# Molecular Prediction of Myeloma Initiation Molecular Prediction of Myeloma Initiation

> **NIH NIH R35** · DANA-FARBER CANCER INST · 2024 · $988,380

## Abstract

SUMMARY
Multiple Myeloma (MM) is the second most common hematologic malignancy and is almost always preceded by
monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Recent
randomized trials have shown that early therapeutic intervention at the stage of SMM can improve progression-
free and overall survival. This indicates that early detection and therapeutic intervention before symptomatic MM
occurs may lead to improved survival and decreased morbidity from other complications such as bone fractures,
renal failure and hospitalizations related to end-organ damage from myeloma. Early detection requires a
comprehensive screening of the population at risk for developing MM. Known risk factors for developing MM
include aging, race (Blacks), and familial history of hematologic malignancies. Our preliminary data of screening
~7,500 ethnically diverse individuals at risk of developing MM using a sensitive quantitative MALDI-TOF mass
spectrometry has shown a prevalence rate of monoclonal protein in 45% in individuals of age >50y and having
an early immune dysregulation that we termed Monoclonal Gammopathy of Indeterminate Potential (MGIP).
MGUS was significantly more prevalent in Black participants and participants with familial hematologic
malignancy (HM) history than in White participants with no family history of HM. To begin to delineate
mechanisms by which these early MGIP clones progress to MGUS and further lead to MM, we plan to explore
the host intrinsic (age, race, germline risk factors) and acquired (inflammation, antigenic activation) risk factors
on the expanding clone and its environment that influence its behavior. We believe the next frontier in MM
research is to understand how one develops myeloma and treat it early before end-organ damage.
Identifying and preventing the development of the earliest stages of MM will lead to transformative approaches
to treatment and serve as a paragon of cancer prevention. We hypothesize that defining risk as ancestry
scores and genomic signatures, instead of defining risk by self-identified race, can improve risk
prediction for MM. Similarly, instead of using chronological age as a risk factor for MM, we will test the
hypothesis that the effective age of the bone marrow niche confers biological risk of developing MM.
Together, we believe that these studies will help define the mechanistic underpinnings of the carcinogenic
process linked to MM. This approach will allow the field to transition from a purely demographic definition of risk
to a biological one.

## Key facts

- **NIH application ID:** 10906223
- **Project number:** 5R35CA263817-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Irene M. Ghobrial
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $988,380
- **Award type:** 5
- **Project period:** 2022-09-06 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906223

## Citation

> US National Institutes of Health, RePORTER application 10906223, Molecular Prediction of Myeloma Initiation Molecular Prediction of Myeloma Initiation (5R35CA263817-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10906223. Licensed CC0.

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