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1. A phase 2 study of isatuximab monotherapy in patients with multiple myeloma who are refractory to daratumumab

Author

Joseph Mikhael, Karim Belhadj-Merzoug, Cyrille Hulin, Laure Vincent, Philippe Moreau, Cristina Gasparetto, Ludek Pour, Ivan Spicka, Ravi Vij, Jeffrey Zonder, Djordje Atanackovic, Nashat Gabrail, Thomas G. Martin, Aurore Perrot, Samira Bensfia, Qilong Weng, Claire Brillac, Dorothée Semiond, Sandrine Macé, Kathryn P. Corzo, and Xavier Leleu

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2021
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2. Data from Carfilzomib Weekly plus Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Multiple Myeloma (IFM 2012-03): A Phase I Trial

Author

Thierry Facon, Cyrille Hulin, Hervé Avet-Loiseau, Philippe Moreau, Michel Attal, Eric G. Voog, Véronique Dorvaux, Jean-Claude Eisenmann, Damien Roos-Weil, Olivier Fitoussi, Jamile Frayfer, Catherine Humbrecht-Kraut, Olivier Decaux, Sophie Rigaudeau, Frédérique Kuhnowski, Sophie Cereja, Laurent Voillat, Fritz Offner, Anna Schmitt, Philippe Rodon, Jean Fontan, Marie-Lorraine Chrétien, Gérard Lepeu, Karim Belhadj-Merzoug, Marie-Odile Pétillon, Arnaud Jaccard, Murielle Roussel, Pascal Lenain, Pascal Bourquard, Jean-Valère Malfuson, Nathalie Meuleman, Carla Araujo, Mourad Tiab, Brigitte Kolb, Lionel Karlin, François Machuron, Alain Duhamel, Stéphanie Guidez, Valentine Richez, Guillemette Fouquet, and Xavier Leleu

Abstract

Purpose:Carfilzomib is a novel generation proteasome inhibitor. The Carmysap trial demonstrated that twice-weekly KMP (carfilzomib, melphalan, prednisone) might challenge the MPV (melphalan, prednisone, bortezomib) standard. We sought to study KMP weekly, allowing to increase carfilzomib's dose with maintained efficacy and improved safety profile.Patients and Methods:IFM2012-03, a phase I multicenter study of KMP weekly in elderly patients with newly diagnosed multiple myeloma (eNDMM), aimed to determine the MTD of carfilzomib. Carfilzomib was given intravenously at 36, 45, 56, and 70 mg/m2/day on days 1, 8, 15, and 22 with melphalan and prednisone, for nine 35-day induction cycles, followed by carfilzomib maintenance for 1 year. Three dose-limiting toxicities (DLT) determined MTD at the lower dose.Results:Thirty eNDMMs were treated, 6 per cohort at 36, 45, and 56 mg/m2 and 12 at 70 mg/m². There was one DLT at 36 mg/m2 (lymphopenia), one at 45 mg/m2 (lysis syndrome), two at 56 mg/m2 (cardiac insufficiency and febrile neutropenia), and two at 70 mg/m2 (vomiting and elevated liver enzymes). The safety profile was acceptable; however, specific attention must be paid to the risk of cardiovascular events, especially for elderly patients. The overall response rate was 93.3%, with 46.6% complete response.Conclusions:The MTD dose of carfilzomib was 70 mg/m2 in this KMP weekly study in eNDMM. Response rates, and especially CR rate, were remarkable in this population, and would benefit from being assessed in a larger-scale study. The IFM2012-03 study demonstrated that the MTD of carfilzomib weekly is 70 mg/m2 in eNDMM, and 56 mg/m2 for patients older than 75 years. Carfilzomib used weekly in combination has a good efficacy and safety profile in eNDMM.

Published
2023
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3. Supplementary Tables from Carfilzomib Weekly plus Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Multiple Myeloma (IFM 2012-03): A Phase I Trial

Author

Thierry Facon, Cyrille Hulin, Hervé Avet-Loiseau, Philippe Moreau, Michel Attal, Eric G. Voog, Véronique Dorvaux, Jean-Claude Eisenmann, Damien Roos-Weil, Olivier Fitoussi, Jamile Frayfer, Catherine Humbrecht-Kraut, Olivier Decaux, Sophie Rigaudeau, Frédérique Kuhnowski, Sophie Cereja, Laurent Voillat, Fritz Offner, Anna Schmitt, Philippe Rodon, Jean Fontan, Marie-Lorraine Chrétien, Gérard Lepeu, Karim Belhadj-Merzoug, Marie-Odile Pétillon, Arnaud Jaccard, Murielle Roussel, Pascal Lenain, Pascal Bourquard, Jean-Valère Malfuson, Nathalie Meuleman, Carla Araujo, Mourad Tiab, Brigitte Kolb, Lionel Karlin, François Machuron, Alain Duhamel, Stéphanie Guidez, Valentine Richez, Guillemette Fouquet, and Xavier Leleu

