(PA-237) Integrative Genomic and Transcriptomic Profiling Reveals Distinct Characteristics of Immunoglobulin D Multiple Myeloma

Immunoglobulin D multiple myeloma (IgD MM) is a rare form of the disease, accounting for less than 2% of all cases. Although a precise IgD MM diagnosis is sometimes overlooked, this MM subtype is clinically known to be associated with rapid disease progression at diagnosis, an aggressive clinical course, and a poor prognosis compared with other MM subtypes. However, the pathogenesis and disease properties, including molecular characteristics, are not well studied.

Methods:   

We collected 37 bone marrow samples from patients diagnosed with MM and isolated the myeloma cells using the CD138 marker. Serum IgD levels were measured in IgD MM candidates to confirm the subtype diagnosis. To identify the genomic and transcriptomic features of IgD MM compared to non-IgD MM, we performed whole-genome and bulk RNA sequencing on the myeloma cells. We analyzed whole-exome and RNA sequencing data from the CD138-positive fraction of bone marrow mononuclear cell (BMMC) samples provided by the Multiple Myeloma Research Foundation (MMRF) CoMMpass study (NCT01454297) to validate our findings.

Results:   

Whole-genome sequencing (WGS) data revealed an average of 8,872 somatic single nucleotide variants (SNVs) and 934 insertions and deletions (indels) in 37 multiple myeloma (MM) patients. Mutational signature analysis showed that SBS9 varied widely among patients. Notably, all four IgD MM patients had significantly high SBS9 signatures. Analyzing RNA-seq data, we found that IgD MM patients with high SBS9 signatures exhibited distinct gene expression patterns. Analysis of differentially expressed genes (DEGs) and pathway gene expression revealed higher expression of genes associated with the DNA repair system and somatic hypermutation in IgD MM patients. Based on the B-cell lineage and plasma cell differentiation process, these patterns of gene expression might suggest that IgD MM develops early in B-cell differentiation. A computational analysis using in-house MM single-cell RNA sequencing data supports this hypothesis by revealing higher pre-B and pro-B cell populations in IgD MM than in non-IgD MM.

We performed an identical analysis on whole-exome and RNA sequencing data from the MMRF database. Of the 30 patients for whom sufficient somatic mutations could be obtained, three patients had a high SBS9 signature and high IGHD gene expression, and were classified as IgD MM candidates. These three patients also showed an upregulation pattern of genes associated with DNA repair systems and somatic hypermutations.

Conclusions:   

Our research revealed that IgD MM has unique characteristics, such as high SBS9 mutational signatures and increased expression of genes related to the DNA repair system and somatic hypermutation. Further research into IgD MM may identify its specific characteristics and underlying pathogenesis, leading to tailored treatments.