HAEMATOLOGY


and there are no signs of organ damage. Active MM is similarly identified when specific criteria are met: a diagnosis requires the identification of at least 10% clonal plasma cells in the bone marrow, plus the presence of one or more of the myeloma-defining events/biomarkers included in the CRAB or SLiM diagnostic criteria. The SLiM framework includes clonal plasma cells in the bone marrow of 60% or greater, a serum involved/ uninvolved free light chain ratio of 100 or greater, or imaging studies that identify at least one focal lesion measuring 5mm or larger.13,15


These criteria underscore


the importance of integrating advanced diagnostic tools and techniques to ensure accurate and timely diagnosis.


Freelite sFLC assays – performed on the Optilite automated analyser – are already widely used as an aid in monitoring MM patients, yet their potential as an aid in the diagnosis of MM remains largely untapped.


and IgE myelomas, which involve the overproduction of less common immunoglobulins.6


These variants are


often more aggressive than IgG and IgA types, requiring specific diagnostic strategies to identify and manage the disease effectively. On the other hand, non-secretory myeloma – a rare subtype affecting 1-2% of patients – is characterised by the production of little to no detectable paraproteins.7 Besides monoclonal intact immunoglobulin paraproteins, additional paraproteins – such as serum free light chains of kappa or lambda subtypes – are also present in almost all of these myeloma subtypes. In light chain-only myeloma, which affects over 15% of myeloma patients, only free light chains are produced in excess. These free light chains are often referred to as Bence Jones proteins when detected in the urine. Crucially, serum free light chain paraproteins are often associated with a kidney damage, such as cast nephropathy, or AL amyloidosis.8 The broad range of myeloma subtypes


mirrors the diverse ways that MM can manifest, requiring clinicians to adopt tailored regimens to ensure accurate diagnosis and effective management.


n Myeloma symptoms MM primarily affects individuals over the age of 65, but its symptoms and progression vary significantly.9 Many patients are initially diagnosed with monoclonal gammopathy of undetermined significance (MGUS), a condition in which plasma cells produce paraproteins but without organ damage associated with myeloma.10


It is worth noting that MGUS patients have 48


decreased overall survival compared to age-matched healthy individuals, although their comorbidities are generally less severe than those seen in MM patients.11


MGUS is usually only detected


incidentally, when routine blood tests reveal elevated paraprotein levels. As a precursor to myeloma, around 1% of patients progress to MM annually.12 Regular monitoring of patients diagnosed with MGUS is therefore essential, as early detection of progression to symptomatic myeloma can significantly reduce the development of end organ damage, therefore improving outcomes. Unfortunately, even the symptoms of advanced MM are often subtle and can easily be mistaken for other conditions, leading to delayed diagnosis. Common signs include persistent bone pain, particularly in the back or ribs, along with recurrent infections, fatigue, weight loss, weakness and shortness of breath.3


As


the disease progresses, more serious complications – including renal failure, hypercalcaemia and bone lesions – may appear. These issues correspond to the diagnostic criteria summarised by the acronym CRAB: calcium elevation, renal dysfunction, anaemia and bone disease.13


n Diagnostic criteria The International Myeloma Working Group (IMWG) established clear criteria for diagnosing MM and its precursor condition in 2003,14


and these criteria


were subsequently updated in 2014 to incorporate new diagnostic markers and improve early detection.13,15


Diagnosis


of MGUS is confirmed when the level of paraprotein in the blood is less than 30g/L, the proportion of abnormal plasma cells in the bone marrow is below 10%,


n Advances in diagnostic approaches While routine blood tests may flag early indicators of MM, such as anaemia or elevated total protein levels, further investigations are required to accurately diagnose the condition, such as serum and urine electrophoresis, and serum free light chain (sFLC) analysis. Additionally, advanced imaging techniques, such as MRI and PET scans, may be employed to identify bone lesions or other organ involvement. Crucially, the detection of 10% or more clonal plasma cells in the bone marrow is essential for the diagnosis of myeloma.15 Historically, serum and urine protein


electrophoresis have been used as the primary tools for the detection of paraproteins. However, the effectiveness of urine electrophoresis is hampered by limited sensitivity, lack of deposition of free light chains into the urine, and the reliance on patients providing urine samples. Together, these factors often result in no or poor detection of the light chain paraproteins, leading to delayed or missed diagnosis of many patients, compromising the reliability of this approach. To address these shortcomings, the National Institute for Health and Care Excellence (NICE) updated its guidelines in 2016 to recommend replacing urine protein electrophoresis with sFLC assays for more dependable detection of the monoclonal free light chain component found in most MM patients.16


Unlike urine


tests, sFLC assays use blood samples, which are collected in 100% of patients suspected of having MM. This eliminates the logistical barriers associated with urine collection and reduces issues related to patient noncompliance. sFLC assays also offer greater sensitivity and quantitative accuracy compared to urine electrophoresis. Additionally, monoclonal free light chains can be detected in the serum of the vast majority of patients with MM – up to 97% – but only in the


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