TY - JOUR
T1 - Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM)
T2 - a randomised, multicentre, open-label, phase 3 study
AU - Attal, Michel
AU - Richardson, Paul G.
AU - Rajkumar, S. Vincent
AU - San-Miguel, Jesus
AU - Beksac, Meral
AU - Spicka, Ivan
AU - Leleu, Xavier
AU - Schjesvold, Fredrik
AU - Moreau, Philippe
AU - Dimopoulos, Meletios A.
AU - Huang, Jeffrey Shang Yi
AU - Minarik, Jiri
AU - Cavo, Michele
AU - Prince, H. Miles
AU - Macé, Sandrine
AU - Corzo, Kathryn P.
AU - Campana, Frank
AU - Le-Guennec, Solenn
AU - Dubin, Franck
AU - Anderson, Kenneth C.
AU - Richardson, Paul G.
AU - Rajkumar, Vincent
AU - Dimopoulos, Meletios A.
AU - Corzo, Kathryn P.
AU - Harrison, Simon
AU - Janowski, Wojt
AU - Kerridge, Ian
AU - Spencer, Andrew
AU - Delforge, Michel
AU - Fostier, Karel
AU - Vlummens, Philip
AU - Wu, Ka Lung
AU - Leblanc, Richard
AU - Pavic, Michel
AU - Sebag, Michael
AU - Hajek, Roman
AU - Maisnar, Vladimir
AU - Pour, Ludek
AU - Gregersen, Henrik
AU - Benbouker, Lotfi
AU - Caillot, Denis
AU - Escoffre-Barbe, Martine
AU - Facon, Thierry
AU - Frenzel, Laurent
AU - Hulin, Cyrille
AU - Karlin, Lionel
AU - Kolb, Brigitte
AU - Pegourie, Brigitte
AU - Perrot, Aurore
AU - Tiab, Mourad
AU - Vincent, Laure
AU - Niederwieser, Dietger
AU - Anagnostopoulos, Achilles
AU - Delimpasi, Sosana
AU - Kyrtsonis, Marie Christine
AU - Symeonidis, Anargyros
AU - Illes, Arpad
AU - Mikala, Gabor
AU - Nagy, Zsolt
AU - Bringen, Sara
AU - Corradini, Paolo
AU - Fabio, Ciceri
AU - Lemoli, Roberto
AU - Liberati, Anna
AU - Nozzoli, Chiara
AU - Zambello, Renato
AU - Iida, Shinsuke
AU - Ikeda, Takashi
AU - Iyama, Satoshi
AU - Matsumoto, Morio
AU - Shimazaki, Chihiro
AU - Sunami, Kazutaka
AU - Suzuki, Kenshi
AU - Uchiyama, Michihiro
AU - Koh, Youngil
AU - Kim, Kihyun
AU - Lee, Jae Hoon
AU - Min, Chang Ki
AU - Blacklock, Hillary
AU - Goodman, Hugh
AU - Neylon, Annette
AU - Simpson, David
AU - Grosicki, Sebastian
AU - Jurczyszyn, Artur
AU - Walter-Croneck, Adam
AU - Warzocha, Krzysztof
AU - Araujo, Luis
AU - Moreira, Claudia
AU - Doronin, Vadim
AU - Mendeleeva, Larisa
AU - Vorobyev, Vladimir
AU - Vranovsky, Andrej
AU - Alegre, Adrian
AU - Gironella, Mercedes
AU - Gonzalez Perez, Marta Sonia
AU - Montes, Carmen
AU - Ocio, Enrique
AU - Rodriguez, Paula
AU - Hardling, Mats
AU - Lauri, Birgitta
AU - Wang, Ming Chung
AU - Yeh, Su Peng
AU - Arat, Mutlu
AU - Demirkan, Fatih
AU - Gulbas, Zafer
AU - Besisik, Sevgi Kalayoglu
AU - Karadogan, Ihsan
AU - Tuglular, Tulin
AU - Unal, Ali
AU - Vural, Filiz
AU - Sive, Jonathan
AU - Streetly, Matthew
AU - Yong, Kwee
AU - Tache, Jason
N1 - Funding Information:
PGR reports a consulting or advisory role for Karyopharm, Oncopeptides, Celgene, Janssen, Takeda, and Sanofi; and research funding from Oncopeptides, Celgene, Takeda, and Bristol-Myers Squibb (BMS). MA reports research funding from Sanofi. SVR reports patents, royalties, and other intellectual property from UpToDate. JS-M reports a consulting or advisory role for Amgen, BMS, Celgene, Janssen, Merck Sharp & Dohme, Novartis, Roche, Sanofi, and Takeda. MB reports a consulting or advisory role for Amgen, Celgene, Janssen-Cilag, and Takeda; and speakers' bureau fees for