Immune-MRD status informs tumor-MRD outcome prognostication in patients with multiple myeloma on lenalidomide maintenance

Abstract

Purpose: Lenalidomide maintenance is the most frequently utilized approach for newly diagnosed multiple myeloma (MM) patients 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 lenalidomide 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. Experimental Design: Here we report the complete and final results of a phase 2, single-arm study of 5 years of continuous lenalidomide maintenance in MM patients 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 PFS to 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 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 while 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.