High-Risk Myeloma Is Demarcated By Immunoglobulin Lambda Light Chain Translocations

Multiple myeloma is the second most common hematological malignancy, and is the consequence of uncontrolled proliferation of antibody-secreting B cells, known as plasma cells. Myeloma causes lytic bone lesions and renal failure and is characterized by heterogeneous genetic mutations and clonal selection. Subsequently, understanding the complex mutational repertoire in the context of myeloma prognosis remains challenging. We report the translocation architecture of 826 newly diagnosed myeloma patients as part of the Clinical Outcomes in Multiple Myeloma to Personal Assessment (CoMMpass) study. These data are compared to other genetic mutations, gene expression, and patient outcome to better understand high-risk disease.

Whole genome sequencing identified 31% of newly diagnosed myelomas as containing an Immunoglobulin heavy chain (IgH) translocation. The vast majority of IgH translocations occurred with CCND1, WHSC1, MYC, or MAF; all of which were upregulated upon translocation. IgH-CCND1 translocations were more likely to express low levels of IgH (25%), but the majority expressed high levels of IgG1 consistent with other myelomas. Conversely, IgH-WHSC, -MYC, and -MAF translocations were more likely to express IgA (31%) and only IgH-MAF translocated myeloma expressed IgA2. IgH translocations primarily occurred at sites of class-switch recombination except for IgH-MYC translocations that originated from IgH intergenic enhancers suggesting that these occur by a distinct mechanism.

MYC translocations occurred in 18% of myelomas and in contrast to IgH, MYC translocation partners were scattered throughout the genome at regions proximal to highly expressed genes. MYC translocations corresponded with MYC amplification which was present in 15% of myelomas, yet half of these contained a translocation. Both types of genetic abnormalities corresponded with increased MYC expression, but neither MYC amplification and/or translocation, nor IgH translocation were prognostic of outcome.

Immunoglobulin lambda light chain (IgL) translocations were the most common translocation (7.1%) that did not involve IgH or MYC. Unlike IgH and MYC translocations, IgL translocations were prognostic of poor progression-free and overall survival. IgL translocations occurred at IgL enhancers and most commonly involved MYC, MAP3K14, 6p24.3, CCND (1,2, and 3), and MAF. IgL translocated patients presented myeloma at a similar age and stage and were treated with similar therapies as compared to other patients. IgL translocated myelomas contained a mutational repertoire that mimicked other myelomas and poor prognosis was independent of the IgL translocation partner, suggesting that the prognostic effect was intrinsic to IgL. Interestingly, myelomas with IgL translocations expressed lower levels of inflammatory cytokines including CCL3 and CCL4, suggesting they are less likely to induce anti-tumor innate immune responses. Taken together these data have important insights into myeloma pathology and implications for identifying high-risk myeloma.