Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study
Mené sur 307 patients atteints d'un myélome multiple réfractaire ou récidivant (durée médiane de suivi : 35,3 mois), cet essai de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité de l'ajout de l'isatuximab à un traitement combinant pomalidomide et faibles doses de dexaméthasone
Background : The primary analysis of the ICARIA-MM study showed significant improvement in progression-free survival with addition of isatuximab to pomalidomide–dexamethasone in relapsed and refractory multiple myeloma. Here, we report a prespecified updated overall survival analysis at 24 months after the primary analysis. Methods : In this randomised, multicentre, open-label, phase 3 study adult patients (aged ≥18years) with relapsed and refractory multiple myeloma who had received at least twoprevious lines of therapy, including lenalidomide and a proteasome inhibitor, andhad an Eastern Cooperative Oncology Group performance status of 0–2 were recruitedfrom 102 hospitals in 24 countries across Europe, North America, and the Asia-Pacificregions. Patients were excluded if they had anti-CD38 refractory disease or previouslyreceived pomalidomide. Patients were randomly assigned (1:1), using an interactiveresponse technology with permuted blocked randomisation (block size of four) and stratifiedby number of previous treatment lines (2–3 vs >3) and aged (<75 vs ≥75 years), to isatuximab–pomalidomide–dexamethasone (isatuximab group) or pomalidomide–dexamethasone(control group). In the isatuximab group, intravenous isatuximab 10 mg/kg was administeredon days 1, 8, 15, and 22 of the first 4-week cycle, and then on days 1 and 15 of subsequentcycles. Both groups received oral pomalidomide 4 mg on days 1–21 of each cycle, andweekly oral or intravenous dexamethasone 40 mg (20 mg if aged ≥75 years) on days 1,8, 15, and 22 of each cycle. Treatment was continued until disease progression, unacceptabletoxicity, or withdrawal of consent. Here' we report a prespecified second interimanalysis of overall survival (time from randomisation to any-cause death), a key secondaryendpoint, in the intention-to-treat population (ie, all patients who provided informedconsent and allocated a randomisation number) at 24 months after the primary analysis.Safety was assessed in all patients who received at least one dose or part dose ofstudy treatment. The prespecified stopping boundary for the overall survival analysiswas when the derived p value was equal to or less than 0·0181. This study is registeredwith ClinicalTrials.gov, NCT02990338, and is active, but not recruiting. Findings : Between Jan 10, 2017, and Feb 2, 2018, 387 patients were screened and 307 randomly assigned to either the isatuximab (n=154) or control group (n=153). Median follow-upat data cutoff (Oct 1, 2020) was 35·3 months (IQR 33·5–37·4). Median overall survivalwas 24·6 months (95% CI 20·3–31·3) in the isatuximab group and 17·7 months (14·4–26·2)in the control group (hazard ratio 0·76 [95% CI 0·57–1·01]; one-sided log-rank p=0·028,not crossing prespecified stopping boundary). The most common grade 3 or worse treatment-emergentadverse events in the isatuximab group versus the control group were neutropenia (76[50%] of 152 patients vs 52 [35%] of 149 patients), pneumonia (35 [23%] vs 31 [21%]), and thrombocytopenia (20 [13%] vs 18 [12%]). Serious treatment-emergent adverse events were observed in 111 (73%) patientsin the isatuximab group and 90 (60%) patients in the control group. Two (1%) treatment-relateddeaths occurred in the isatuximab group (one due to sepsis and one due to cerebellarinfarction) and two (1%) occurred in the control group (one due to pneumonia and onedue to urinary tract infection). Interpretation : Addition of isatuximab plus pomalidomide–dexamethasone resulted in a 6·9-month differencein median overall survival compared with pomalidomide–dexamethasone and is a new standardof care for lenalidomide-refractory and proteasome inhibitor-refractory or relapsedmultiple myeloma. Final overall survival analysis follow-up is ongoing.