IgM-MM is predominantly a pre-germinal center disorder and has a distinct genomic and transcriptomic signature from WM

Immunoglobulin M (IgM) multiple myeloma (MM) is a rare disease subgroup. Its differentiation from other IgM-producing gammopathies such as Waldenstrom macroglobulinemia (WM) has not been well characterized but is essential for proper risk assessment and treatment. In this study, we investigated genomic and transcriptomic characteristics of IgM-MM samples using whole-genome and transcriptome sequencing to identify differentiating characteristics from non-IgN1-MM and WM. Our results suggest that IgM-MM shares most of its defining structural variants and gene-expression profiling with MM, but has some key characteristics, including t(11;14) translocation, chromosome 6 and 13 deletion as well as distinct molecular and transcription-factor signatures. Furthermore, IgM-MM translocations were predominantly characterized by V(H)D(H)J(H) recombination-induced breakpoints, as opposed to the usual class-switching region breakpoints; coupled with its lack of class switching, these data favor a pre-germinal center origin. Finally, we found elevated expression of clinically relevant targets, including CD20 and Bruton tyrosine kinase, as well as high BCL2/BCL2L1 ratio in IgM-MM, providing potential for targeted therapeutics.

Automated summary

Research on Immunoglobulin M (IgM) multiple myeloma (MM) identified distinguishing characteristics from other IgM-producing gammopathies, including unique translocations, chromosome deletions, and molecular signatures. IgM-MM is likely to originate from a pre-germinal center and shows potential for targeted therapeutics in clinical settings.