OA-12: Predictors of unsustained measurable residual disease (MRD) negativity in transplant-eligible multiple myeloma (MM) patients

Introduction: The role of sustained MRD negativity as a biomarker to stop treatment is being investigated in transplant-eligible MM. Thus, it is important to identify risk-factors of MRD resurgence and/or progressive disease (PD) among patients achieving undetectable MRD to avoid undertreating them.

Methods: Transplant-eligible MM patients enrolled in the GEM2012MENOS65/GEM2014MAIN clinical trials who achieved MRD negativity by NGF (limit of detection, 2x10-6) were analyzed. A multivariate Fine-Gray statistical model was applied to the dataset, subsequently fitting a weighted Cox model to assess the cumulative incidence of MRD resurgence and/or PD. Death without PD was considered a competing event.

Results: A total of 267/458 (58%) patients achieved MRD negativity by NGF after induction (n=125), HDT/ASCT (n=77), consolidation (n=32) or after the first year of maintenance therapy (n=33) and were eligible for the analysis. After a median follow-up of 73 months since the first MRD negative assessment, 145/267 (54%) patients remained progression-free and had sustained MRD negativity until last time to follow up, while 111/267 (42%) patients had MRD resurgence (n=71) and/or PD (n=40), and 11/267 (4%) patients died without PD. The overall cumulative incidence of an MRD resurgence and/or PD event at 73 months was 44%. Time from achievement of first MRD negativity until MRD resurgence was similar in patients with or without subsequent disease progression (21 [8-34] and 25 [13-47] months, respectively, P=.188). The median PFS since MRD resurgence until PD or death was 39 months.
The only prognostic factors at diagnosis that predicted MRD resurgence and/or PD were an International staging system (ISS) 3 and ≥0.01% CTCs. LDH levels and the R-ISS were not significantly associated, while a high-risk cytogenetic status tended towards significance. Treatment randomization with Bu-Mel or Mel-200 HDT in the GEM2012MENOS65 trial, and with IRD vs RD in the GEM2014MAIN trial also had no impact. Patients who achieved MRD negativity after induction ( < 6 months) had significantly lower risk of MRD resurgence and/or PD than those who achieved MRD negativity at a later time point.
Because of the potential complementarity provided by patients’ ISS, CTC levels (≥0.01% ) and the time to achievement of first MRD negative assessment, the three risk factors were modeled for a more accurate prediction of MRD resurgence and/or PD. Accordingly, patients having none versus one versus two or more risk factors showed 5-year rates of MRD resurgence and/or PD of 16%, 33% and 57%, respectively (P <.001).

Conclusions: We present a dynamic model to predict the risk of MRD resurgence and/or PD after MRD negativity. This dynamic model relies on three easily measurable risk factors. The insights it offers can prove valuable in the careful selection of transplant-eligible MM patients for whom treatment cessation due to MRD negativity is being investigated in clinical trials or its implementation is being considered in routine practice.