International Myeloma Working Group molecular classification of multiple myeloma: spotlight review

Abstract

Myeloma is a malignant proliferation of monoclonal plasma cells. Although morphologically similar, several subtypes of the disease have been identified at the genetic and molecular level. These genetic subtypes are associated with unique clinicopathological features and dissimilar outcome. At the top hierarchical level, myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes. The latter is mainly composed of cases harboring IgH translocations, generally associated with more aggressive clinical features and shorter survival. The three main IgH translocations in myeloma are the t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Trisomies and a more indolent form of the disease characterize hyperdiploid myeloma. A number of genetic progression factors have been identified including deletions of chromosomes 13 and 17 and abnormalities of chromosome 1 (1p deletion and 1q amplification). Other key drivers of cell survival and proliferation have also been identified such as nuclear factor-B-activating mutations and other deregulation factors for the cyclin-dependent pathways regulators. Further understanding of the biological subtypes of the disease has come from the application of novel techniques such as gene expression profiling and array-based comparative genomic hybridization. The combination of data arising from these studies and that previously elucidated through other mechanisms allows for most myeloma cases to be classified under one of several genetic subtypes. This paper proposes a framework for the classification of myeloma subtypes and provides recommendations for genetic testing. This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials.

An abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma in the bortezomib era

“…Although certain recurrent genetic changes such as t(4;14), t(14;16), chromosome 13q14 deletion and loss of 17p13 on cytogenetics have been recognized to be indicative of poor prognosis, only monosomy 13 and some 13q14 deletions as well as 17p13 deletions can be readily detected on metaphase karyotyping. As the prognostic significance of 13q deletion is now thought to be a surrogate of its association with nonhyperdiploid MM, it is hence not considered in the subsequent survival analyses [14]. Many of the other rearrangements are cryptic.…”

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

“…Staging of myeloma using the Durie-Salmon Staging (DSS) [29] or the International Staging System (ISS) [30,31] provides prognostic information but is not helpful in making therapeutic choices. A risk-stratification model that relies on a number of independent molecular cytogenetic markers to assess disease aggressiveness is useful for both counseling and therapeutic decision-making [32]. At the Mayo Clinic, newly diagnosed myeloma is stratified into standard-, intermediate-, and high-risk disease using the Mayo stratification for myeloma and risk-adapted therapy (mSMART) classification (Table II) [21,33].…”

Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma in Older Adults

“…The expanded plasma cells usually overproduce a complete monoclonal immunoglobulin or some part thereof (eg, light chain only). 9,10 The transition in some cases from MGUS to MM is thought to be caused by additional biological abnormalities (eg, genomic, bone marrow microenvironmental) that lead to further clonal proliferation. 9 Once MGUS has progressed to MM, end organ damage begins because of infiltration of the neoplastic plasma cells into the bones and organ systems, damage mediated by circulating monoclonal proteins (eg, cast nephropathy), or both.…”