Genetic Predictors of Mortality in Patients with Multiple Myeloma

Abstract

Multiple myeloma (MM) is a heterogeneous disease featured by clonal plasma cell proliferation and genomic instability. The advent of next-generation sequencing allowed unraveling the complex genomic landscape of the disease. Several recurrent genomic aberrations including immunoglobulin genes translocations, copy number abnormalities, complex chromosomal events, transcriptomic and epigenomic deregulation, and mutations define various molecular subgroups with distinct outcomes. In this review, we describe the recurrent genomic events identified in MM impacting patients’ outcome and survival. These genomic aberrations constitute new markers that could be incorporated into a prognostication model to eventually guide therapy at every stage of the disease.

Optical Genome Mapping Reveals the Complex Genetic Landscape of Myeloma

“…Loss of chromosome 13 remains the most prevalent event of the two, while targeted deletions are rarer in this cohort, concordant with previous studies [39]. Loss of chromosome 13 was detected in both primary genetic classes, including seven with non-hyperdiploid cases with an IGH rearrangement (samples 02, 03, 07, 12, 41, 44, 45) and five with HDM (samples 01, 30,33,38,42). Gene content within the 13q deleted region showed that the DLEU1 and DLEU2 genes were included within this region (samples 06, 24), while the RB1 gene was deleted in only one of the two cases (minimal region of deletion at 13q14.2q14.3).…”

“…We also identified two cases of t(4;14) (sample 07 and 45; 10%) and a single case of t(6;14) (sample 12), t(14;16) (sample 02) and t(14;20) (sample 44) (Figure 1c-f and Figure S3). While a high frequency (~15%) of IGH translocations involving loci other than the canonical partners (e.g., TXNDC5, B2M, JUND, JUN) is reported in the literature [9,30], such abnormalities were not identified in this small cohort. However, we did uncover two variant translocations (t(14;16;8;8) and t(11;14;19)), both involving at least three translocation partners.…”

“…Interestingly, in our cohort, the gene NRAS was also identified within this recurrent region of deletion (Figure S6). This is of particular interest as both TENT5C and NRAS are known to be mutated in 9.4% and 17.5% of myeloma cases, respectively [30], and activating mutations of the NRAS gene were shown to significantly reduce myeloma sensitivity to single-agent bortezomib but not high-dose dexamethasone [58,59]. It is interesting to consider if a deletion of NRAS could have the opposing effect and increase sensitivity to bortezomib in these patients.…”

Population pharmacokinetics and exposure–response analyses of daratumumab plus pomalidomide/dexamethasone in relapsed or refractory multiple myeloma

“…Multiple myeloma (MM) is a haematologic malignancy characterized by abnormal proliferation of clonal plasma cells. 1 MM is a heterogeneous disease and, while early stages are asymptomatic, progression lowers resistance to infection; causes skeletal damage; and leads to hypercalcaemia, renal failure, anaemia and osteolytic lesions. 2,3 While standard of care has evolved and has offered improvements in overall survival, the majority of MM patients will eventually fail to respond to current treatments.…”

“…Multiple myeloma (MM) is a haematologic malignancy characterized by abnormal proliferation of clonal plasma cells 1 . MM is a heterogeneous disease and, while early stages are asymptomatic, progression lowers resistance to infection; causes skeletal damage; and leads to hypercalcaemia, renal failure, anaemia and osteolytic lesions 2,3 .…”