multiple myeloma

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pathophysiology

• clonal proliferation — post-germinal centre plasma cells expand in bone marrow
• protein production — secretion of monoclonal protein (IgG > IgA > light chain only); non-secretory myeloma is rare (~3%)
• bone disease — myeloma cells secrete RANKL $\to$ osteoclast activation + osteoblast inhibition $\to$ lytic lesions and hypercalcaemia
• renal injury:
  • cast nephropathy (most common) — free light chains precipitate in distal tubules
  • hypercalcaemia — vasoconstriction and volume depletion
  • AL amyloidosis — light chain amyloid deposition in glomeruli
• immunoparesis — suppression of normal plasma cells $\to$ functional hypogammaglobulinaemia $\to$ infection risk (especially encapsulated organisms)

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clinical presentation

• bone pain — back and ribs; worse with movement
• constitutional — fatigue, weight loss
• recurrent infections — pneumonia, pyelonephritis
• CRAB features:
  • Calcium elevation
  • Renal insufficiency
  • Anaemia (normocytic, normochromic; marrow replacement ± renal failure)
  • Bone lesions (lytic)

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diagnosis and investigations

screening — the triad

To rule out myeloma, order all three:

1. serum protein electrophoresis (SPEP) — quantifies M-spike
2. serum free light chains (sFLC) — detects light chain myeloma missed by SPEP
3. immunofixation (IFE) — identifies the type of paraprotein (e.g. IgG kappa)

confirmation

• bone marrow aspirate and biopsy:
  • required for diagnosis ($\ge$10% clonal plasma cells)
  • FISH/cytogenetics — essential for risk stratification (del(17p), t(4;14), t(14;16), gain(1q) = high risk)
• 24-hour urine (UPEP) — detects Bence-Jones proteins; assesses renal light chain burden

imaging

• whole-body low-dose CT or PET-CT — gold standard for detecting lytic lesions (Hillengass, Lancet Oncol. 2019)
• MRI — if CT/PET-CT is negative but suspicion remains (detects marrow infiltration before cortical destruction; required to assess SLiM “M” criterion)
• PET-CT — preferred for extramedullary disease and non-secretory myeloma monitoring

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diagnostic criteria

feature	MGUS	smouldering MM	multiple myeloma
M-protein	< 30 g/L	$\ge$ 30 g/L	any amount
marrow plasma cells	< 10%	10–60%	$\ge$ 10% (or plasmacytoma)
end-organ damage	absent	absent	present (CRAB or SLiM)
progression risk	~1%/year	~10%/year	N/A
management	observe	observe (or trial)	treat

defining malignancy — CRAB vs SLiM

Diagnosis of MM requires $\ge$10% clonal plasma cells plus $\ge$1 of:

CRAB (classic end-organ damage):

• C — calcium > 2.75 mmol/L (or > 0.25 above upper limit of normal)
• R — renal: CrCl < 40 mL/min or creatinine > 177 µmol/L
• A — anaemia: Hb < 100 g/L or > 20 g/L below baseline
• B — bone: $\ge$1 lytic lesion on CT, PET-CT, or MRI

SLiM (biomarkers of malignancy):

Patients meeting these criteria have >80% risk of developing CRAB within 2 years — treated as active MM.

• S — sixty: $\ge$60% clonal plasma cells in marrow
• Li — light chains: involved FLC $\ge$ 100 mg/L and ratio $\ge$ 100
• M — MRI: > 1 focal lesion ($\ge$ 5 mm)

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management

transplant eligibility

The first decision. Based on physiologic age and frailty (typically age < 70–75 in Canada).

• eligible: induction $\to$ autologous stem cell transplant (ASCT) $\to$ maintenance
• ineligible: induction (often continuous or longer duration) $\to$ maintenance

induction therapy

Modern therapy uses triplets or quadruplets. Quadruplets are now preferred in current guidelines (Hicks, JCO. 2026).

transplant-eligible:

• first-line: D-VRd (daratumumab (Darzalex) + bortezomib + lenalidomide + dexamethasone) or Isa-VRd (isatuximab (Sarclisa) + VRd)
• alternative: VRd, KRd (carfilzomib + lenalidomide + dexamethasone)

transplant-ineligible:

• first-line: DRd (daratumumab + lenalidomide + dexamethasone), D-VRd, or Isa-VRd for fit patients
• alternative: VRd, KRd, Isa-Rd

adjunctive care

bone protection — for all symptomatic patients (Terpos, Lancet Oncol. 2021):

• bisphosphonates (pamidronate or zoledronic acid) — up to 2 years, then clinical judgement
• denosumab — preferred in renal impairment; requires ongoing maintenance dosing (or a single bisphosphonate dose on discontinuation to prevent rebound)

VTE prophylaxis — required on IMiDs (lenalidomide) (Farge, Lancet Oncol. 2022):

risk-stratify using the SAVED score:

variable	points
Surgery (within 90 days)	+2
Asian race	−3
VTE history	+3
Elderly (age $\ge$ 80)	+1
Dexamethasone: high dose (> 160 mg/30 days)	+2
Dexamethasone: standard dose (120–160 mg/30 days)	+1

• score < 2 (low risk): aspirin 81–325 mg daily
• score $\ge$ 2 (high risk): LMWH, apixaban 2.5 mg BID, rivaroxaban 10 mg daily, or warfarin
• duration: while on IMiD therapy

infection prophylaxis:

• acyclovir — shingles prophylaxis with bortezomib
• vaccinations — influenza, pneumococcal, COVID-19

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emergencies

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special considerations

• transplant timing — early ASCT (upfront) vs delayed (at first relapse) shows equal overall survival with novel agents, but early ASCT improves progression-free survival; early ASCT remains standard (Cowan, JAMA. 2022)
• renal failure — cast nephropathy is classic, but consider AL amyloidosis if patient has albuminuria (dipstick positive) rather than Bence-Jones proteinuria (dipstick negative; requires sulphosalicylic acid test or UPEP)
• peripheral neuropathy — major dose-limiting toxicity of bortezomib; subcutaneous administration reduces risk compared to IV
• MGUS monitoring — low risk (M-protein < 15 g/L, IgG type, normal FLC ratio): monitor every 2–3 years; any risk factor present: bone marrow biopsy, whole-body CT, monitor yearly lifelong (Liu, JAMA Intern Med. 2025)

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related plasma cell dyscrasias

• AL amyloidosis — light chain deposition in organs (renal, cardiac, liver, nerves, GI); diagnosis requires all 4: clonal plasma cell disorder + systemic syndrome + amyloid on biopsy (apple-green birefringence on Congo red) + light chain restriction; treatment similar to myeloma
• Waldenström macroglobulinaemia — lymphoplasmacytic lymphoma + monoclonal IgM; key features include hyperviscosity syndrome, neuropathy, cold agglutinin disease, cryoglobulinaemia; treat with plasmapheresis for hyperviscosity, chemoimmunotherapy with rituximab