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Multiple myeloma
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Exam Tips
- Use SLiM-CRAB framing: biomarkers (>=60% clonal marrow plasma cells, free light-chain ratio >=100 with involved light chain >=100 mg/L, >1 focal MRI lesion) or classic end-organ damage (hyperCalcaemia, Renal impairment, Anaemia, Bone lesions).
- In OSCE/viva, state immediate admission indications: suspected spinal cord compression, significant hypercalcaemia, or AKI.
- Remember non-secretory myeloma exists, so negative electrophoresis does not fully exclude disease if clinical suspicion remains high.
- Back pain plus anaemia/raised ESR/renal dysfunction in older adults should trigger myeloma blood tests and urgent haematology referral.
- Differentiate from Waldenstrom: IgM paraprotein with hyperviscosity and lymphadenopathy/organomegaly is more typical of Waldenstrom than classic myeloma.
Definition
Multiple myeloma is a malignant plasma-cell disorder in which a clonal population expands within bone marrow and produces a monoclonal immunoglobulin (or light chains), causing progressive end-organ injury. It is usually preceded by MGUS and may pass through a smouldering phase before symptomatic disease with myeloma-defining events (classically CRAB features or specific biomarker criteria).
Pathophysiology
Genetically abnormal post-germinal-centre plasma cells clonally proliferate in the marrow microenvironment and secrete monoclonal protein (M-protein) and/or free light chains. Cytokine signalling (including IL-6 and RANKL pathway activation) drives osteoclast activity and suppresses osteoblasts, producing lytic bone disease, pain, fractures, and hypercalcaemia; light chains precipitate in renal tubules (cast nephropathy), causing AKI/CKD. Marrow infiltration and inflammatory effects cause normocytic anaemia and immunoparesis, increasing infection risk; high paraprotein burden can cause hyperviscosity. See Figure: plasma-cell/osteoclast interaction and CRAB organ damage diagram in standard haematology texts.
Risk Factors
- Increasing age (incidence rises from around 50 years; many diagnoses occur at 75 years and over)
- Male sex
- Black ethnicity (higher risk than White or Asian populations)
- Family history of myeloma or MGUS (especially first-degree relative)
- MGUS (progression risk about 1% per year)
- Smouldering myeloma (higher early progression risk, especially first 5 years)
- Obesity/overweight
- Autoimmune disease association (for example pernicious anaemia)
- Occupational/environmental exposures (for example firefighting, dioxin, Agent Orange)
Clinical Features
Symptoms
- Persistent unexplained bone pain, often back or thoracic
- Fatigue and reduced exercise tolerance
- Weight loss
- Symptoms of hypercalcaemia (constipation, thirst, polyuria, confusion, abdominal pain, weakness)
- Recurrent infections (especially respiratory)
- Hyperviscosity symptoms (headache, visual disturbance, mucosal bleeding, cognitive slowing, breathlessness)
- Red-flag symptoms of spinal cord compression (weakness, sensory change, gait difficulty, sphincter disturbance)
Signs
- May be normal early on
- Pallor from anaemia
- Bony tenderness or pathological fracture
- Dehydration/confusion in hypercalcaemia
- Neurological deficits or spinal tenderness/deformity if cord compression
- Occasional hepatomegaly, splenomegaly, or lymphadenopathy
Investigations
Full blood count:Normocytic, normochromic anaemia is common; leukopenia may occur
Urea, creatinine, electrolytes, eGFR:Renal impairment/AKI from light-chain nephropathy or dehydration
Corrected serum calcium:Hypercalcaemia from osteolysis (severe hypercalcaemia is an admission trigger)
ESR or plasma viscosity:Often raised; supports suspicion with compatible symptoms
Serum protein electrophoresis with immunofixation:Monoclonal paraprotein (M-spike); may be negative in non-secretory myeloma
Serum free light chains and ratio:Involved free light chain elevation and abnormal ratio; very high ratio is myeloma-defining biomarker
Urine Bence-Jones protein (urine electrophoresis/immunofixation):Monoclonal light chains in urine
Peripheral blood film:Rouleaux formation may be seen with paraproteinaemia
Imaging (whole-body low-dose CT or MRI; X-ray of painful sites if needed):Lytic lesions, osteopenia, fractures, vertebral collapse, possible cord compression
Bone marrow aspirate/trephine with cytogenetics:Clonal plasma cells (typically >=10%) confirming plasma-cell neoplasm
Beta-2 microglobulin, albumin, LDH:Used for risk stratification/staging; higher beta-2 microglobulin implies poorer prognosis
Management
Lifestyle Modifications
- Urgent same-day assessment for spinal cord compression symptoms; avoid delay for outpatient workup
- Hydration advice (unless contraindicated), sick-day renal protection, and prompt treatment of intercurrent infection
- Bone protection measures: falls risk reduction, physiotherapy, mobility aids, and smoking/alcohol risk-factor modification
- Vaccination strategy (inactivated influenza, pneumococcal, COVID-19 as appropriate) and infection-prevention counselling
- Early palliative/supportive care input for pain, fatigue, and psychosocial needs
Pharmacological Treatment
Acute hypercalcaemia and renal-protective supportive care
- Sodium chloride 0.9% IV (rehydration, rate individualized to volume status/comorbidity)
- Zoledronic acid 4 mg IV single dose over at least 15 minutes after rehydration (adjust/avoid in significant renal impairment)
Admit urgently for moderate-severe hypercalcaemia or AKI. Monitor fluid balance closely (heart failure risk), U&Es, calcium, and renal function.
