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Genetics in Myeloma: Genetic Technologies and Their Application

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Genetics in Myeloma: Genetic Technologies and Their Application British Medical Bulletin, 2015, 113:15–30 doi: 10.1093/bmb/ldu041 Advance Access Publication Date: 6 February 2015 Genetics in myeloma: genetic technologies and their application to screening approaches Downloaded from https://academic.oup.com/bmb/article/113/1/15/284455 by guest on 27 September 2021 in myeloma Polly J. Talley†,*, Andrew D. Chantry‡, and Clive H. Buckle‡ †Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Western Bank, Sheffield S10 2TH, UK, and ‡Sheffield Myeloma Research Team (SMaRT), Department of Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK *Correspondence address. E-mail: [email protected] Accepted 19 December 2014 Abstract Background: Despite advances in the treatment of multiple myeloma (MM), it remains an incurable malignant disease. Myeloma genetics is intrinsically complex, but it offers an opportunity to categorize the disease and apply a personalized medicine approach. Areas of agreement: Research into the genetics of myeloma is moving at a fast pace and is highlighting areas and patient cohorts likely to benefit from specific treatment. Targeting residual disease is likely to be crucial to improved clinical outcome. Areas of controversy: Patients in clinical trials are more likely to receive genetic diagnosis than non-trial patients, for whom access is ad hoc and dependent upon regional commissioning arrangements. Areas timely for developing research: Relating genetics to potential treat- ment pathways will become crucial for improved myeloma outcomes. Universal access to standardized genetic testing will facilitate modern perso- nalized treatments. Key words: myeloma, diagnosis, personalized medicine, genetic technologies Introduction the bone marrow (BM) and overproduction of cir- Multiple myeloma (also known as plasma cell culating monoclonal immunoglobulin (paraprotein). myeloma) is a neoplastic disorder characterized by an The paraprotein product circulates in blood and abnormal monoclonal proliferation of plasma cells in is deposited in various tissues including the renal © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected] 16 P. J. Talley et al., 2015, Vol. 113 tubules, causing substantial renal impairment, and in 65 and 74 at diagnosis, and 37% are over 75. MM is other organs including the heart and the gut. At these diagnosed in younger people, with 37% of patients sites, the paraprotein is prone to transformation into aged 65 or under, and 2% below 40 years of age.5 a degradation-resistant protein known as amyloid, MM is not a disease that is seen in children.1 which significantly impairs organ function. Malig- Myeloma is likely to increase in incidence in the UK nant plasma cells secrete osteoclast-activating factors in line with the ageing population. Data suggest that and osteoblast-deactivating factors leading to destruc- MM is more common in men than in women (ratio tive, osteolytic bone disease. Malignant plasma cells 7.1:4.3), and more common in Black people than in accumulate within the BM effectively crowding out people of Asian or Caucasian descent (ratio ∼2:1).1,5 Downloaded from https://academic.oup.com/bmb/article/113/1/15/284455 by guest on 27 September 2021 normal haemopoietic tissue leading to BM failure There is a 3.7-fold increased risk to first-degree manifesting as anaemia, thrombocytopaenia and leu- family members of patients with MM, suggesting kopaenia as well as impaired cellular and antibody- some inherited component.1 mediated immunity. Fifteen per cent of MM patients have no symptoms Plasma cell neoplasms progress through distinct at presentation, and a high paraprotein may be discov- clinical phases: monoclonal gammopathy of unknown ered following routine screening. Approximately 40% significance (MGUS), asymptomatic myeloma or present with more substantial morbidity including smouldering myeloma (SM), plasma cell myeloma, anaemia, renal failure and skeletal disease including progressing to plasma cell leukaemia. Other clinical pathological fractures, hypercalcaemia, spinal cord phases following treatment can include myeloma in compression or generalized bone loss (osteoporosis). remission (termed ‘plateau phase’), relapsed myeloma Less critical symptoms can include backache, bone and refractory myeloma (where disease is non- pain, anaemia and tiredness. Diagnosis is dependant responsive to treatment). Plasma cell myeloma is on results from a number of clinical tests, including full defined by the presence of >10% clonal plasma cells in blood count and chemical analysis, serum and urine the BM, a paraprotein and the presence of end-organ electrophoresis, BM morphology, radiography