# Project 3: Early detection and prevention of MM progression

> **NIH NIH P50** · MAYO CLINIC ARIZONA · 2023 · $392,040

## Abstract

PROJECT SUMMARY
Multiple myeloma (MM) is a malignant plasma cell neoplasm leading to anemia, hypercalcemia, renal
insufficiency and bone lesions. It is preceded by a common benign monoclonal plasma cell expansion called
monoclonal gammopathy of undetermined significance (MGUS) that shares the same initiating events seen in
MM. These include recurrent immunoglobulin gene translocations, and hyperdiploidy. There is a third clinical
entity in between these two, smoldering multiple myeloma (SMM), in which there has been more extensive
plasma cell expansion than MGUS, but the malignant features of MM are not seen. This project is focused on
using genetics to more precisely demarcate benign from malignant plasma cells and develop a patho-genetic
definition of MM. We hypothesize that an accumulation of secondary genetic events mark the progression from
a benign to malignant state. These events involve a handful of pathways common to many cancers:
MYC/MAX, MAPK (NRAS, KRAS, BRAF, FGFR3, PTPN11, NF1), NFKB (TRAF3, TRAF2, CYLD, BIRC2/3,
MAPK3K14), TP53/MDM2, RB1/CDKN2C, Others (DIS3, FAM46C). One of these pathways is dysregulated in
>95% of MM and <5% of MGUS, and we postulate that individually or in combination they can be used to
define malignant plasma cells. There is also increasing evidence of a role of the tumor microenvironment in
progression of SMM, and recently clonal hematopoiesis has been associated with increased inflammation, and
more rapid progression of MM. We will use next generation sequencing to identify clonal hematopoiesis, and to
characterize the genetic events present in patients with MGUS, SMM and MM, and correlate these with the
clinical course. We will validate our findings in an independent cohort of patients with SMM enrolled on
prospective randomized clinical trials. Ultimately, we hope that a genetic definition will allow both the early
detection and prompt treatment of MM, resulting in the prevention of the malignant consequences of MM, and
prolonged survival for patients.

## Key facts

- **NIH application ID:** 10706331
- **Project number:** 5P50CA186781-08
- **Recipient organization:** MAYO CLINIC ARIZONA
- **Principal Investigator:** Marta Chesi
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $392,040
- **Award type:** 5
- **Project period:** 2015-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10706331

## Citation

> US National Institutes of Health, RePORTER application 10706331, Project 3: Early detection and prevention of MM progression (5P50CA186781-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10706331. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*