Bortezomib Plus Dexamethasone Induction Improves Outcome of Patients With t(4;14) Myeloma but Not Outcome of Patients With del(17p)

Centre Hospitalier Universitaire, Nantes, France.
Journal of Clinical Oncology (Impact Factor: 18.43). 10/2010; 28(30):4630-4. DOI: 10.1200/JCO.2010.28.3945
Source: PubMed


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.

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    • "Upon progression of the disease, MM cells accumulate additional genetic alterations, such as recurrent losses of 13q14 and 17p13 and gains of 1q21 and 9q34. The translocations t(14;16), t(14;20), t(4;14) as well as gains of 1q21 and losses of 17p13 and, to some extent, also 13q14 deletions were defined as high risk factors (Fonseca et al, 2009; Munshi et al, 2011; Munshi & Avet-Loiseau, 2011; Neben et al, 2012; Shaughnessy et al, 2007), although there is some evidence that initial treatment with novel agents, e.g., the proteasome inhibitor bortezomib, may overcome the adverse prognosis of an underlying t(4;14) or 17p13 deletion (Avet-Loiseau et al, 2010; Bergsagel et al, 2013; Caltagirone et al, 2014; Neben et al, 2012; Sonneveld et al, 2013). In addition, bortezomib was also described to have a positive influence in relapsed/refractory MM (Dimopoulos et al, 2014; Richardson et al, 2014; Walter-Croneck et al, 2014). "
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    ABSTRACT: Multiple myeloma (MM) is a plasma cell neoplasm that presents with a major biological and clinical heterogeneity. We here investigated the spectrum of clonal and subclonal mutations of DIS3, an active part of the exosome complex, that may play a role in the development or progression of MM. The whole coding sequence of DIS3 was subjected to deep sequencing in 81 uniformly-treated MM patients and 12 MM cell lines and the overall occurrence of DIS3 mutations as well as the presence of DIS3 mutations in minor and major subclones were correlated with cytogenetic alterations and clinical parameters. Our study identified DIS3 mutations in 9/81 patients that were associated with 13q14 deletions and IGH translocations on the cytogenetic level. Specifically, we detected seven novel somatic DIS3 single nucleotide variants (SNVs) and defined three hot spot mutations within the RNB domain. Lastly, we found a trend towards a shorter median overall survival for patients with DIS3 mutations, and patients carrying DIS3 mutations in minor subclones of their tumours showed a significantly worse response to therapy compared to patients with DIS3 mutations in the major subclone. © 2014 John Wiley & Sons Ltd.
    British Journal of Haematology 12/2014; 169(1). DOI:10.1111/bjh.13256 · 4.71 Impact Factor
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    • "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. "
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    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.
    09/2014; 2014:526568. DOI:10.1155/2014/526568
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    • "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) [28]. Do analizy włączono 54 pacjentów, którzy mieli tę niekorzystną aberrację w ponad 60% komórek nowotworowych. "
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    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.
    Acta haematologica Polonica 07/2014; 45(3). DOI:10.1016/j.achaem.2014.06.002
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