TY - JOUR
T1 - Minimal Residual Disease-Based End Point for Accelerated Assessment of Clinical Trials in Multiple Myeloma
T2 - A Pooled Analysis of Individual Patient Data from Multiple Randomized Trials
AU - Shi, Qian
AU - Paiva, Bruno
AU - Pederson, Levi D.
AU - Dimier, Natalie
AU - Talpes, Ela
AU - Prior, Thomas J.
AU - Orfao, Alberto
AU - Moreau, Philippe
AU - Sonneveld, Pieter
AU - Kumar, Shaji K.
AU - Dixon, Jesse G.
AU - Patel, Reshma
AU - Bartlett, Blake J.
AU - Schecter, Jordan
AU - McCarthy, Phillip
AU - Hose, Dirk
AU - Seckinger, Anja
AU - Mattia, D'Agostino
AU - Goldschmidt, Hartmut
AU - Oliva, Stefania
AU - Owen, Roger G.
AU - Anderson, Kenneth C.
AU - San-Miguel, Jesús
AU - Durie, Brian G.M.
AU - Munshi, Nikhil
N1 - Publisher Copyright:
© 2025 by American Society of Clinical Oncology.
PY - 2025/4/10
Y1 - 2025/4/10
N2 - PURPOSE:Newly approved drugs and combinations treating multiple myeloma (MM) have resulted in substantial improvements in patients' survival. To deliver rapid access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to evaluate the minimal residual disease-negative complete response (MRD-CR) as an intermediate end point for progression-free survival (PFS) and overall survival (OS) in newly diagnosed (ND) transplant-eligible (NDTE) patients, ND transplant-ineligible (NDTinE) patients, and patients with relapsed/refractory (RR) MM.PATIENTS AND METHODS:Individual patient data from 20 randomized multicenter trials were collected. Eleven studies (4,773 patients) with sufficient data were analyzed to evaluate whether 9- or 12-month MRD-CR classified at a 10-5 threshold could be reasonably likely to predict the clinical benefit of new agents regarding PFS and OS. Global odds ratio (OR) was estimated using the bivariate Plackett Copula model. Supportive evaluation included correlations of the treatment effects on MRD-CR end points and PFS/OS, evaluated by both linear regression (R2weighted least squared) and Copula (R2Copula) models.RESULTS:The analysis demonstrated that both 9- and 12-month MRD-CR strongly correlated with PFS at patient level in NDTE patients, NDTinE patients, and patients with RRMM. Global ORs ranged from 3.06 to 16.24, all with 95% CIs excluding 1.0. Encouraging trial-level correlations (R2, 0.61-0.70) were observed by pooling three populations and were stronger (R2, 0.67-0.78) in the ND population. Similar results were observed for OS.CONCLUSION: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 end point to support accelerated approvals, in future trials in NDTE patients, NDTinE patients, and patients with RRMM.
AB - PURPOSE:Newly approved drugs and combinations treating multiple myeloma (MM) have resulted in substantial improvements in patients' survival. To deliver rapid access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to evaluate the minimal residual disease-negative complete response (MRD-CR) as an intermediate end point for progression-free survival (PFS) and overall survival (OS) in newly diagnosed (ND) transplant-eligible (NDTE) patients, ND transplant-ineligible (NDTinE) patients, and patients with relapsed/refractory (RR) MM.PATIENTS AND METHODS:Individual patient data from 20 randomized multicenter trials were collected. Eleven studies (4,773 patients) with sufficient data were analyzed to evaluate whether 9- or 12-month MRD-CR classified at a 10-5 threshold could be reasonably likely to predict the clinical benefit of new agents regarding PFS and OS. Global odds ratio (OR) was estimated using the bivariate Plackett Copula model. Supportive evaluation included correlations of the treatment effects on MRD-CR end points and PFS/OS, evaluated by both linear regression (R2weighted least squared) and Copula (R2Copula) models.RESULTS:The analysis demonstrated that both 9- and 12-month MRD-CR strongly correlated with PFS at patient level in NDTE patients, NDTinE patients, and patients with RRMM. Global ORs ranged from 3.06 to 16.24, all with 95% CIs excluding 1.0. Encouraging trial-level correlations (R2, 0.61-0.70) were observed by pooling three populations and were stronger (R2, 0.67-0.78) in the ND population. Similar results were observed for OS.CONCLUSION: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 end point to support accelerated approvals, in future trials in NDTE patients, NDTinE patients, and patients with RRMM.
UR - https://www.scopus.com/pages/publications/85218714244
U2 - 10.1200/JCO-24-02020
DO - 10.1200/JCO-24-02020
M3 - Article
C2 - 39938021
AN - SCOPUS:85218714244
SN - 0732-183X
VL - 43
SP - 1289
EP - 1301
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 11
ER -
