Chromatin-informed cell-free DNA approach for detection of clinically measurable disease in multiple myeloma

Multiple myeloma (MM) is monitored using bone marrow-based minimal residual disease (MRD) assays, which provide high sensitivity but require repeated invasive sampling and are limited to a single anatomical site. Cell-free DNA (cfDNA) offers a minimally invasive alternative, yet most cfDNA approaches rely on prior tumor profiling to identify patient-specific genomic alterations for subsequent tracking in plasma. Here, we developed MATADOR, a myeloma-specific, tumor-agnostic framework that leverages cfDNA fragmentation patterns at a fixed set of myeloma-specific chromatin-accessible regulatory regions. These regions were defined using single-nucleus ATAC-seq data from an independent MM cohort and used to quantify plasma cfDNA fragmentation at these loci without patient-specific tumor profiling. Using these locus-specific features alone, MATADOR distinguished clinically measurable from unmeasurable disease in a held-out test set with an area under the receiver operating characteristic curve (AUROC) of 0.94. These findings establish chromatin-informed cfDNA fragmentomics as a minimally invasive approach for disease assessment in MM without individualized tumor profiling, enabling blood-based assessment of disease beyond the constraints of bone marrow sampling.

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Publication Details

Journal
Blood Advances
Published
2026-10-06
DOI
https://doi.org/10.1182/bloodadvances.2026022335
Primary Topic
Multiple Myeloma Research and Treatments
Type
article
Field-Weighted Citation Impact
0.00
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article

Chromatin-informed cell-free DNA approach for detection of clinically measurable disease in multiple myeloma

Benjamin T. Diamond, Dionysios Christos Watson, David Glen Coffey, Damian J. Green et al.
Blood Advances
Multiple Myeloma Research and Treatments
article

Chromatin-informed cell-free DNA approach for detection of clinically measurable disease in multiple myeloma

Benjamin T. Diamond, Dionysios Christos Watson, David Glen Coffey, Damian J. Green, Urvi Ashok Shah, Dor David Abelman, Alexander M. Lesokhin, Dickran Gano Kazandjian, Hani Hassoun, Sham Mailankody, Neha Korde, Chrissy Sessa, Jonathan Harry Schatz, Edus Houston Warren, Trevor J. Pugh, Sacha Gnjatic, Ola Landgren, Michele Ceccarelli, Eric L. Smith, Ping Luo, Noa A. Perry, Ava Amidei
article en

Abstract

Multiple myeloma (MM) is monitored using bone marrow-based minimal residual disease (MRD) assays, which provide high sensitivity but require repeated invasive sampling and are limited to a single anatomical site. Cell-free DNA (cfDNA) offers a minimally invasive alternative, yet most cfDNA approaches rely on prior tumor profiling to identify patient-specific genomic alterations for subsequent tracking in plasma. Here, we developed MATADOR, a myeloma-specific, tumor-agnostic framework that leverages cfDNA fragmentation patterns at a fixed set of myeloma-specific chromatin-accessible regulatory regions. These regions were defined using single-nucleus ATAC-seq data from an independent MM cohort and used to quantify plasma cfDNA fragmentation at these loci without patient-specific tumor profiling. Using these locus-specific features alone, MATADOR distinguished clinically measurable from unmeasurable disease in a held-out test set with an area under the receiver operating characteristic curve (AUROC) of 0.94. These findings establish chromatin-informed cfDNA fragmentomics as a minimally invasive approach for disease assessment in MM without individualized tumor profiling, enabling blood-based assessment of disease beyond the constraints of bone marrow sampling.

Blood Advances
University Health Network (CA), Memorial Sloan Kettering Cancer Center (US), University of Miami (US), Princess Margaret Cancer Centre (CA), Fred Hutch Cancer Center (US), Dana-Farber Cancer Institute (US), Sylvester Comprehensive Cancer Center (US), Algoma University (CA), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 12%
Multiple Myeloma Research and Treatments
DOIOpen Access PDFOpenAlex
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