Multiple myeloma

Overview

Second most common haematological malignancy in the UK; a plasma cell dyscrasia producing a monoclonal paraprotein (M-protein) causing end-organ damage (CRAB). Median age at diagnosis ~70 years; more common in men and Black African/Caribbean populations.

Investigations

🥇 First-line

•

•FBC - normocytic normochromic anaemia; rouleaux on blood film

•Serum protein electrophoresis (SPEP) + immunofixation - detects M-protein monoclonal spike; identifies heavy and light chain type

•Serum free light chains (kappa/lambda ratio) - sensitive for light-chain and non-secretory disease

•24-hour urine protein electrophoresis - detects Bence-Jones protein

•U&E, calcium, albumin, LDH, beta-2 microglobulin - end-organ damage + staging

•Whole-body low-dose CT (WBLDCT) - preferred skeletal survey (NICE 2016); superior to plain X-rays for lytic lesions

🏆 Gold standard

•Bone marrow trephine biopsy - confirms ≥10% clonal plasma cells; CD138+ on immunohistochemistry; FISH for cytogenetics (del(17p), t(4;14) = high risk)

🥈 Second-line

•MRI spine - investigation of choice for suspected spinal cord compression

Differential Diagnosis

•MGUS - most common cause of incidental paraprotein in older adult; paraprotein <30 g/L, <10% plasma cells, no CRAB

•Waldenström's macroglobulinaemia - IgM paraprotein; lymphadenopathy + hyperviscosity; no lytic bone disease

•Solitary plasmacytoma - single focus of clonal plasma cells without systemic myeloma; treated with radiotherapy

•AL amyloidosis - misfolded light chain deposition; macroglossia, cardiomyopathy, nephrotic syndrome; may coexist with myeloma

•Metastatic bone disease - lytic lesions from breast, lung, kidney, thyroid, prostate; no paraprotein; bone scan shows hot lesions (vs cold in myeloma)

Management

Myeloma is currently incurable in the vast majority; key early decision is eligibility for autologous stem cell transplantation (ASCT), determined by age and fitness.

•Induction therapy (transplant-eligible): VRd - bortezomib (proteasome inhibitor) + lenalidomide (IMiD) + dexamethasone

•Followed by ASCT in eligible patients - improves progression-free survival

•Maintenance: lenalidomide post-ASCT

•Bone protection: zoledronic acid (bisphosphonate) - reduces skeletal events in all patients with active myeloma

•Hypercalcaemia: vigorous IV hydration + bisphosphonates

•VTE prophylaxis: standard with lenalidomide + dexamethasone

🚨

Spinal cord compression = medical emergency. Back pain + neurological deficit (leg weakness, sensory level, urinary retention) → immediate MRI spine + high-dose IV dexamethasone + urgent radiotherapy or surgical decompression. Do not wait for full myeloma workup.

Complications

Key complications

Pathological fractures - vertebral collapse most common

Spinal cord compression - emergency

Renal failure - cast nephropathy; avoid NSAIDs, contrast, dehydration

Infections - leading cause of death; encapsulated organisms + herpes zoster

Hypercalcaemia - IV fluids + bisphosphonates

Hyperviscosity - plasmapheresis urgently

VTE - especially with lenalidomide-based therapy

AL amyloidosis - macroglossia, cardiomyopathy, nephrotic syndrome

Prognosis

•Incurable in the vast majority; relapsing-remitting course

•Median overall survival improved from ~3 years (1990s) to 6-8+ years with modern regimens (proteasome inhibitors, IMiDs, monoclonal antibodies)

•Poor prognostic factors: high R-ISS stage, del(17p)/t(4;14) cytogenetics, poor performance status, renal impairment at diagnosis

•MGUS carries ~1% per year risk of progression to myeloma or related disorder

Pathophysiology (high-yield)

•Clonal plasma cell expansion → massive overproduction of single immunoglobulin (M-protein) + suppression of normal immunoglobulins → hypogammaglobulinaemia → recurrent infections

•RANKL + DKK-1 production → osteoclast activation without osteoblast activity → lytic lesions → hypercalcaemia

•Free light chains filtered → precipitate in renal tubules → cast nephropathy → renal failure

•Bone marrow crowding → suppressed haemopoiesis → normocytic normochromic anaemia

•Paraprotein type: IgG ~55%, IgA ~25%, free light chains only ~20%; free light chains in urine = Bence-Jones proteins

Spectrum of Plasma Cell Dyscrasias

MGUS vs smouldering vs active myeloma

Feature	MGUS	Smouldering myeloma	Active myeloma
Paraprotein	<30 g/L	≥30 g/L or	Any level
Plasma cells (BM)	<10%	10-60%	≥10% + CRAB/SLiM
CRAB features	None	None	Present
Treatment	Observe (~1%/yr risk)	Observe	Required

🎯

SLiM criteria - myeloma-defining events that mandate treatment even without CRAB: Serum free light chain ratio ≥100; cLional bone marrow plasma cells ≥60%; MRI >1 focal lesion ≥5 mm. These predict near-certain organ damage within 2 years.

Presentation - CRAB Criteria

•C - Hypercalcaemia - polydipsia, polyuria, constipation, confusion ('bones, stones, groans, thrones'); from osteoclast-driven bone resorption

•R - Renal impairment - cast nephropathy from light chain precipitation; may be asymptomatic

•A - Anaemia - normocytic normochromic; fatigue, breathlessness

•B - Bone lesions - most common symptom (~70%); axial back pain, lytic lesions, pathological fractures including vertebral collapse

•Recurrent infections - especially bacterial (pneumonia, UTI); due to hypogammaglobulinaemia

•Hyperviscosity - headache, visual disturbance, confusion, mucosal bleeding; especially with IgA or high IgG

•Neurological - spinal cord compression (back pain + radiculopathy/myelopathy), peripheral neuropathy

💡

Suspect myeloma in any patient >50 years with unexplained back pain + raised ESR, unexplained hypercalcaemia, or renal impairment with proteinuria. A raised total protein with low albumin (reverse albumin-globulin ratio) is a classic clue.

Staging - Revised ISS (R-ISS)

R-ISS staging

Stage	Criteria	Prognosis
Stage I	Beta-2 microglobulin <3.5 mg/L + albumin ≥35 g/L + standard-risk cytogenetics + normal LDH	Best
Stage II	Neither Stage I nor Stage III	Intermediate
Stage III	Beta-2 microglobulin ≥5.5 mg/L + high-risk cytogenetics [del(17p), t(4;14), t(14;16)] OR elevated LDH	Poorest