c-Myc plays a pivotal role in multiple myeloma (MM) pathogenesis; and the BET protein BRD4 is a key regulator of c-Myc transcription. Recently, a pathophysiologic role in MM has also been attributed to the AP-1 family member JunB. Approaches to target transcription factors (TFs), such as c-Myc and JunB, currently emerge among the most promising novel anti-MM strategies, with a potentially high therapeutic index. However, redundancy phenomena represent a major challenge for targeting c-Myc- or JunB-mediated tumor proliferation programs.MZ-1 is a novel proteolysis-targeting chimera combining the recognition sequence for the E3-ligase Von-Hippel-Lindau with JQ1, a moiety that targets BRD4. Indeed, beyond direct inhibition by JQ1, MZ-1 significantly decreased BRD4 as well as c-Myc protein levels in MM cell lines and primary cells. Consequently, MZ-1 inhibited MM cell growth through G0/G1 arrest; and induced tumor cell death. Moreover, patient-derived BMSC- or exogenous IL-6- induced BRD4/c-Myc upregulation in MM cells was inhibited by MZ-1 treatment, indicating that targeting BRD4, at least in part, overcomes the protective effect of the microenvironment. Of note, MZ-1 did not have an impact on BMSCs/IL-6- induced upregulation of JunB RNA or protein levels. Conversely, dox-induced knockdown of BMSC/IL-6-triggered JunB upregulation in TetshJunB/MM.1S cells did not decrease BRD4/c-Myc RNA or protein levels. Similar data were obtained in other MM cell lines and primary cells. RNAseq, unbiased GSEA, and luciferase reporter assays of representative target genes further supported the co-existence of c-Myc- and JunB-mediated proliferative programs, which are initiated by the same stimuli. Importantly, MZ-1 in combination with dox-induced knockdown of BMSC/IL-6-triggered JunB upregulation in TetshJunB/MM.1S cells significantly decreased both BRD4/c-Myc as well as JunB protein levels; synergistically inhibited tumor cell proliferation and induced cell death. Similar results were obtained in other MM cell line and primary cells upon treatment with MZ-1 and transient siJunB. Finally, our preliminary results show the synergistic in vivo activity of MZ-1 in BMSC:TetshJunB/MM.1S versus BMSC:TetshSCR/MM.1S-carrying doxycyclin- treated NSG mice. Taken together, these data for the first time delineate the existence of distinct c-Myc and JunB transcriptional programs that contribute to MM proliferation. They thereby provide the preclinical rationale for the development of therapeutic strategies that combine targeting of distinct transcriptional programs to improve outcome in MM.Vallet:Roche Pharmaceuticals: Consultancy; Pfizer: Honoraria; MSD: Honoraria. Podar:Celgene: Consultancy, Honoraria; Amgen Inc.: Honoraria; Roche Pharmaceuticals: Research Funding; Takeda: Consultancy; Janssen Pharmaceuticals: Consultancy, Honoraria.