Background Transcription factors (TF) are convergence points of signaling cascades that coordinate cell differentiation, proliferation and survival and are commonly deregulated in cancer, including multiple myeloma (MM). They contribute to the initiation of MM, promote tumor cell growth and drug resistance. Both cMyc, a merging point of the PI3K-, and JunB, a merging point of the MEK/MAPK signaling pathway, play pivotal roles in MM pathogenesis. Exciting novel approaches to inhibit TFs like proteolysis-targeting-chimera (PROTAC) promise to lead to selective tumor cell death with little consequence for normal cells. However, redundancy phenomena of TF-programs are likely to challenge their efficacy. Here, we report our final results on the combined targeting of distinct cMyc and JunB transcriptional programs. Methods Following CRISPR-loss-of-function screens for cMyc and JunB across MM cell lines and correlation analyses in MM patient datasets, the functional relevance of Brd4/cMyc- and MEK/JunB-induced TF programs was delineated using genomic and pharmacological approaches in 2D and 3D models of the BM microenvironment. Specifically, effects of single or combined targeting of cMyc- and JunB-induced transcriptional programs were analyzed by FACS, WB, qPCR and luciferase assays. In vitro and ex vivo results were finally verified in a MM xenograft mouse model. Results While CRISPR-loss-of-function screens of MM cell lines confirmed the dependency on cMyc and JunB, we did not observe correlative expression levels among these TFs, neither in the publicly available GSE6477 nor in the CoMMpass dataset. In contrast, a significant positive correlation was observed between MEK and JunB, and Brd4 and cMyc expression levels, respectively. The existence of two distinct Brd4/cMyc and MEK/JunB transcriptional programs in MM cells was supported by stable cMyc levels and resultant transcriptional activity upon JunB knockdown, and vice versa. Likewise, MZ-1, a novel PROTAC which targets Brd4, resulted in inhibition of BMSC/IL-6-induced cMyc but not JunB-upregulation. Conversely, neither the MEK inhibitor trametinib nor doxycycline-induced knockdown of BMSC/IL-6-triggered JunB upregulation in TetshJunB/MM.1S cells reduced Brd4/cMyc mRNA/protein levels. Importantly, the activity of MZ-1 and trametinib was predicted by Brd4 and JunB expression levels using mathematical scoring models, respectively. Moreover, combinations of MZ-1 with trametinib or JunB knockdown synergistically inhibited tumor cell proliferation and induced cell death in a 2D and a dynamic 3D model of the MM-BM milieu. Finally, our results were verified in BMSC:TetshJunB/MM.1S vs BMSC:TetshSCR/MM.1S-carrying NSG mice treated with MZ-1 with/without doxycycline or trametinib. Conclusions In summary, our data demonstrate for the first time the existence of non-overlapping cMyc and JunB-regulated transcriptional programs providing the rationale for combined cMyc:JunB targeting strategies for MM therapy.