New research suggests that advanced blood tests may help detect precursor conditions of multiple myeloma (MM), potentially enabling earlier intervention and improved patient outcomes.
MM is the second most common blood cancer in the United States, with more than 35,000 cases expected in 2024. The disease arises from malignant plasma cells that overproduce dysfunctional B lymphocytes and often develops from precursor conditions.
Monoclonal gammopathy of undetermined significance (MGUS) is an early, typically asymptomatic stage characterized by the presence of M proteins in the blood, carrying an approximately 1% annual risk of progression to MM. Smoldering multiple myeloma (SMM) represents an intermediate stage, with about a 10% annual risk of progression—particularly within the first five years—and is genetically distinct from MM.
MRD and ctDNA Testing for Precursor Conditions
Monitoring the transition from MGUS and SMM to overt MM is critical, but current strategies are often invasive and limited. Traditionally, diagnosis relies on bone marrow (BM) aspirates and biopsies, which can be painful and carry risks, making frequent monitoring impractical.
Peripheral blood (PB) liquid biopsy offers a minimally invasive alternative, analyzing circulating tumor-related markers shed into the bloodstream from the bone marrow.
Minimal residual disease (MRD) testing detects very low levels of malignant cells remaining after treatment, often missed by conventional methods, and serves as a sensitive indicator of relapse risk. Circulating tumor DNA (ctDNA) testing detects fragments of tumor-derived DNA in the blood, providing a non-invasive way to monitor disease burden in real time. ctDNA can reveal emerging mutations, clonal evolution, and early disease progression, helping clinicians adjust therapy proactively.
Combined, MRD and ctDNA testing allow for a more precise, personalized approach to monitoring MM, guiding treatment decisions and potentially improving long-term survival.
Mapping Disease Progression Through Liquid Biopsy
In the study, researchers used liquid biopsy to analyze circulating plasma cells in 68 patients, including 11 with MGUS, 21 with SMM, 19 with newly diagnosed MM (NDMM), and 17 with relapsed/refractory MM (RRMM).
Using multi-channel immunofluorescence staining and machine learning-assisted rare event detection, investigators identified plasma cells based on CD138 and BCMA expression. They also examined phenotypic subpopulations that correlated with disease stage.
Among these, the D | CD138 | BCMA-Membrane phenotype was the strongest predictor of disease progression, increasing consistently from MGUS to SMM and overt MM. Multivariate models using these phenotypes differentiated precursor states from full-blown MM with 86% accuracy. Changes in BCMA and CD45 expression also suggested evolving immune profiles during disease progression or treatment.
The authors concluded that specific circulating plasma cell subsets, particularly D | CD138 | BCMA-Membrane cells, may help distinguish MGUS and SMM from overt MM.
These findings highlight the potential of peripheral blood–based liquid biopsy as a non-invasive tool for early detection and monitoring of multiple myeloma. The study also underscores the heterogeneity of circulating plasma cells, offering insights into disease biology and supporting more individualized treatment strategies.
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