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Dive into the research topics where Michel Attal is active.

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Featured researches published by Michel Attal.


Leukemia | 2007

Bone marrow mesenchymal stem cells are abnormal in multiple myeloma

Jill Corre; Karène Mahtouk; Michel Attal; Mélanie Gadelorge; Anne Huynh; Sandrine Fleury-Cappellesso; Clotaire Danho; Patrick Laharrague; Bernard Klein; Thierry Rème; Philippe Bourin

Recent literature suggested that cells of the microenvironment of tumors could be abnormal as well. To address this hypothesis in multiple myeloma (MM), we studied bone marrow mesenchymal stem cells (BMMSCs), the only long-lived cells of the bone marrow microenvironment, by gene expression profiling and phenotypic and functional studies in three groups of individuals: patients with MM, patients with monoclonal gamopathy of undefined significance (MGUS) and healthy age-matched subjects. Gene expression profile independently classified the BMMSCs of these individuals in a normal and in an MM group. MGUS BMMSCs were interspersed between these two groups. Among the 145 distinct genes differentially expressed in MM and normal BMMSCs, 46% may account for a tumor-microenvironment cross-talk. Known soluble factors implicated in MM pathophysiologic features (i.e. IL (interleukin)-6, DKK1) were revealed and new ones were found which are involved in angiogenesis, osteogenic differentiation or tumor growth. In particular, GDF15 was found to induce dose-dependent growth of MOLP-6, a stromal cell-dependent myeloma cell line. Functionally, MM BMMSCs induced an overgrowth of MOLP-6, and their capacity to differentiate into an osteoblastic lineage was impaired. Thus, MM BMMSCs are abnormal and could create a very efficient niche to support the survival and proliferation of the myeloma cells.


Leukemia | 2007

Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials

Philippe Moreau; Michel Attal; F Garban; Cyrille Hulin; Thierry Facon; Gerald Marit; Mauricette Michallet; Chantal Doyen; S Leyvraz; Mohamad Mohty; M Wetterwald; Claire Mathiot; Denis Caillot; Christian Berthou; L Benboubker; Laurent Garderet; C Chaleteix; C Traullé; J G Fuzibet; J Jaubert; Thierry Lamy; Philippe Casassus; M Dib; B Kolb; V Dorvaux; B Grosbois; I Yakoub-Agha; Jean Luc Harousseau; Hervé Avet-Loiseau

One hundred de novo multiple myeloma patients with t(4;14) treated with double intensive therapy according to IFM99 protocols were retrospectively analyzed. The median overall survival (OS) and event-free survival (EFS) were 41.4 and 21 months, respectively, as compared to 65 and 37 for patients included in the IFM99 trials without t(4;14) (P<10−7). We identified a subgroup of patients presenting at diagnosis with both low β2-microglobulin <4 mg/l and high hemoglobin (Hb) ⩾10 g/l (46% of the cases) with a median OS of 54.6 months and a median EFS of 26 months, respectively, which benefits from high-dose therapy (HDT); conversely patients with one or both adverse prognostic factor (high β2-microglobulin and/or low Hb) had a poor outcome. The achievement of either complete response or very good partial response after HDT was also a powerful independent prognostic factor for both OS and EFS.


Leukemia | 2013

Prognostic utility of intact immunoglobulin Ig'κ/Ig'λ ratios in multiple myeloma patients.

Arthur R. Bradwell; Harding S; Fourrier N; Claire Mathiot; Michel Attal; P. Moreau; Jean Luc Harousseau; Hervé Avet-Loiseau

To determine whether isotype matched immunoglobulin (Ig; Ig′κ/Ig′λ) ratios had prognostic significance in patients with intact Ig multiple myeloma (MM). Novel immunoassays measuring serum concentrations of the Ig heavy chain/light chain (HLC) subsets IgGκ, IgGλ, IgAκ and IgAλ were compared with monoclonal protein (‘M-spike’) quantification by serum protein electrophoresis, β2-microglobulin (β2-M), albumin, serum free light chain (FLC) and cytogenetic markers in relation to outcome in 339 MM patients. Abnormal IgGκ/IgGλ and IgAκ/IgAλ ratios present in the respective tumor isotypes at clinical presentation were predictive of shorter progression-free survival (PFS) (hazard ratio (HR) 1.9; P=0.0002), predominantly due to the suppression of the uninvolved (polyclonal) Ig of the same isotype as the tumor (HR 1.8; P=0.002). No significant associations were observed between PFS and M-spike concentrations, suppression of non-tumor Igs of different isotypes or FLC κ/λ ratios. β2-M and HLC ratios were independently prognostic (P=0.045 and P=0.001). A staging system using β2-M and extreme HLC ratios (<0.01 or >200) had greater prognostic value than the widely used ISS staging system (HR 1.7; P=0.00002 vs HR 1.3; P=0.017). These results suggest that HLC ratios may have a role in clinical management of MM.


