Progression-free survival as a surrogate endpoint in myeloma clinical trials: an evolving paradigm

TY - JOUR

T1 - Progression-free survival as a surrogate endpoint in myeloma clinical trials: an evolving paradigm

AU - Pawlyn, Charlotte

AU - Schjesvold, Fredrik H

AU - Cairns, David A

AU - Wei, L J

AU - Davies, Faith

AU - Nadeem, Omar

AU - Abdulhaq, Haifaa

AU - Mateos, Maria-Victoria

AU - Laubach, Jacob

AU - Weisel, Katja

AU - Ludwig, Heinz

AU - Rajkumar, S Vincent

AU - Sonneveld, Pieter

AU - Jackson, Graham

AU - Morgan, Gareth

AU - Richardson, Paul G

N1 - © 2024. The Author(s).

PY - 2024/8/12

Y1 - 2024/8/12

N2 - Measurement of overall survival (OS) remains the gold standard for interpreting the impact of new therapies for multiple myeloma in phase 3 trials. However, as outcomes have improved, it is increasingly challenging to use OS as the primary endpoint if timely approval of novel agents is to be ensured to enable maximum benefit for patients. Surrogate endpoints of OS, such as progression-free survival (PFS) and response to treatment, have contributed to approval decisions by the Food and Drug Administration (FDA) and European Medicines Agency as endpoints demonstrating clinical benefit, and the FDA has recently supported the use of minimal residual disease (MRD) as an accelerated approval endpoint in multiple myeloma. This review aims to address situations in which the use of PFS as a surrogate endpoint warrants careful interpretation especially for specific subgroups of patients and considers ways to ensure that studies can be designed to account for possible discordance between PFS and OS. The utility of subgroup analyses, including the potential for those not pre-specified, to identify target populations for new agents is also discussed.

AB - Measurement of overall survival (OS) remains the gold standard for interpreting the impact of new therapies for multiple myeloma in phase 3 trials. However, as outcomes have improved, it is increasingly challenging to use OS as the primary endpoint if timely approval of novel agents is to be ensured to enable maximum benefit for patients. Surrogate endpoints of OS, such as progression-free survival (PFS) and response to treatment, have contributed to approval decisions by the Food and Drug Administration (FDA) and European Medicines Agency as endpoints demonstrating clinical benefit, and the FDA has recently supported the use of minimal residual disease (MRD) as an accelerated approval endpoint in multiple myeloma. This review aims to address situations in which the use of PFS as a surrogate endpoint warrants careful interpretation especially for specific subgroups of patients and considers ways to ensure that studies can be designed to account for possible discordance between PFS and OS. The utility of subgroup analyses, including the potential for those not pre-specified, to identify target populations for new agents is also discussed.

KW - Humans

KW - Multiple Myeloma/mortality

KW - Progression-Free Survival

KW - Clinical Trials as Topic

KW - Neoplasm, Residual

KW - Biomarkers

U2 - 10.1038/s41408-024-01109-4

DO - 10.1038/s41408-024-01109-4

M3 - SCORING: Review article

C2 - 39134544

VL - 14

SP - 134

JO - BLOOD CANCER J

JF - BLOOD CANCER J

SN - 2044-5385

IS - 1

ER -