# Project 2 - IMiD Resistance in Patients and Humanized Mice with Multiple Myeloma

> **NIH NIH U54** · MAYO CLINIC ARIZONA · 2021 · $314,462

## Abstract

PROJECT 2 SUMMARY ABSTRACT 
Multiple myeloma (MM) is a slowly proliferating tumor of post-germinal center plasma cells that causes bone 
destruction, marrow failure, immuneparesis and renal failure and results in over ten thousand deaths each year 
in the USA. For many years a class of drugs termed immunomodulatory drugs (IMiDs) have been used in the 
clinic with remarkable activity against MM and a few other hematopoietic neoplasms (Chronic Lymphocytic 
Leukemia, NonHodgkin Lymphoma and Myelodysplastic Syndrome with 5q- deletion). Although many patients 
have a favorable initial IMiD response, most will eventually relapse with loss of sensitivity to the IMiD (acquired 
resistance to IMiDs). Patients also differ in their initial responses to IMiD therapy. While some enjoy 
`exceptional' responses to IMiD treatment (defined as time to progression of 72 months or longer) others 
exhibit innate resistance and thus never respond. The exact mechanism of IMiD action and resistance in MM 
remains elusive, although it is clear that IMiDs trigger the CRBN-dependent degradation of the hematopoietic 
transcription factor Ikaros. Almost every MM tumor is characterized by super enhancer-mediated oncogene 
dysregulation via insertion of such enhancers into the MYC locus or via recurrent IgH enhancer translocations 
to a number of oncogenes. Our preliminary data further indicate that many these critical super-enhancers 
driving oncogene expression in MM exhibit high Ikaros occupancy, and that their enhancer function is 
consequently often Ikaros-dependent. Our hypothesis is that tumor cell-autonomous IMiD resistance is caused 
by super-enhancers driving oncogene expression that retain their function in the presence of IMiDs. The work 
presented here studies IMiD resistance using three different approaches. First, with the goal of identifying 
genetic determinants of innate and acquired IMiD resistance, we will examine structural variations (primarily 
DNA translocations) that mobilize super-enhancers to oncogenes in patient samples that have been banked in 
the Mayo Clinic biobank. Secondly, we have >80 genetically annotated MM cell lines with a range of responses 
to IMiDs that will be tested for their response to IMiDs in terms of proliferation and changes in gene 
expression/protein levels (including MYC). Additionally we will examine synergies between IMiDs and a 
number of novel rational drug partners including next generation BET inhibitors (BETi), CBP/p300 inhibitor and 
a combination BETi/p300 inhibitor. Thirdly, IMiD response mediated by the inter-play between tumor cell and 
host will be studied in an orthotopic, immunocompetent humanized mouse model of MM in which both the 
tumor and the host are capable of responding to IMiDs. Our ultimate goal is to rationally optimize the activity of 
IMiDs, which would have a profound impact on the clinical history of MM, both avoiding IMiD resistance in 
newly diagnosed patients and reversing IMiD resistance in ...

## Key facts

- **NIH application ID:** 10232131
- **Project number:** 5U54CA224018-04
- **Recipient organization:** MAYO CLINIC ARIZONA
- **Principal Investigator:** SHAJI Kunnathu KUMAR
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $314,462
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232131

## Citation

> US National Institutes of Health, RePORTER application 10232131, Project 2 - IMiD Resistance in Patients and Humanized Mice with Multiple Myeloma (5U54CA224018-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10232131. Licensed CC0.

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