Abstract

Supplementary tables 1 to 5

Published
2023
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4. Supplementary Figures from Carfilzomib Weekly plus Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Multiple Myeloma (IFM 2012-03): A Phase I Trial

Author

Thierry Facon, Cyrille Hulin, Hervé Avet-Loiseau, Philippe Moreau, Michel Attal, Eric G. Voog, Véronique Dorvaux, Jean-Claude Eisenmann, Damien Roos-Weil, Olivier Fitoussi, Jamile Frayfer, Catherine Humbrecht-Kraut, Olivier Decaux, Sophie Rigaudeau, Frédérique Kuhnowski, Sophie Cereja, Laurent Voillat, Fritz Offner, Anna Schmitt, Philippe Rodon, Jean Fontan, Marie-Lorraine Chrétien, Gérard Lepeu, Karim Belhadj-Merzoug, Marie-Odile Pétillon, Arnaud Jaccard, Murielle Roussel, Pascal Lenain, Pascal Bourquard, Jean-Valère Malfuson, Nathalie Meuleman, Carla Araujo, Mourad Tiab, Brigitte Kolb, Lionel Karlin, François Machuron, Alain Duhamel, Stéphanie Guidez, Valentine Richez, Guillemette Fouquet, and Xavier Leleu

Abstract

Supplementary Figure 1. Complementary survival curves for the whole cohort (n=30). (A) Event Free Survival (EFR); (B) Time to new treatment (TTNT); (C) Duration of response (DOR). Supplementary Figure 2. Progression Free Survival and Overall Survival according to cytogenetic risk (n=30). (A) PFS according to cytogenetic risk; (B) OS according to cytogenetic risk.

Published
2023
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5. Daratumumab plus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: frailty subgroup analysis of MAIA

Author

Thierry Facon, Gordon Cook, Saad Z. Usmani, Cyrille Hulin, Shaji Kumar, Torben Plesner, Cyrille Touzeau, Nizar J. Bahlis, Supratik Basu, Hareth Nahi, Hartmut Goldschmidt, Hang Quach, Mohamad Mohty, Christopher P. Venner, Katja Weisel, Noopur Raje, Benjamin Hebraud, Karim Belhadj-Merzoug, Lotfi Benboubker, Olivier Decaux, Salomon Manier, Denis Caillot, Jon Ukropec, Huiling Pei, Rian Van Rampelbergh, Clarissa M. Uhlar, Rachel Kobos, Sonja Zweegman, CHU Lille, Leeds Institute of Cancer and Pathology [U.K.], The Levine Cancer Institute, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Mayo Clinic [Rochester], University of Southern Denmark (SDU), Centre hospitalier universitaire de Nantes (CHU Nantes), University of Calgary, University of Wolverhampton, Karolinska University Hospital [Stockholm], Karolinska Institute, UniversitätsKlinikum Heidelberg, University of Melbourne, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Alberta, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Massachusetts General Hospital [Boston], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor [Créteil], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Janssen Research & Development, Amsterdam UMC - Amsterdam University Medical Center, This study was sponsored by Janssen Research & Development, LLC. The authors thank the patients who participated in this study and their families, as well as the study co-investigators, research nurses, and coordinators at each of the clinical sites. Medical writing and editorial support were provided by Grace Wang, PharmD, of Cello Health Communications/MedErgy, and were funded by Janssen Global Services, LLC., Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Amsterdam UMC, Hematology, CCA - Cancer Treatment and quality of life, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent

Subjects
Cancer Research, health care facilities, manpower, and services, [SDV]Life Sciences [q-bio], Dexamethasone, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Humans, Multiple Myeloma/diagnosis, Lenalidomide, Retrospective Studies, Frailty, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Antibodies, Monoclonal, Hematology, Dexamethasone/therapeutic use, 3. Good health, [SDV] Life Sciences [q-bio], Frailty/diagnosis, Lenalidomide/therapeutic use, Oncology, 030220 oncology & carcinogenesis, Multiple Myeloma, human activities, 030215 immunology
Abstract