Leukemia | 2013

Consolidation with VTd significantly improves the complete remission rate and time to progression following VTd induction and single autologous stem cell transplantation in multiple myeloma

Xavier Leleu; Guillemette Fouquet; Benjamin Hebraud; Murielle Roussel; Denis Caillot; Marie Lorraine Chretien; Bertrand Arnulf; Raphael Szalat; Laurent Garderet; Lina Benajiba; Brigitte Pegourie; Caroline Regny; Bruno Royer; Alexis Caulier; Anne-Marie Stoppa; Sylvain Garciaz; Cyrille Touzeau; C Chaleteix; J-P Fermand; Hervé Avet Loiseau; Thierry Facon; Michel Attal; P. Moreau

Consolidation with VTd significantly improves the complete remission rate and time to progression following VTd induction and single autologous stem cell transplantation in multiple myeloma


Leukemia | 2010

Stem cell collection in patients with de novo multiple myeloma treated with the combination of bortezomib and dexamethasone before autologous stem cell transplantation according to IFM 2005-01 trial

P. Moreau; Cyrille Hulin; Gerald Marit; Denis Caillot; Thierry Facon; P Lenain; Christian Berthou; Brigitte Pegourie; Anne-Marie Stoppa; Philippe Casassus; Mauricette Michallet; L Benboubker; H Maisonneuve; Chantal Doyen; S Leyvraz; Claire Mathiot; Hervé Avet-Loiseau; Michel Attal; Jean Luc Harousseau

Stem cell collection in patients with de novo multiple myeloma treated with the combination of bortezomib and dexamethasone before autologous stem cell transplantation according to IFM 2005–01 trial


Blood | 2016

Serum free light chains, not urine specimens, should be used to evaluate response in light-chain multiple myeloma.

Thomas Dejoie; Jill Corre; Helene Caillon; Cyrille Hulin; Aurore Perrot; Denis Caillot; Eileen Boyle; Marie-Lorraine Chretien; Jean Fontan; Karim Belhadj; Sabine Brechignac; Olivier Decaux; Laurent Voillat; Philippe Rodon; Olivier Fitoussi; Carla Araujo; Lotfi Benboubker; Charlotte Fontan; Mourad Tiab; Pascal Godmer; Odile Luycx; Olivier Allangba; Jean-Michel Pignon; Jean-Gabriel Fuzibet; Laurence Legros; Anne Marie Stoppa; Mamoun Dib; Brigitte Pegourie; Frédérique Orsini-Piocelle; Lionel Karlin

Guidelines for monitoring multiple myeloma (MM) patients expressing light chains only (light-chain MM [LCMM]) rely on measurements of monoclonal protein in urine. Alternatively, serum free light chain (sFLC) measurements have better sensitivity over urine methods, however, demonstration that improved sensitivity provides any clinical benefit is lacking. Here, we compared performance of serum and urine measurements in 113 (72κ, 41λ) newly diagnosed LCMM patients enrolled in the Intergroupe Francophone du Myélome (IFM) 2009 trial. All diagnostic samples (100%) had an abnormal κ:λ sFLC ratio, and involved (monoclonal) FLC (iFLC) expressed at levels deemed measurable for monitoring (≥100 mg/L). By contrast, only 64% patients had measurable levels of monoclonal protein (≥200 mg per 24 hours) in urine protein electrophoresis (UPEP). After 1 and 3 treatment cycles, iFLC remained elevated in 71% and 46% of patients, respectively, whereas UPEP reported a positive result in 37% and 18%; all of the patients with positive UPEP at cycle 3 also had elevated iFLC levels. Importantly, elevated iFLC or an abnormal κ:λ sFLC ratio after 3 treatment cycles associated with poorer progression-free survival (P = .006 and P < .0001, respectively), whereas positive UPEP or urine immunofixation electrophoresis (uIFE) did not. In addition, patients with an abnormal κ:λ sFLC ratio had poorer overall survival (P = .022). Finally, early normalization of κ:λ sFLC ratio but not negative uIFE predicted achieving negative minimal residual disease, as determined by flow cytometry, after consolidation therapy (100% positive predictive value). We conclude that improved sensitivity and prognostic value of serum over urine measurements provide a strong basis for recommending the former for monitoring LCMM patients.


