Time‐to‐event surrogate end‐points in multiple myeloma randomised trials from 2005 to 2019: A surrogacy analysis

• Published in: British journal of haematology Vol. 200; no. 5; pp. 587 - 594
• Main Authors: Etekal, Tommy, Koehn, Kelly, Sborov, Douglas W., McClune, Brian, Prasad, Vinay, Haslam, Alyson, Berger, Katherine, Booth, Christopher, Al Hadidi, Samer, Abdallah, Al‐Ola, Goodman, Aaron, Mohyuddin, Ghulam Rehman
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-03-2023
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers - analysis; Clinical trials; Disease-Free Survival; end-point; Hematology; Humans; Multiple myeloma; Multiple Myeloma - therapy; overall survival; Progression-Free Survival; Proportional Hazards Models; randomised controlled trial; Randomized Controlled Trials as Topic; Survival; overall survival; randomised controlled trial; multiple myeloma; end-point; progression-free survival
• ISSN: 0007-1048; 1365-2141; 1365-2141
• DOI: 10.1111/bjh.18568

Summary
Use of surrogate end‐points such as progression‐free survival (PFS) and other time‐to‐event (TTE) end‐points is common in multiple myeloma (MM) clinical trials. This systematic review characterises all published randomised controlled trials (RCTs) in MM using PFS or other TTE end‐points between 2005 and 2019 and assesses strength of surrogacy of PFS for overall survival (OS). The association between OS hazard ratios (HRs) and PFS HRs was evaluated with linear regression, and the coefficient of determination with Pearson's correlation. We identified 88 RCTs of which 67 (76%) used PFS as the primary/co‐primary end‐point. One trial indicated whether progression was biochemical or clinical. Of the variance in OS, 39% was due to variance in PFS. Correlation between PFS and OS was weak (0.62, 95% confidence interval [CI] 0.38–0.78). In newly diagnosed MM, 43% of the variance in OS was due to changes in PFS. The correlation between PFS and OS was weak (0.65, 95% CI 0.30–0.84). In relapsed/refractory MM, 58% of the variance in OS was due to changes in PFS. Correlation between PFS and OS was medium (0.76, 95% CI 0.42–0.91). We demonstrate that PFS and progression characteristics are characterised poorly in MM trials and that PFS is a poor surrogate for OS in MM.