In the phase 3 MAIA study of patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab plus lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd). We present a subgroup analysis of MAIA by frailty status. Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit, intermediate, non-frail (fit + intermediate), or frail. Of the randomized patients (D-Rd, n = 368; Rd, n = 369), 396 patients were non-frail (D-Rd, 196 [53.3%]; Rd, 200 [54.2%]) and 341 patients were frail (172 [46.7%]; 169 [45.8%]). After a 36.4-month median follow-up, non-frail patients had longer PFS than frail patients, but the PFS benefit of D-Rd versus Rd was maintained across subgroups: non-frail (median, not reached [NR] vs 41.7 months; hazard ratio [HR], 0.48; P P = 0.003). Improved rates of complete response or better and minimal residual disease (10–5) negativity were observed for D-Rd across subgroups. The most common grade 3/4 treatment-emergent adverse event in non-frail and frail patients was neutropenia (non-frail, 45.4% [D-Rd] and 37.2% [Rd]; frail, 57.7% and 33.1%). These findings support the clinical benefit of D-Rd in transplant-ineligible NDMM patients enrolled in MAIA, regardless of frailty status.

Published
2022
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6. A phase 2 study of isatuximab monotherapy in patients with multiple myeloma who are refractory to daratumumab

Author

Ravi Vij, Dorothée Semiond, Aurore Perrot, Claire Brillac, Thomas G. Martin, Djordje Atanackovic, Kathryn P. Corzo, Jeffrey A. Zonder, Sandrine Macé, Cristina Gasparetto, Philippe Moreau, Ludek Pour, Joseph Mikhael, Cyrille Hulin, Qilong Weng, Karim Belhadj-Merzoug, Laure Vincent, Samira Bensfia, Nashat Gabrail, Xavier Leleu, and Ivan Spicka

Subjects
Isatuximab, Oncology, medicine.medical_specialty, business.industry, MEDLINE, Phases of clinical research, Daratumumab, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Hematology, medicine.disease, Text mining, Refractory, Internal medicine, Medicine, In patient, business, Multiple myeloma, RC254-282
Published
2021

7. Carfilzomib maintenance in newly diagnosed non-transplant eligible multiple myeloma

Author

Sophie Cereja, Damien Roos-Weil, Laurent Voillat, Marie-Odile Petillon, Véronique Dorvaux, Marie-Lorraine Chretien, Nathalie Meuleman, Hervé Avet-Loiseau, Arthur Bobin, Olivier Fitoussi, Carla Araujo, Murielle Roussel, Eric Voog, Frédérique Kuhnowski, Intergroupe Francophone du Myelome Multiple, Jean Claude Eisenmann, Mourad Tiab, Catherine Humbrecht-Kraut, Thierry Facon, Jean-Valère Malfuson, Brigitte Kolb, Karim Belhadj-Merzoug, Philippe Rodon, Pascal Bourquard, Lionel Karlin, Olivier Decaux, Maeva Kyheng, Valentine Richez, Sophie Rigaudeau, Jamile Frayfer, Xavier Leleu, Philippe Moreau, Arnaud Jaccard, Alain Duhamel, Aurore Perrot, Pascal Lenain, Cyrille Hulin, Cécile Gruchet-Merouze, Jean Fontan, Anna Schmitt, Stéphanie Guidez, Fritz Offner, INSERM CIC 0802 (INSERM - CHU de Poitiers), Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Limoges, Hôpital Henri Mondor, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut Bergonié [Bordeaux], UNICANCER, Institut Curie [Paris], CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Strasbourg, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Bordeaux [Bordeaux], Amgen, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Université de Poitiers, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Oncology, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], MEDLINE, Antineoplastic Agents, Newly diagnosed, Maintenance Chemotherapy, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Humans, Multiple myeloma, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, 0303 health sciences, business.industry, Hematology, medicine.disease, Carfilzomib, Progression-Free Survival, 3. Good health, chemistry, 030220 oncology & carcinogenesis, Multiple Myeloma, business, Oligopeptides
Abstract

International audience

Published
2022
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8. Apixaban for the prevention of thromboembolism in immunomodulatory‐treated myeloma patients: Myelaxat, a phase 2 pilot study

