# Multi-hit TP53 confers the poorest survival in multiple myeloma in the era of novel therapies

## TL;DR

This study finds that multiple TP53 gene abnormalities in multiple myeloma patients lead to the worst survival outcomes, even with modern treatments.

## Contribution

The study identifies multi-hit TP53 as the most detrimental high-risk genetic abnormality in multiple myeloma patients treated with novel therapies.

## Key findings

- Patients with multi-hit TP53 had the shortest progression-free and overall survival compared to other high-risk abnormalities.
- The relative risk of early progression was nearly three times higher for multi-hit TP53 patients.
- TP53 alterations, especially multi-hit TP53, were more prevalent in later disease stages and associated with distinct blood markers.

## Abstract

Multiple myeloma (MM) with high-risk (HR) genetic abnormalities has poor prognosis, despite the use of novel therapeutic agents. However, the individual contribution of specific HR genetic abnormalities or their co-occurrence to poor outcomes, especially in the era of novel agents, remains unclear. This study evaluated the impact of multi-hit TP53 (del(17p) and TP53 mutation or ≥ 2 TP53 mutations) compared with other HR abnormalities on progression-free survival (PFS), overall survival (OS) and blood signature in a real-world cohort of 204 patients with MM treated with novel agents (median follow-up 28 months). Patients with multi-hit TP53 (10.4%) had the shortest PFS and OS compared with those with single HR abnormalities (p ≤ 0.011) or with co-occurrence of ≥ 2 other HR abnormalities (p ≤ 0.002), regardless of therapy line. The relative risk of early progression in patients with multi-hit TP53 was almost three times higher than that of patients with other HR abnormalities. The prevalence of TP53 alterations increased in later disease stages: multi-hit TP53 was detected in 7.6% of patients with ≤ 1 prior therapy line and in 36.4% of patients with ≥ 2 prior lines. Patients with multi-hit TP53 also differed in blood signature, particularly in counts of white blood cells, lymphocytes, serum creatinine and β2-microglobulin levels compared with those with other HR abnormalities. In conclusion, multi-hit TP53 is associated with the poorest survival among all HR subgroups in MM. Considering that TP53 alterations accumulate during MM progression and are associated with drug resistance even in the context of novel therapies, our study further emphasizes the need for routine evaluation of both del(17p) and TP53 mutations. Patients with multi-hit TP53 should be prioritized for inclusion in trials of novel therapeutic strategies.

The online version contains supplementary material available at 10.1186/s10020-025-01392-2.