Carmen Gonzalez

The clinical significance of 1 or 2 measurable residual disease (MRD) assessments is established in multiple myeloma (MM). However, how to stratify patients according to ≥3 MRD assessments remains unknown. The traits of MRD resistance and whether treatment of persistent MRD vs relapse could improve outcomes remains unknown. MRD dynamics were computed using next-generation flow cytometry and CONNECTOR in 539 patients with newly diagnosed MM with ≥3 assessments in the GEM2012MENOS65/GEM2014MAIN and GEM2017FIT trials. Molecular and immune profiling were performed in matched diagnostic and MRD samples. The survival impact of treating persistent MRD vs relapse was investigated with anti–B-cell maturation antigen (anti-BCMA) chimeric antigen receptor (CAR) T cells in MIcγ1hCRBN mice. Computed MRD dynamics based on 3610 MRD assessments identified 5 subgroups with different survival. Patients with late-sustained MRD response had excellent outcomes, similar to those with early sustained MRD response. Patients with volatile results and those with primarily and resurgent MRD resistance had dismal survival. MRD dynamics outperformed transplant eligibility and the Revised International Staging System. These results were validated in 249 patients with MM treated in routine practice. Multiomics characterization of MRD dynamics in patients and mouse models of MRD resistance revealed genomic evolution, transcriptional adaptation, and a proinflammatory tumor-immune microenvironment. Increasing clonality and exhaustion of endogenous T cells throughout disease progression urged investigating whether MRD interception with anti-BCMA CAR T cells could improve outcomes. Infusion at MRD resistance prolonged mouse survival compared with identical treatment at relapse. In summary, MRD dynamics is the strongest predictor of progression and may help tailoring treatment to prevent additional tumor and immune alterations before relapse.

Measurable residual disease (MRD) is an early endpoint of treatment efficacy in some hematological malignancies, but several questions remain unanswered to endorse its use in acute myeloid leukemia (AML). We leveraged PETHEMA real-world outcomes of 2623 newly-diagnosed AML patients fit for intensive therapy and in complete remission (CR) after one cycle, to investigate if MRD assessment using flow cytometry is more sensitive than morphological CR, what is the optimal MRD cutoff, the individual-patient-level association between MRD negative CR and overall survival (OS), and if MRD negative rates after different induction regimens associate with different OS. MRD was detected in 68% of patients and presence of MRD levels ≥0.01–<0.1% associated with inferior OS. MRD negative CR using the 0.01% cutoff showed independent prognostic value and was significantly correlated with OS at the individual patient-level (Global odds ratio 1.23; 95% CI, 1.02–1.40). However, significance was lost in specific subgroups defined by genetic risk and post-consolidation treatment. The relationship between treatment effect in MRD negative CR rates and OS after different induction regimens was generally observed. Altogether, these results support formal studies to investigate the role of MRD as an early endpoint of treatment efficacy in specific subgroups of AML patients.

List of somatic mutations detected in normal cells.

Distribution of B-cell differentiation stages.

Overall survival (OS) according to MRD.

Frequency of non-clonotypic clones.

Characteristics and methods of study cohorts.

Number of somatic variants detected in normal cells.

Differentially expressed genes in non-clonotypic cells.

Differentially expressed genes in clonotypic cells.