Medicine chapters
Multiple myeloma
A cancer of bone marrow plasma cells that makes a monoclonal paraprotein and causes high calcium, kidney damage, anaemia and lytic bone lesions (CRAB).
- Myeloma is a malignant clone of plasma cells in the marrow that secretes a monoclonal paraprotein (usually IgG, then IgA) and unbound light chains (Bence Jones protein).
- Remember CRAB: hyperCalcaemia, Renal impairment, Anaemia, Bone lytic lesions; plus infections, high ESR and rouleaux.
- Diagnose with marrow clonal plasma cells ≥10% plus a myeloma-defining event; treat with combination therapy (e.g. bortezomib, thalidomide or lenalidomide, dexamethasone) and autologous stem cell transplant in fit patients.
On this page
Overview
Multiple myeloma is a plasma cell cancer that grows within the bone marrow. The clone makes a single, useless immunoglobulin (the paraprotein or M band) and excess unbound light chains.
It is mainly a disease of older people (median age over 60; rare under 40), more common in men and in people of African descent. It is the commonest primary malignant tumour of bone (metastases are still commoner overall).
It is incurable for most patients, but modern drug combinations have greatly improved survival.
Pathophysiology: why each feature happens
| Mechanism | Result |
|---|---|
| Plasma cells crowd the marrow | Anaemia, later neutropenia and low platelets |
| Myeloma cells activate osteoclasts (via RANK ligand; IL-6 supports growth) and suppress osteoblasts | Lytic lesions, bone pain, fractures, hypercalcaemia |
| Paraprotein in plasma | High ESR, rouleaux, raised total protein, rarely hyperviscosity |
| Normal immunoglobulins suppressed (immune paresis) | Recurrent infections (commonest cause of death) |
| Unbound (excess) light chains filtered by the kidney | Bence Jones proteinuria, cast nephropathy ("myeloma kidney"), AL amyloidosis |
Because osteoblasts are not activated, the alkaline phosphatase is usually normal and an isotope bone scan is often negative, even with widespread lytic lesions.
Paraprotein types
- IgG about 55%, IgA about 20%; IgM and IgD rare.
- About 15% are light chain only (Bence Jones myeloma); about 5% are non-secretory.
Clinical presentation
- Bone pain, most often backache from vertebral involvement; pathological fractures; vertebral collapse with loss of height.
- Anaemia: tiredness, pallor.
- Recurrent infections, especially chest infections.
- Renal impairment: may be the first sign.
- Hypercalcaemia: thirst, polyuria, constipation, vomiting, confusion ("bones, stones, groans and moans").
- Hyperviscosity (uncommon in myeloma; more typical of IgM): headache, blurred vision, confusion, bleeding.
- Spinal cord compression from a soft-tissue plasmacytoma or vertebral collapse.
- Some are found only by a high ESR or raised total protein on routine tests.
CRAB = Calcium up, Renal failure, Anaemia, Bone lesions.
Laboratory investigations
| Test | Finding |
|---|---|
| Full blood count | Normocytic normochromic anaemia; WBC and platelets normal or low |
| ESR | Very high (paraprotein) |
| Blood film | Rouleaux (red cells stacked like coins); circulating plasma cells in plasma cell leukaemia |
| Total protein | Normal or raised; albumin may be low |
| Serum protein electrophoresis + immunofixation | A sharp monoclonal band (M spike) in the gamma region, and low normal immunoglobulins |
| Serum light chain (FLC) assay | Abnormal kappa:lambda ratio |
| Urine electrophoresis | Bence Jones protein (unbound light chains) |
| Calcium | Normal or raised |
| Alkaline phosphatase | Usually normal |
| Urea and creatinine | May be raised |
| β2-microglobulin, albumin, LDH | For staging and prognosis |
| Bone marrow aspirate/trephine | Clonal plasma cells (kappa or lambda restricted) — key test |
| Imaging | Low-dose whole-body CT, PET-CT or whole-body MRI show lytic lesions; plain films show punched-out lesions in the skull ("pepper-pot skull"); MRI spine for back pain or cord compression |
Bence Jones protein is not picked up by the ordinary urine dipstick for protein (which detects albumin). It needs urine electrophoresis or a serum light chain (FLC) test.
A plain skeletal survey is less sensitive than CT or MRI, and an isotope bone scan may be normal. Do not use a bone scan to exclude myeloma.
Diagnostic criteria
Active (symptomatic) myeloma needs clonal plasma cells ≥10% in the marrow (or a biopsy-proven plasmacytoma) plus at least one myeloma-defining event:
CRAB (end-organ damage):
- Calcium: above 2.75 mmol/L.
- Renal: creatinine above 177 µmol/L or clearance below 40 mL/min.
- Anaemia: Hb below 100 g/L, or more than 20 g/L below normal.
- Bone: one or more lytic lesions of at least 5 mm on X-ray, CT or PET-CT.
Biomarkers (high risk even without CRAB):
- Marrow clonal plasma cells ≥60%.
- Involved:uninvolved serum light chain (FLC) ratio ≥100.
- More than one focal lesion on MRI.
A paraprotein alone does not make the diagnosis of myeloma. You need marrow plasma cells and end-organ damage (or a biomarker).
