acePrognostic Significance of Cell-Free DNA Derived 5-Hydroxymethylcytosine Signatures in Newly Diagnosed Multiple Myeloma
While survival outcomes in multiple myeloma (MM) have improved with contemporary combination therapies, predicting disease trajectories for individual patients at diagnosis remains a significant challenge. We investigate the prognostic value of a noninvasive biomarker-cell-free DNA (cfDNA)‑derived 5-hydroxymethylcytosine (5hmC) signature-in newly diagnosed MM, aiming to improve risk stratification at diagnosis. In this prospective cohort study, 321 patients with newly diagnosed MM were enrolled between 2010 and…
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In a prospective study of 321 patients with newly diagnosed multiple myeloma enrolled between 2010 and 2017, investigators measured 5-hydroxymethylcytosine modifications in cell-free DNA collected at diagnosis and built an 18-gene weighted prognostic score using elastic net Cox modeling and machine learning.
The score provided independent prognostic information for overall survival and progression-free survival in a validation set, which matters for noninvasive risk stratification at diagnosis, but the authors note that independent validation in contemporary treatment settings is still required before clinical adoption.
- Prospective cohort of 321 newly diagnosed multiple myeloma patients enrolled 2010-2017 with follow-up through 2022 and median follow-up 70.5 months.
- Genome-wide 5hmC modifications in gene bodies were profiled from cfDNA collected at diagnosis and compared to bone marrow-derived tumor cells.
- Elastic net regularization with Cox model identified 18 key genes to build a weighted prognostic score validated in a held-out validation set.
- During follow-up 127 deaths occurred and the score remained associated with OS and PFS at 24-, 48-, and 72-month follow-up periods.
A machine-learning derived weighted score from 18 cfDNA 5hmC-modified genes at diagnosis predicted overall and progression-free survival in newly diagnosed multiple myeloma after adjusting for stage and other clinical factors.
The rundown
Researchers profiled genome-wide 5hmC in cfDNA at diagnosis from 321 newly diagnosed MM patients and used elastic net regularized Cox modeling to select 18 genes for a weighted prognostic score.
In validation, the score was independently associated with overall survival and progression-free survival after controlling for stage, LDH and treatment type, and associations persisted at 24, 48 and 72 months.
Sources
- Peer-reviewedJCO Precision Oncology2026-07-23
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