Optimizing oncology drug development: systematic review of 22 years of myeloma randomized controlled trials

Although myeloma represents a key success story in oncology, some drugs have failed to meet primary endpoints in randomized controlled trials (RCTs), despite promising early phase activity. This analysis aimed to understand factors that increase the likelihood of meeting primary endpoints in myeloma RCTs.

Myeloma RCTs published through October 2023 were identified using MEDLINE, PubMed, Embase, and the Cochrane Registry. Studies were classified as head-to-head (substituting 1 regimen for another) or add-on (adding 1 drug to existing regimen). Trials were considered successful if they achieved statistical significance for primary outcomes. Logistic regression identified predictors of meeting trial endpoints.

A total of 145 comparisons from 123 RCTs were included. Only 2 factors were independently associated with meeting primary endpoints in multivariate analysis. Higher median participant age was associated with lower odds of meeting the primary endpoint (odds ratio [OR] per 1-year increase = 0.90, 95% confidence interval [CI] = 0.83 to 0.98). Overall survival (OS) was the primary endpoint in 20 of 145 comparisons, of which 3 of 20 met their endpoint. Selecting OS as primary endpoint was associated with reduced likelihood of success compared with progression-free survival by 94% (OR = 0.06, 95% CI = 0.01 to 0.23). Head-to-head design was not associated with lower success rates than add-on design (OR = 0.59; 95% CI = 0.22 to 1.62).

Two key factors predicted higher likelihood of meeting endpoints: younger patient age and primary endpoints other than OS. Although head-to-head design is considered riskier, it was not associated with decreased success. This analysis aims to better inform clinicians, industry, and regulators in myeloma drug development.