Experimental Hematology | 2013

Evolving strategies with immunomodulating drugs and tandem autologous/allogeneic hematopoietic stem cell transplantation in first line high risk multiple myeloma patients.

Mauricette Michallet; Mohamad Sobh; Jean El-Cheikh; Stéphane Morisset; Anne Sirvent; Oumedaly Reman; Jérôme Cornillon; Reza Tabrizi; Noel Milpied; Jean-Luc Harousseau; Hélène Labussière; Franck-Emmanuel Nicolini; Michel Attal; Philippe Moreau; Mohamad Mohty; Didier Blaise; Hervé Avet-Loiseau

We prospectively evaluated in high-risk myeloma patients the efficacy and toxicity of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) followed by reduced-intensity conditioning (RIC) and allogeneic (allo)-HSCT with bortezomib and donor lymphocyte infusions introduction after allo-HSCT (group 1). Results were compared with results from tandem auto-RIC-allo-HSCT without bortezomib (group 2). Groups 1 and 2 were compared to matched patients not receiving allo-HSCT from the Intergroupe Francophone du Myélome prospective studies. Allo-HSCT groups included 25 patients (12 in group 1, 13 in group 2). All patients engrafted. There were 8 acute GVHD (7 grade II [3 in group 1], 1 grade III in group 1)] and 11 chronic GVHD (3 limited [in group 1], 8 extensive [1 in group 1]). Matched population included 36 controls for group 1 and 39 for group 2. After a median follow-up of 55 months (range, 3-142 months), median overall survival was not reached in group 1 versus 65 months (51-not reached [NR]) in its matched group (p = 0.027); it was 96 months (49-NR) in group 2 versus 91 months (32-NR) in its matched group (p = 0.77). Median progression-free survival was 49 months (29-NR) in group 1 and was 25 months (range, 21-35 months) in its matched group (p = 0.0045); it was 31 months (22-NR) in group 2 and 28 months (range, 21-40 months) in its matched group (p = 0.0776). Tandem auto-RIC-allo-HSCT including new molecules and immunomodulation after transplantation could be used as a first-line treatment for high-risk myeloma patients.


Leukemia | 2018

Heavy+light chain monitoring correlates with clinical outcome in multiple myeloma patients

Mauricette Michallet; C Chapuis-Cellier; T Dejoie; C Lombard; H Caillon; Mohamad Sobh; P. Moreau; Michel Attal; Hervé Avet-Loiseau

Novel anti-myeloma agents have improved patient response rates, which are historically based on reductions of the M-protein. These methods can be inaccurate for quantifying M-proteins at low concentrations. We compared the consistency and clinical impact of response assignment by electrophoretic and heavy+light chain (HLC) immunoassays post-consolidation in 463 newly diagnosed patients. The two methods gave similar assignments in patients with partial (PR; 79% agreement) or complete response (⩾CR; 92%). However, in patients achieving very good PR (VGPR) there was poor concordance between methods (45%). Median progression-free survival (PFS) for standard VGPR patients was 34.5 months; HLC responses stratified these patients further into PR, VGPR and ⩾CR, with median PFS of 21.3, 28.9 months and not reached, respectively; P<0.001. At this time, abnormal HLC ratios had better concordance with multiparametric flow cytometry (sensitivity 10−4) (37 and 34% positive, respectively), compared to immunofixation (62% positive). In addition, HLC-pair suppression was identified in 38% of patients and associated with shorter PFS (30.6 months vs not reached; P<0.001). We conclude that HLC monitoring could augment electrophoretic assessments in patients achieving VGPR. The prognostic significance of HLC responses might partly depend on the patients’ ability to recover their immune system, as determined by normalisation of HLC measurements.


