Clinical implications of cytogenetic and molecular aberrations in multiple myeloma

Abstract

Multiple myeloma (MM) is an incurable haematological malignancy affecting approximately 7:100,000 people. Monoclonal gammopathy of undetermined significance (MGUS) and 'smouldering' MM precede symptomatic MM. Cytogenetics in MM is the most powerful prognostication tool incorporated into different classifications, including the Revised International Staging System (R-ISS) and the Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART). Methods commonly used to test for cytogenetic aberrations include conventional karyotyping and fluorescence in situ hybridisation (FISH), although the difficulty of obtaining metaphases in plasma cells results in low yields.Therefore, new genomic tools are essential to explore the complex landscape of genetic alterations in MM. These include next generation sequencing, a highly sensitive method to monitor minimal residual disease. The serial evolution of MGUS to MM is accompanied by a range of heterogenous genetic abnormalities, divided into primary (involving mostly chromosome 14 translocations and trisomies) and secondary genetic aberration events (involving mostly 17p, 1p, 13q deletions, 1q gain, or MYC translocations). Based on the primary genetic aberration results, strong prognostic features of MM have been identified with distinct clinical characteristics. High risk aberrations include 17p deletion, t(4;14), t(14;16), t(14;20) and chromosome 1 abnormalities. The incorporation of novel drugs and maintenance strategies in conjunction with autologous stem cell transplantation partially overcome the adverse effect of some of these genetic aberrations. Nonetheless, survival remains worse in this group compared to standard risk patients. Clinical decisions regarding treatment should be based on the cytogenetic results. The establishment of individualised and mutation--targeted therapies are of the greatest importance in future studies.

The importance of cytogenetic and molecular aberrations in multiple myeloma

“…Symptomatic MM then develops as a result of secondary, random CA. The final stage of evolution in genetic changes is extramedullary MM/plasma cell leukemia (PCL) (Figure 1) [13][14][15][16][17].…”

A pooled analysis of outcomes according to cytogenetic abnormalities in patients receiving ixazomib- vs placebo-based therapy for multiple myeloma

“…Although identification of certain cytogenetic abnormalities has guided stratification of high-risk patients and helped to characterize prognosis, not all patients with high-risk cytogenetic abnormalities exhibit the same response to therapy, and the efficacy of available treatment options varies according to the presence of particular cytogenetic abnormalities [ 12 ]. Accordingly, treatment decisions should be based on individual cytogenetic data [ 18 ]. At present, clinical trials assessing response to MM therapy according to specific cytogenetic abnormalities are limited [ 19 ], and the IMWG has stated that the analysis of cytogenetic subgroups in trials comparing different treatments is an important goal [ 12 ].…”

Aberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?

“…Patients can roughly be divided into two groups, namely the hyperdiploid group and the non-hyperdiploid group. The hyperdiploid group is characterized by odd-numbered chromosome trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, while the non-hyperdiploid group is characterized by primary translocations involving chromosomes t(11,14)(q13;q32), t(4,14)(p16;q32), t(6,14)(p21;q32), t(14,16)(q32;q23), and t(14,20)(q32;q12) ( Figure 1 ) ( 22 , 23 ). Patients in the hyperdiploid group and patients harboring the t(6,14)(p21;q32) and t(11,14)(q13;q32) translocation have a more favorable prognosis, while patients harboring one of the other primary translocations have a poor prognosis ( 23 ).…”

“…The hyperdiploid group is characterized by odd-numbered chromosome trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, while the non-hyperdiploid group is characterized by primary translocations involving chromosomes t(11,14)(q13;q32), t(4,14)(p16;q32), t(6,14)(p21;q32), t(14,16)(q32;q23), and t(14,20)(q32;q12) ( Figure 1 ) ( 22 , 23 ). Patients in the hyperdiploid group and patients harboring the t(6,14)(p21;q32) and t(11,14)(q13;q32) translocation have a more favorable prognosis, while patients harboring one of the other primary translocations have a poor prognosis ( 23 ). On top, many non-recurrent secondary translocations and mutations are acquired during disease progression, including the translocation of the MYC gene, gain-of-function mutations in several oncogenes (NRAS, KRAS, BRAF, and CCND1), and loss-of-function mutations in tumor suppressor genes such as p15, p16, and P53 ( Figure 1 ) ( 24 – 28 ).…”