffisance rénale chronique (55%). Tous les patients ont une dysfonction tubulaire avec une hypophosphorémie associée à une hypouricémie, la créatinémie médiane est de 141 µmol/L (de 94 à 298 µmol/L). 19/21 patients ont eu une biopsie rénale, avec des inclusions cristallines dans le cytoplasme des cellules tubulaires dans 40% des cas. Des cristaux intra-histiocytaires évoquant le diagnostic d’histiocytoses cristallines ont été vus chez cinq patients.18 patients ont eu une chimiothérapie, majoritairement afin de préserver la fonction rénale. 9 patients ont reçu du melphalan à haute dose sans complications majeures. Six patients ont reçu un traitement à base de bortezomib, avec de fréquentes neuropathies de grade III conduisant à l’arrêt du traitement. Les IMIDs sont généralement des traitements de seconde ligne, avec une tolérance acceptable et une bonne efficacité.La réponse hématologique globale est satisfaisante. Les paramètres tubulaires s’améliorent chez 6 patients (33%) et dans tous les cas la créatinémie se stabilise jusqu’à ce que le taux de chaînes légères libre remonte.En conclusion, la chimiothérapie peut être proposée en ciblant l’hémopathie sous jacente. La récupération rénale est meilleure dans le cas d'un traitement précoce

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

Solitary Plasmacytoma Treated by Lenalidomide-Dexamethasone in Combination with Radiation Therapy: Clinical Outcomes

International audiencePurpose: The study evaluates the results of the concurrent use of lenalidomide-dexamethasone with intensity modulated radiation therapy (IMRT) for solitary plasmacytoma in terms of toxicity and outcome. Methods and Materials: Forty-six patients were treated for histologically proven solitary plasmacytoma (SP) between June 2007 and June 2018 in our Department (Curie Institute, Paris, France). All patients received IMRT. The median total dose was 40 Gy (range, 40-46). Prescription of concurrent lenalidomide-dexamethasone with radiation therapy was left to the discretion of the referring hematologist-oncologist and started the first day of radiation therapy for 4 cycles. Results: Twenty-seven solitary plasmacytoma were treated with IMRT alone and 19 with lenalidomide-dexamethasone in association with IMRT. At 5 years, the local control, multiple myeloma–free survival (MMFS), and progression-free survival (PFS) rates were 96.3%, 85.4%, and 60%. MMFS and PFS were significantly higher in the IMRT plus lenalidomide-dexamethasone group compared with IMRT alone group (100% vs 77.1%, P = .02 and 81.7% vs 48.4%, P = .047, respectively). No major toxicity was found in either group. Conclusions: Lenalidomide-dexamethasone in association with IMRT in the treatment of solitary plasmacytoma is safe and improves MMFS and PFS. Further prospective and comparative studies are needed to confirm these results

Fungal infections in patients treated with ibrutinib: two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis

International audienceLetters to the edito

The spectrum of neutrophilic dermatoses associated with monoclonal gammopathy: Association with IgA isotype and inflammatory profile

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Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies

The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in cancer progression and in host immunity. Idelalisib was the first of this class to be approved with the second-generation Pi3 kinase inhibitors copanlisib, duvelisib and umbralisib, subsequently being approved in the United States. Real-world data are lacking, however, in relation to the incidence and toxicity of Pi3 kinase inhibitor-induced colitis. We here review, in the first instance, the general landscape of the Pi3K inhibitors in the context of hematological malignancies, with a focus on the adverse gastrointestinal side effects reported by various clinical trials. We further review the available worldwide pharmacovigilance data in relation to these drugs. Finally, we describe our own real-world experience with idelalisib-induced colitis management in our center and in a national setting