# Biomarkers of Cellular Senescence and their Association with Frailty, Clinical Outcomes, and Survival in Multiple Myeloma

## TL;DR

This study explores how biomarkers of cellular aging relate to frailty and survival in multiple myeloma patients, identifying potential new tools for predicting outcomes.

## Contribution

The study introduces a 5-factor SASP model that outperforms existing methods in predicting survival in multiple myeloma.

## Key findings

- SASP factors like GDF-15, TNF-RI, IL-6, and IL-8 correlate with frailty in multiple myeloma patients.
- A 5-factor SASP model predicts overall survival better than chronological age and clinical frailty assessments.
- SASP factors are linked to treatment outcomes, including toxicity and healthcare use.

## Abstract

Frailty predicts adverse outcomes in multiple myeloma (MM), yet an objective frailty biomarker is lacking. Circulating senescence-associated secretory phenotype (SASP) factors correlate with frailty and adverse outcomes in chronic diseases, but their relevance in MM is unclear. In this study, we investigated the relationship between 36 plasma SASP factors, frailty, and clinical outcomes in: (1) a historical cohort using stored specimens from 59 patients with newly diagnosed MM, and (2) a prospective cohort of 36 patients initiating new MM treatment. Several SASP factors were significantly associated with frailty after adjusting for age, sex, and body mass index; GDF-15, TNF-RI, IL-6, and IL-8 showed positive correlations with both cumulative-deficit based and physical frailty indices. Additionally, significant age-adjusted associations were observed between SASP factors and treatment outcomes, including overall survival (OS), high-grade toxicity, and healthcare utilization. We developed a 5-factor SASP model that demonstrated superior predictive performance for OS compared to chronological age, R-ISS stage, and clinical frailty, and TNF-RI alone (5-year OS AUC: 0.90). These findings highlight the association between senescence biomarkers and frailty and OS, and support further investigation of SASP factors as objective frailty biomarkers in MM.