MYC Inhibition Potentiates CD8+ T Cells Against Multiple Myeloma and Overcomes Immunomodulatory Drug Resistance

Purpose: Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, are fundamental to multiple myeloma (MM) treatment, but resistance often develops. IMiDs induce cytotoxicity by promoting cereblon-dependent proteasomal degradation of IKZF1 and IKZF3, leading to the downregulation of the oncogenic transcription factors IRF4 and MYC. However, clinical resistance to IMiDs independent of cereblon or IKZF1/3 has not been thoroughly explored. In this study, we investigated the roles of IRF4 and MYC in IMiD resistance.

Experimental Design: Using bone marrow aspirates from IMiD-naïve and refractory MM patients, we examined IKZF1/3 protein levels and IRF4/MYC gene expression after ex vivo pomalidomide treatment through flow cytometry and qPCR. We also evaluated ex vivo sensitivity to the MYC inhibitor MYCi975 using flow cytometry.

Results: Our findings revealed that while pomalidomide commonly induced IKZF1/3 degradation in MM cells, it did not affect MYC gene expression in most IMiD-refractory samples. We further demonstrated that MYCi975 had potent anti-MM effects in both IMiD-naïve and -refractory samples. Surprisingly, we identified CD8+ T cells from MM patients as key mediators of MYCi975-induced cytotoxicity in primary MM samples. Additionally, MYCi975 enhanced the cytotoxic function of memory CD8+ T cells. Lastly, we observed a synergistic effect between MYCi975 and pomalidomide in IMiD-refractory samples, suggesting that restoring MYC downregulation could re-sensitize refractory MM to IMiDs.

Conclusions: Our study highlights MYC as a critical vulnerability in MM across different disease stages and suggests that MYCi975 may offer a promising therapeutic approach for MM patients, particularly when combined with IMiDs.