MGUS, smouldering and active myeloma
| Feature | MGUS | Smouldering myeloma | Active myeloma |
|---|---|---|---|
| Marrow clonal plasma cells | Under 10% | 10-60% | 10% or more |
| Paraprotein | Small (under 30 g/L) | IgG or IgA 30 g/L or more (and/or marrow 10-60%) | Any |
| End-organ damage / biomarkers | None | None | Present |
| Risk of progression | About 1% per year | About 10% per year | — |
| Management | Monitor | Close monitoring | Treat |
Staging and prognosis
The International Staging System (ISS) uses serum β2-microglobulin and albumin:
- Stage I: β2M under 3.5 mg/L and albumin 35 g/L or more.
- Stage III: β2M 5.5 mg/L or more.
- Stage II: neither I nor III.
The revised ISS adds LDH and high-risk genetics (del(17p), t(4;14), t(14;16)). Hyperdiploidy is favourable.
β2-microglobulin 6.1 mg/L, albumin 30 g/L
β2M is 5.5 mg/L or more → ISS stage III
(Stage I would need β2M below 3.5 and albumin 35 or more)
Treatment
Supportive care (and emergencies)
| Problem | Management |
|---|---|
| Hypercalcaemia | IV saline first, then an IV bisphosphonate (pamidronate or zoledronic acid); steroids help |
| Renal impairment | Fluids, correct calcium, stop NSAIDs and nephrotoxins, treat the myeloma quickly; dialysis if needed |
| Spinal cord compression | Urgent MRI, high-dose dexamethasone, then radiotherapy (or surgery) |
| Hyperviscosity | Plasmapheresis; transfuse slowly |
| Bone pain | Analgesia (avoid NSAIDs), radiotherapy, long-term bisphosphonate |
| Fractures | Orthopaedic fixation; vertebroplasty or kyphoplasty |
| Anaemia | Transfusion; erythropoietin |
| Infection | Prompt antibiotics; vaccination |
Long-term bisphosphonates (e.g. zoledronic acid) reduce fractures, cord compression and bone pain. Watch for osteonecrosis of the jaw.
NSAIDs are avoided in myeloma because they worsen kidney injury.
Specific (anti-myeloma) therapy
Drugs are used in combinations (for example bortezomib, thalidomide and dexamethasone):
| Class | Examples | Note |
|---|---|---|
| Steroids | Dexamethasone, prednisolone | Part of most regimens |
| Proteasome inhibitors | Bortezomib (subcutaneous), carfilzomib, ixazomib | Bortezomib: peripheral neuropathy |
| Immunomodulatory drugs | Thalidomide, lenalidomide, pomalidomide | Risk of venous thrombosis; thalidomide is teratogenic |
| Alkylating agents | Melphalan, cyclophosphamide | High-dose melphalan before stem cell transplant |
| Monoclonal antibodies | Daratumumab (anti-CD38), elotuzumab | Used in combinations |
- Autologous stem cell transplant after induction in younger, fit patients prolongs remission and survival.
- Relapse is expected; each later remission tends to be shorter.
Complications
- Infections (immune paresis, neutropenia, treatment).
- Acute kidney injury: cast nephropathy, hypercalcaemia, dehydration, NSAIDs, contrast, AL amyloid.
- Pathological fractures, vertebral collapse, cord compression.
- AL amyloidosis: heart failure, nephrotic syndrome, macroglossia, neuropathy, carpal tunnel.
- Hyperviscosity; bleeding.
- Acquired Fanconi syndrome (proximal tubular damage from light chains).
Quick revision
- Plasma cell clone → paraprotein (IgG > IgA) + excess unbound light chains (Bence Jones).
- CRAB: calcium, renal, anaemia, bone.
- High ESR, rouleaux, M spike, punched-out lesions.
- ALP normal; isotope bone scan often negative; CT/MRI better than plain films.
- Diagnosis: marrow plasma cells ≥10% + CRAB or biomarker (≥60% plasma cells, light chain ratio ≥100, more than one MRI lesion).
- MGUS: under 10% plasma cells, no damage, about 1% per year progress.
- Hypercalcaemia: IV saline then bisphosphonate; cord compression: dexamethasone + radiotherapy; hyperviscosity: plasmapheresis.
- Avoid NSAIDs; infection is the commonest cause of death.
- Treatment: bortezomib + thalidomide/lenalidomide + dexamethasone; autologous transplant if fit.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Pathoma: Fundamentals of Pathology).
FAQ
Why is the alkaline phosphatase normal in myeloma?
Myeloma stimulates osteoclasts but suppresses osteoblasts, and alkaline phosphatase comes from osteoblast activity, so it usually stays normal.
What is Bence Jones protein?
It is the excess unbound immunoglobulin light chain (kappa or lambda) made by the plasma cell clone and passed in the urine.
Is a paraprotein enough to diagnose myeloma?
No. Myeloma also needs clonal plasma cells of at least 10% in the marrow plus end-organ damage or a high-risk biomarker; a paraprotein alone may be MGUS.
What causes kidney failure in myeloma?
Mainly light chains blocking the tubules (cast nephropathy), helped by hypercalcaemia, dehydration, NSAIDs and sometimes amyloid.
What is the first step for hypercalcaemia in myeloma?
Rehydration with intravenous saline, followed by an intravenous bisphosphonate such as zoledronic acid or pamidronate.