Author

Brigitte Pegourie, Frédérique Orsini-Piocelle, Charles Zarnitsky, Benoit Bareau, Jean-Gabriel Fuzibet, Eric Voog, Philippe Rodon, Sophie Auger-Quittet, Xavier Leleu, Olivier Decaux, Eileen M Boyle, Bohrane Slama, Lotfi Benboubker, Gilles Pernod, Philippe Rey, Bruno Royer, Lionel Karlin, Cecile Leyronnas, Karim Belhadj-Merzoug, Manuel Cliquennois, Mourad Tiab, and J.-L. Bosson

Subjects
Male, medicine.medical_specialty, Pyridones, Prednisolone, Deep vein, Context (language use), Asymptomatic, Dexamethasone, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, cardiovascular diseases, Lenalidomide, Melphalan, Aged, Aspirin, business.industry, Venous Thromboembolism, Hematology, Middle Aged, Thalidomide, Clinical trial, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Pyrazoles, Female, Apixaban, medicine.symptom, Multiple Myeloma, business, 030215 immunology, medicine.drug
Abstract

The risk of venous thromboembolism (VTE) is higher in myeloma patients receiving immunomodulatory compounds. A VTE prophylaxis using low-molecular-weight heparin or aspirin is therefore proposed. Apixaban is an oral direct anti-Xa. Several studies have shown the efficacy and safety of apixaban in VTE prophylaxis compared to enoxaparin. The objective of this prospective phase 2 pilot study was to assess the risk of VTE and bleeding in patients with myeloma treated with immunomodulatory compounds lenalidomide (len) or thalidomide (thal), using apixaban in a preventive scheme. Myeloma patients requiring Melphalan-Prednisone-Thalidomide in the first line, or Lenalidomide-Dexamethasone in the relapse setting received apixaban, 2.5 mg x 2/day for 6 months. Venous (pulmonary embolism-PE, or symptomatic proximal or distal deep vein thrombosis-DVT, or all proximal asymptomatic events detected by systematic proximal bilateral compression ultrasound) or arterial thrombotic events, and bleeding events (ISTH 2005) were registered. One hundred and four patients were enrolled (mean age 69.8 ± 7.8 years), 11 in first line and 93 in relapse. Two venous thrombotic events were observed, for example, an asymptomatic proximal DVT and a symptomatic distal DVT, in the context of apixaban stopped 14 days before, due to lenalidomide-induced thrombocytopenia. No PE or arterial cardiovascular events were reported. Only one major and 11 CRNM hemorrhages were reported. These data must now be confirmed on a randomized large study.

Published
2019
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9. Carfilzomib Weekly plus Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Multiple Myeloma (IFM 2012-03): A Phase I Trial

Author

Pascal Lenain, Sophie Rigaudeau, Cyrille Hulin, Jean Fontan, Catherine Humbrecht-Kraut, Marie-Lorraine Chretien, Hervé Avet-Loiseau, Frédérique Kuhnowski, Philippe Moreau, Jean Claude Eisenmann, Karim Belhadj-Merzoug, Murielle Roussel, Damien Roos-Weil, Marie-Odile Petillon, Alain Duhamel, Brigitte Kolb, Stéphanie Guidez, Jean Valère Malfuson, Véronique Dorvaux, Michel Attal, Anna Schmitt, Nathalie Meuleman, Valentine Richez, Sophie Cereja, François Machuron, Lionel Karlin, Olivier Decaux, Laurent Voillat, Thierry Facon, Fritz Offner, Mourad Tiab, Olivier Fitoussi, Pascal Bourquard, Guillemette Fouquet, Gérard Lepeu, Arnaud Jaccard, Xavier Leleu, Philippe Rodon, Jamile Frayfer, Carla Araujo, and Eric Voog

Subjects
Male, Melphalan, Oncology, Cancer Research, medicine.medical_specialty, Maximum Tolerated Dose, Population, Drug Administration Schedule, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Prednisone, immune system diseases, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, cardiovascular diseases, education, Survival rate, neoplasms, Response Evaluation Criteria in Solid Tumors, Multiple myeloma, Aged, Aged, 80 and over, education.field_of_study, Bortezomib, business.industry, Hematopoietic Stem Cell Transplantation, Sciences bio-médicales et agricoles, medicine.disease, Carfilzomib, Survival Rate, Treatment Outcome, chemistry, 030220 oncology & carcinogenesis, Female, Patient Safety, Multiple Myeloma, business, Oligopeptides, Febrile neutropenia, 030215 immunology, medicine.drug
Abstract

