Despite development of several effective therapies for multiple myeloma (MM), the prognosis of patients with partial deletion of chromosome 17 (del(17p)) and TP53 aberrations remains poor. By applying comprehensive multi-omics profiling analyses (whole exome and transcriptome sequencing plus proteomics) and functional ex vivo drug screening to samples from 167 patients with MM, we uncovered novel therapeutic vulnerabilities specific to TP53 mutated MM. Our findings revealed a distinct sensitivity profile to a range of inhibitors (mitotic, topoisomerase, HDAC, HSP90, IGF1R and PI3K/AKT/mTOR inhibitors) irrespective of 17p deletion status. Conversely, no increase in sensitivity was observed for monoallelic TP53 (del(17p) with WT TP53) when compared to other samples, highlighting the remaining unmet clinical need. Notably, plicamycin, an RNA synthesis inhibitor linked to modulation of chromatin structure and increased transcription, emerged as particularly eXicacious for TP53 mutated MM. The increased sensitivity correlated with higher protein expression of the drug targets: HDAC2, HSP90AA1 and multiple ribosomal subunits. Additionally, we observed increased RNA expression of G2M checkpoint, E2F targets and mTORC1 signaling in our cohort and the MMRF-CoMMpass (NCT01454297) study in TP53 mutated MM. Harmonization of multi-omics data with ex vivo drug screening results revealed that TP53 mutated MM is functionally distinct from MM with monoallelic TP53, and demonstrates that MM with mutated TP53, with and without del(17p), may be targetable by approved drugs. These results further indicate the need for regular monitoring by sequencing to identify these patients.

KEY POINTS TP53 mutation in myeloma confers sensitivity to multiple compounds, including approved drugs, irrespective of del(17p) status.

TP53 mutated myeloma links to higher expression of drug targets involved in cell proliferation, mRNA processing, and chromatin modulation.

C.A.H has received funding from BMS/Celgene, Kronos Bio, Novartis, Oncopeptides, WNTResearch, and Zentalis Pharmaceuticals for research unrelated to this work, and honorarium from Amgen and Autolus. R.S. has received research funding from Amgen, BMS/Celgene and Takeda administered by Hospital Science Centers, unrelated to this work. All other authors declare no conflicts of interest.

The project was supported by grants from the Sigrid Juselius Foundation, Cancer Foundation of Finland, and Research Council of Finland (grants 334781, 320185, 352265, and 357686) to C.A.H. D.T. was supported by the University of Helsinki Doctoral Program of Biomedicine and personal grants from the Cancer Foundation of Finland and the Finnish Cultural Foundation.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by an ethical advisory committee of the Helsinki University Hospital and Comprehensive Cancer Center (239/13/03/00/2010 and 303/13/03/01/2011). The patients provided informed consent for the use of their samples and data, and the samples were taken using approved protocols and in accordance with the Declaration of Helsinki. The patients were anonymized prior to receiving their samples and their data securely handled according to GDPR standards.

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The ex vivo drug sensitivity, DNA sequencing, RNA sequencing, and proteomic data generated in this study will be deposited in the Zenodo public repository upon acceptance of the manuscript for publication. Additionally, this study was supplemented with publicly available data from the Multiple Myeloma Research Foundation Researcher Gateway (https://research.themmrf.org/).