Transcriptional signature of TP53 biallelic inactivation identifies a group of multiple myeloma patients without this genetic condition but with dismal outcome

Biallelic inactivation of TP53 has been included in the definition of double‐hit (DH) multiple myeloma (MM), which entails an ominous prognosis. However, this condition, or even the presence of high‐risk cytogenetic abnormalities, cannot accurately capture the 15%–20% of the MM population with a median overall survival below 24 months. This prompted us to look for other MM patients who might have transcriptional characteristics similar to those with DH‐TP53. In the present study, we analysed RNA‐seq, whole‐genome and whole‐exome sequencing data from 660 newly diagnosed MM (NDMM) patients from the MMRF (Multiple Myeloma Research Foundation) CoMMpass study to characterize the transcriptional signature of TP53 double‐hit (DH‐TP53) MM. We found 78 genes that were exclusively deregulated in DH‐TP53 patients. A score based on these genes identified a group of 50 patients who shared the same transcriptional profile (DH‐TP53‐like group) whose prognosis was particularly unfavourable [median overall survival (OS) < 2 years], despite not harbouring the biallelic inactivation of TP53. The prognostic value of the DH‐TP53 score was externally validated using gene expression data from 850 NDMM patients analysed by microarrays. Furthermore, our DH‐TP53 score refined the traditional prognostic stratification of MM patients according to the cytogenetic abnormalities and International Staging System (ISS).