Carfilzomib is a novel generation proteasome inhibitor. The Carmysap trial demonstrated that twice-weekly KMP (carfilzomib, melphalan, prednisone) might challenge the MPV (melphalan, prednisone, bortezomib) standard. We sought to study KMP weekly, allowing to increase carfilzomib's dose with maintained efficacy and improved safety profile., info:eu-repo/semantics/published

Published
2019

10. PF592 IMPACT OF AGE ON EFFICACY AND SAFETY OF DARATUMUMAB IN COMBINATION WITH LENALIDOMIDE AND DEXAMETHASONE (D-RD) IN PATIENTS WITH TRANSPLANT-INELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM): MAIA

Author

Hartmut Goldschmidt, L. Garderet, Noopur Raje, Maria Krevvata, M. Qi, Shaji Kumar, Torben Plesner, Lotfi Benboubker, Christopher Chiu, Cyrille Hulin, J. Wang, Clarissa M. Uhlar, Christopher P. Venner, Thierry Facon, Michael O'Dwyer, Katja Weisel, Salomon Manier, Hareth Nahi, Nizar J. Bahlis, Supratik Basu, Cyrille Touzeau, Benjamin Hebraud, Rachel Kobos, Hang Quach, Karim Belhadj-Merzoug, Saad Usmani, Denis Caillot, R. Van Rampelbergh, Gordon Cook, Olivier Decaux, and Robert Z. Orlowski

Subjects
Oncology, medicine.medical_specialty, business.industry, Daratumumab, Hematology, Newly diagnosed, medicine.disease, Transplant ineligible, Internal medicine, medicine, In patient, business, Multiple myeloma, Dexamethasone, Lenalidomide, medicine.drug
Published
2019
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11. PF607 MAINTENANCE WITH WEEKLY CARFILZOMIB IN ELDERLY NEWLY DIAGNOSED MULTIPLE MYELOMA (IFM 2012–03)

Author

G. Fouquet, Brigitte Kolb, T. Facon, Lionel Karlin, Karim Belhadj-Merzoug, H. Avet-Loiseau, A. Duhamel, Pascal Lenain, Pascal Bourquard, P. Moreau, X. Leleu, M. Tiab, M. Attal, Cyrille Hulin, A. Bobin, and A. Jaccard

Subjects
Oncology, medicine.medical_specialty, chemistry.chemical_compound, chemistry, business.industry, Internal medicine, medicine, Hematology, Newly diagnosed, business, medicine.disease, Carfilzomib, Multiple myeloma
Published
2019
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12. Carfilzomib Weekly Plus Melphalan and Prednisone in Newly Diagnosed Elderly Multiple Myeloma (IFM 2012-03)

Author

Mourad Tiab, Xavier Leleu, Pascal Bourquard, Philippe Moreau, Laurent Voillat, Brigitte Kolb, Jean Fontan, Arnaud Jaccard, Marie-Odile Petillon, Thierry de Revel, Olivier Decaux, Philippe Rodon, Anna Schmitt, Jean Claude Eisenmann, Frédérique Kuhnowski, Véronique Dorvaux, Nathalie Meuleman, Gérard Lepeu, Damien roos Weil, Marie-Lorraine Chretien, Murielle Roussel, Olivier Fitoussi, Karim Belhadj-Merzoug, Michel Attal, Sophie Cereja, Thierry Facon, Catherine Humbrecht-Kraut, Lionel Karlin, Fritz Offner, Carla Araujo, Eric Voog, Jamile Frayfer, Pascal Lenain, Cyrille Hulin, Sophie Rigaudeau, Service d'Hématologie, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Hôpital Général de La Roche sur Yon, CRLCC Henri Becquerel, CHU Pontchaillou [Rennes], Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Contrôle de la Réponse Immune B et des Lymphoproliférations ( CRIBL ), Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre hospitalier d'Avignon, CH Avignon, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Service d'hématologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -hopital Jean Minjoz, Centre Hospitalier Chalon-sur-Saône William Morey, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier de Meaux, Centre hospitalier régional Metz-Thionville ( CHR Metz-Thionville ), Hôpital Universitaire de Vandoeuvre les Nancy, Laboratoire d'Hématologie [Rangueil], Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital de Rangueil, Service d'Hématologie Clinique, Centre hospitalier universitaire de Nantes ( CHU Nantes ), Hôpital Claude Huriez, and Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille )

