Chromosome 1 abnormalities in elderly patients with newly diagnosed multiple myeloma treated with novel therapies

Caltagirone, S; Ruggeri, Marina; Aschero, Simona; Gilestro, Milena; Oddolo, Daniela; Bringhen, Sara; Musolino, Caterina; Baldini, Luca; Musto, Pellegrino; Petrucci, Maria Teresa; Gaïdano, Gianluca; Passera, Roberto; Bruno, Benedetto; Palumbo, Antônio; Boccadoro, Mario; Omedè, Paola

doi:10.3324/haematol.2014.103853

Cited by 18 publications

(19 citation statements)

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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 , ; Munshi et al , ; Munshi & Avet‐Loiseau, ; Neben et al , ; Shaughnessy et al , ), 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 , ; Bergsagel et al , ; Caltagirone et al , ; Neben et al , ; Sonneveld et al , ). In addition, bortezomib was also described to have a positive influence in relapsed/refractory MM (Dimopoulos et al , ; Richardson et al , ; Walter‐Croneck et al , ).…”

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confidence: 99%

The molecular spectrum and clinical impact of DIS3 mutations in multiple myeloma

et al. 2014

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SummaryMultiple 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.

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confidence: 99%

The molecular spectrum and clinical impact of DIS3 mutations in multiple myeloma

et al. 2014

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“…A previous study also reported that the frequency of CNAs was highest in chr 1. Especially, elderly patients aged 65 years or older are more likely to have abnormalities when they are treated with novel therapies [1]. Also, the copy number of the genes in the 1q21 region, which showed the most chromothripsis-like patterns, was amplified in resistant patients.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple myeloma (MM) is a malignant disease caused by an abnormal proliferation of plasma cells [1]. According to the 2014 Ministry of Health and Welfare Cancer Registration Statistics, MM is the third most common cancer among hematologic malignancies in Korea [2].…”

Section: Introductionmentioning

confidence: 99%

Chromothripsis in Treatment Resistance in Multiple Myeloma

Lee

Yoon

et al. 2017

Genomics Inform

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Multiple myeloma (MM) is a malignant disease caused by an abnormal proliferation of plasma cells, of which the prognostic factors include chromosomal abnormality, β-2 microglobulin, and albumin. Recently, the term chromothripsis has emerged, which is the massive but highly localized chromosomal rearrangement in response to a one-step catastrophic event. Many studies have shown an association of chromothripsis with the prognosis in several cancers; however, few studies have investigated it in MM. Here, we studied the association between chromothripsis-like patterns and treatment resistance or prognosis. First, we analyzed nine MM cell lines (U266, MM.1S, RPMI8226, KMS-11, KMS-12-BM, KMS-12-PE, KMS-28-BM, KMS-28-PE, and NCI-H929) and bone marrow samples of four patients who were diagnosed with MM by next-generation sequencing-based copy number variation analysis. The frequency of the chromothripsis-like pattern was observed in seven cell lines. We analyzed the treatment-induced chromothripsis-like patterns in KMS-12-BM and KMS-12-PE cells. As a result, breakpoints and chromothripsis-like patterns were increased after drug treatment in the relatively resistant KMS-12-BM. We further analyzed the patients’ results according to the therapeutic response, which was divided into sensitive and resistant, as suggested by the International Myeloma Working Group. The chromothripsis-like pattern was more frequently observed in the resistant group. In the sensitive group, the frequency of the chromothripsis-like pattern decreased after treatment, whereas the resistant group showed increased chromothripsis-like patterns after the treatment. These results suggest that the chromothripsis-like pattern is associated with treatment response in MM.

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“…Thalidomide maintenance was associated with higher toxicity, including neuropathy, constipation, elevated creatinine, and skin toxicity [108]. In patients treated onstudy with VMPT-VT versus VMP, thalidomide maintenance was felt to be associated with worse OS in patients harboring abnormalities in chromosome 1 (HR 3.08, 95 % CI 1.04-9.14, p = 0.042) or deletion 17p (HR 4.28, 95 % CI 1.59-11.54, p = 0.004) [109].…”

Section: Maintenance Therapymentioning

confidence: 98%

Management of Elderly Patients with Plasma Cell Myeloma

2015

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Plasma cell myeloma (PCM) is a hematologic malignancy that primarily affects the elderly. Approximately two-thirds of patients are aged 65 years or older at diagnosis. Major advances in testing, treatment, and supportive care have resulted in substantial improvement in overall survival in younger, standard-risk, PCM patients over the past 3 decades. However, this positive impact progressively diminishes with advancing age, with some studies showing no improvement in survival outcomes in the elderly. Slow improvement in survival for elderly PCM patients is likely multifactorial, influenced by factors such as age-related physiologic changes, increased comorbidities, decreased treatment tolerance, socioeconomic barriers, and possible differences in disease biology. The standard approach of basing treatment decisions on age and performance status does not account for this complexity, and can be insufficient to determine the risks and benefits of treatment. Comprehensive geriatric assessment (CGA) produces a more thorough iteration of the factors influencing an individual's treatment risk, and can potentially identify targets for intervention to lower risk. Ongoing studies are looking at developing and refining the tools available for risk screening and assessment. Treating elderly PCM patients with novel agent-based regimens with or without autologous stem cell transplantation has improved response rates and survival in some studies, but elderly PCM patients have benefitted less than their younger counterparts from recent advances in PCM treatment. Personalizing treatment decisions, based on predictions of risk, determined by geriatric assessment, and response, determined by precision medicine (our understanding of the genetic, molecular, and cellular pathways that drive an individual's cancer) will help maximize the benefit and minimize the risk of PCM treatment for each patient. Continued evaluation of new strategies and treatments for PCM in clinical trials specifically designed for elderly patients is needed to continue to improve outcomes for elderly PCM patients in the future.

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Chromosome 1 abnormalities in elderly patients with newly diagnosed multiple myeloma treated with novel therapies

Cited by 18 publications

References 50 publications

The molecular spectrum and clinical impact of DIS3 mutations in multiple myeloma

The molecular spectrum and clinical impact of DIS3 mutations in multiple myeloma

Chromothripsis in Treatment Resistance in Multiple Myeloma

Management of Elderly Patients with Plasma Cell Myeloma

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