Abstract 6640: The characteristics of IgD subtype myeloma with distinctive genomic mutational signature and gene expression patterns

Abstract Background: Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells that produce monoclonal immunoglobulins. Among its subtypes, immunoglobulin D multiple myeloma (IgD MM) is rare, accounting for less than 2% of all MM cases. IgD MM is often associated with rapid disease progression at diagnosis, an aggressive clinical course, and a poor prognosis compared with other MM subtypes. Methods: Samples were collected from patients diagnosed with MM through bone marrow examination, and myeloma cells were isolated using the CD138-positive marker. Paired datasets (n=37), including whole genome sequencing (WGS) and bulk RNA sequencing (RNA-seq), were generated and analyzed. We utilized whole exome sequencing (WES) and RNA-seq data from the CD138-positive fraction of bone marrow mononuclear cell (BMMC) samples provided by the Multiple Myeloma Research Foundation (MMRF) CoMMpass study. Results: The WGS data revealed an average of 8, 872 single nucleotide variants (SNVs) and 934 insertions and deletions (Indels) of somatic mutations in 37 MM patients, respectively. Using these somatic mutations, we performed a mutational signature analysis to infer the cause of the malignancy and were able to identify different proportions of mutational signatures in each MM patient. Interestingly, among the single base substitution (SBS) 9 signature varied widely between patients, four patients with non-IgG and non-IgA heavy chain and lambda light chain myeloma had significantly high SBS9 signature. Notably, three IgD MM patients were included exclusively in the high SBS9 signature group and not in the low SBS9 signature group (p = 0.001). Analyzing RNA-seq data, we found that the high and low SBS9 signature groups had different gene expression patterns. In particular, differentially expressed genes (DEGs) analysis suggested features of IgD myeloma, including high expression of IGHD, in high SBS9 signature group. Pathway gene expression analysis showed higher expression of genes associated with the DNA repair system and somatic hypermutation in IgD MM patients. We performed the identical mutation signature analysis on WES data of 784 MM patients from the MMRF database. Of the 30 patients for whom sufficient somatic mutations could be obtained, there were three IgD MM candidates with a high SBS9 signature, whereas there were no IgD MM candidates in the low SBS9 signature group. Similarly, three high SBS9 patients with suspected IgD MM showed characteristic gene expression patterns and upregulation of the DNA repair system. Conclusions: We found that IgD MM has distinctive features, including high SBS9 mutation signatures and upregulation of genes related to the DNA repair system and somatic hyper-mutation. Further research into IgD MM may reveal the detailed characteristics and underlying mechanisms of IgD MM and lead to tailored treatments. Citation Format: Sheehyun Kim, Hyundong Yoon, Youngil Koh, Sung-Soo Yoon. The characteristics of IgD subtype myeloma with distinctive genomic mutational signature and gene expression patterns [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6640.