Open AccessComprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities
Author(s) -
Nicola Giesen,
Nagarajan Paramasivam,
Umut Toprak,
Daniel Hübschmann,
Jing Xu,
Sebastian Uhrig,
Mehmet K. Samur,
Stella Bähr,
Martina Fröhlich,
Sadaf S. Mughal,
K. Elias,
Anna Jauch,
Carsten MüllerTidow,
Benedikt Brors,
Nikhil C. Munshi,
Hartmut Goldschmidt,
Niels Weinhold,
Matthias Schlesner,
Marc S. Raab
Publication year - 2022
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2021.279360
Subject(s) - genome instability , biology , gene , genetics , dna repair , transcriptome , homologous recombination , drug resistance , carfilzomib , cancer research , dna damage , proteasome inhibitor , proteasome , dna , gene expression
The outcomes of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) remain poor. We performed whole genome and transcriptome sequencing of 39 heavily pretreated relapsed/refractory MM (RRMM) patients to identify mechanisms of resistance and potential therapeutic targets. We observed a high mutational load and indications of increased genomic instability. Recurrently mutated genes in RRMM, which had not been previously reported or only observed at a lower frequency in newly diagnosed MM, included NRAS, BRAF, TP53, SLC4A7, MLLT4, EWSR1, HCFC2, and COPS3. We found multiple genomic regions with bi-allelic events affecting tumor suppressor genes and demonstrated a significant adverse impact of bi-allelic TP53 alterations on survival. With regard to potentially resistance conferring mutations, recurrently mutated gene networks included genes with relevance for PI and IMiD activity, the latter particularly affecting members of the Cereblon and the COP9 signalosome complex. We observed a major impact of signatures associated with exposure to melphalan or impaired DNA double-strand break homologous recombination repair in RRMM. The latter coincided with mutations in genes associated with PARP inhibitor sensitivity in 49% of RRMM patients, a finding with potential therapeutic implications. In conclusion, this comprehensive genomic characterization revealed a complex mutational and structural landscape in RRMM and highlights potential implications for therapeutic strategies.