Subjects
Melphalan, Cancer Research, medicine.medical_specialty, [ SDV ] Life Sciences [q-bio], business.industry, Immunology, Cell Biology, Hematology, Newly diagnosed, medicine.disease, Biochemistry, Pulmonary hypertension, Carfilzomib, chemistry.chemical_compound, Peripheral neuropathy, Oncology, chemistry, Prednisone, Internal medicine, medicine, business, Intensive care medicine, Multiple myeloma, Febrile neutropenia, medicine.drug
Abstract

Background. New standards with increasing efficacy that are also characterized with improving the quality of life are needed for elderly myeloma patients. Although MPT and MPV regimens are remarkable in terms of efficacy, quality of life while on treatment with these 2 regimens remain an issue. The Carmysap twice weekly carfilzomib-based phase 2 study has demonstrated that Carfilzomib at the MTD of 36mg/m² might challenge bortezomib in the VMP standard. However, it has become routine practice to use bortezomib on a weekly schedule, with maintained efficacy and an improved safety profile. We sought to demonstrate that Carfilzomib Weekly plus Melphalan and Prednisone will prove strongly efficacious with acceptable safety profile and quality of life to newly diagnosed elderly multiple myeloma (eNDMM). Methods . IFM2012-03 (also called carmysap weekly) is a phase 1/2 multicenter open label single arm study to determine MTD during the phase 1 part and VGPR+CR rate during the phase 2 part of the study. The inclusion/exclusion criteria of interest were eNDMM (65 and older), with symptomatic and measurable disease, with absolute neutrophils ≥1 G/L, untransfused platelet count ≥75 G/L, hemoglobine ≥8.5 g/dL and clairance creatinine ≥ 30ml/min. We report herein the phase 1 part of the study which last cohort was completed at ASH abstract deadline. For the phase 1 part of the study, each cohort was 6 patients based, and started at 36mg/m² of carfilzomib on days 1, 8, 15, 22 using IV, 30 minutes infusion, route followed by a 13-day rest period per 35-days cycles, melphalan given at 0.25mg/kg/j and oral prednisone 60mg/m², both on days 1 to 4. The subsequent cohorts' doses for carfilzomib were 45, then 56 and finally 70mg/m². 9 cycles were planned as induction followed by a maintenance phase of weekly carfilzomib monotherapy given at 36mg/m² weekly for one year. The MTD was determined when ˃2 DLTs were observed. DLTs were considered during cycle 1 if any hematologic toxicity of grade 4 intensity or preventing administration of 2 or more of the 4 carfilzomib doses of the first treatment cycle, grade ≥3 febrile neutropenia, grade ≥3 gastrointestinal toxicities, any other grade ≥3 nonhematologic toxicity considered related to CMP by the principal investigator, grade ≥ 3 peripheral neuropathy persisting for more than 3 weeks after discontinuation of study drugs. Results. 26 NDMM patients recruited, 24 treated in the study, 6 per cohort at 36 mg/m² carfilzomib +MP, then 45 then 56, and finally at 70mg/m² which cohort cycle 1 is up and running. The median age was 74 with 10 patients older than 75 and sex ratio M/F 65. There was a DLT at 36 mg/m² carfilzomib (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3). At ASH deadline, all patients from cohort 36 of carfilzomib have completed induction and maintenance up to cycle 6, 5/6 of cohort 45 have completed induction and started the maintenance phase, 5/6 of cohort 56 have completed cycle 6 of induction and pursue within the induction phase, and finally all patients from cohort 70 of carfilzomib are undergoing cycle 1. There are 22 SAE reported for a total of 171 cycles administered of carfilzomib +MP. So far, 3 patients (out of 24) have stopped treatment, including the 2 patients with DLTs, lysis syndrome and cardiac failure, and one patient that presented with pulmonary hypertension later in the disease course on cycle 5 of the 56mg/m² carfilzomib +MP cohort. And, an extra 3 patients have had Carfilzomib dose reduction, 2 patients at 36 from 45 and one at 45 from 56, for neutropenia grade 4, thrombocytopenia grade 4, and Dyspnea grade 3, respectively. Conclusion. The MTD of weekly carfilzomib in the combination to Melphalan and Prednisone could be determined at 70mg/m² in elderly NDMM, demonstrating the good safety profile of carfilzomib in this regimen and fragile population. The complete dataset of the entire study will be updated at ASH with response rate, survival and safety profile. Disclosures Leleu: Chugai: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Karlin:Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Fitoussi:Sandoz: Membership on an entity's Board of Directors or advisory committees. Moreau:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Published
2015

