Clinical Implications of Residual Immunophenotypically Normal Plasma Cells within Bone Marrow at Various Disease Stages in Multiple Myeloma

Introduction Residual normal plasma cells (NPCs) within bone marrow (BM) act as competitors of abnormal plasma cells, playing an important clinical role during the malignant transformation and disease aggressiveness in plasma cell disorders. Previous studies have described the relationship between the persistence of NPCs and survival outcomes at several timepoints, but its clinical significance remain to be fully elucidated across various disease courses. Following the clearance of tumor plasma cells post-treatment, the numerical or proportional alterations in NPCs during the minimal residual disease (MRD) phase could also indicate the evolution of response depth and changes in the immune microenvironment. To date, however, there has been a scarce of research specifically addressing residual NPCs at the MRD stage. Methods In light of this, we conducted a comprehensive retrospective study utilizing a substantial flow cytometry dataset comprising 1363 MM patients and nearly 5000 MRD samples across all disease courses from the National Longitudinal Cohort of Hematological Diseases in China (NICHE, NCT04645199). Results Our results revealed that 47 (4.5%) newly diagnosed myeloma patients with high NPC ratio (≥5%) within bone marrow (BM) exhibited distinct indolent features, characterized by lower tumor burden, reduced frequencies of cytopenia, immunoparesis, and high-risk cytogenetics. Importantly, high residual NPC ratio at diagnosis or relapse was independently associated with favorable survival outcomes. Furthermore, high absolute level of NPCs at undetectable MRD timepoint was also related with superior clinical benefit and immune reconstitution. Among MRD-positive patients, NPCs ratio within BMPCs was significantly negatively correlated with residual tumor cell levels post-treatment. In addition to MRD status, grouping based on NPC ratio (< 50%, 50-90%, ≥90%) at MRD phase demonstrated better risk stratification for detectable MRD patients compared to residual tumor log levels. The dynamic NPC ratio time-dependent model could classify patients into three groups with diverse longitudinal change trends, which lead to distinct survival outcomes. Conclusions Collectively, the persistence of residual NPCS serves not only as a valuable complementary biomarker for risk stratification but also provides valuable insights on reclassifications and kinetics of MRD.