multiple myeloma

multiple myeloma

A clonal plasma cell malignancy characterized by the overproduction of monoclonal immunoglobulin (M-protein) or light chains, resulting in classic end-organ damage (CRAB) or high-risk biomarkers (SLiM).

pathophysiology

• Clonal Proliferation: Post-germinal centre plasma cells proliferate in bone marrow.
• Protein Production: Secretion of monoclonal protein (IgG > IgA > Light Chain only) or non-secretory (rare).
• Bone Disease: Myeloma cells secrete RANKL $\to$ osteoclast activation + osteoblast inhibition $\to$ lytic lesions/hypercalcaemia.
• Renal Injury:
  • Cast Nephropathy: Free light chains (FLC) precipitate in distal tubules (most common).
  • Hypercalcaemia: Vasoconstriction/diuresis.
  • Amyloidosis: AL amyloid deposition in glomeruli.
• Immunoparesis: Suppression of normal plasma cells $\to$ functional hypogammaglobulinaemia $\to$ infection risk (encapsulated organisms).

clinical presentation

• Bone Pain: Back/ribs; worse with movement.
• Constitutional: Fatigue, weight loss.
• Recurrent Infections: Pneumonia, pyelonephritis.
• “CRAB” Features:
  • Calcium elevation (symptomatic or incidental).
  • Renal insufficiency.
  • Anaemia (normocytic, normochromic; marrow replacement + renal failure).
  • Bone lesions (lytic).

diagnosis & investigations

1. screening (the triad)

To rule out MM, order ALL THREE:

1. Serum Protein Electrophoresis (SPEP): Quantifies M-spike (paraprotein).
2. Serum Free Light Chain (sFLC): Measures Kappa/Lambda ratio (detects light chain myeloma missed by SPEP).
3. Immunofixation (IFE): Identifies the type of protein (e.g., IgG Kappa).

the "normal" spep

20% of myelomas are Light Chain Only. These patients may have a normal or hypogammaglobulinaemic SPEP (no M-spike) but a massively deranged sFLC ratio. If you suspect MM and only order an SPEP, you will miss 1 in 5 cases.

2. confirmation

• Bone Marrow Aspirate/Biopsy:
  • Required for diagnosis ($\ge$10% clonal plasma cells).
  • FISH/Cytogenetics: Essential for risk stratification (e.g., del(17p), t(4;14), gain(1q) = High Risk).
• 24-hr Urine (UPEP): Detects Bence-Jones proteins; assesses renal risk.

3. imaging

• Low-Dose Whole Body CT (LDCT): The gold standard for screening lytic lesions.
• MRI: Used if CT is negative but suspicion remains high (detects marrow infiltration before cortical destruction).
• PET-CT: Preferred for extramedullary disease or non-secretory monitoring.

Skeletal survey

Largely obsolete. It requires >30% bone loss for visualisation. A “negative skeletal survey” does NOT rule out bone disease.

diagnostic criteria & differential

Feature	MGUS	Smoldering MM (SMM)	Multiple Myeloma (MM)
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% per year	10% per year	N/A (Already Malignant)
Management	Observe	Observe (or trial)	Treat

defining malignancy: CRAB vs SLiM

Diagnosis of MM requires $\ge$10% clonal plasma cells PLUS one of the following:

1. Classic End-Organ Damage (CRAB)

• C: Calcium $>2.75$ mmol/L (or $>0.25$ above ULN).
• R: Renal (CrCl $<40$ mL/min or Cr $>177$ µmol/L).
• A: Anaemia (Hb $<100$ g/L or $>20$ g/L below baseline).
• B: Bone lesions ($\ge 1$ lytic lesion on CT/PET/MRI).

2. Biomarkers of Malignancy (SLiM Criteria) Patients with these findings have >80% risk of developing CRAB within 2 years; treated as active MM.

• S: Sixty percent ($\ge 60$) clonal plasma cells in marrow.
• Li: Involved Light Chain $\ge 100$ mg/L and Light chain ratio $\ge 100$.
• M: MRI showing $>1$ focal lesion ($\ge 5$mm).

management principles

1. transplant eligibility

The first decision node. 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.

2. induction therapy (the standard of care)

Modern therapy uses “Triplets” or “Quadruplets.”

• Backbone: Corticosteroid (Dexamethasone) + Proteasome Inhibitor (Bortezomib) + IMiD (Lenalidomide).
• Recent Advance (Quadruplets): Addition of anti-CD38 monoclonal antibody (Daratumumab) to the backbone (e.g., D-VRd) significantly improves depth of response (MRD negativity) and progression-free survival.

3. adjunctive care

• Bone Protection: Bisphosphonates (Pamidronate or Zoledronic Acid) or Denosumab for all symptomatic patients.
• VTE Prophylaxis: Required for patients on IMiDs (Lenalidomide). Aspirin or LMWH/DOAC depending on risk score (SAVED score).
• Infection Prophylaxis: Acyclovir (shingles prophylaxis with Bortezomib), Flu/Pneumococcal/COVID vaccines.

emergencies & complications

spinal cord compression

• Back pain + Neuro findings = Medical Emergency.
• Dx: Urgent MRI Spine (entire spine).
• Tx: High-dose Dexamethasone + Urgent Radiation Oncology consult (or Neurosurgery if instability/bony retropulsion).

hyperviscosity syndrome

• Seen in IgM (Waldenström) or high-load IgA/IgG MM.
• Sx: Mucosal bleeding, blurry vision (“sausage linking” of retinal veins), dyspnoea, confusion.
• Tx: Plasmapheresis (Avoid red cell transfusion prior to pheresis; increases viscosity).

acute kidney injury (myeloma kidney)

• Precipitated by dehydration, NSAIDs, contrast.
• Tx: Aggressive hydration to washout light chains, avoid nephrotoxins, treat hypercalcaemia. High-dose Dexamethasone helps reduce light chain load rapidly.

special considerations

• Transplant Timing: Early ASCT (upfront) vs. Delayed ASCT (at first relapse) shows equal Overall Survival in the era of novel agents, but Early ASCT improves Progression-Free Survival. In Canada, early ASCT remains standard for eligible patients.
• Renal Failure: Light chain cast nephropathy is the classic mechanism, but consider AL Amyloidosis if patient has albuminuria (dipstick positive) rather than Bence-Jones proteinuria (dipstick negative, requires sulphosalicylic acid test/UPEP).
• Peripheral Neuropathy: A major dose-limiting toxicity of Bortezomib (proteasome inhibitor). Subcutaneous administration has reduced this risk compared to IV.