13. IFM2012-03

Author

Xavier Leleu, Guillemette Fouquet, Lionel Karlin, Brigitte Kolb, Mourad Tiab, Carla Araujo, Nathalie Meuleman, Jv Malfuson, Pascal Bourquard, Pascal Lenain, Murielle Roussel, Arnaud Jaccard, Marie-Odile Petillon, Karim Belhadj-Merzoug, Gerard Lepeu, Marie-Lorraine Chretien, Jean Fontan, Philippe Rodon, Anna Schmitt, Fritz Offner, Laurent Voillat, Sophie Cereja, Frederique Kuhnowski, Sophie Rigaudeau, Olivier Decaux, Catherine Humbrecht-Kraut, Jamile Frayfer, Olivier Fitoussi, Damien Roos Weil, Jean Claude Eisenmann, Veronique Dorvaux, Eric G. Voog, Cyrille Hulin, Michel Attal, Philippe Moreau, and Thierry Facon

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Background. Melphalan plus prednisone and bortezomib combination is the most frequent standard of care used upfront for newly diagnosed elderly myeloma (eNDMM). Despite significant improvements with bortezomib sub-cutaneous administration and weekly schedule, safety profile issues remain with MPV, that only can be resolved with lowering the doses, albeit of the potential loss of efficacy. Carfilzomib (K), a novel generation proteasome inhibitor, has different safety profile with absence of neuropathy. Carmysap, a phase I/II trial of twice weekly Carfilzomib plus MP in eNDMM, demonstrated carfilzomib MTD at 36mg/m2. The safety profile appeared otherwise good for this frail population. We hypothesized that Carfilzomib can be used on a weekly schedule allowing to increase the dose of Carfilzomib given its positive safety profile. Methods. IFM2012-03 (carmysap weekly) is a phase 1/2 multicenter symptomatic eNDMM (65 and older) study to determine MTD during the phase 1 part and VGPR+CR rate (IMWG criteria) during the phase 2 part of KMP (Carfilzomib Weekly Plus Melphalan and Prednisone) regimen. Inclusion criteria required absolute neutrophils ≥1G/L, untransfused platelet count ≥75G/L, hemoglobine ≥8.5g/dL and clairance creatinine ≥30ml/min. Induction comprised nine 5 weeks cycles. K is given 36, 45, 56 and 70 mg/m2 on days 1, 8, 15, 22 IV route in combination to oral Melphalan 0.25mg/kg/j and oral prednisone 60mg/m2, both on days 1 to 4. Maintenance. Carfilzomib. 36 mg/m2 weekly, every two weeks IV route for 1 year. Melphalan and Prednisone is not pursued at maintenance. Analysis is done on ITT. Recruitment was 6 patients per cohort, 3 DLTs defined MTD at the lower N-1 dose. We will report at ASH the results of the phase 1 and 2. Results. 32 NDMM recruited, 30 treated in the study, 6 per cohort at K 36 mg/m², 45, 56, and 70 twice per DSMB request. The median age was 76 with 2/3rd older than 75, sex ratio M/F 1.2, R-ISS 2 and 3 in 80%.There was one DLT at K 36 (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3) and 2 at 70 (vomiting grade 3 and liver cholestase enzyme grade 3) across the 2 70 cohorts. As a whole for the study, the ORR is 87.5%, with 45.7% at least in CR. At data cut-off, with a median follow-up at 15 months, one patient had progressed and 2 had died of whom one of cardiac dysfunction considered K related at 56. The safery profile appeared well tolerated, however, 22 SAE were reported for a total of greater than 200 cycles administered of KMP. Of particular interest, 19 SAEs were reported across the K 56 and 70 cohorts, 6 of which were cardiovascular origin. Conclusion. IFM2012-03, KMP weekly, Carfilzomib plus Melphalan and Prednisone in elderly NDMM has reached RP2D at 70mg/m2 of K. The SAE signal at the highest dose of K 70 raise concerns on using K 70 in patients older than 75-80 years old, and the DSMB may recommend for these patients to limit the RP2D at 56mg/m2 of K. Updated data for phase 1 and 2 portions will be presented at ASH for the first time. Disclosures Leleu: TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Karlin:celgene: Consultancy, Honoraria; Bristol: Consultancy; takeda: Consultancy; janssen-cilag: Consultancy, Honoraria; amgen: Consultancy, Honoraria. Meuleman:Celgene: Consultancy; Bristol-Myers-Squibb: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Roussel:AMGEN: Consultancy, Other: lecture fees, Research Funding; sanofi: Other: lecture fees; celgene: Consultancy, Other: lecture fees, Research Funding; janssen: Consultancy, Other: lecture fees; BMS: Other: lecture fees. Decaux:The Binding Site: Other: supply of free light chain assays , Research Funding; SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding. Hulin:celgene: Honoraria; Bristol: Honoraria; Janssen: Honoraria; Amgen: Honoraria; takeda: Honoraria. Attal:amgen: Consultancy, Research Funding; sanofi: Consultancy; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding. Moreau:Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Facon:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Novartis: Consultancy; Millenium/Takeda: Consultancy.

