A meta-analysis of six randomized clinical trials, encompassing 3,283 patients with newly diagnosed multiple myeloma (NDMM), suggests that achieving minimal residual disease (MRD) negativity can serve as a surrogate endpoint for progression-free survival (PFS). The study, published in PubMed, indicates a strong correlation between treatment-induced MRD negativity and improved PFS, potentially accelerating drug development in this challenging disease.
The research addresses the increasing need for quicker endpoints in multiple myeloma trials, as therapeutic advancements have extended survival times, making traditional PFS endpoints less practical. The meta-analysis evaluated whether MRD status could fulfill Prentice's criteria for surrogacy, essential for accelerated drug approval.
Key Findings
The meta-analysis incorporated data from studies evaluating various treatment combinations, including immunomodulatory drugs (IMiDs), proteasome inhibitors, and antibody therapies, with or without autologous stem cell transplantation (ASCT). MRD negativity was assessed using next-generation flow (NGF) and next-generation sequencing (NGS) techniques.
"Our meta-analysis suggested that MRD status met both Prentice’s criteria for PFS surrogacy," the researchers stated. The treatment effect on the odds ratio (OR) for MRD-negative response strongly correlated with the hazard ratio (HR) for PFS, with a coefficient of determination of 0.97.
Implications for Clinical Trials
The study's findings support the use of MRD negativity as a surrogate endpoint in clinical trials for NDMM. This could lead to faster drug development and approval processes, bringing new therapies to patients more quickly. The FDA has shown increasing interest in MRD as a potential endpoint, holding workshops to explore its role in hematologic cancer trials.
Methodological Considerations
The meta-analysis adhered to stringent criteria, including randomized trials with experimental and control treatments, defined MRD measurement time points, and detailed MRD subset information. Statistical analyses followed FDA guidelines for surrogate endpoint validation.
Limitations of the analysis include the use of study-level data, a limited number of available studies, differing cutoff levels for MRD (10^-4 to 10^-5), different MRD measurement approaches, the imputation of MRD status for missing measurements in a defined subset of patients, and the measurement of MRD in various response subgroups with dissimilar predefined time periods.
Expert Commentary
Experts in the field suggest that the standardization of MRD testing methods, as recommended by the International Myeloma Working Group (IMWG), is crucial for cross-study comparisons and the development of treatment algorithms based on MRD status.
Conclusion
The meta-analysis provides compelling evidence supporting MRD negativity as a surrogate endpoint for PFS in NDMM, potentially transforming clinical trial design and drug development in multiple myeloma. The results of this study-level meta-analysis support the use of MRD status as a surrogate endpoint in clinical trials for patients with NDMM.
