# Integrating liquid biopsy-based epigenetic and imaging modalities to evaluate disease response in multiple myeloma

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2023 · $691,734

## Abstract

PROJECT SUMMARY
Multiple myeloma (MM) affects ~35,000 adult patients in the United States and causes ~12,000 deaths each
year. Novel immunomodulatory drugs and effective multidrug combinations have improved the prognosis for
patients, but the vast majority of patients eventually relapse. Even among patients achieve a complete
response, ~25% progress within 2 years. Most MM relapses can be attributed to the persistence of measurable
(minimal) residual disease (MRD). MRD status has emerged as one of the most important prognostic markers,
has therapeutic implications, and is incorporated in the International Myeloma Working Group response criteria
for therapeutic response assessment. The gold standard of MRD assessment includes multiparameter flow
cytometry and next-generation sequencing (NGS) based on bone marrow aspirates. However, evaluation of
MRD using only bone marrow aspirates is prone to false-negatives due to patchy disease involvement,
hemodilution of bone aspirate, and extramedullary disease. In addition, bone marrow biopsy is an invasive
procedure, hence cannot be performed frequently to monitor MRD. Positron emission tomography/computed
tomography (PET/CT) is complementary to bone marrow assessment although gaps remain. We have shown
that the 5-hydroxymethylcytosine (5hmC), a stable epigenetic marks generated from active DNA
demethylation, in plasma cell-free DNA (cfDNA) could be complementary to PET/CT and was associated with
overall survival of patients with MM. Here we propose to apply the highly sensitive mapping of genome-wide
5hmC in cfDNA to identify the optimal combination of serial cfDNA-based 5hmC markers with PET/CT for
detecting emergence of MRD. Our central hypothesis is that altered 5hmC signatures in cfDNA are associated
with clinically detectable disease by PET/CT and/or NGS, thus offering opportunities for accurate yet less
invasive approaches to complement bone marrow-based MRD assessment by NGS. Specifically, we propose
to identify 5hmC in cfDNA associated with MRD-positivity (Aim 1), determine cfDNA-based temporal dynamics
of 5hmC and fluorodeoxyglucose (FDG)-PET/CT changes associated with MRD (Aim 2), and evaluate
performance of different MRD modalities in real-world patients (Aim 3). To address these aims, we have
assembled an interdisciplinary team with extensive and complementary expertise. The study leverages the
established resources of the UChicago Myeloma Epidemiology Study and our leadership in three clinical trials
with banked serial blood samples, bone marrow-paired peripheral blood, and known MRD status by NGS. The
knowledge gained from this application may improve clinical utilization of MRD in clinical decision making by
proper combination of serial MRD assessments (i.e., cfDNA, PET/CT, and bone marrow) for sensitive tracking
of MRD as well as provide novel insights into the epigenetic contribution to MM progression. Identifying
patients at high risk of progression after successful treatment will allow ...

## Key facts

- **NIH application ID:** 10651370
- **Project number:** 1R01CA280637-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** BRIAN C-H CHIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $691,734
- **Award type:** 1
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10651370

## Citation

> US National Institutes of Health, RePORTER application 10651370, Integrating liquid biopsy-based epigenetic and imaging modalities to evaluate disease response in multiple myeloma (1R01CA280637-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10651370. Licensed CC0.

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