Genomically Smoldering Multiple Myeloma Is Not a Distinct Entity But a Collection of Monoclonal Gammopathy of Undetermined Significance or Multiple Myeloma

PURPOSE The diagnosis of smoldering multiple myeloma (SMM) primarily relies on clinical features such as plasma cell involvement, immunoglobulin protein levels, and end-organ damage. However, as early intervention becomes a priority, the role of genomic features in differentiating risk is gaining attention. METHODS This study analyzed next-generation sequencing data from 224 precursor condition samples with 51 patients having paired SMM and multiple myeloma (MM) and 1,779 samples from newly diagnosed MM to identify genomic features linked to progression in SMM and those with a low-risk nonprogressor precursor condition. RESULTS Our findings from paired samples revealed no significant differences in somatic alterations and clonal structures between SMM and MM samples from the same patient. This indicates that plasma cells in progressor SMM are genomically pre-equipped with changes that define myeloma. Over 80% of driver mutations were present at both time points, and more than 66% of progressor samples showed only minor clonal changes. We further compared genomic changes between nonprogressor and progressor SMM. Nonprogressor plasma cells showed significantly lower mutational load and the absence of copy number alterations on chromosome 8. They reduced focal genomic loss compared with progressor plasma cells. A scoring system using genomic features predictively identified patients with low-risk SMM unlikely to progress, validated on 101 additional independent samples, and additive clinical value of genomic classification was further shown in combination with 20/2/20. CONCLUSION In summary, the genomic distinctions now suggest that a proportion of SMMs with progressor phenotype are akin to MM, whereas nonprogressor SMM has monoclonal gammopathy of undetermined significance–like characteristics. The results should influence further investigation in larger studies to inform future diagnostic criteria and trial designs.