A Prospective Long-term Observational Study in Patients With Monoclonal Gammopathy of Undetermined Significance
A Prospective Long-term Observational Study in Patients With Monoclonal Gammopathy of Undetermined Significance
Multiple Myeloma (MM) is a rare blood cancer affecting over 5000 people a year in the UK. All cases of myeloma start with a condition called monoclonal gammopathy of undetermined significance (MGUS). MGUS occurs in approximately 3.2% of people aged 50 and over. Only a small proportion of these people - around 1% each year - will develop myeloma. Most people with MGUS have no symptoms, but a small number of people will suffer complications. This group are referred to as having monoclonal gammopathy of clinical significance (MGCS).
People with myeloma frequently experience long delays in diagnosis; the delays are longer than for any other cancer. Although we know that MGUS leads to myeloma, most cases of MGUS are only found 'incidentally' when the person is having blood tests for something else. And the people who have MGUS do not have consistent testing or follow up. This situation means that 80 - 90% of people who are diagnosed with myeloma did not have an earlier MGUS diagnosis.
Earlier diagnosis of myeloma might be possible with better understanding MGUS and how it should be monitored. The SECURE study will help with this. It will help confirm the rate at which people with MGUS progress to a diagnosis of myeloma. It will further understanding of screening, diagnosis, and monitoring patterns of people with MGUS and MGCS in the UK.
The study aims to find out more about the role of family history and demographic factors in the development of MGUS. It will also find out more about the psychological impact of an MGUS diagnosis and individual quality of life.
Patients with MGUS will be identified by their clinical care team and invited to participate in the SECURE study. Participants will be required to answer surveys and questionnaires annually for a period of 5 years or until their disease changes. The study will recruit participants from 20 NHS sites in the UK. Some will be asked to provide blood samples. SECURE is funded by Cancer Research UK (CRUK) and the National Institute for Health Research (NIHR).
Myeloma affects 5820 people/year in the UK and is the advanced stage of a clonal plasma cell disorder with a distinct precursor state, termed monoclonal gammopathy of undetermined significance (MGUS). The term monoclonal gammopathy refers to the aberrant amounts of monoclonal immunoglobulin produced by the dysregulated plasma cell clone. MGUS is heterogenous in its clinical presentation, with varying levels of both aberrant and suppression of normal immunoglobulins. Myeloma is the only clinical state currently offered therapy, although a minority of MGUS patients experience complications such as amyloidosis, kidney disorders, osteoporosis, and skin and nervous system manifestations. MGUS patients with these clinical complications are referred to as having monoclonal gammopathy of clinical significance (MGCS). In MGCS, the morbidity is driven by secreted protein rather than clone size which often is significantly smaller than in myeloma patients. Myeloma care costs are substantial relative to the overall cancer chemotherapy spend worldwide. Earlier detection is a high priority for patients and improves survival: 84% of people with myeloma survive for >5 years if diagnosed at the earliest stage, compared with only 26% if diagnosed at advanced stage. Despite the widespread availability of diagnostic serological techniques, myeloma is most frequently diagnosed late (>3-6 months post symptom presentation) and has the longest diagnostic delay of any cancer, with emergency presentations in >30% of newly diagnosed myeloma patients who have shortened survival. Most avoidable delays occur in primary care for reasons including inconsistent MGUS testing and follow-up, highlighting the need for improved connectivity between primary care (screening), immunology (initial investigations) and haematology (ongoing management) for effective diagnosis and management of myeloma and precursor states. Because MGUS precedes all myelomas, an early diagnosis strategy is to regularly monitor people with MGUS for progression to myeloma. Progression risk is ~1%/year with a general MGUS population prevalence of 3.2% in individuals >50 years. Unfortunately, MGUS is often diagnosed incidentally and 80-90% of myelomas are diagnosed without first receiving an MGUS diagnosis. Given population-level MGUS screening would be impractical and expensive, research is required to understand clinical symptoms. However, the need to regularly monitor a higher number of patients with MGUS would place a huge burden on GPs. There is a lack of well-defined prediction models for the MGUS-MGCS/ myeloma transition that can be applied in clinical care. Although the size of the aberrant monoclonal protein and subtype (non-IgG) does broadly prognosticate progression to myeloma, only 20-30% of MGUS patients belong to this group.
