Causes and Diagnosis of Multiple Myeloma
What is multiple myeloma?
Multiple myeloma (MM) is a type of cancer that affects plasma cells, a white blood cell that secretes antibodies (also known as immunoglobulins) in response to substances foreign to the body (antigens). The condition is characterised by uncontrolled proliferation of plasma cells in the bone marrow, and a corresponding over-production of a monoclonal protein (M-protein). The M-protein can either be an intact immunoglobulin and/or a free light chain (FLC). M-proteins can be used to guide diagnosis, treatment and monitoring. Myeloma is called ‘multiple’ because there are frequently numerous bone marrow sites around the body where the tumour cells grow, including the spine, skull, pelvis, rib cage, as well as other bones around the shoulders and hips.
Causes and risk factors
MM is a common haematological malignancy with a worldwide yearly incidence of approximately 160,000 cases.1 It is more common in people over the age of 60, and has a mean age of diagnosis of 72. Like many cancers, the exact causes of MM are largely unknown, however, precancerous conditions – including monoclonal gammopathy of unknown significance (MGUS) and smouldering myeloma – may progress to a malignant stage, and require constant monitoring to ensure timely diagnosis of progression and intervention.
Diagnosis
Diagnosing MM is often difficult, as initial symptoms are generally non-specific and similar to other diseases. Fatigue is a common early sign, which patients frequently associate with their age, and therefore, delay seeing a physician and, ultimately, their diagnosis. It isn’t until more significant symptoms appear – such as bone pain, renal impairment and recurrent infections – that they seek medical advice. Even then, a firm diagnosis can still be challenging as physicians may often suspect and investigate other, more prevalent, causes of the symptoms before identifying MM. This is why increasing awareness of MM is crucial, not only to encourage patients to seek medical advice if experiencing these symptoms, but also to guide physicians towards this possibility earlier in the diagnostic pathway.
Diagnosing and starting treatment as early as possible is critical for patients, largely because of the damage the cancer can cause to their organs – most frequently the kidneys – in more advanced stages.
CRAB clinical manifestations
CRAB stands for:
• Hypercalcaemia – elevated calcium in the blood
• Renal insufficiency – improper kidney function
• Anaemia – red blood cell deficiency
• Bone lesions – abnormal tissue mass within a bone
A variety of tests – including a bone marrow biopsy, and blood and skeletal analyses – are performed to confirm if any CRAB symptoms are present and help to risk stratify the cancer into either rapid, intermediate or low risk of progression. Clinicians will then classify and quantify the specific M-protein responsible for the disease, calculate the FLC ratio and look for specific genetic abnormalities.
Together, these diagnostic procedures give physicians a detailed assessment of the status of MM in the patient, which can guide treatment options and estimate a patient’s prognosis.
Studies have shown that fewer complications and better overall survival (OS) can be achieved when patients diagnosed with the pre-malignant conditions discussed above, allowing close monitoring to detect progression to MM earlier.
However, the majority of cases are diagnosed when the cancer has become, or is at risk of being, ‘active’. This occurs when the proportion of plasma cells in the bone marrow is greater than 10 per cent – with the normal value falling between two and three per cent – and when at least one CRAB condition is detected. MM is also considered active if plasma cells constitute more than 60 per cent of total cell count in the bone marrow, when the free light chain (FLC) ratio is higher than 100 (if the FLC produced by the tumour is >100 mg/L) or when there is more than 1 lesion when the skeleton is examined by MRI.
Treatment and monitoring
There has been tremendous progress in treating MM – owing to the availability of new drugs and treatment regimens – that have vastly improved patient outcomes, making survival of more than 10 years possible in younger patients eligible for stem cell transplants. However, the cancer remains incurable; a number of myeloma cells always survive each treatment round – known as drug-resistant clones – that eventually multiply again, resulting in relapse or recurrence of the disease. For this reason, patients are continuously monitored following treatment to identify how deep the response is and to quickly identify when they relapse, allowing new treatment to start as soon as possible.
Measuring M-proteins in the serum and urine remains the gold standard way to gauge treatment success. Newly diagnosed MM patients will show elevated levels of monoclonal proteins, and as effective treatment eliminates M-protein-producing malignant plasma cells, there is a reduction of M-protein in the serum and urine of the patient. These changes can be identified and quantified by serum protein electrophoresis (SPEP), urine electrophoresis (UPEP), immunofixation electrophoresis (IFE), or serum FLC (sFLC) analysis.
