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Prashant Kapoor, MD, FACP


Therapeutic Implications of Novel Genomic Mutations in Resistant Multiple Myeloma

By: Emily Rhode
Posted: Thursday, October 20, 2022

Findings presented in Haematologica suggest that patients with highly pretreated relapsed or refractory multiple myeloma may exhibit marked genomic instability with impaired DNA repair mechanisms, notably homologous recombination repair (HRR), compared with patients who have newly diagnosed myeloma. The genomic analysis, performed by Marc S. Raab, MD, of the Heidelberg University Hospital, Germany, and colleagues, revealed multiple recurrently mutated genes not previously reported or observed at such high frequencies in patients with multiple myeloma, including genes linked to PARP inhibitor sensitivity.

The authors used whole-genome and transcriptome sequencing to study tumor samples from 39 heavily pretreated patients with resistant multiple myeloma, who had a median number of five previous lines of therapy. All patients had relapsed after receiving treatment with immunomodulatory drugs and proteasome inhibitors, and their disease was at least double-refractory. These data were compared with whole-genome sequencing data from 21 patients with newly diagnosed disease.

Results showed a significant increase in chromosomal and nucleotide aberrations in relapsed or refractory multiple myeloma compared with newly diagnosed disease, as well as significantly higher mutational loads in the former. Of note, genomic instability was also significantly higher in relapsed or refractory multiple myeloma compared with newly diagnosed disease (P = .004).  

“Based on our observation that [relapsed or refractory multiple myeloma] is characterized by marked genomic instability, which enables [multiple myeloma] cells to rapidly adapt to selective therapeutic pressure, treatment strategies focused on exploiting impaired HRR should be evaluated within prospective clinical trials,” the authors concluded. “Such strategies might be particularly useful in the current era of novel immunotherapies in [multiple myeloma], as recent reports suggest genomic instability as a mechanism of resistance to [chimeric antigen receptor T-cell] treatment.”

Disclosure: For full disclosures of the study authors, visit

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