External Control arms (ECAs) help to evaluate the effectiveness of a new treatment by comparing its outcomes with those of a similar group of patients who received standard care or a different treatment. Plitidepsin (P) 5 mg/m2 i.v. on Day 1 and 15 every four weeks (q4wk) plus low-dose dexamethasone (LD-DXM) (40 mg weekly) was evaluated versus (vs) LD-DXM alone (40 mg weekly) in patients with relapsed/refractory multiple myeloma (r/r MM) exposed to ³3-6 prior treatment lines in the randomized phase III ADMYRE trial. In absence of a randomized study with P+LD-DXM vs POM+LD-DXM (approved in a similar population to the ADMYRE trial), a direct matched comparison between P+LD-DXM (ADMYRE data) and pomalidomide (POM) (4 mg orally on Day 1 through Day 21) +LD-DXM (40 mg orally on Day 1, 8, 15 and 22 q4wk; 20 mg in patients > 75 years) as an ECA was conducted using individual patient-level data from several contemporary POM trials. Data from 8 phase II/III studies evaluating POM+LD-DXM contemporaneous to the ADMYRE trial and with a similar design were used for the analysis. A first analysis (ECA1) showed that P+LD-DXM was non-inferior to POM+LD-DXM in terms of overall survival (OS): median OS was 11.8 vs. 13.9 months; hazard ratio (HR)=1.009 (95% CI, 0.812-1.254; two-sided log-rank test p=0.9336). In patients <75 years, median OS was 13.0 vs. 13.8 months; and HR was 0.910 (95%CI, 0.718-1.154) (two-sided log-rank test p=0.4366). Safety profile showed a lower rate of grade ≥3 hematological treatment-related adverse events (TRAEs) (neutropenia 2.5% vs. 37.1%; thrombocytopenia 2.5% vs. 13.2%) and infections (8.1% vs. 18.7%) for P+DXM, and a higher rate of grade ≥1 gastrointestinal TRAEs (52.8% vs. 27.4%), grade ≥3 blood creatine phosphokinase (14.3% vs. 0%) and grade ≥3 myalgia (5.6% vs. 0%). A second analysis (ECA2) compared POM+LD-DXM with the LD-DXM alone arm included in ADMYRE and showed a treatment effect in OS (HR=0.762; 95%CI, 0.566-1.026) similar to that observed in the ADMYRE trial (HR=0.797, 95%CI, 0.596-1.067). In patients < 75 years, the HR was 0.748 (95%CI, 0.543-1.031) (two-sided log-rank test p=0.0760). Safety profile of POM+LD-DXM was associated to a higher rate of AEs, as expected for a combination. In conclusion, P+LD-DXM can be considered an alternative therapeutic option in r/r MM as this comparison in terms of OS shows that P+LD-DXM is non-inferior to POM+LD-DXM with an advantageous safety profile in terms of hematological and infection events.

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2025
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