In a pooled analysis reported in the Journal of Clinical Oncology, Shi et al found that a clinical trial endpoint of complete response with minimal residual disease (also known as measurable residual disease) at the 10-5 threshold (MRD-CR) at 9 or 12 months could be used to support accelerated approval of drugs for treatment of multiple myeloma.
Study Details
The study included individual-level data from 4,733 patients from 11 randomized multicenter trials. The aim was to determine whether 9- or 12-month MRD-CR can be used to predict clinical benefit of new agents as an intermediate endpoint for progression-free and overall survival that might support the accelerated approval of these agents. The intermediate endpoint was evaluated in the settings of newly diagnosed, transplant-eligible (NDTE); newly diagnosed, transplant-ineligible (NDTI); and relapsed or refractory (RR) disease.
Key Findings
MRD-CR at 9 months was significantly associated with patient-level progression-free survival among NDTE patients (global odds ratio [OR] = 3.6), NDTI patients (global OR = 9.80), and RR patients (global OR = 8.24), and significantly associated with patient-level overall survival in all three groups (global ORs = 2.81, 10.34, and 6.60, respectively). MRD-CR at 12 months was also significantly associated with patient-level progression-free survival in all three groups (global ORs = 4.45, 11.95, and 16.24) and overall survival in the two groups in which association could be determined (global ORs = 5.16, 7.08, and not evaluable, respectively).
The trial-level correlation (R2) for MRD-CR at 9 months with progression-free survival for the three groups pooled was 0.70 (95% confidence interval [CI] = 0.47–0.92), with correlation among all ND patients of 0.73 (95% CI = 0.39–1.00). Trial-level correlation with overall survival for the three groups pooled was 0.69 (95% CI = 0.51–0.87), with a higher correlation among ND patients (0.78, 95% CI = 0.51–1.00). The correlation for MRD-CR at 12 months was 0.66 (95% CI = 0.34–0.98) for progression-free survival for all three groups, with a higher correlation in ND patients (0.78, 95% CI = 0.49–1.00). The correlation with overall survival was 0.60 (95% CI = 0.29–0.92) for the three groups pooled, with a higher correlation in ND patients (0.78, 95% CI = 0.53–1.00).
The investigators concluded: “Our findings provided the support for use of MRD-CR classified at a 10-5 threshold at either 9 or 12 months after starting of the treatment as an intermediate endpoint to support accelerated approvals in future trials in NDTE patients, [NDTI] patients, and patients with RR [multiple myeloma].”
Qian Shi, PhD, of the Department of Quantitative Health Sciences, Mayo Clinic, Rochester, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by the International Myeloma Foundation and International Myeloma Society. For full disclosures of the study authors, visit ascopubs.org.
