🧬 Abnormal Immunoglobulin — Assessment & Management

The myeloma CRAB criteria (Hypercalcaemia, Renal impairment, Anaemia, Bone lesions) represent end-organ damage attributable to the plasma-cell disorder and, with the SLiM biomarkers, are the myeloma-defining events that trigger treatment — the mere presence of a paraprotein without CRAB criteria does not constitute myeloma (it may be MGUS or smouldering myeloma). The clinical significance: a patient with a paraprotein of 25 g/L but no anaemia, normal renal function, normal calcium, and no bone lesions does not have symptomatic myeloma and does not need immediate treatment (they have either MGUS or smouldering myeloma and need monitoring). A patient with a paraprotein of 15 g/L but Hb 85 g/L, creatinine 180 μmol/L, calcium 2.8 mmol/L, and lytic bone lesions on imaging has symptomatic myeloma requiring urgent treatment regardless of the paraprotein level. Serum free light chain (FLC) measurement is a key test for plasma cell dyscrasias — it detects myelomas that do not secrete intact immunoglobulin (approximately 15-20% of myelomas produce only free light chains, which are not detected on standard SPEP). An involved:uninvolved ratio ≥100 with an involved FLC of at least 100 mg/L is a myeloma-defining biomarker; lesser abnormalities are common without malignancy, particularly in renal impairment, so an abnormal ratio alone is not diagnostic.

MGUS (Monoclonal Gammopathy of Undetermined Significance) is the most common plasma cell dyscrasia — it is present in approximately 3-4% of adults over 50 and increases to approximately 7% over 75. The vast majority of MGUS patients never develop myeloma — the overall risk of progression from MGUS to myeloma or a related disorder is approximately 1% per year; it varies with Mayo MGUS risk stratification (risk factors: paraprotein ≥15 g/L, non-IgG paraprotein, abnormal serum FLC ratio) — about 5% at 20 years with none of these factors (low-risk MGUS) rising to about 58% at 20 years with all three. The clinical implication: MGUS does not need treatment — it needs monitoring. GPs must understand that an incidentally discovered paraprotein on protein electrophoresis is most likely MGUS and is not a diagnosis of myeloma. The GP's role: arrange haematology referral or advice and guidance for formal MGUS characterisation and risk stratification, then follow the haematology monitoring plan — BSH 2023: bloods at about 6 months, then annual follow-up for many patients, with longer intervals for selected low-risk patients; high-intermediate and high-risk MGUS usually remain under haematology. GP monitoring only where the haematology letter explicitly delegates it.

Bence Jones protein (BJP) testing deserves special attention — the traditional 24-hour urine BJP test (heat precipitation method) is relatively insensitive and is being replaced by: urine immunofixation electrophoresis (uIFE — more sensitive and specific for free light chain detection in urine) and serum free light chain assay (extremely sensitive, detects free light chains in serum that are subsequently excreted in urine). The modern myeloma screen should include both serum immunofixation and serum FLC assay — this detects the large majority of plasma cell dyscrasias without requiring a 24-hour urine collection, although no single test excludes myeloma. The 24-hour urine BJP remains useful for quantifying the degree of light chain excretion (used to monitor treatment response in light-chain myeloma) but is no longer the primary diagnostic test. GPs requesting initial myeloma workup should request: SPEP + immunofixation + serum FLC + FBC + renal function + calcium — this comprehensive screen takes one blood sample and identifies most plasma cell dyscrasias; urine testing is reserved for when serum FLC is unavailable or haematology advises.

The myeloma-defining events (MDEs) are an important update to myeloma diagnosis — prior to 2014, myeloma required CRAB criteria (end-organ damage) to initiate treatment. The 2014 IMWG update introduced three additional trigger points based on biomarkers that predict >80% risk of progression to end-organ damage within 2 years: (1) involved:uninvolved serum FLC ratio ≥100 with an involved FLC of at least 100 mg/L; (2) bone marrow clonal plasma cells ≥60%; (3) >1 focal bone lesion on MRI. These MDEs allow treatment to be initiated before actual end-organ damage develops, improving outcomes. The clinical implication: a patient with 'smouldering myeloma' who has a serum FLC ratio of 150:1 now meets criteria for treatment initiation as 'myeloma with MDE,' even without anaemia, renal impairment, hypercalcaemia, or bone lesions. This is a specialist decision — but GPs should be aware that 'no CRAB criteria' no longer automatically means no treatment for all smouldering myeloma patients.

