Genomic characterization of hematopoietic stem and progenitor cells in multiple myeloma to study patterns of disease evolution

Abstract

Cases of secondary myelodysplastic syndrome and secondary acute myeloid leukemia (sMDS/sAML) have increasingly been documented in successfully treated multiple myeloma (MM) patients. Even though pathogenic alterations in MM have been well characterized in the malignant plasma cell fraction, little is known about the mechanisms leading to sMDS/sAML. Also, it is unknown if molecular-level alterations can be detected in the hematopoietic stem and progenitor cells (HSPCs) of MM patients. To characterize the HSPC fraction of MM patients and to identify those that harbor mutations associated with MDS/AML potentially predisposing the patients to the development of secondary diseases, and to study the clonal evolution of MM, next-generation sequencing analysis was performed. The results demonstrate that mutations in genes associated with MDS/AML are frequently detected in the HSPCs of MM patients. In 20 of the 51 HSPC-enriched MM samples, a total of 42 mutations in 23 genes were detected. When the measured variant allele frequency (VAF) in the mutated samples was compared, substantial variance between the patients was noticed. Most of the mutations observed had a low VAF, more specifically 29/42 mutations had a VAF below 10 %. Notably, exposure to alkylating agents during cancer treatment and relapse-status were significantly associated with a higher VAF (both, P<0.01), which is an indication of clonal expansion. Intriguingly, three patients shared mutations specific for MDS/AML in both the HSPC fraction and the plasma cell fraction. Thus, MM patients with detectable MDS/AML associated mutations in HSPCs seem to present two different clonal evolution patterns during MM development: the malignant plasma cell population may arise from a genetically distinct subpopulation as well as from the genetically normal cell population. To conclude, mutations in genes associated with MDS/AML were fairly frequently detected in the HSPCs of MM patients. For some patients, the mutations detected in the HSPCs were also observed in the malignant plasma cells, suggesting that MM can arise from a mutation-bearing, premalignant stem cell progenitor. In the future, it remains of great importance to further the understanding of the difference between malignant and benign clonal hematopoiesis, and to assess whether MDS/AML associated mutations also play a role in the pathogenesis of MM.