Optimal MRD-based end point to support response-adapted treatment cessation in newly diagnosed multiple myeloma

• Sustained minimal residual disease negativity below 10-5 is the best predictor of outcomes in newly diagnosed multiple myeloma.

• Similar results are seen among patients who achieve deep response and cease therapy for predicting the risk of progression or MRD resurgence

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 endpoint for treatment cessation is unknown. Using data from a phase II clinical trial and a prospective institutional database, we tested the predictive performance of 5 short-term efficacy endpoints among 221 patients who received QUAD+ASCT followed by treatment cessation if minimal residual disease (MRD by next generation sequencing) negative for two consecutive timepoints. Efficacy endpoints tested were IMWG-defined stringent complete response (sCR), MRD<10-5 (single datapoint), MRD<10-6, sustained MRD (S-MRD, two consecutive assessments at least 1 year apart) <10-5and S-MRD<10-6. We built five parallel Cox regression models for each efficacy endpoint with progression free survival (PFS) as the outcome. Best fitting models were determined using Akaike's information criterion (AIC) and Heagerty & Zheng C-index. The best fitting model (AIC 417.2, C-stat 0.757) was based on S-MRD<10-5 (HR=0.23, 95% C.I. 0.11-0.47). Similar results were seen for predicting 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 best predictive models for risk of MRD resurgence or progression in the setting of fixed duration therapy. NCT03224507