Amgen, BMS, Celgene, and Janssen-Cilag. IS reports a consulting or advisory role and speakers' bureau for Amgen, BMS, Celgene, Janssen-Cilag, Novartis, and Takeda. XL reports honoraria from Abbvie, Amgen, BMS, Carsgen Therapeutics, Celgene, Janssen-Cilag, Karyopharm Therapeutics, Merck, Mundipharma, Novartis, Oncopeptides, Pierre Fabre, Roche, Sanofi and Takeda; a consulting or advisory role for Abbvie, Amgen, BMS, Carsgen Therapeutics, Celgene, Gilead Sciences, Janssen-Cilag, Karyopharm Therapeutics, Merck, Mundipharma, Novartis, Oncopeptides, Roche, and Takeda; and travel and accommodation expenses from Takeda. FS reports honoraria from Abbvie, Amgen, Celgene, Janssen China R&D, Novartis, and Takeda; a consulting or advisory role for Adaptive Biotechnologies, Amgen, Bayer, BMS, Celgene, Janssen China R&D, Oncopeptides, and Takeda; and research funding from Amgen and Janssen China R&D. PM reports honoraria from Amgen, Celgene, Janssen-Cilag, Novartis, and Takeda; and a consulting or advisory role for Amgen, Celgene, Janssen, Novartis, and Takeda. MAD reports honoraria from Celgene, Takeda, BMS, Janssen, and Amgen; and a consulting or advisory role for Amgen, BMS, Celgene, Janssen-Cilag, and Takeda. JS-YH reports research funding from Sanofi. JM reports consultancy and honoraria from Amgen, BMS, Celgene, Janssen, and Takeda; and is a clinical trials investigator for Amgen, Janssen, Karyopharm, Oncopeptides, and Sanofi. MC reports honoraria from Abbvie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GlaxoSmithKline, Janssen-Cilag, and Takeda; and a consulting or advisory role for Abbvie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GlaxoSmithKline, Janssen-Cilag, and Takeda. HMP reports honoraria and a consulting or advisory role from Amgen, Celgene, Janssen China R&D, Novartis, and Takeda; and research funding from Sanofi and Takeda. KCA reports stock and other ownership interests, and patents, royalties, and other intellectual property in C4 Therapeutics and OncoPep; and a consulting or advisory role for BMS, Celgene, Gilead Sciences, Janssen Oncology, Millennium, and Sanofi. SM, KPC, FC, SL-G, and FD are employees of Sanofi.
Funding Information:
This study was sponsored by Sanofi (Cambridge, MA, USA). We thank the participating patients and their families, the study centres and investigators for their contributions to the study, the members of the data monitoring committee (Gareth Morgan, Ludwig Heinz, James Neaton, Gary Schiller) and the following individuals working for or on behalf of Sanofi: Helgi van de Velde (data interpretation and manuscript review); Marlène Inchauspe and Laure Malinge (statistical support); Damien Arnal, Charlotte Cheinin, and Jean-Christophe Quirot (statistical programming support); Guillaume Bartoletti, Thierry Bourlard, Thomas Colineau, Pascale Joffre-Malamas, Ashley Koczur, Tina Patel, Stacie Poole, Cédric Radigue, Lorène Simonot, and Diane Stash (clinical trial management); Sylvie Assadourian, Fatima Menas, Laurent Mayrargue, Marie-Laure Risse, Emanuel Palatinsky, and Samira Bensfia (medical data review); Aruna Seth (editorial support); and Mike Healy and Alison E Schroeer (graphics support).
