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Efficacy of melflufen in relapsed and refractory multiple myeloma patients with mutated or deleted TP53

ABSTRACT: Despite the development of several new treatments for multiple myeloma (MM) clinical challenges remain for patients with relapsed/refractory disease. This is especially so for the high-risk subgroup of patients with del(17p) who have poor response and significantly shorter survival compared to patients without this aberration. Here, we report the clinical efficacy of melphalan flufenamide (melflufen) in patients with del(17p) from the OCEAN randomized, open label, head-to-head, phase III clinical trial. In the del(17p) subgroup, melflufen plus dexamethasone treatment resulted in favorable progression free survival compared to the pomalidomide plus dexamethasone arm. To understand the superior efficacy of melflufen in TP53 mutated MM, we compared drug response between melflufen and melphalan in primary MM cells from patients with del(17p)/TP53 mutated disease. In line with the clinical data ex vivo sensitivity to melfufen was independent of the TP53 mutation status. To better understand the mechanism of action of melflufen, we investigated DNA damage, apoptosis kinetics and mitochondrial function in TP53 wild type and double mutant (TP53-/-) myeloma cells after treatment with melflufen, melphalan or cyclophosphamide. Melflufen demonstrated superior in vitro efficacy in comparison to the other two alkylators. Comparison of gene expression profiles and DNA damage pathway alterations upon drug treatment in the TP53 wild type and double mutant MM cell lines revealed qualitative differences between melflufen and melphalan. Our insights into the molecular mechanisms of melflufen activity in mutant TP53 genetic background support its clinical efficacy and application in the del(17p) and mutant TP53 MM patient population.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254959 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Background Toxicity of the oral and gastrointestinal mucosa induced by high-dose melphalan is a clinical challenge with no documented prophylactic interventions or predictive tests. The aim of this study was to describe molecular changes in human oral mucosa and to identify biomarkers correlated with the grade of clinical mucositis. Methods and Findings Ten patients with multiple myeloma (MM) were included. For each patient, we acquired three buccal biopsies, one before, one at 2 days, and one at 20 days after high-dose melphalan administration. We also acquired buccal biopsies from 10 healthy individuals that served as controls. We analyzed the biopsies for global gene expression and performed an immunohistochemical analysis to determine HLA-DRB5 expression. We evaluated associations between clinical mucositis and gene expression profiles. Compared to gene expression levels before and 20 days after therapy, at two days after melphalan treatment, we found gene regulation in the p53 and TNF pathways (MDM2, INPPD5, TIGAR), which favored anti-apoptotic defense, and upregulation of immunoregulatory genes (TREM2, LAMP3) in mucosal dendritic cells. This upregulation was independent of clinical mucositis. HLA-DRB1 and HLA-DRB5 (surface receptors on dendritic cells) were expressed at low levels in all patients with MM, in the subgroup of patients with ulcerative mucositis (UM), and in controls; in contrast, the subgroup with low-grade mucositis (NM) displayed 5–6 fold increases in HLA-DRB1 and HLA-DRB5 expression in the first two biopsies, independent of melphalan treatment. Moreover, different splice variants of HLA-DRB1 were expressed in the UM and NM subgroups. Conclusions Our results revealed that, among patients with MM, immunoregulatory genes and genes involved in defense against apoptosis were affected immediately after melphalan administration, independent of the presence of clinical mucositis. Furthermore, our results suggested that the expression levels of HLA-DRB1 and HLA-DRB5 may serve as potential predictive biomarkers for mucositis severity

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Efficacy of melflufen in relapsed and refractory multiple myeloma patients with mutated or deleted TP53

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