Abstract Purpose: Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, are a cornerstone of multiple myeloma (MM) therapies, yet the disease inevitably becomes refractory. IMiDs exert cytotoxicity by inducing cereblon-dependent proteasomal degradation of IKZF1 and IKZF3, resulting in downregulation of the oncogenic transcription factors IRF4 and MYC. To date, clinical IMiD resistance independent of cereblon or IKZF1/3 has not been well explored. Here, we investigated the roles of IRF4 and MYC in this context. Experimental Design: Using bone marrow aspirates from patients with IMiD-naïve or refractory MM, we examined IKZF1/3 protein levels and IRF4/MYC gene expression following ex vivo pomalidomide treatment via flow cytometry and qPCR. We also assessed ex vivo sensitivity to the MYC inhibitor MYCi975 using flow cytometry. Results: We discovered that although pomalidomide frequently led to IKZF1/3 degradation in MM cells, it did not affect MYC gene expression in most IMiD-refractory samples. We subsequently demonstrated that MYCi975 exerted strong anti-MM effects in both IMiD-naïve and -refractory samples. Unexpectedly, we identified a cluster of differentiation 8+ (CD8+ T) cells from patients with MM as crucial effectors of MYCi975-induced cytotoxicity in primary MM samples, and we discovered that MYCi975 enhanced the cytotoxic functions of memory CD8+ T cells. We lastly observed synergy between MYCi975 and pomalidomide in IMiD-refractory samples, suggesting that restoring MYC downregulation can re-sensitize refractory MM to IMiDs. Conclusions: Our study supports the concept that MYC represents an Achilles’ heel in MM across disease states and that MYCi975 may be a promising therapeutic for patients with MM, particularly in combination with IMiDs.