Cytogenetics is an important prognostic parameter in multiple myeloma (MM). Patients presenting with either t(4;14) or del(17p) are known to have a short event-free survival (EFS) and overall survival (OS). Some preliminary data suggest that bortezomib is able to overcome these prognostic parameters.
A series of 507 patients with newly diagnosed MM who received four cycles of bortezomib-dexamethasone induction therapy before high-dose melphalan were analyzed for both t(4;14) and del(17p).
We found that both t(4;14) and del(17p) remain prognostic parameters, even in the context of bortezomib treatment. However, it is important to note that bortezomib significantly improves the prognosis (in terms of both EFS and OS) of patients with t(4;14), compared with patients treated with vincristine, doxorubicin, and dexamethasone induction therapy. In contrast, no improvement was observed for del(17p) patients.
Short-term bortezomib induction improves outcome of patients with t(4;14) but not the outcome of patients with del(17p). However, both abnormalities remain prognostic factors predicting both EFS and OS despite bortezomib induction.
"A particular mention is required for t(4;14), as historically this has been considered a high-risk feature. However, with the implementation of newer agents, especially the proteasome inhibitor bortezomib, these patients are demonstrating far greater survival [20, 27], and so it is proposed here that the translocation be considered an intermediate-risk lesion. "
[Show abstract][Hide abstract] ABSTRACT: Molecular studies have shown that multiple myeloma is a highly genetically heterogonous disease which may manifest itself as any number of diverse subtypes each with variable clinicopathological features and outcomes. Given this genetic heterogeneity, a universal approach to treatment of myeloma is unlikely to be successful for all patients and instead we should strive for the goal of personalised therapy using rationally informed targeted strategies. Current DNA sequencing technologies allow for whole genome and exome analysis of patient myeloma samples that yield vast amounts of genetic data and provide a mutational overview of the disease. However, the clinical utility of this information currently lags far behind the sequencing technology which is increasingly being incorporated into clinical practice. This paper attempts to address this shortcoming by proposing a novel genetically based "traffic-light" risk stratification system for myeloma, termed the RAG (Red, Amber, Green) model, which represents a simplified concept of how complex genetic data may be compressed into an aggregate risk score. The model aims to incorporate all known clinically important trisomies, translocations, and mutations in myeloma and utilise these to produce a score between 1.0 and 3.0 that can be incorporated into diagnostic, prognostic, and treatment algorithms for the patient.
"Ponadto analizowano te anomalie łącznie, w tym translokację t(4;14), dla której znane są korzyści leczenia bortezomibem. Z kolei badacze z francuskiej grupy IFM (Intergroupe Francophone du Myelome), porównujący efekty terapii indukcyjnych VD i VAD, nie uzyskali satysfakcjonujących wyników leczenia bortezomibem u pacjentów z del(17p) . Do analizy włączono 54 pacjentów, którzy mieli tę niekorzystną aberrację w ponad 60% komórek nowotworowych. "
[Show abstract][Hide abstract] ABSTRACT: A remarkable progress, which has been made during the last two decades in the multiple myeloma (MM) treatment, is mainly associated with the introduction to MM therapy three new drugs - thalidomide, lenalidomide and bortezomib. Global improvement of prognosis in MM, confirmed by numerous clinical trials and epidemiological studies, is mainly a consequence of very favorable results obtained in patients in the standard-risk group. However, in patients affected by prognostically unfavorable chromosomal aberrations, who constitute approximately 25% of all MM patients, only a slight improvement in the prognosis has become possible. Interestingly, the effectiveness of various new drugs for patients in the high-risk group appears to be different. The results of clinical trials indicate that currently bortezomib seems to be the most effective drug for patients with unfavorable cytogenetic abnormalities, especially patients with translocation t(4;14). In the present article the published data on the efficacy of bortezomib in first-line therapy in patients with unfavorable cytogenetic abnormalities are reviewed. The principles of risk stratification and individualization of therapy in MM are also discussed.
"In keeping with the unifying event of cyclin D deregulation, í µí±¡(4; 14) with MMSET and/or FGFR3 overexpression have been shown to upregulate CCND2, and in some instances CCND1, through an unknown mechanism . It is interesting to note that despite the poor prognosis associated with í µí±¡(4; 14) a clear survival advantage in these tumours has recently been demonstrated through early treatment with the proteasome inhibitor bortezomib  , with a suggestion that prolonged bortezomib treatment can overcome the adverse prognosis altogether  . This point demonstrates that future myeloma prognostication is likely to be determined by the success of therapeutically targeting high-risk lesions through a personalised approach. "
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma is a malignant proliferation of monoclonal plasma cells leading to clinical features that include hypercalcaemia, renal dysfunction, anaemia, and bone disease (frequently referred to by the acronym CRAB) which represent evidence of end organ failure. Recent evidence has revealed myeloma to be a highly heterogeneous disease composed of multiple molecularly-defined subtypes each with varying clinicopathological features and disease outcomes. The major division within myeloma is between hyperdiploid and nonhyperdiploid subtypes. In this division, hyperdiploid myeloma is characterised by trisomies of certain odd numbered chromosomes, namely, 3, 5, 7, 9, 11, 15, 19, and 21 whereas nonhyperdiploid myeloma is characterised by translocations of the immunoglobulin heavy chain alleles at chromosome 14q32 with various partner chromosomes, the most important of which being 4, 6, 11, 16, and 20. Hyperdiploid and nonhyperdiploid changes appear to represent early or even initiating mutagenic events that are subsequently followed by secondary aberrations including copy number abnormalities, additional translocations, mutations, and epigenetic modifications which lead to plasma cell immortalisation and disease progression. The following review provides a comprehensive coverage of the genetic and epigenetic events contributing to the initiation and progression of multiple myeloma and where possible these abnormalities have been linked to disease prognosis.
Advances in Hematology 04/2014; 2014(6):864058. DOI:10.1155/2014/864058
Ji Eun Jang, June-Won Cheong, Soo-Jeong Kim, Hyunsoo Cho, Cheolwon Suh, Hyewon Lee, Hyeon-Seok Eom, Ho-Young Yhim, Won-Sik Lee, Chang-Ki Min, Jae Hoon Lee, Joon Seong Park, Jin Seok Kim
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