Myeloma is a type of bone marrow cancer that affects 5820 people/year in the UK (Cancer Research UK). Earlier detection is a high priority for patients. Not only does earlier detection improve 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; Bloodwise) but the earlier that myeloma is diagnosed and treated, the more effectively the symptoms associated with this disease are controlled. These symptoms include bone, kidney and immune system complications, which can impact significantly on patients’ overall well-being. Unfortunately, patients with myeloma have the longest intervals from initial symptom reporting to diagnosis of all common cancers, with the most consultations in primary care before referral. New approaches are therefore needed to diagnose this cancer earlier.
Every myeloma arises from a preceding condition called Monoclonal Gammopathy of Undetermined Significance (MGUS), which occurs in ~3% of people aged over 50. People with MGUS are at higher risk of developing myeloma and are regularly monitored with blood-based tests so that progression to myeloma can be detected at the earliest stage. However, because MGUS is largely symptomless, it is often diagnosed incidentally and 80–90% of myelomas are diagnosed without first receiving an MGUS diagnosis. Further, only 1% of individuals with MGUS develop myeloma every year and the risk factors for MGUS to myeloma progression have been difficult to define. To enable earlier detection, it is therefore necessary to both improve the identification of people with symptomless MGUS so that a greater proportion of this high-risk population can be monitored and to develop more sophisticated ways to assess risk of progression to myeloma to avoid overwhelming current MGUS monitoring services. There are several projects underway in Oxford that aim to address these objectives.
Oxford Myeloma Projects
Oxford is well-placed for myeloma research due to its multi-disciplinary clinical and scientific expertise across the breadth of the myeloma care pathway, from primary care academics adept at interrogating big data, through to nationally renowned secondary care haematology and immunology hospital departments who jointly manage thousands of patients with MGUS and myeloma.
Myeloma Research in Primary Care
Dr Constantinos Koshiaris, Dr Jason Oke and Dr Brian Nicholson (Nuffield Department of Primary Care Health Sciences) have previously worked on improving myeloma diagnosis in primary care. Their work, published in collaboration with the University of Exeter in the British Journal of General Practice, demonstrated that a simple combination of two blood measurements – plasma viscosity or erythrocyte sedimentation rate and haemoglobin levels – could be sufficient to diagnose patients.
To continue this work, Myeloma UK has funded Dr Constantinos Koshiaris in collaboration with Associate Professor Kassim Javaid (Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences) to use a similar approach to identify which patients are most likely to have received a diagnosis of MGUS from their primary care records. They will classify which characteristics increase or decrease the risk of being diagnosed with MGUS and finally identify predictors which could flag up MGUS patients that are at a higher risk of progression to myeloma or other related complications.
Improving risk stratification of pre-malignant conditions
Oxford is coordinating the £6.9m Janssen-funded OxPLoreD project, recruiting a prospective cohort of 1650 patients with lymphoproliferative disorders (including MGUS). Led by Professor Anna Schuh (Department of Oncology), researchers will study genetic and immune markers in the blood and bone marrow. The aim is to identify markers in the DNA and the immune system of people who go on to develop cancer, whilst also identifying those at low risk who do not need follow up in specialist cancer centres.
Dr Karthik Ramasamy (Oxford University Hospitals NHS Trust) is taking a similar approach with a £3.2m CRUK-funded study focused on investigating biomarkers that can predict progression from another pre-malignant condition for myeloma called smouldering myeloma. Patients with smouldering myeloma have an even higher risk of progressing to myeloma (51% over 5 years) compared to patients with MGUS (7% over 5 years). Working with Kwee Yong (University College London) and Irene Ghobrial (Harvard University), the researchers are investigating genomic factors, imaging, liquid biopsy and the immune environment to build an integrative risk model for smouldering myeloma to myeloma progression.
The markers identified in these two studies will be able to help categorise patients into low or high risk of progression to myeloma. This will guide clinical monitoring strategies so that those at the lowest risk can be tested less frequently, reducing demand on clinical services and patient anxiety. Another outcome is that by robustly and accurately identifying the patients who are at highest risk of developing myeloma, in the future it may be possible to give interventional treatment earlier.
Early Intervention
An advantage of detecting disease earlier is that treatments can be applied sooner when they are more likely to be successful. By taking this approach one step earlier and targeting groups at the highest risk of getting cancer with well-tolerated therapeutics, in the future it may be possible to delay or even prevent development of the disease, or better treat the associated symptoms.
Dr Karthik Ramasamy is the UK lead for an international phase II clinical trial investigating the use of the bone-targeting agent Denosumab to arrest the progression of smouldering myeloma to myeloma. Funded by Amgen Ltd, the DEFENCE study (DEnosumab For the rEductioN of the smouldering myeloma transformatioN inCidence ratE) is measuring the time to progress to myeloma and/or bone-related complications in the denosumab-treated compared to the placebo-treated groups.
With these projects (and more in the pipeline), Oxford researchers are aiming to make a real difference to how people with myeloma are diagnosed, leading to better outcomes and improved survival.
The work described on this page has received funding from Myeloma UK, Cancer Research UK, Janssen and Amgen.