Challenges with traditional monitoring techniques
SPEP and IFE are adequate techniques for many patients with MM but, crucially, they are less accurate in some forms of the cancer, such as light chain multiple myeloma, as well as oligosecretory and non-secretory myelomas, where patients have low or non-detectable levels of M-protein respectively. Other challenges associated with these methods include:
• The M-protein can overlap with other proteins in patients with IgA and IgM MM subtypes, making quantification imprecise.
• The long half-life of intact immunoglobulins in the blood can be problematic when rapid assessment of treatment success is needed.
• The use of antibody-based therapeutics – such as daratumumab and elotuzumab – can skew electrophoresis results, and therapeutic monoclonal antibodies can be misinterpreted as evidence of residual disease.
• Also, the amount of FLC in the urine is dependent on kidney function, therefore FLCs may not always be present in the urine so cannot be measured.
Assays aimed at evaluating sFLCs have helped overcome some of these barriers, providing accurate detection and monitoring of all types of MM and related diseases.
What exactly are FLCs? And what is the Freelite® assay?
Plasma cells in the bone marrow produce light chains – subdivided into κ and λ – which bind together with heavy chains, to form immunoglobulins. A portion of the light chains does not bind to the heavy chain counterpart, and is secreted as free light chain. In a healthy individual, the κ and λ FLC in the serum are a product of all the plasma cells clones and are therefore called polyclonal FLC. In patients with MM, one specific plasma cell clone multiplies, and there is an overproduction of monoclonal free light chains of a specific type (either κ or λFLC). This skews the ratio between κ and λ FLCs in the blood, indicating a problem with plasma cells.
Therefore, these proteins are excellent biomarkers for MM and related diseases, and measurement of them forms the basis of the Binding Site’s highly sensitive and specific Freelite® assay. sFLCs have a much shorter half-life – two to six hours – compared to intact immunoglobulins, making them preferable for monitoring disease rapid changes in monoclonal protein concentrations. sFLC assays are also more sensitive and convenient than urine analysis, and can be used alongside intact immunoglobulin measurements to improve patient management.
sFLCs and MM guidelines
The International Myeloma Working Group (IMWG) guidelines for diagnosis of MM recommend sFLC assays for diagnostic screening panels, and sFLC analysis as a ‘biomarker of malignancy’ to define the presence of MM. The guidelines for monitoring MM (Kumar 2016) also recommend that sFLCs are used for treatment evaluation in patients where the levels of other markers are below reliable concentrations, for example, when serum M-protein is 10 g/L or less, and urine M-protein is 200 mg or less over 24 hours. Responses can be partial – indicated by a ≥ 50% reduction in the difference between involved and uninvolved sFLC levels (dFLC) – or very good partial (VGPR), with a 90 per cent or higher reduction of sFLC. Finally, sFLC is recommended to determine stringent complete response, which is the normalisation of sFLC ratio, and the absence of evidence of the disease from a bone marrow biopsy and serum and urine IFE. All the thresholds and medical decision points for sFLC presented in the guidelines, have been established with Freelite®.
What’s next for MM treatment and monitoring?
Novel therapies have achieved unprecedented improvements in progression-free survival and OS in patients with MM. Research continues into improving treatment strategies, as well as trying to provide more sensitive and specific approaches to diagnosis and ongoing therapeutic monitoring. Reservoirs of tumour cells lead to residual disease which results in inevitable relapses in patients, making the measurement of the minimal residual disease (MRD) an important prognostic factor, as it demonstrates the degree of success from treatment. New methods to improve MRD assessment continue to be developed, including mass spectrometry, which can accurately detect and measure even very low concentrations of serum monoclonal proteins, making it an exciting area of research.
Living with MM
MM diagnosis can be devastating; however, patients are generally living longer, owing to the improvements in treatment and care. In the UK, and around the world, there are various support groups for people dealing with similar situations. The International Myeloma Foundation is a great source of information, and national organisations – such as Myeloma UK and Blood Cancer UK – can provide additional support and tools to help patients cope with their MM diagnosis, and their ongoing journey through treatments.
References
1. Ludwig H, Novis Durie S, et al. Multiple Myeloma Incidence and Mortality Around the Globe; Interrelations Between Health Access and Quality, Economic Resources, and Patient Empowerment. Oncologist. 2020;25(9):e1406-e1413. doi:10.1634/theoncologist.2020-0141