OBJECTIVES: OS is the gold standard for evaluating the clinical benefit of RRMM treatments. Validated surrogate endpoints could predict improvement in OS earlier, thereby helping to expedite the approval of new regimens. This study aimed to investigate trial-level surrogacy of PFS for OS in the RRMM population.

METHODS: Forty-three phase II and III randomized controlled trials of systemic treatments in the target population were identified via an umbrella review of systematic literature reviews. Linear regression of the reported log PFS and OS hazard ratios (HRs; same data cut within each trial where possible) was performed (frequentist framework) and summarized in terms of the parameters and the weighted Pearson’s correlation coefficient (R). Bivariate meta-analysis (Bayesian framework) was also assessed and summarized in terms of the corresponding parameters. Several sensitivity analyses were explored, including a scenario including OS HRs reported based on the longest available follow-up per trial (possibly different data cut than PFS HR), and a scenario restricting to studies including any double-class refractory (DCR) patients. Cross-validation analyses determined whether the models were robust.

RESULTS: Based on the observed correlations between PFS and OS, a 10% increase in PFS HR results in a 5.8% (95% confidence interval: 4.2%-7.4%) increase in OS HR in the frequentist regression and 5.7% (95% credible interval: 4.0%-7.4%) increase in OS HR in the bivariate meta-analysis. In cross-validation, prediction intervals captured 100% of reported OS HRs in the bivariate meta-analysis. Results were similar among trials including any DCR patients (6.4% [3.1%-9.9%] in the frequentist regression and 6.0% [2.3%-9.9%] in the bivariate meta-analysis). Using the longest OS follow-up reduced the percentage increase in OS HR in both the frequentist regression (5.1% [3.4%-6.8%]) and the bivariate meta-analysis (4.4% [2.8%-6.1%]).

CONCLUSIONS: PFS is a valid surrogate for OS among the RRMM patients, particularly those with more refractory diseases.