Key Facts

Multiple myeloma is a haematological malignancy characterised by clonal proliferation of plasma cells in the bone marrow, producing a monoclonal immunoglobulin (paraprotein). It causes a constellation of features including bone destruction, renal failure, anaemia, and immunosuppression.

Epidemiology

• Approximately 5,900 new cases per year in the UK
• Median age at diagnosis: 70 years
• More common in males (M:F ratio 1.5:1)
• 2-3 times more common in Black African/Caribbean populations
• Incidence is rising due to ageing population and improved detection

Aetiology

• Exact cause unknown; virtually all cases preceded by MGUS → smouldering myeloma → active myeloma
• Risk factors: increasing age, male sex, Black ethnicity, family history, obesity, prior MGUS
• MGUS progresses to myeloma at a rate of approximately 1% per year
• Genetic abnormalities: t(4;14), t(14;16), del(17p) confer high-risk disease

Pathophysiology

• Clonal plasma cells proliferate in the bone marrow and produce monoclonal immunoglobulin (paraprotein/M-protein)
• Bone destruction: myeloma cells activate osteoclasts (via RANKL) and inhibit osteoblasts → lytic lesions, pathological fractures, hypercalcaemia
• Renal impairment: light chain deposition, hypercalcaemia, hyperuricaemia, amyloidosis, cast nephropathy
• Anaemia: marrow infiltration, chronic disease, renal impairment
• Immunoparesis: suppression of normal immunoglobulins → recurrent infections
• Hyperviscosity: rare, more common in IgA myeloma and Waldenström macroglobulinaemia

Bone Disease

• Bone pain (most common presenting symptom, ~70%) – especially back and ribs
• Pathological fractures – vertebral compression fractures, long bone fractures
• Spinal cord compression – oncological emergency

Systemic Features

• Fatigue and lethargy (anaemia)
• Recurrent infections (immunoparesis) – pneumonia, UTIs
• Weight loss

Renal Disease

• Present in 20-30% at diagnosis
• May present as AKI or CKD
• Myeloma kidney (cast nephropathy) – most common cause

Hypercalcaemia

• Confusion, constipation, polyuria, polydipsia, nausea
• Present in ~30% at diagnosis

Hyperviscosity Syndrome (rare)

• Visual disturbance, headache, mucosal bleeding, confusion

Red Flags

• Spinal cord compression: back pain with leg weakness, saddle anaesthesia, urinary retention → MRI spine within 24 hours
• Hypercalcaemia with confusion → medical emergency
• Neutropenic sepsis during treatment
• Acute renal failure with disproportionately raised urea/creatinine

Bedside

• Urine dipstick: may be negative (Bence Jones protein not detected by standard dipstick)
• ECG: hypercalcaemia (short QT), hyperkalaemia

Bloods

• FBC: normocytic normochromic anaemia, may show rouleaux on blood film
• U&Es: renal impairment, raised calcium
• Bone profile: hypercalcaemia, raised ALP (if fractures)
• Serum protein electrophoresis (SPEP): M-protein band
• Serum free light chains (sFLC): kappa/lambda ratio (abnormal ratio confirms clonality)
• Serum immunoglobulins: immunoparesis (low uninvolved Ig classes)
• Beta-2 microglobulin: prognostic marker (ISS staging)
• LDH and albumin: for staging
• Blood film: rouleaux formation
• ESR: markedly elevated (often >100 mm/h)
• Serum viscosity: if hyperviscosity suspected

Imaging

• Whole-body low-dose CT (preferred over skeletal survey per NICE NG35) – detects lytic lesions
• MRI whole spine: if spinal cord compression suspected
• PET-CT: for solitary plasmacytoma or suspected extramedullary disease

Special Tests

• Bone marrow aspirate and trephine: ≥10% clonal plasma cells confirms diagnosis; cytogenetics/FISH for risk stratification
• Urine Bence Jones protein: urine protein electrophoresis for light chains
• 24-hour urine protein: quantify proteinuria

Non-pharmacological

• MDT discussion at specialist haematology centre
• Adequate hydration: ≥3L/day to prevent renal complications
• Avoid nephrotoxic drugs: NSAIDs, aminoglycosides, IV contrast with caution
• Spinal precautions if vertebral disease
• Psychological support and patient education

Pharmacological

First-line (transplant-eligible, typically <70 years):

• Induction: VRd regimen – bortezomib 1.3 mg/m² SC (days 1, 4, 8, 11) + lenalidomide 25mg OD (days 1-14) + dexamethasone 40mg weekly × 4-6 cycles
• Followed by autologous stem cell transplant (ASCT)
• Lenalidomide maintenance 10mg OD until progression

First-line (transplant-ineligible):

• VRd (dose-attenuated) or VMP (bortezomib, melphalan, prednisolone)
• Daratumumab-VMP (ALCYONE trial) or Daratumumab-Rd (MAIA trial) now standard

Supportive care:

• Zoledronic acid 4mg IV monthly for bone protection (continue for 2 years minimum)
• Erythropoietin for anaemia if Hb <100 g/L
• Prophylactic aciclovir 400mg BD (VZV reactivation with bortezomib)
• Thromboprophylaxis: aspirin 75mg OD or LMWH with lenalidomide/thalidomide
• IV immunoglobulin replacement if recurrent infections with low IgG

Relapsed disease:

• Carfilzomib, pomalidomide, isatuximab, elotuzumab, selinexor, CAR-T therapy (ide-cel, cilta-cel)

Referral Criteria

• All suspected myeloma → urgent 2-week-wait haematology referral
• Spinal cord compression → emergency oncology/neurosurgery
• Acute renal failure → nephrology

• Median overall survival: 5-7 years with modern therapy
• Transplant-eligible patients: median survival 7-10 years
• High-risk cytogenetics [t(4;14), del(17p), t(14;16)]: median survival 2-3 years
• ISS Stage I (β2M <3.5, albumin ≥35): median survival 62 months
• ISS Stage III (β2M ≥5.5): median survival 29 months
• R-ISS now incorporates cytogenetics and LDH for improved prognostication
• 10-year survival approximately 30% overall

International Staging System (ISS)

CRAB Criteria for End-Organ Damage

Landmark Trials