Dataset Information

The Role of Clonal Evolution on Progression, Blood Parameters, and Response to Therapy in Multiple Myeloma.

ABSTRACT:

Introduction

A variety of biomarkers are considered for diagnosis (e.g., β2-microgobulin, albumin, or LDH) and prognosis [e.g., cytogenetic aberrations detected by fluorescence in situ hybridization (FISH)] of multiple myeloma (MM). More recently, clonal evolution has been established as key. Little is known on the clinical implications of clonal evolution.

Methods

We performed in-depth analyses of 25 patients with newly diagnosed MM with respect to detailed clinical information analyzing blood samples collected at several time points during follow-up (median follow-up: 3.26 years since first diagnosis). We split our cohort into two subgroups: with and without new FISH clones developing in the course of disease.

Results

Each subgroup showed a characteristic chromosomal profile. Forty-three percent of patients had evidence of appearing new clones. The patients with new clones showed an increased number of translocations affecting chromosomes 14 (78% vs. 33%; p = 0.0805) and 11, and alterations in chromosome 4 (amplifications and translocations). New clones, on the contrary, were characterized by alterations affecting chromosome 17. Subsequent to the development of the new clone, 6 out of 9 patients experienced disease progression compared to 3 out of 12 for patients without new clones. Duration of the therapy applied for the longest time was significantly shorter within the group of patients developing new clones (median: 273 vs. 406.5 days; p = 0.0465).

Discussion

We demonstrated that the development of new clones, carrying large-scale alterations, was associated with inferior disease course and shorter response to therapy, possibly affecting progression-free survival and overall survival as well. Further studies evaluating larger cohorts are necessary for the validation of our results.

SUBMITTER: Sandmann S

PROVIDER: S-EPMC9343617 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

The Role of Clonal Evolution on Progression, Blood Parameters, and Response to Therapy in Multiple Myeloma.

Sandmann Sarah S Karsch Katharina K Bartel Peter P Exeler Rita R Brix Tobias J TJ Mai Elias K EK Varghese Julian J Lenz Georg G Khandanpour Cyrus C

Frontiers in oncology 20220719

<h4>Introduction</h4>A variety of biomarkers are considered for diagnosis (e.g., β2-microgobulin, albumin, or LDH) and prognosis [e.g., cytogenetic aberrations detected by fluorescence <i>in situ</i> hybridization (FISH)] of multiple myeloma (MM). More recently, clonal evolution has been established as key. Little is known on the clinical implications of clonal evolution.<h4>Methods</h4>We performed in-depth analyses of 25 patients with newly diagnosed MM with respect to detailed clinical inform ...[more]

PMID: 35928862

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Project description:Multiple Myeloma (MM) arises from malignant transformation and deregulated proliferation of clonal plasma cells (PCs) harbouring heterogeneous molecular anomalies. The effect of evolving mutations on clone fitness and their cellular prevalence shapes the progressing myeloma genome and impacts clinical outcomes. Although clonal heterogeneity in MM is well established, which subclonal mutations emerge/persist/perish with progression in MM and which of these can be targeted therapeutically remains an open question. In line with this, we have sequenced pairwise whole exomes of 62 MM patients collected at two time points, i.e., at diagnosis and on progression. Somatic variants were called using a novel ensemble approach where a consensus was deduced from four variant callers (Illumina's Dragen, Strelka2, SomaticSniper and SpeedSeq) and actionable/druggable gene targets were identified. A marked intraclonal heterogeneity was observed. Branching evolution was observed among 72.58% patients, of whom 64.51% had low TMBs (<10) and 61.29% had 2 or more founder clones. The hypermutator patients (with high TMB levels ≥10 to ≤100) showed a significant decrease in their TMBs from diagnosis (median TMB 77.11) to progression (median TMB 31.22). A distinct temporal fall in subclonal driver mutations was identified recurrently across diagnosis to progression e.g., in PABPC1, BRAF, KRAS, CR1, DIS3 and ATM genes in 3 or more patients suggesting such patients could be treated early with target specific drugs like Vemurafenib/Cobimetinib. An analogous rise in driver mutations was observed in KMT2C, FOXD4L1, SP140, NRAS and other genes. A few drivers such as FAT4, IGLL5 and CDKN1A retained consistent distribution patterns at two time points. These findings are clinically relevant and point at consideration of evaluating multi time point subclonal mutational landscapes for designing better risk stratification strategies and tailoring time to time risk adapted combination therapies in future.

Dataset Information

The Role of Clonal Evolution on Progression, Blood Parameters, and Response to Therapy in Multiple Myeloma.

Introduction

Methods

Results

Discussion

Publications

The Role of Clonal Evolution on Progression, Blood Parameters, and Response to Therapy in Multiple Myeloma.

Similar Datasets

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