Nature Communications | 2017

Expressed fusion gene landscape and its impact in multiple myeloma

Alice Cleynen; Raphael Szalat; M. Kemal Samur; S. Robiou du Pont; Laure Buisson; E. Boyle; M. L. Chretien; Kenneth C. Anderson; Stephane Minvielle; P. Moreau; Michel Attal; Giovanni Parmigiani; Jill Corre; Nikhil C. Munshi; Hervé Avet-Loiseau

Multiple myeloma is a plasma cell malignancy characterized by recurrent IgH translocations and well described genomic heterogeneity. Although transcriptome profiles in multiple myeloma has been described, landscape of expressed fusion genes and their clinical impact remains unknown. To provide a comprehensive and detailed fusion gene cartography and suggest new mechanisms of tumorigenesis in multiple myeloma, we performed RNA sequencing in a cohort of 255 newly diagnosed and homogeneously treated multiple myeloma patients with long follow-up. Here, we report that patients have on average 5.5 expressed fusion genes. Kappa and lambda light chains and IgH genes are main partners in a third of all fusion genes. We also identify recurrent fusion genes that significantly impact both progression-free and overall survival and may act as drivers of the disease. Lastly, we find a correlation between the number of fusions, the age of patients and the clinical outcome, strongly suggesting that genomic instability drives prognosis of the disease.Multiple myeloma is a malignancy of plasma cells in the blood. Here, the authors establish the landscape of fusion genes within this disease, identifying novel recurrent fusion genes that impact survival and may drive disease progression.


Annals of Oncology | 2016

Safe and prolonged survival with Long-term exposure to Pomalidomide in Relapsed/Refractory Myeloma

Guillemette Fouquet; Brigitte Pegourie; Margaret Macro; Marie-Odile Petillon; Lionel Karlin; Denis Caillot; Murielle Roussel; Bertrand Arnulf; Claire Mathiot; Gerald Marit; Brigitte Kolb; Anne-Marie Stoppa; Sabine Brechiniac; Valentine Richez; Philippe Rodon; Anne Banos; Marc Wetterwald; L. Garderet; Bruno Royer; Cyrille Hulin; Lotfi Benbouker; Olivier Decaux; Martine Escoffre-Barbe; Jean-Paul Fermand; Michel Attal; H. Avet-Loiseau; Philippe Moreau; Thierry Facon; Xavier Leleu

BACKGROUND The IFM2009-02 trial studied pomalidomide (4 mg daily, 21/28 versus 28/28) and dexamethasone in very advanced relapsed or refractory multiple myeloma (RRMM). We observed that 40% of patients had a prolonged progression-free survival (PFS) and subsequently overall survival (OS). We sought to analyze the characteristics of these patients and study the effect of long exposure to pomalidomide. DESIGN We separated the studied population into two groups: 3 months to 1 year (<1 year) and more than 1 year (≥1 year) of treatment with pomalidomide and dexamethasone based on clinical judgment and historical control studies. We then analyzed the characteristics of patients according to duration of treatment. RESULTS The overall response rate (ORR) for the <1-year group was 43%, the median PFS 4.6 months [95% confidence interval (95% CI) 3.8-6.4] with only 6% at 12 months, and the median OS was 15 months (11.7-20.3) and 40% at 18 months. For the ≥1-year group, the response rate and survival were strikingly different, ORR at 83%, median PFS 20.7 months (14.7-35.4), median OS not reached, and 91% at 18 months. CONCLUSION Pomalidomide and dexamethasone favored prolonged and safe exposure to treatment in 40% of heavily treated and end-stage RRMM, a paradigm shift in the natural history of RRMM characterized with a succession of shorter disease-free intervals and ultimately shorter survival. Although an optimization of pomalidomide-dexamethasone regimen is warranted in advanced RRMM, we claim that pomalidomide has proven once more to change the natural history of myeloma in this series, which should be confirmed in a larger study.

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Philippe Moreau

French Institute of Health and Medical Research

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Hervé Avet-Loiseau

French Institute of Health and Medical Research

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Chantal Doyen

Université catholique de Louvain

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