Presence of Small Subclonal Populations of High-Risk Genetic Events at Diagnosis in Multiple Myeloma

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In a study reported in the Journal of Clinical Oncology, Lannes et al found that single-cell genomics could identify the presence of high-risk copy number abnormalities (CNAs) in small subclonal populations at diagnosis of multiple myeloma in many patients.

The investigators stated, “Multiple myeloma is characterized by CNAs, some of which influence patient outcomes and are sometimes observed only at relapse(s), suggesting their acquisition during tumor evolution. However, the presence of microsubclones may be missed in bulk analyses. Here, we use single-cell genomics to determine how often these high-risk events are missed at diagnosis and selected at relapse.”

Study Details

The study involved use of single-cell CNA sequencing in 81 patients, including 66 at diagnosis, 9 at first relapse, and 6 in presymptomatic stages. A cohort of 956 patients with newly diagnosed disease or in first relapse with available cytogenetic data was analyzed to determine the relationship between enrichment of CNA risk events and impact on survival.

Key Findings

Of the 81 patients evaluated, 74 (91%) had 2 to 16 subclones identified on single-cell CNA sequencing. Of these, 19 (26%) had a subclone with high-risk features—ie, del(17p), del(1p32), or 1q gain. All 19 were among the 66 patients evaluated at diagnosis (accounting for 29% of this population).

In one patient assessed through clinical course, the subclonal 1q gain increased in frequency from 16% at diagnosis to 72% postinduction and 92% at first relapse.

In the cohort of patients with cytogenetic and clinical information, 1q gain frequency increased from 30.2% at diagnosis to 43.6% at relapse (odds ratio = 1.78, 95% confidence interval = 1.58–2.00).

Survival analyses showed that progression-free survival and overall survival curves for patients with 1q gain identified at diagnosis were superimposable with those for patients who appeared to acquire 1q gain at relapse. As stated by the investigators, “This strongly suggests that many patients had 1q gains at diagnosis in microclones that were missed by bulk analyses.”

The investigators concluded, “These data suggest that identifying these scarce aggressive cells may necessitate more aggressive treatment as early as diagnosis to prevent them from becoming the dominant clone.”

Hervé Avet-Loiseau, MD, PhD, of the Myeloma Oncogenesis Lab, IUCT Oncopole, Toulouse, France, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Riney Foundation, the U.S. National Institutes of Health, and Fondation ARC. For full disclosures of the study authors, visit

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