Published
2016
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14. Contents, Vol. 80, 1988

Author

S.H. Advani, Angelo Rosolen, El Mouzan, Jerrold Fried, Pierre Colonna, V.R. Pai, Antonio Girolami, K.S. Nadkarni, P. Usai, F. Lauria, Nili Shaked, C. BIum, Bayard D. Clarkson, M. Baccarani, C.N. Nair, Yusuke Furukawa, J. Martirn, M. Cavo, A. Brisson-Lougarre, R. Navone, Subhash C. Gulati, S. Murgia, M.O. Al Sohaibani, S. Lannelli, Bracha Ramot, Mirghani A.M Ahmad, M.T. Petrini, Jean-Marie Andrieu, B.S. Charak, S.M. Karandikar, Alessandra Casonato, G. Valente, L. Azzoni, P. Galieni, S. Alie-Daram, P.A. Kurkure, S. Tura, Murat Tuncer, Tawfiq Henni, J. Grozdea, Isaac Ben-Bassat, Anna Rosa Lazzaro, P. Mazza, S.K. Pai, Shinobu Sakamoto, Yusuf M Al Gindan, Dan Douer, K.S. Tapan, F. Gherlinzoni, Zohara Jerushalmy, Jens Atzpodien, Annunziata Gloghini, R. Bierme, Jonathan E. Kolitz, M.A. Baldussi, Hiroyuki Nakamura, Eftal A. Yücel, David Wisniewski, R. Gopal, P.M. Parikh, Yasusada Miura, Mohamed Al Fadel Saleh, Marzia Cozzi, H Vergnes, C. Serra, Mati Shaklai, Antonino Carbone, Chihiro Shimazaki, A. Das Gupta, Karim Belhadj-Merzoug, Talma Englender, Semra Dündar, Paul Froom, and Ernest Beutler

Subjects
Hematology, General Medicine
Published
1988
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16. Subject Index, Vol. 80, 1988

Author

Zohara Jerushalmy, F. Gherlinzoni, David Wisniewski, Annunziata Gloghini, Angelo Rosolen, M.T. Petrini, Bayard D. Clarkson, Shinobu Sakamoto, A. Brisson-Lougarre, Talma Englender, F. Lauria, C. BIum, Yusuke Furukawa, Yasusada Miura, P.A. Kurkure, K.S. Tapan, M.A. Baldussi, Jonathan E. Kolitz, Marzia Cozzi, L. Azzoni, Mohamed Al Fadel Saleh, Alessandra Casonato, P. Usai, Chihiro Shimazaki, A. Das Gupta, J. Grozdea, Karim Belhadj-Merzoug, Semra Dündar, Subhash C. Gulati, Paul Froom, Ernest Beutler, Murat Tuncer, Anna Rosa Lazzaro, S.K. Pai, R. Bierme, Jens Atzpodien, P.M. Parikh, Eftal A. Yücel, G. Valente, S. Alie-Daram, K.S. Nadkarni, H Vergnes, S. Lannelli, Pierre Colonna, V.R. Pai, P. Mazza, M.O. Al Sohaibani, P. Galieni, R. Gopal, R. Navone, S.H. Advani, Antonio Girolami, El Mouzan, Jerrold Fried, S. Tura, Tawfiq Henni, Nili Shaked, C.N. Nair, Mirghani A.M Ahmad, S. Murgia, J. Martirn, Yusuf M Al Gindan, Bracha Ramot, M. Cavo, Dan Douer, C. Serra, Antonino Carbone, Jean-Marie Andrieu, Mati Shaklai, B.S. Charak, S.M. Karandikar, Hiroyuki Nakamura, M. Baccarani, and Isaac Ben-Bassat

Subjects
Index (economics), Statistics, Subject (documents), Hematology, General Medicine, Mathematics
Published
1988
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