# Therapy-induced Damage to the Host Bone Marrow as a Promoter of Treatment Resistance in Multiple Myeloma

> **NIH NIH P20** · UNIV OF ARKANSAS FOR MED SCIS · 2023 · $136,800

## Abstract

PROJECT SUMMARY/ABSTRACT 
 Multiple myeloma (MM) is the most common malignancy of the bone marrow (BM) and remains incurable for 
the vast majority of patients. It has been known for some time that cells in the host BM niche are crucial to MM 
growth and that interactions between MM and the host BM microenvironment can facilitate disease progression 
and relapse. Current treatment standards for newly diagnosed MM include high-dose melphalan with autologous 
stem cell transplantation followed by prolonged maintenance therapy with an immunomodulatory drug. While the 
effects of these agents on MM cells have been studied extensively, the effects of cytotoxic therapy on the host 
BM microenvironment remain poorly understood. Cytopenias, immunoparesis, and the development of acute 
leukemias are adverse consequences of cytotoxic therapy-induced damage to the host BM niche that have long 
been reported on and have a significant impact on the disease course. Intriguingly, recent research has shown 
that cytotoxic therapy-induced damage to the cells of the tumor-surrounding microenvironment leads to 
alterations that foster disease relapse. Given the intimate relationship between MM cells and the host BM niche, 
we hypothesize that cytotoxic therapy leads to quantitative and qualitative changes in the host BM 
microenvironment that can promote MM growth and progression. To address this hypothesis, we will investigate 
transcriptional changes in cell populations within the host BM niche before, during, and after cytotoxic therapy 
using single-cell RNA sequencing technology (Aim 1). The analysis of proliferation, senescence, and variation 
of cancer-promoting pathways within these subtypes will unravel the specific alterations induced by cytotoxic 
therapy. Furthermore, we will determine how cytotoxic therapy alters the regulation of immune cells and their 
interplay with other cells of the BM niche. Aim 2 will study how these processes differ in patients who relapse 
early (<2 years) and in those who relapse late (>5 years). The findings will identify the role of these immune 
populations in MM response to immunomodulatory drug therapy. To determine whether cytotoxic therapy- 
induced damage can be overcome, we will use our in-house SCID–rab mouse model (Aim 3). We will investigate 
the impact of inhibiting TGF-β, a cytokine that has been found to be elevated in patients after cytotoxic therapy 
and has been associated with tumor recurrence. Successful completion of these studies will provide a 
mechanistic explanation of how cytotoxic therapy-induced damage to the BM microenvironment can promote 
MM relapse. This will allow for the development of more effective therapies for MM, which is the long-term goal 
of this work.

## Key facts

- **NIH application ID:** 10667662
- **Project number:** 5P20GM109005-09
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Carolina Schinke
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $136,800
- **Award type:** 5
- **Project period:** 2015-06-24 → 2024-01-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10667662

## Citation

> US National Institutes of Health, RePORTER application 10667662, Therapy-induced Damage to the Host Bone Marrow as a Promoter of Treatment Resistance in Multiple Myeloma (5P20GM109005-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10667662. Licensed CC0.

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