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/12/7
Y1 - 2019/12/7
N2 - Background: Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. Methods: We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2–3 vs >3) and age (<75 years vs ≥75 years). Treatments were assigned based on a permuted blocked randomisation scheme with a block size of four. The isatuximab–pomalidomide–dexamethasone group received isatuximab intravenously on days 1, 8, 15, and 22 in the first 28-day cycle, then on days 1 and 15 in subsequent cycles. Both groups received oral pomalidomide on days 1 to 21 in each cycle, and oral or intravenous dexamethasone on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. Dose reductions for adverse reactions were permitted for pomalidomide and dexamethasone, but not for isatuximab. The primary endpoint was progression-free survival, determined by an independent response committee and assessed in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. This study is registered at ClinicalTrials.gov, number NCT02990338. Findings: Between Jan 10, 2017, and Feb 2, 2018, we randomly assigned 307 patients to treatment: 154 to isatuximab–pomalidomide–dexamethasone, and 153 to pomalidomide–dexamethasone. At a median follow-up of 11·6 months (IQR 10·1–13·9), median progression-free survival was 11·5 months (95% CI 8·9–13·9) in the isatuximab–pomalidomide–dexamethasone group versus 6·5 months (4·5–8·3) in the pomalidomide–dexamethasone group; hazard ratio 0·596, 95% CI 0·44–0·81; p=0·001 by stratified log-rank test. The most frequent treatment-emergent adverse events (any grade; isatuximab–pomalidomide–dexamethasone vs pomalidomide–dexamethasone) were infusion reactions (56 [38%] vs 0), upper respiratory tract infections (43 [28%] vs 26 [17%]), and diarrhoea (39 [26%] vs 29 [20%]). Adverse events with a fatal outcome were reported in 12 patients (8%) in the isatuximab–pomalidomide–dexamethasone group and 14 (9%) in the pomalidomide–dexamethasone group. Deaths due to treatment-related adverse events were reported for one patient (<1%) in the isatuximab–pomalidomide–dexamethasone group (sepsis) and two (1%) in the pomalidomide–dexamethasone group (pneumonia and urinary tract infection). Interpretation: The addition of isatuximab to pomalidomide–dexamethasone significantly improves progression-free survival in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor. Funding: Sanofi. Video Abstract: [Figure presented]
AB - Background: Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. Methods: We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2–3 vs >3) and age (<75 years vs ≥75 years). Treatments were assigned based on a permuted blocked randomisation scheme with a block size of four. The isatuximab–pomalidomide–dexamethasone group received isatuximab intravenously on days 1, 8, 15, and 22 in the first 28-day cycle, then on days 1 and 15 in subsequent cycles. Both groups received oral pomalidomide on days 1 to 21 in each cycle, and oral or intravenous dexamethasone on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. Dose reductions for adverse reactions were permitted for pomalidomide and dexamethasone, but not for isatuximab. The primary endpoint was progression-free survival, determined by an independent response committee and assessed in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. This study is registered at ClinicalTrials.gov, number NCT02990338. Findings: Between Jan 10, 2017, and Feb 2, 2018, we randomly assigned 307 patients to treatment: 154 to isatuximab–pomalidomide–dexamethasone, and 153 to pomalidomide–dexamethasone. At a median follow-up of 11·6 months (IQR 10·1–13·9), median progression-free survival was 11·5 months (95% CI 8·9–13·9) in the isatuximab–pomalidomide–dexamethasone group versus 6·5 months (4·5–8·3) in the pomalidomide–dexamethasone group; hazard ratio 0·596, 95% CI 0·44–0·81; p=0·001 by stratified log-rank test. The most frequent treatment-emergent adverse events (any grade; isatuximab–pomalidomide–dexamethasone vs pomalidomide–dexamethasone) were infusion reactions (56 [38%] vs 0), upper respiratory tract infections (43 [28%] vs 26 [17%]), and diarrhoea (39 [26%] vs 29 [20%]). Adverse events with a fatal outcome were reported in 12 patients (8%) in the isatuximab–pomalidomide–dexamethasone group and 14 (9%) in the pomalidomide–dexamethasone group. Deaths due to treatment-related adverse events were reported for one patient (<1%) in the isatuximab–pomalidomide–dexamethasone group (sepsis) and two (1%) in the pomalidomide–dexamethasone group (pneumonia and urinary tract infection). Interpretation: The addition of isatuximab to pomalidomide–dexamethasone significantly improves progression-free survival in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor. Funding: Sanofi. Video Abstract: [Figure presented]
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U2 - 10.1016/S0140-6736(19)32556-5
DO - 10.1016/S0140-6736(19)32556-5
M3 - Article
C2 - 31735560
AN - SCOPUS:85076003168
VL - 394
SP - 2096
EP - 2107
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10214
ER -