Further, risk factors for MGUS-MGCS/myeloma progression have been difficult to define, leading to largely non-standardised approaches to detection, risk stratification and ongoing monitoring, contributing to the diagnostic delay. Patients presenting with myeloma report bone pain as the most common symptom at diagnosis and >80% have bone lesions on imaging at diagnosis. Patients diagnosed with MGUS show significantly higher incidence of death due to co-morbidities such as fractures (including all hospital-related morbidities from long-term hospital admission such as hospital-acquired infection), thrombi formation, organ failure and infection, compared with non-MGUS controls. Further, >18% of MGUS patients incidentally diagnosed and with no prior history of osteoporosis will suffer from a vertebral fracture.
This project is an observational study, whereby investigators hope to understand, via qualitative analysis, the existing screening and monitoring patterns, along with current routes for MGUS and MGCS diagnosis, in the UK. Investigators also hope to improve the understanding of demographic associations and family linkage, as there has been recent evidence that supports higher risk and earlier MGUS progression in Black people and evidence of higher risk in those with immediate relatives with the disease.
Furthermore, as there is limited information available to understand the psychological needs after diagnosis and during the progression of the disease, the study will also focus on quality of life of patients and requirements for psychological services provided to participants. Investigators hope to use both standardised and non-standardised scales during baseline and annual follow-ups.
Metabolomics studies will be undertaken in the Phenome Centre-Birmingham (PC-B); a £8M facility applied for the large scale targeted and untargeted study of metabolites present in human biofluids and tissues, with a significant focus on precision/stratified medicine. A number of studies have applied metabolomics to the study of plasma cell dyscrasias. A 2013 study used Proton NMR-based metabolite analyses of archived serial paired serum and urine samples from MM patients at different stages of disease. The study showed discrimination between active disease at diagnosis, remission and relapsed disease and identified elevated acetyl carnitine as a novel marker of active disease. A more recent study identified that elevated levels of 2-hydroxyglutarate (2-HG) in the blood are associated with higher levels of c-MYC expression in MM and a shorter time to progression. More recently we have analysed serial samples obtained in Birmingham from 12 MGUS patients before and after their progression to MM and in a second cohort, serial samples from MM patients at diagnosis (before treatment), during treatment and in remission. Statistical analysis identified a number of metabolites which were altered in their relative concentration between pre- and post-MM diagnosis. For example, serum sphingosine-1-phosphate (S1P) levels were higher in MGUS individuals prior to their progression to MM (p<0.05, mean fold change of 7.5) and this change in S1P levels was progressively reversed during MM therapy and in first remission. SECURE study serum samples will be analysed using ultra-performance liquid chromatography-mass spectrometry (Ultimate3000 UPLC system coupled to an electrospray ionisation Q Exactive Plus mass spectrometer).
Characterisation of germline genetic variants in study participants will be undertaken using methodology that is state-of-the art at the end of the planned observation period to identify variants and risk scores associated with and potentially predictive of development of MGUS or progression to MM. The myeloma group in the Division of Genetics and Epidemiology at The Institute of Cancer Research (ICR) has been pioneering the discovery of germline genetic risk variants for MM, their functional annotation, as well as development of polygenic risk scores. An ongoing program of activities is focused on functional characterisation, in particular also investigating the interplay with non-coding mutations in the tumour genome, which will inform interpretation of findings generated via SECURE and support development of individualised risk stratification tools.
Colleagues from the Mayo clinic have shown post translational modification of light chains is a biomarker of progression from MGUS to myeloma, in a screened MGUS cohort. In addition, a recent paper has shown N-lined glycosylation transcriptional programs are significantly upregulated in plasma cells from patients with AL amyloidosis in comparison to patients with myeloma and normal controls. Within SECURE, investigators will be using a mass spectrometry platform established by Binding site to longitudinally profile glycosylation patterns in light chains of MGUS patients and test whether this is a potential biomarker for progression to myeloma and or amyloidosis.
Clinical impact: A factual understanding of progression of Monoclonal gammopathy to Myeloma in a UK population is needed. This study will provide additional information on diagnostic routes, screening for MGCS, monitoring patterns and both psychological impact as well as health resource utilisation of this patient population. This will allow us to risk stratified monitoring of patients with MGUS, and streamline pathways with intent to early diagnosis of MGCS. Additional data on family linkage, QoL and HRU helps develop a framework for enhanced clinical management of MGUS.
Inclusion Criteria:
• Any individual with a confirmed or suspected case of MGUS
Exclusion Criteria:
richard.brouwer@ouh.nhs.uk07594301699