Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial.

Administration, Intravenous Aged Anti-Inflammatory Agents / therapeutic use Antibodies, Monoclonal, Humanized / therapeutic use Dexamethasone / therapeutic use Drug Therapy, Combination Female Humans Immunologic Factors / therapeutic use Male Middle Aged Multiple Myeloma / drug therapy Oligopeptides / therapeutic use Progression-Free Survival Prospective Studies Recurrence Thalidomide / analogs & derivatives

Journal

Lancet (London, England)

ISSN: 1474-547X

Titre abrégé: Lancet

Pays: England

ID NLM: 2985213R

Informations de publication

Date de publication:
19 06 2021

Historique:

received: 11 12 2020

revised: 16 01 2021

accepted: 02 03 2021

pubmed: 8 6 2021

medline: 12 1 2022

entrez: 7 6 2021

Statut: ppublish

Résumé

Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib-dexamethasone versus carfilzomib-dexamethasone in patients with relapsed multiple myeloma. This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285. Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77-not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32-0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients. The addition of isatuximab to carfilzomib-dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population. Sanofi. VIDEO ABSTRACT.

Sections du résumé

BACKGROUND

METHODS

This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285.

FINDINGS

Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77-not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32-0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients.

INTERPRETATION

The addition of isatuximab to carfilzomib-dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population.

FUNDING

Sanofi. VIDEO ABSTRACT.

Identifiants

DOI: 10.1016/S0140-6736(21)00592-4 PMID: 34097854

pubmed: 34097854

pii: S0140-6736(21)00592-4

doi: 10.1016/S0140-6736(21)00592-4

pii:

doi:

Substances chimiques

Anti-Inflammatory Agents 0

Antibodies, Monoclonal, Humanized 0

Immunologic Factors 0

Oligopeptides 0

Thalidomide 4Z8R6ORS6L

carfilzomib 72X6E3J5AR

Dexamethasone 7S5I7G3JQL

pomalidomide D2UX06XLB5

isatuximab R30772KCU0

Banques de données

ClinicalTrials.gov

['NCT03275285']

Types de publication

Clinical Trial, Phase III Journal Article Multicenter Study Randomized Controlled Trial

Langues

eng

Sous-ensembles de citation

Pagination

2361-2371

Investigateurs

Philippe Moreau (P)

Meletios-Athanasios Dimopoulos (MA)

Joseph Mikhael (J)

Kwee Yong (K)

Marcelo Capra (M)

Thierry Facon (T)

Roman Hajek (R)

Ivan Spicka (I)

Ross Baker (R)

Kim Kihyun (K)

Gracia Martinez (G)

Min Chang-Ki (M)

Ludek Pour (L)

Xavier Leleu (X)

Albert Oriol (A)

Koh Youngil (K)

Kenshi Suzuki (K)

Tom Martin (T)

Hang Quach (H)

Andrew Lim (A)

Helen Crowther (H)

Hanlon Sia (H)

Cyrille Hulin (C)

Mohamad Mohty (M)

Gabor Mikala (G)

Zsolt Nagy (Z)

Marta Reinoso Segura (M)

Laura Rosinol (L)

Munci Yagci (M)

Mehmet Turgut (M)

Mamta Garg (M)

Gurdeep Parmar (G)

Brad Augustson (B)

Nelson Castro (N)

Edvan Crusoe (E)

Tomas Pika (T)

Sosana Delimpasi (S)

Kenichi Ishizawa (K)

Anup George (A)

Tatiana Konstantinova (T)

Javier De La Rubia (J)

Kim Sung-Hyun (K)

Angelo Maiolino (A)

Anthony Reiman (A)

Richard LeBlanc (R)

Shigeki Ito (S)

Junji Tanaka (J)

Alexander Luchinin (A)

Irina Kryuchkova (I)

Joaquin Martinez (J)

Jesse Shustik (J)

Lionel Karlin (L)

Anargyros Symeonidis (A)

Miklos Egyed (M)

Mario Petrini (M)

Michele Cavo (M)

Michihiro Uchiyama (M)

Hilary Blacklock (H)

Mutlu Arat (M)

James Griffin (J)

Hannah Hunter (H)

Tonda Buck (T)

Achilles Anagnostopoulos (A)

Konstantinos Konstantopoulos (K)

Tamas Masszi (T)

Sara Bringhen (S)

Barbara Gamberi (B)

Yawara Kawano (Y)

Kim Jin Seok (K)

Hakan Ozdogu (H)

Fahir Ozkalemkas (F)

Commentaires et corrections

Type : CommentIn

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of interests PM reports honoraria from Amgen, Celgene, Janssen, Novartis, and Takeda; and a consulting or advisory role for Amgen, Celgene, Janssen, Novartis, and Takeda. M-AD reports consulting or advisory role for Amgen, Bristol Myers Squibb (BMS), Celgene, Janssen, and Takeda. JM reports honoraria from Celgene, Takeda, BMS, Janssen, and Amgen; and a consulting or advisory role for Amgen, BMS, Celgene, Janssen-Cilag, and Takeda. KY reports a consulting or advisory role for Amgen, Janssen, and Takeda; speaker's bureau for Amgen and Takeda; and research funding from Amgen and Sanofi. MC reports speaker's bureau for Amgen, Janssen, and Sanofi. TF reports an advisory role for Amgen, BMS, Celgene, Karyopharm, Oncopeptides, Roche, Sanofi, and Takeda; and speaker's bureau for Takeda. RH reports personal fees from AbbVie, Amgen, BMS, Celgene, Pharma Mar, Novartis, and Takeda; and grants from Novartis and Takeda. IS reports a consulting or advisory role for Amgen, BMS, Celgene, Janssen-Cilag, Novartis, and Takeda; and speakers' bureau for Amgen, BMS, Celgene, Janssen-Cilag, Novartis, and Takeda. TM reports research funding from Amgen and Sanofi. M-LR, GA, and SM are employed by Sanofi and may hold shares or stock options in the company. RB reports research funding from AbbVie, Acerta Pharma, Alexion, Amgen, Bayer, BMS, Boehringer Ingelheim, Celgene, CSL Behring, Daiichi Sankyo, Jansen-Cilag, MorphoSys, Pfizer, Portola, Rigel Pharmaceuticals, Roche, Sanofi, Takeda, and Technoclone; and consulting or advisory roles for Jansen-Cilag and Roche. KK reports research funding from BMS and Janssen; and honoraria from Amgen, BMS, Janssen, and Takeda. AO reports honoraria from Amgen, Celgene, and Janssen. KS reports honoraria from AbbVie, Amgen, BMS, Celgene, Jansen, Novartis, ONO, Sanofi, and Takeda; and consulting or advisory roles for AbbVie, BMS, and Celgene. All other authors declare no competing interests.