People often get confused by the different tests for myeloma. Once you get a grasp of the terminology and importantly a tiny bit of the pathology (I promise there isn’t much…) it makes a lot more sense.
Myeloma is a cancer of plasma cells. ‘Normal’ plasma cells are B cells that have been exposed to an antigen, and matured so that their primary function is to make immunoglobulin. Myeloma occurs when a plasma cell gains an oncogenic mutation leading to enhanced proliferation. These ‘myeloma cells’ proliferate and in almost all cases secrete a protein which is immunoglobulin-like, but performs no immune function.
Going back to a little bit of physiology, immunoglobulin is made up of 2 elements; the heavy chain (e.g. IgG, IgA, IgM) and an associated light chain (kappa or lambda). For example IgG Kappa or IgA lambda.
This is important to help understand the tests that are performed for myeloma. Around 75% of myeloma cases produce a clonal protein with the heavy and light chains e.g. IgG kappa myeloma. This clonal ‘whole’ immunoglobulin-like protein is called a paraprotein. Around 20% of myeloma cases secrete only a clonal light chain e.g. lambda light chain myeloma. This is why we need to test for both heavy chains and light chains, otherwise we may miss 20% of myeloma cases if we only investigate for the heavy chains.
Serum electrophoresis (SEPHS) is the primary test for a paraprotein. SEPHS ‘pulls’ apart proteins by size. On the left is an amateur but educational sketch of a normal electrophoresis result, showing proteins spread along the plate by size from left to right. On the right is SEPHS showing a monoclonal ‘spike’/’band’. This represents a paraprotein, and if detected, the lab will perform serum immunofixation which measures the type and amount of the paraprotein e.g. IgG kappa 13g/L.
For around 75% of patients this will be enough information for a diagnosis, but we must also test for light chains as 20% of myeloma cases only secrete light chains. The two ways to test for light chains are;
As you may have guessed, haematologists think the Bence Jones is a pretty poor test now we have SLFC, and that if SFLC is available this should be used first-line as it will ‘miss’ less cases of myeloma, and also cause fewer false positives.
Below is a flowchart to help put some of that information together;
If either a paraprotein or clonal light chain (or both) are detected, this suggests a plasma cell disorder. Plasma cell disorders are monoclonal gammopathy of undetermined significance (MGUS), myeloma, amyloidosis or lymphoplasmacytic lymphoma (which deserves a whole blog to itself). All cases of myeloma will have been preceded by MGUS, even if it was not known about beforehand (but not all MGUS cases will become myeloma – in fact very few will).
The difference between MGUS and myeloma is the number of plasma cells in the bone marrow (10% or more needed for diagnosis of myeloma) and importantly whether any end organ damage is present. MGUS is incredibly common, and the risk of transformation to myeloma is very low (1% per year). There are certain risk factors which make transformation more likely such as a paraprotein over 15g/L or an IgA paraprotein. A ‘low risk’ example-a 6g/L IgG kappa MGUS, with a normal serum free light chain (SFLC) ratio has only a 5% chance of transformation to myeloma at 20 years. A 17g/L IgA kappa MGUS with an abnormal SFLC ratio is higher risk, but still has a relatively low risk of transformation to myeloma of 58% at 20 years (I use a tool like https://qxmd.com/calculate/calculator_148/mgus-prognosis to risk stratify).
End organ damage is caused by two elements in the myeloma pathology;
A brief section about amyloidosis and then lymphoplasmacytic lymphoma.
This table helps put together some of those test results with clinical features.
|Bone marrow plasma cells||End organ damage|
Kappa:Lambda ratio under 100
Kappa:Lambda ratio under 100
Does not always have to be significantly raised
Kappa:Lambda ratio usually over 100
|≥10%||Yes (hyperCalcaemia, Renal impairment, Anaemia, Bony pain aka ‘CRAB’)|
Ratio may be abnormal
|Variable||Yes – heart failure, nephrotic syndrome, neuropathy (peripheral and autonomic)|
|Lymphoplasmacytic lymphoma aka Waldenstrom’s macroglobulinaemia||IgM||Bone marrow usually performed but plasma cell % not diagnostic. Lymph node can also be used as biopsy source.||Lymphadenopathy, night sweats, fever and weight loss.|
We hope that this has been useful to break down some of the anxieties about myeloma and its tests. You can find more on the Buku Medicine app…
Buku Medicine is a free App, available internationally, that I created (initially as Buku Haematology) with Prof Steve O’Brien from the Freeman Hospital, Newcastle, UK 3 years ago. I found as a junior haematology registrar that many questions we were asked could be avoided altogether with no need for specialist discussion with an easy to access resource like an App. This is the case for up to 21% of referrals to haematology. For those haematology queries that could not be avoided altogether, the App can recommend history/investigations for a further 60% of queries, and through that expedite patient care so the referrer can call the haematologist with the patient history and investigations fully prepped.
We have expanded the app over the last 3 years, and it is now installed on clinician devices in two North-East England NHS trusts, has the support of the regional haematology consultant body, is in the NHS App library and has over 13,000 active users.
In recent months we have also added renal and endocrine specialties to the app as their specialties are similar to haematology in the nature of many of the queries posed. We plan to add further modules in the coming months too.
The app can be downloaded from Apple and Google play AppStores, and if you like it please give us reviews on the AppStores to help promote our work.