Page 233 - Haematologica Vol. 109 - July 2024

ARTICLE - ICARIA-MM final overall survival analysis
P.G. Richardson et al.
supporting the overall favorable benefit of the regimen. Although cross-trial comparisons must be conducted with caution, final OS analysis of the phase II ELOQUENT-3 trial demonstrated that elotuzumab, a monoclonal antibody tar- geting signaling lymphocytic activation molecule F7, in com- bination with Pd, significantly improved OS after a minimum follow-up of 45 months.20 The proportion of patients with International Staging System Stage 3 at study entry (12% vs. 22%) in the triplet combination groups was substantially lower in ELOQUENT-3 than in ICARIA-MM. Among relevant adverse prognostic factors, there was a trend toward more patients with gain(1q21) in the Isa-Pd (49.4%) versus Pd arm (39%) in ICARIA-MM; the proportion of patients with gain(1q21) in the elotuzumab and Pd arms was similar in ELOQUENT-3.21 There were more patients aged >65 years in the Isa-Pd (64.9%) versus Pd arm (54.2%), whereas it was balanced between the elotuzumab and Pd arms (63% vs. 61%).21 The use of subsequent anti-CD38 therapy was balanced between the two arms in ELOQUENT-3 (53.3% in the elotuzumab arm vs. 49.2% in the Pd arm), which may have impacted OS. Results from the phase III APOLLO trial investigating daratumumab–pomalidomide–dexamethasone versus Pd demonstrated clinically meaningful OS benefit with the daratumumab combination (34.4 vs. 23.7 months; HR=0.82, 95% CI: 0.61-1.11; not statistically significant), with a HR similar to that observed in ICARIA-MM (HR=0.78, 95% CI: 0.59-1.02).22 Patients in APOLLO received fewer prior lines of therapy and were less refractory versus patients in the ICARIA-MM study (median prior lines, 2 vs. 3; 80% vs. 94% refractory to lenalidomide; 48% vs. 77% refractory to a PI; 42% vs. 72% refractory to both lenalidomide and a PI). Long-term follow-up of the OPTIMISMM trial investigating pomalidomide-bortezomib-dexamethasone versus borte- zomib-dexamethasone demonstrated a slight trend toward OS benefit (35.6 vs. 31.6 months, HR=0.94, 95% CI: 0.77-1.15; not statistically significant).23,24 These findings combined with the clinically meaningful OS benefit demonstrated in ICARIA-MM with the Isa-Pd combination indicate the value of treating patients with RRMM using a regimen that includes pomalidomide and a monoclonal antibody. Limitations of the current study include its open-label na- ture, the absence of patients refractory to previous daratu- mumab therapy, and the imbalance of the subsequent use of daratumumab that may have affected the power to detect statistically significant OS. Other limitations of OS analyses in general include the decreased number of deaths compared with cases of disease progression at any time point and the resulting decreased power of OS analysis; the influence of competing risks of death and crossover therapy on patient survival time; and the fact that median OS is approximately 1 year longer than median PFS, wherein several lines of therapy can impact OS with lesser effects of the initial experiment.25 In summary, the final OS analysis of this large, multi- center study confirmed that Isa-Pd continued to be effica- cious and well tolerated after follow-up of approximately
52 months, contributing to a clinically meaningful bene- fit with a 6.9-month improvement in median OS, further supporting its position as a standard-of-care therapy for patients with RRMM and informing real-world practice.26
Disclosures
PGR reports research funding from Bristol Myers Squibb/Cel- gene, Karyopharm, Oncopeptides, and Takeda and participa- tion on an entity’s board of directors or advisory committee for AstraZeneca, Bristol Myers Squibb/Celgene, GlaxoSmith- Kline, Karyopharm, Oncopeptides, Protocol Intelligence, Regeneron, Secura Bio, Sanofi, and Takeda. AP reports hon- oraria from AbbVie, Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, Sanofi, and Takeda. JS-M reports honoraria from AbbVie, Amgen, Bristol Myers Squibb/Cel- gene, GlaxoSmithKline, Haemalogix, Janssen, Karyopharm, Merck Sharp & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda. MB reports honoraria from Amgen, Celgene, Janssen, Sanofi, and Takeda and participation on an entity’s board of directors or advisory committee for Amgen, Janssen, Oncopeptides, and Takeda. IS reports honoraria from Amgen, Bristol Myers Squibb, Celgene, Janssen-Cilag, Novartis, PharmaMar, Sanofi, and Takeda. FS reports research funding from Celgene, GlaxoSmithKline, Janssen, Oncopep- tides, Sanofi, and Targovax; honoraria from AbbVie, Amgen, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Jans- sen, Novartis, Oncopeptides, Pfizer, Sanofi, SkyliteDX, and Takeda; and participation on an entity’s board of directors or advisory committee for AbbVie, Celgene, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, and Takeda. PM reports honoraria from AbbVie, Amgen, Celgene, GlaxoSmithKline, Janssen, and Sanofi. MAD reports honoraria from Amgen, BeiGene, Bristol Myers Squibb, Janssen, and Takeda. JM re- ports honoraria from Amgen, Bristol Myers Squibb/Celgene, Takeda, Janssen, and Sanofi and participation on an entity’s board of directors or advisory committees for Amgen, Bristol Myers Squibb/Celgene, Janssen, Oncopeptides, Sanofi, and Takeda. MC reports consulting fees from Amgen, Bristol My- ers Squibb/Celgene, GlaxoSmithKline, Janssen, and Sanofi and honoraria from Amgen, Bristol Myers Squibb/Celgene, GlaxoSmithKline, Janssen, and Sanofi. SM, FD, RZ, and MCM are employees of Sanofi and may hold stock and/or stock options. KCA reports consulting fees from AstraZeneca, Janssen, Pfizer, and Precision Biosciences. XL, S-YH, and HMP have no conflicts of interest to disclose.
Contributions
PGR, AP, JS-M, MB, IS, XL, FS, PM, MAD, S-YH, JM, MC, and HMP were investigators in the study and contributed to data acquisition. PGR and AP were co-primary investigators of the ICARIA-MM study. PGR, SM, RZ, FD, and MCM contributed to the analysis, verification, and interpretation of data for the work. KCA was the chairman of the study Steering Commit- tee. All authors revised the work for important intellectual content and assume responsibility for data integrity and the
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