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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 ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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