MRD dynamics predicts progression and reveals a vulnerable state for immunotherapy interception in multiple myeloma

Area of Science:

• Hematology
• Oncology
• Immunology

Background:

• The clinical significance of one or two measurable residual disease (MRD) assessments is established in multiple myeloma (MM).
• Stratifying patients based on ≥3 MRD assessments and understanding MRD resistance traits remain unknown.
• The potential benefit of treating persistent MRD versus relapse is unclear.

Purpose of the Study:

• To analyze MRD dynamics in newly-diagnosed multiple myeloma (MM) patients with ≥3 MRD assessments.
• To identify patient subgroups based on MRD dynamics and their survival outcomes.
• To investigate the impact of treating persistent MRD versus relapse using anti-BCMA CAR T cells in a preclinical model.

Main Methods:

• Computed MRD dynamics using next-generation flow cytometry and Connector in 539 MM patients across three trials.
• Performed molecular and immune profiling on matched diagnostic and MRD samples.
• Investigated survival impact of treating persistent MRD vs relapse with anti-BCMA CAR T cells in mice.

Main Results:

• MRD dynamics identified five distinct patient subgroups with varying survival outcomes from 3,610 assessments.
• Patients with early or late sustained MRD response showed excellent outcomes, while volatile or resistant MRD predicted dismal survival.
• MRD dynamics outperformed transplant-eligibility and R-ISS staging and were validated in routine practice.

Conclusions:

• MRD dynamics is a powerful predictor of progression in multiple myeloma, surpassing current staging systems.
• Understanding MRD dynamics and resistance mechanisms (genomic evolution, immune adaptation) can inform treatment strategies.
• Early intervention with therapies like anti-BCMA CAR T cells during MRD resistance may improve survival compared to treatment at relapse.