MRD, ctDNA Testing May Help Diagnose Multiple Myeloma Precursor Conditions

New data show that specific tests may help diagnose precursor conditions of multiple myeloma (MM), potentially saving lives through early intervention.

MM is the second most common blood cancer in the United States, with over 35,000 cases expected in 2024. It arises from malignant plasma cells that overproduce dysfunctional B lymphocytes.

MM often develops from precursor conditions. Monoclonal gammopathy of undetermined significance (MGUS) is an early, usually asymptomatic stage marked by the presence of M proteins in the blood, with about a 1% annual risk of progression to MM.

Smoldering multiple myeloma (SMM) is an intermediate stage with a higher progression risk—roughly 10% per year, especially in the first 5 years after diagnosis—and is genomically distinct from MM.¹

MRD and ctDNA for Diagnosing MGUS and SMM

Understanding how MGUS and SMM evolve into overt MM is critical, yet current strategies for monitoring this transition are limited and often invasive.

“Traditionally, MM diagnosis and monitoring rely on bone marrow (BM) evaluation via aspirate and biopsy. This procedure is invasive with the potential for complications, thus being impractical for repetitive disease evaluation,” the authors of the study wrote.²

“In contrast, peripheral blood [PB] liquid biopsy offers a promising, minimally invasive alternative for disease detection and monitoring by analyzing circulating tumor-related analytes released into the bloodstream from the [bone marrow].”²

Minimal residual disease (MRD) and circulating tumor DNA (ctDNA) testing are powerful tools for monitoring cancer, including multiple myeloma. MRD testing identifies very small numbers of malignant cells that remain after treatment, often undetectable by conventional methods, and serves as a highly sensitive indicator of treatment response and risk of relapse.³

ctDNA testing involves detecting fragments of tumor-derived DNA circulating in the bloodstream, providing a non-invasive way to track disease burden in real time. Unlike traditional biopsies, ctDNA can reveal emerging mutations, clonal evolution, and early signs of disease progression, enabling clinicians to adjust therapy proactively.³

Combined, MRD and ctDNA testing offer a more precise and personalized approach to patient monitoring, helping guide treatment decisions, predict outcomes, and potentially improve long-term survival.

Defining MGUS and SMM Progression Through Liquid Biopsy

In this study, the investigators used a liquid biopsy approach to detect and characterize circulating plasma cells across different disease states 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 combined with machine learning-assisted rare event detection, the investigators identified plasma cells based on CD138 and BCMA expression and examined distinct phenotypic subpopulations that correlated with disease stage.²

Among the phenotypes analyzed, the D | CD138 | BCMA-Membrane phenotype was the most predictive of disease progression, showing a consistent increase in incidence from MGUS to SMM and overt MM (P < .005). Multivariate modeling of these phenotypes differentiated precursor states from overt MM with 86% accuracy. Furthermore, changes in BCMA and CD45 expression patterns suggested evolving immune cell profiles as the disease progressed or in response to treatment.²

“Our findings highlight the potential utility of specific circulating cell subsets, particularly D | CD138 | BCMA-Memb phenotypic PCs, in differentiating between precursor states [MGUS and SMM] and overt disease [NDMM and RRMM]” the authors wrote.²

These findings highlight the potential of peripheral blood–based liquid biopsy as a non-invasive tool for detecting and monitoring MM. The study also emphasizes the heterogeneity of circulating plasma cells, which could provide insights into disease biology and help guide individualized treatment strategies

REFERENCES

1. Gerlach A. Multiple myeloma precursor diseases: advancing diagnosis and treatment for MGUS and SMM. Pharmacy Times. September 25, 2024. Accessed December 4, 2025. https://www.pharmacytimes.com/view/multiple-myeloma-precursor-diseases-advancing-diagnosis-and-treatment-for-mgus-and-smm

2. Shishido SN, Mason J, Kamal M, et al. Characterizing circulating rare cells in peripheral blood for detecting and monitoring multiple myeloma and precursor states. npj Precis. Onc. December 2, 2025. Doi:10.1038/s41698-025-01175-2

3. Peng Y, Mei W, Ma K, Zeng C. Circulating Tumor DNA and Minimal Residual Disease (MRD) in Solid Tumors: Current Horizons and Future Perspectives. Front Oncol. November 18, 2021. doi: 10.3389/fonc.2021.763790.