Sustained MRD Negativity by NGS Is the Optimal Endpoint for Treatment Cessation in Myeloma
This study of 221 multiple myeloma patients treated with quadruplet induction and autologous transplant found that sustained MRD negativity below 10^-5 by next-generation sequencing (two consecutive assessments at least one year apart) was the strongest predictor of progression-free survival for treatment cessation decisions. This endpoint outperformed single-timepoint MRD, deeper 10^-6 thresholds, and conventional stringent complete response. The results provide a clear, actionable NGS-based MRD endpoint to guide response-adapted fixed-duration therapy.
The original study
Optimal MRD-based end point to support response-adapted treatment cessation in newly diagnosed multiple myeloma.
- Authors
- Giri S, Dhakal B, Callander NS, Medvedova E, Godby K, Dholaria BR, et al.
- Journal
- Blood
- Type
- Journal Article, Clinical Trial, Phase II
- PMID
- 40193714
Original abstract
The therapeutic success of first-line quadruplet (QUAD) induction therapy and autologous stem cell transplantation (ASCT) has reinvigorated an interest in fixed-duration therapy, yet optimal short-term efficacy end point for treatment cessation is unknown. Using data from a phase 2 clinical trial and a prospective institutional database, we tested the predictive performance of 5 short-term efficacy end points among 221 patients who received QUAD + ASCT followed by treatment cessation if minimal residual disease (MRD) by next-generation sequencing negative for 2 consecutive time points. Efficacy end points tested were International Myeloma Working Group-defined stringent complete response, MRD <10-5 (single data point), MRD <10-6, sustained MRD (S-MRD; 2 consecutive assessments at least 1 year apart) <10-5, and S-MRD <10-6. We built 5 parallel Cox regression models for each efficacy end point with progression-free survival (PFS) as the outcome. Best fitting models were determined using the Akaike information criterion (AIC) and Heagerty and Zheng C-index. The best fitting model (AIC, 417.2; C statistic, 0.757) was based on S-MRD <10-5 (hazard ratio, 0.23; 95% confidence interval, 0.11-0.47). Similar results were seen for predicting the risk of progression/MRD resurgence among 121 patients undergoing MRD-guided treatment cessation. S-MRD <10-5 is the best predictor of PFS and yields the best predictive models for the risk of MRD resurgence or progression in the setting of fixed-duration therapy. This trial was registered at www.clinicaltrials.gov as #NCT03224507.