and damage,1,2 which can be summarized by the acronym, genetic analysis. CRAB. Treatment strategies are conventionally divided into intensive and non-intensive regimens. The former • HyperCalcaemia feature chemotherapy using a combination of steroids • Renal insufficiency (e.g. dexamethasone), alkylating agents (e.g. cyclo- • Anaemia phosphamide) and immunomodulatory agents (e.g. • Bone lesions thalidomide or lenalidomide) plus or minus a prote- Hypercalcaemia results from bone destruction and is asome inhibitor (e.g. bortezomib or carfilzomib) for 3 fi seen in 20% of patients at diagnosis. Renal insuf - younger (<60 years), fitter patients, followed by ciency and ultimate failure is due to tubular damage autologous stem cell transplantation. High-dose mel- ∼ resulting from proteinuria. Anaemia is seen in 67% phalan (i.e. 200 mg/m2) is used as a consolidation of patients, and results from effacement of BM by therapy prior to autologous stem cell transplantation, plasma cells and renal damage resulting in loss of further reducing plasma cell load within the BM. erythropoietin. Osteolytic disease is seen in 70% of Non-intensive regimens comprise similar combina- 1,4 patients with MM. tions used at attenuated doses and without autolo- Myeloma is the 17th most common cancer in the gous stem cell transplantation.4,6 UK accounting for 1.5% of all new cases reported Immunomodulatory drugs, such as lenalidomide (source: Cancer Research UK, 2009). This equates to (and other thalidomide analogues), have been shown ∼5000 new patients being diagnosed with myeloma to have clinical efficacy in the treatment of myeloma. in the UK per year. MM is a cancer of older adults: Recent work has shown that these immunomodu- the majority of cases occur in patients over the age of latory drugs can bind to and inhibit the cereblon 65. Twenty-six per cent of patients are aged between ubiquitin ligase. Furthermore, lenalidomide-bound Review of genetic screening in myeloma, 2015, Vol. 113 17 cereblon acquires the ability to target two specific immunoglobulin (Ig) antibody molecule is composed lymphoid transcription factors, IKZF1 and IZKF3, oftwoheavychainandtwolightchainproteins.These both known to play a central role in B and T cell are encoded by the IGH gene for the heavy chain, biology, for selective ubiquitination and degrad- located on chromosome 14, and the IGK and IGL ation.7,8 Proteasome inhibitors are also extremely genes for the light chain, located on chromosomes 2 effective in myeloma treatment. The proteasome is an and 22, respectively.15 Variable gene segments at these intracellular enzyme complex that breaks down loci undergo irreversible rearrangement, at the DNA damaged proteins. The exquisite sensitivity of myeloma level, and this creates individual B cells with specificity to proteasome inhibitors remains largely unexplained, for a single antigen. In summary, the several stages of Downloaded from https://academic.oup.com/bmb/article/113/1/15/284455 by guest on 27 September 2021 although the drugs are thought to act in a multifaceted B-cell development each represent a change to the and extensive mechanistic fashion. They have been genomic DNA involving the variable (V), diversity (D) thought to stimulate apoptotic pathways, inhibit the and junctional (J) gene segments of the immunoglobu- NF-KB pathway, down-regulate expression of genes lin genes. These stages can be divided into three pro- associated with DNA repair and induce an endoplasmic cesses, all of which generate double-stranded DNA – reticulum stress response.9 11 Bisphosphonates are an breaks: VDJ recombination, somatic hypermutation important class of drugs used to treat bone manifesta- and IgH-switch recombination.17,18 tions in MM. They are potent inducers of osteoclast Following maturation, plasma cells have under- apoptosis, thereby reducing elevated bone resorption gone the final stages of development and home to the associated with MM. BM.17 These cells are long-lived, terminally differen- Shorter survival times correlate with higher clinical tiated and non-dividing. They are highly dependent stage at diagnosis, renal insufficiency, degree of on the BM microenvironment where their survival is marrow replacement, increased proliferative activity favoured by survival factors found in permissive and certain karyotypic abnormalities.12 Although sig- niches.19,20 nificant advances have been made in MM treatment Plasma cells interact with the BM microenviron- over the past two decades, and it is now regarded as ment via a number of complex interactions, which are highly treatable, myeloma remains almost always crucial to tumour survival and disease progression.19 incurable. The only wholly curative option available The BM microenvironment is made up of extracellul- for the treatment
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