Dynamics of minimal residual disease and its clinical implications in multiple myeloma: A retrospective real-life analysis.

Background: Minimal residual disease (MRD) testing is a promising approach to tailor the treatment of multiple myeloma (MM). However, several major concerns remain to be addressed before moving it into daily practice, most of which stem from the dynamic nature of the MRD status. Thus, it is crucial to understand the MRD dynamics and propose its clinical implications.

Methods: We retrospectively analysed the data of patients with newly diagnosed MM (NDMM) who had flow cytometry-based MRD tests at multiple time points after initiation of therapy. The impact of undetectable MRD (including attainment, duration and loss) on clinical outcomes was analysed.

Results: In a cohort of 220 patients with NDMM, attainment of MRD^- offered favourable outcomes (P < 0.0001 for both progression-free survival (PFS) and overall survival (OS)), regardless of baseline risk factors. Notably, MRD^- duration ≥12 months was associated with an 83 % (95 % confidence interval (CI), 0.09-0.34; P < 0.0001) or 69 % (95 % CI, 0.13-0.76; P = 0.0098) reduction in risk of progression/death or death, while the longer MRD^- was sustained, the better the outcome was. Loss of MRD^- led to poor PFS (hazard ratio (HR) 0.01, 95 % CI 0-0.06, P < 0.0001) and OS (HR 0.03, 95 % CI 0-0.24, P = 0.0008). Most patients (70 %) who lost MRD^- status carried high-risk cytogenetic abnormalities (HRCAs). While MRD^- was temporally inconsistent with conventional therapeutic responses (eg ≥ complete remission or very good partial response), it predicted disease progression or recurrence more robustly than the latter. Last, the predictive value of the MRD status was independent of baseline risk factors (eg high-risk cytogenetic abnormality, International Staging System (ISS) or Revised (R-)ISS staging).

Conclusions: Longitudinal assessment of MRD during the treatment course and follow-up is required for monitoring disease progression or relapse, to guide treatment decisions. Accordingly, a prospective study is currently ongoing to investigate the feasibility and benefit of the MRD-tailored therapy according to the longitudinal changes of the MRD status.