Plasma cell myeloma (PCM), also known as multiple myeloma (MM) or myeloma, is a cancer of the bone marrow. It is a neoplastic disorder characterised by an abnormal clonal proliferation of plasma cells in the bone marrow (BM) and the consequent overproduction of circulating monoclonal immunoglobulin (paraprotein). Myeloma is defined by the presence of ≥10% clonal plasma cells in the bone marrow, a paraprotein and the presence of end organ damage, including hypercalcaemia, renal insufficiency, anaemia and bone lesions.
Over the past two decades the treatment of myeloma has seen huge advances leading to significantly improved outcomes, specifically as a result of the introduction of new classes of therapeutic agents including immunomodulatory agents (IMiDs), proteasome inhibitors, monoclonal antibodies and improved stem cell transplantation techniques. It is usually possible to reduce disease load substantially and induce a remission phase in the patient’s myeloma. However, complete elimination of residual disease is not possible, and the disease almost invariably begins to recrudesce resulting in relapse, and so, in the majority of cases, myeloma remains an incurable disease.
Bone disease is seen in approximately 70% of patients at diagnosis, but with a range of severity. It is estimated that over 90% of patients exhibit evidence of bone disease at some stage throughout the course of their disease.
Myeloma genetics is intrinsically complex and highly heterogeneous; there is no single, discrete genetic aberration that causes the typical phenotype seen in myeloma, rather a range of characteristic aberrations in key regions of the genome. Clonal evolution drives a tendency for myeloma to accumulate genetic aberrations over time. Despite this complexity, genetic analysis offers an opportunity to categorise the disease, offer prognosis based on these categorisations and potentially apply a personalised medicine approach to therapy. Access to diagnostic genetic testing in myeloma is ad hoc and highly dependent upon whether patients are entered into national trials and local commissioning arrangements, even then the techniques employed and the exact nature of the testing vary dramatically.
This project assessed the role of five different genetic techniques used in the diagnosis of myeloma; cytogenetic analysis, fluorescence in situ hybridisation (FISH), multiplex ligation-dependant probe amplification (MLPA), DNA array and targeted next generation sequencing (NGS). These data, alongside current recommendations, were used to design and propose appropriate diagnostic testing strategies in myeloma, and to inform national best practice.
Alongside this work, and through collaboration with UKNEQAS (GenQA), a quality assessment and assurance programme was introduced for the genetic testing of myeloma patients, with the aim of not only providing quality assurance in this area, but in order to create a more consistent and equitable service through provision of an educational component to the scheme.
The final aim related to myeloma bone disease was to explore, using targeted NGS, a possible association between high risk variants in bone related genes and bone phenotype, which if proven, would allow a more personalised and targeted approach to the treatment of bone manifestations associated with myeloma.
