Analysis of Deep Whole-Genome Sequencing in Patients With Multiple Myeloma Identifies Superior Outcome Subgroup

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In a study of genome-wide somatic alterations in multiple myeloma reported in the Journal of Clinical Oncology, Samur et al identified a subgroup of patients with superior outcomes who are not adequately identified by traditional risk markers.

The study involved analysis of deep whole-genome sequencing from 183 newly diagnosed patients who received lenalidomide, bortezomib, and dexamethasone alone or with autologous stem cell transplant in the IFM/DFCI 2009 study.

Key Findings

Multiple myeloma subgroups showed two patterns of acquisition of mutational changes, with both featuring an early high contribution of age-related mutations that declined by mid- to late-stage disease. In the high-risk group, the APOBEC signature targeting C>G is activated and predominates in the intermediate phase of disease progression. In the standard-risk group, DNA damage–associated mutations appear early and accumulate gradually over time.

Patients with low genomic scar score (GSS) had significantly better progression-free and overall survival vs other patient groups. Analysis incorporating other genomic risk features showed that patients with the combination of low GSS and chromosome 9 gain (representing 17% of the patient cohort) had significantly better overall survival (4-year rate of 100%) vs other subgroups. Overall survival was intermediate in patients with low GSS and no chromosome 9 gain and in those with high GSS and chromosome 9 gain. The findings regarding the superior outcome subgroup were validated in an independent data cohort of 577 patients (5-year overall survival probability = 93%).

Although hyperdiploidy is associated with better prognosis in multiple myeloma, identification of this superior outcome subgroup permitted distinction of patients with low- and high-risk hyperdiploid multiple myeloma. Additional genomic characteristics of the low GSS and chromosome 9 gain subgroup included significantly lower mutational load, significant contribution from age-related (single-base substitution 1) mutations, and a higher frequency of NRAS mutations (46% vs 16% in other groups).

Overall survival in the superior outcome subgroup was independent of International Staging System and minimal residual disease status.

The investigators concluded, “This is a comprehensive study identifying genomic markers of a good-risk group with prolonged survival. Identification of this patient subgroup will affect future therapeutic algorithms and research planning.”

Mehmet Kemal Samur, PhD, of the Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article. 

Disclosure: The study was supported by grants from the National Institutes of Health and VA Healthcare System and by Celgene Corporation. For full disclosures of the study authors, visit

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