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

Abstract

BACKGROUND:

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.

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.

• Authors: Philippe Moreau, Meletios-Athanasios Dimopoulos, Joseph Mikhael, Kwee Yong, Marcelo Capra, Thierry Facon, Roman Hajek, Ivan Špička, Ross Baker, Kihyun Kim, Gracia Martinez, Chang-Ki Min, Ludek Pour, Xavier Leleu, Albert Oriol, Youngil Koh, Kenshi Suzuki, Marie-Laure Risse, Gaelle Asset, Sandrine Macé, Thomas Martin, IKEMA study group
• Journal: Lancet (London, England) (Lancet) Vol. 397 Issue 10292 Pg. 2361-2371 (06 19 2021) ISSN: 1474-547X [Electronic] England
• PMID: 34097854 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Antibodies, Monoclonal, Humanized
• Immunologic Factors
• Oligopeptides
• Thalidomide
• carfilzomib
• Dexamethasone
• pomalidomide
• isatuximab

Topics

• 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, therapeutic use)