Myeloma bone disease modification
- Zoledronic acid 4 mg IV every 3-4 weeks
- Pamidronate disodium 90 mg IV infusion every 4 weeks (alternative)
Check renal function before each dose; risk of osteonecrosis of jaw, so arrange dental assessment and avoid invasive dental procedures when possible.
Analgesia (stepwise, individualized)
- Paracetamol 1 g orally every 4-6 hours when required (maximum 4 g/day)
- Morphine sulfate immediate-release 5-10 mg orally every 4 hours when required (opioid-naive adults; titrate carefully)
Avoid or minimize NSAIDs because of nephrotoxicity risk in myeloma/AKI. With opioids, prescribe laxative and monitor sedation/respiratory depression.
Disease-directed systemic therapy (specialist haematology)
- Bortezomib-based combinations (for example with dexamethasone and an IMiD/alkylator, protocol-dependent)
- Lenalidomide-based regimens and maintenance in selected patients
- High-dose melphalan with autologous stem-cell transplant in eligible patients
Regimens are stage-, fitness-, cytogenetic-, and line-of-therapy-specific. Key safety issues: teratogenicity (lenalidomide/thalidomide pregnancy-prevention programme), peripheral neuropathy risk (bortezomib/thalidomide), and increased VTE risk with IMiDs plus steroids (requires thromboprophylaxis assessment).
Surgical / Interventional
- Orthopaedic fixation for impending or actual pathological long-bone fracture
- Vertebroplasty or kyphoplasty for selected painful vertebral compression fractures
- Neurosurgical/orthopaedic spinal decompression when mechanical instability or cord compression requires operative management
Complications
- Pathological fractures from osteolytic bone disease
- Spinal cord compression
- Acute and chronic kidney injury (cast nephropathy/light-chain related)
- Hypercalcaemia
- Recurrent and severe infections due to immunoparesis
- Anaemia and marrow failure features
- Bleeding or thrombosis from haemostatic abnormalities
- Peripheral neuropathy (disease- or treatment-related)
Prognosis
Multiple myeloma is generally treatable but not usually curable, with a relapsing-remitting course and progressively shorter responses over time. Outcomes have improved substantially with modern therapy and supportive care; UK data indicate roughly 84.5% 1-year survival and about 57% 5-year survival, but prognosis is worse with advanced stage, older age, renal impairment, marked anaemia, hypercalcaemia, high beta-2 microglobulin, and extensive bone disease.
Sources & References
🏥BMJ Best Practice(2)
💊BNF Drug References(14)
- Calcium polystyrene sulfonate[contraindications]
- Carfilzomib [Specialist drug][management.pharmacological]
- Daratumumab[management.pharmacological]
- Elotuzumab [Specialist drug][management.pharmacological]
- Elranatamab [Specialist drug][management.pharmacological]
- Isatuximab [Specialist drug][management.pharmacological]
- Ixazomib [Specialist drug][management.pharmacological]
- Melphalan [Specialist drug][management.pharmacological]
- Panobinostat [Specialist drug][management.pharmacological]
- Pomalidomide [Specialist drug][management.pharmacological]
- Selinexor [Specialist drug][management.pharmacological]
- Talquetamab [Specialist drug][management.pharmacological]
- Teclistamab [Specialist drug][management.pharmacological]
- Thalidomide [Specialist drug][management.pharmacological]
✅NICE Guidelines(1)
- Multiple myeloma[overview]
📖Textbook References(20)
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1409)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1410)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1409, 1410)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1410)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1332)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1113, 1114)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1112, 1113)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 991, 992)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1838)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 877, 878)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1407)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1821)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1409, 1410)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 263)[context]
- David Randall PhD MRCP (Editor), John Booth PhD MRCP (Editor), K - Kumar and Clark's Clinical Medicine (2025, American Elsevier Publishing Co.) - libgen.li.pdf(pp. 1113, 1114)[context]
- [Williams, Bailey and Love's Short Practice of Surgery] Norman Williams, Christopher Bulstrode, P Ronan O'Connell - Bailey & Love's Short Practice of Surgery 26E (2013, CRC Press) - libgen.li.pdf(pp. 1223)[context]
- [Williams, Bailey and Love's Short Practice of Surgery] Norman Williams, Christopher Bulstrode, P Ronan O'Connell - Bailey & Love's Short Practice of Surgery 26E (2013, CRC Press) - libgen.li.pdf(pp. 546, 547)[context]
- [Williams, Bailey and Love's Short Practice of Surgery] Norman Williams, Christopher Bulstrode, P Ronan O'Connell - Bailey & Love's Short Practice of Surgery 26E (2013, CRC Press) - libgen.li.pdf(pp. 544, 545)[context]
- [Williams, Bailey and Love's Short Practice of Surgery] Norman Williams, Christopher Bulstrode, P Ronan O'Connell - Bailey & Love's Short Practice of Surgery 26E (2013, CRC Press) - libgen.li.pdf(pp. 544)[context]
- [Williams, Bailey and Love's Short Practice of Surgery] Norman Williams, Christopher Bulstrode, P Ronan O'Connell - Bailey & Love's Short Practice of Surgery 26E (2013, CRC Press) - libgen.li.pdf(pp. 490)[context]