The AL amyloidosis diagnosis is one of the most frequently delayed and misdiagnosed conditions in medicine — AL amyloid results from the deposition of misfolded immunoglobulin light chain fibrils in organs (heart, kidneys, liver, peripheral nerves, autonomic nervous system, soft tissues). The average time from symptom onset to diagnosis is approximately 2-3 years. The clinical presentations that should prompt a myeloma/amyloid screen: (1) restrictive cardiomyopathy with heart failure without prior cardiac disease (amyloid heart — the most common cause of death in AL amyloid); (2) nephrotic syndrome (heavy proteinuria without haematuria — amyloid kidney); (3) peripheral sensorimotor neuropathy + autonomic dysfunction (amyloid nerves); (4) macroglossia (enlarged tongue — virtually pathognomonic of AL amyloid when present); (5) periorbital bruising (raccoon eyes) from amyloid deposits in facial skin vessels. In any of these presentations, a serum FLC assay + SPEP + immunofixation (amyloid screen) should be performed as part of the diagnostic workup.

The lenalidomide VTE risk is a clinically important prescribing safety concern in myeloma management — lenalidomide (an immunomodulatory drug used in myeloma treatment) in combination with dexamethasone has a venous thromboembolism risk of approximately 15-20% without prophylaxis. Thromboprophylaxis is mandatory during lenalidomide + dexamethasone therapy: a LMWH or a DOAC for higher-risk patients, or aspirin for lower-risk patients, per the haematology protocol (dose per NICE/SPC / specialist). GPs who receive discharge medications for myeloma patients on lenalidomide should ensure: (1) that anticoagulation or antiplatelet prophylaxis is prescribed and the patient is taking it; (2) that the patient knows the symptoms of DVT and PE; (3) that the lenalidomide is on the clinical record with the associated anticoagulation. The contraception requirement for lenalidomide is also critical — lenalidomide is teratogenic (thalidomide analogue), and all men and women of reproductive age receiving it must use effective contraception. In the UK this is managed through the lenalidomide Pregnancy Prevention Programme (MHRA) via the haematology centre, but GPs should be aware of this requirement when reviewing medications.

Spinal cord compression in myeloma is the most devastating acute orthopaedic complication and requires rapid GP recognition — approximately 5-10% of myeloma patients develop spinal cord compression during the course of their disease. The pathology: lytic vertebral lesions weaken vertebral bodies → pathological fracture or direct plasmacytoma extension → compression of the spinal cord or cauda equina. The cardinal symptoms are: new or acutely worsening thoracic or lumbar back pain (particularly if band-like with radiation around the chest wall), leg weakness (bilateral), urinary retention or incontinence, and bowel dysfunction. The safe action: neurological symptoms or signs → immediate MSCC coordinator/acute oncology contact and whole-spine MRI within 24 hours; severe spinal pain without neurology → MSCC advice within 24 hours and whole-spine MRI within 1 week (NICE NG234). The treatment window is narrow — spinal cord injury that has been present for more than 12-24 hours before treatment begins often results in permanent neurological deficit. Dexamethasone 16 mg orally (or equivalent parenteral dose) as soon as possible when MSCC is suspected (NICE NG234) reduces cord oedema; continue only under the specialist pathway, and avoid it before tissue diagnosis where lymphoma is a significant alternative and there is no neurological emergency.

Myeloma UK is the leading UK charity for myeloma patients and GPs should routinely recommend it — the organisation provides exceptional patient education resources, maintains a myeloma specialist nurse helpline, runs patient support groups, advocates for treatment access, and funds research. Their website (myeloma.org.uk) has downloadable condition-specific guides for MGUS, smouldering myeloma, active myeloma, and relapsed myeloma — written by myeloma specialists and reviewed by patients. The specialist nurse helpline (0800 980 3332) provides telephone advice and is particularly valuable for patients who have questions outside of their haematology appointments. GPs who ensure newly diagnosed myeloma and MGUS patients receive this resource at the diagnosis consultation provide a significant quality-of-life benefit.

The MGUS progression monitoring safety net requires specific patient education that is often not given at the time of the MGUS diagnosis — patients must know the symptoms of myeloma progression so they can self-report them between annual monitoring blood tests. The key symptoms: persistent bone pain (particularly back or ribs — lytic bone lesions), unexplained fatigue (anaemia from marrow infiltration), thirst and excessive urination (hypercalcaemia), recurrent infections, leg weakness or numbness (peripheral neuropathy from amyloid, or spinal cord compression). A myeloma patient who develops sudden severe back pain should attend the GP the same day — not wait for the next scheduled appointment; back pain with leg weakness, numbness or bladder or bowel problems needs emergency assessment straight away (999 or A&E). GPs should explicitly tell MGUS patients: 'If you develop significant new bone pain or any of these symptoms between your annual blood tests, please contact us immediately rather than waiting for your next appointment.'