# Epigenomic markers of circulating cell-free DNA and treatment outcome in multiple myeloma

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $645,738

## Abstract

PROJECT SUMMARY
Multiple myeloma (MM) is a heterogeneous group of disorders with distinct bone marrow dependence, clinical
features, prognosis, and response to therapy. Despite the best available treatments, MM is generally incurable
and patients will eventually develop relapsed/refractory disease. Early relapse is associated with poor clinical
outcomes and overall survival. There are currently no effective markers that can predict which patients will
have early relapse. The long-term goal is to better understand the role of epigenetics in treatment outcomes of
MM and develop a non-invasive, clinically convenient approach for predicting relapse. The overall objective of
this application is to evaluate 5-hydroxymethylcytosines (5hmC) and 5-methylcytosines (5mC) in circulating
cell-free DNA (cfDNA) from MM patients as markers for predicting patients at high risk of early relapse at the
time of diagnosis. It is known that greater epigenetic heterogeneity is linked with poorer survival and relapse.
We propose that sensitive and robust cfDNA-based epigenetic markers may offer greater convenience and
minimal invasiveness for predicting early relapse in MM. In addition to 5mC, changes in 5hmC, an abundant
and stable modified cytosine with a distinct gene regulatory function from 5mC, have been implicated in cancer
development and pathobiology. However, due to technological constraints, previous studies of cancer
epigenetics have largely interpreted modified cytosines as 5mC only, and no study has evaluated the distinct
roles of 5hmC and 5mC in the therapeutic significance for MM. To fill the current research and technical gaps
and consider the high impact of developing a minimally invasive blood test for MM, we will utilize a highly
sensitive and robust technique developed by our team, the nano-Seal-Seq (a chemical labeling technique
integrated with the next-generation sequencing), to accurately determine 5hmC and 5mC profiles in cfDNA and
CD138+ myeloma “cancer” cells from bone marrow. The central hypothesis is that the 5hmC/5mC signatures
in cfDNA at diagnosis can distinguish MM patients by early relapse status. In Aim 1, we will profile 5hmC and
5mC in cfDNA from ~240 MM patients (relapse within 12 months [early relapse, n=120] vs. >12 months [late
relapse, n=120] of starting initial therapy) to develop an integrated predictive index for early relapse. We will
validate the 5hmC/5mC markers in two independent replication population of ~750 MM patients. In Aim 2, we
will profile 5hmC/5mC in 300 genomic DNA from CD138+ myeloma cells from patients with paired plasma
cfDNA to determine a bone marrow-based predictive index, of which the performance will be compared with
that of the cfDNA markers. In Aim 3, we will investigate change of 5hmC/5mC in serial cfDNA over time in 130
patients to characterize its therapeutic significance. The proposed research is highly significant, because it is
expected to vertically advance understanding of the biological basis...

## Key facts

- **NIH application ID:** 9969358
- **Project number:** 5R01CA223662-03
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** BRIAN C-H CHIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $645,738
- **Award type:** 5
- **Project period:** 2018-07-06 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969358

## Citation

> US National Institutes of Health, RePORTER application 9969358, Epigenomic markers of circulating cell-free DNA and treatment outcome in multiple myeloma (5R01CA223662-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9969358. Licensed CC0.

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