Growing Acceptance of Minimal Residual Disease (MRD) As a Primary Endpoint in Multiple Myeloma (MM) Clinical Trials

OBJECTIVES: MRD negativity is superseding conventional complete response (CR) and has been proposed as a surrogate endpoint for progression-free survival (PFS) and overall survival (OS) in MM. Several recent meta-analyses have confirmed that the achievement of MRD negativity can be an important prognostic factor in MM. Against this backdrop, we assessed the adoption of MRD as a primary endpoint in clinical trial design over the last 10 years.

METHODS: All active, recruiting or completed trials published on clinicaltrials.gov with a start date between 2014 and 2023 were reviewed. Outcomes fields were further analysed to establish whether MRD was included as a primary or secondary endpoint. A targeted literature search was undertaken to validate findings and assess MRD measurement parameters (including use of next-generation flow cytometry (NGF) and next-generation gene sequencing (NGS)), where available.

RESULTS: From 2014-2016 approximately 10% of MM trials measured MRD, this proportion tripled by 2022-2023. While almost all studies measured MRD as a secondary or tertiary endpoint in 2014-2017, MRD was studied as a primary outcome in 38% (18/47) of MM trials in 2023. A similar number of trials recruiting newly diagnosed and relapse-refractory patients included MRD as an endpoint.

CONCLUSIONS: A surrogate endpoint that can rapidly predict survival could accelerate drug development and bring innovative new products to patients more quickly. To date, the biggest challenge for using MRD negativity has been variability in measurement techniques due to lack of standardisation of laboratory technology among hospitals which has complicated data comparisons across clinical trials. This analysis showed that inclusion of MRD is gaining momentum, suggesting a growing acceptance of MRD negativity as a viable primary endpoint in both the newly diagnosed and relapsed-refractory setting, likely influenced by the publication of IMWG guidelines and an international consensus statement for harmonization of performing and reporting MRD.