Page 226 - Haematologica Vol. 109 - July 2024

ARTICLE - ICARIA-MM final overall survival analysis Introduction
Multiple myeloma (MM) primarily remains an incurable dis- ease, and although novel agents have improved response and survival rates, almost all patients relapse either on or after these treatments.1-4 Treatment choice for relapsed and refractory MM (RRMM) is determined by refractoriness and exposure to prior drugs.5
Due to the need for novel treatments for RRMM, mono- clonal antibodies targeting CD38 have emerged, such as daratumumab and isatuximab.6-9 Isatuximab is a mono- clonal antibody targeting a specific epitope of the human cell-surface antigen CD38, which is widely and uniformly expressed on myeloma cells.10-12
Isatuximab was investigated in combination with pomalid- omide and dexamethasone (Pd) in a phase III, randomized, multicenter, open-label trial (ICARIA-MM; clinicaltrials gov. Identifier: NCT02990338).13 After a median follow-up of 11.6 months, median progression-free survival (PFS) was 11.5 (95% confidence interval [CI]: 8.9-13.9) months with isatuximab–pomalidomide–dexamethasone (Isa-Pd) and 6.5 (95% CI: 4.5-8.3) months with Pd alone.13 Median over- all survival (OS) was not reached in either treatment arm (hazard ratio [HR]=0.687; 95% CI: 0.461-1.023; P=0.0631).13 Results from a prespecified updated analysis at 24 months after the primary analysis reported a median OS of 24.6 months (95% CI: 20.3-31.3) with Isa-Pd versus 17.7 months (95% CI: 14.4-26.2) months with Pd (HR=0.76, 95% CI: 0.57-1.01).14
Based on the primary results of ICARIA-MM, isatuximab has been approved in several countries in combination with Pd for adult patients with RRMM who have received ≥2 previous therapies, including lenalidomide and a pro- teasome inhibitor (PI).11,15
This analysis of ICARIA-MM reports the final OS, conducted when 220 deaths occurred.
Methods
Study design and participants
ICARIA-MM is a prospective, multicenter, randomized, open-label, parallel-group phase III study conducted at 102 sites in 24 countries (Online Supplementary Appendix, page 2-3). Detailed inclusion and exclusion criteria, study design, randomization and masking, and procedures have been previously described and are detailed in the Online Supplementary Appendix, page 4-7.13,14
Briefly, eligible patients were ≥18 years old, had RRMM, received ≥2 previous therapies, and had failed therapy with lenalidomide and a PI (alone or in combination). Failure to therapy included progression on or within 60 days, intol- erance to lenalidomide or the PI, or disease progression within 6 months after achieving at least a partial response (PR). Patients refractory to previous anti-CD38 therapy, with
P.G. Richardson et al.
prior pomalidomide exposure, with an Eastern Cooperative Oncology Group Performance Status >2, an ongoing toxic effect grade >2 from previous therapy (grade according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03), with active primary amyloid light-chain amyloidosis, or concomitant plasma cell leu- kemia were excluded.
The trial complied with the International Conference on Harmonization Good Clinical Practice Guideline and the Declaration of Helsinki. All participating institutional re- view boards and ethics committees approved the study protocol, and patients provided written informed consent.
Randomization and masking
Following eligibility confirmation, patients were random- ized using an interactive response technology (IRT) system in a 1:1 ratio to the Isa-Pd (isatuximab) arm or to the Pd (control) arm. Randomization was stratified by age (<75 vs. ≥75 years) and number of previous lines of therapy (2 or 3 vs. >3).
Procedures
Intravenous isatuximab 10 mg/kg was administered on days1,8,15,and22ofcycle1anddays1and15forsub- sequent cycles. Intravenous or oral dexamethasone 40 mg (20 mg if age ≥75 years) was administered on days 1, 8, 15, and 22, and oral pomalidomide 4 mg was administered on days 1-21. Premedication and isatuximab preparation were described previously.13,14
Outcomes
The primary endpoint of ICARIA-MM was PFS as determined by the IRC. No PFS per IRC update is provided based on this additional follow-up. Key secondary endpoints include overall response rate (ORR) and OS. ORR was defined as the proportion of patients with complete response (CR), stringent CR, very good partial response (VGPR), and PR as best overall response, assessed by IRC using the Interna- tional Myeloma Working Group criteria. No updated ORR per IRC is provided. OS was defined as the time from the date of randomization to date of death from any cause. If death was not observed before the analysis data cutoff date, OS was censored at the last date that the patient was known to be alive or at the cutoff date, whichever was first. Exploratory endpoints included PFS2, ORR on further therapy (best overall response reported by the investigator), PFS on the first line of further therapy, and time to next treatment (TTNT). Additional definitions and methods are detailed in the Online Supplementary Appendix, page 4-7 and have been defined previously.14,16
Statistical analysis
Based on the primary efficacy endpoint (PFS) using the assumptions that the control arm had a median PFS of 4.0 months; the Isa-Pd arm was assessed to have 40%
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