Immune MRD Status Informs Tumor MRD Outcome Prognostication in Patients with Multiple Myeloma on Lenalidomide Maintenance

Abstract Purpose: Lenalidomide (Len) maintenance is the most frequently utilized approach for newly diagnosed patients with multiple myeloma following induction therapy with/without consolidative high-dose melphalan and autologous stem cell transplantation. Baseline and longitudinal measurable residual disease (MRD) negative status is a well-established positive predictive sign in Len maintenance patients. However, the clinical utility of serial MRD assessments remains uncertain, as there is no consensus on the clinical management of MRD resurgence (MRDres) or stable remissions in patients positive for MRD. Patients and Methods: In this study, we report the complete and final results of a phase II, single-arm study of 5 years of continuous Len maintenance in patients with multiple myeloma following unrestricted upfront therapy, along with exploratory peripheral blood T cell profiling experiments performed via high-dimensional spectral cytometry. Results: Patients with MRDres had inferior progression-free survival compared with those with sustained MRD negativity at the 1- and 2-year landmarks (P = 0.036, P = 0.0014, respectively); however, myeloma progression only occurred within 2 years of MRDres in 36% of patients, with no progression observed in the remaining 64% of patients at the last follow-up. Exploratory peripheral blood T cell profiling experiments throughout the trial period identified an immune signature of early relapse in patient cohorts both negative and positive for MRD at the start of maintenance therapy. T cell profiles enriched with activated cytotoxic effectors predicted early relapse, whereas quiescent T cell profiles enriched with naïve T cell populations predicted durable remissions. Conclusions: This “immune MRD” status showed predictive potential and segregated patients with MRDres and early disease progression from patients with sustained remission despite MRDres.