Harvey's Garden

Multiple myeloma

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4 min read

Epidemiology

Etiology

Pathophysiology

  • Neoplastic proliferation of plasma cells
    • Bone marrow infiltration by malignant plasma cells → suppression of hematopoiesis → leukopenia, thrombocytopenia, anemia
    • Cell proliferation → pro-osteoclastogenic factors (e.g., TNF-α, IL-1, RANK-L) → osteolytic lesions → hypercalcemia
  • Overproduction of monoclonal immunoglobulin and/or light chains → dysproteinemia (a state of pathologically increased synthesis of immunoglobulins and/or their subunits) → kidney damage (e.g., myeloma cast nephropathy) and/or paraprotein tissue deposition (may cause amyloidosis)
    • Nonfunctioning antibodies → functional antibody deficiency
    • ↑ Serum viscosity → hyperviscosity syndrome

Warning

Hypercalcemia in MM is not related to PTHrP!

Clinical features

  • Often asymptomatic
  • Bone pain, especially back pain (most common symptom)
  • Symptoms of hypercalcemia, e.g. constipation
  • Foamy urine (caused by Bence Jones proteins in urine)

Mnemonic

hyperCalcemia, Renal insufficiency, Anemia, Bone lytic lesions

Diagnostics

  • Initial / Screening:
    • SPEP (Serum Protein Electrophoresis) & UPEP (Urine Protein Electrophoresis) with Immunofixation: Demonstrates monoclonal paraprotein spike (M-spike).
    • Serum Free Light Chain (SFLC) Assay: Quantifies kappa/lambda light chain ratio (highly sensitive).
    • Urinalysis vs. 24-hr Urine Total Protein:
      • Standard U/A dipstick is negative or trace for protein (dipstick detects only albumin, not Bence-Jones light chains).
      • 24-hr urine protein is markedly elevated (detects Bence-Jones proteins).
    • Peripheral Blood Smear: Rouleaux formation (RBC stacking due to elevated serum paraprotein neutralizing negative RBC charges).
  • Key Labs:
    • CBC: Normocytic, normochromic anemia.
    • Chemistry: ↑ Ca²⁺, ↑ BUN/Cr, normal or low albumin with elevated total protein (“protein-albumin gap” > 4 g/dL).
    • Inflammatory Markers: Markedly elevated ESR (> 100 mm/hr).
    • Prognostic Labs: Elevated β2-microglobulin (correlates with tumor burden) and LDH.
  • Imaging:
    • Whole-body low-dose CT (WBLDCT) or Whole-body PET/CT / MRI: Modality of choice for detecting focal bone lesions.
    • Skeletal Survey (Plain X-rays): Demonstrates classic “punched-out” osteolytic lesions without surrounding sclerosis, diffuse osteopenia, or pathologic fractures.
    • High-Yield Pearl: Technetium-99m bone scan is contraindicated / unreliable (bone scans detect osteoblastic activity; MM lesions are purely osteolytic, causing false-negative scans).

Bone marrow biopsy

  • Cytology: clusters of plasma cells
    • Mildly organized monoclonal cells
    • Perinuclear lucent zone
      • Active Golgi apparatus
    • Clockface nuclei: Chromatin in the periphery of the nucleus resembles a cartwheel or clock face arrangement.
    • Intracytoplasmic crystalline inclusion bodies containing IgG

Differential diagnostics

Waldenström macroglobulinemia

  • Pathophysiology: Clonal B-cell/lymphoplasmacytic neoplasm producing excess monoclonal IgM; associated with MYD88 L265P mutation (>90%).
  • Clinical Presentation:
    • Hyperviscosity Syndrome:
      • Neurologic: Headache, dizziness, confusion, ataxia, stroke-like symptoms.
      • Visual: Blurry vision; fundoscopy shows dilated, tortuous “sausage-link” retinal veins and retinal hemorrhages. c
      • Bleeding: Epistaxis, gingival oozing (IgM impairs platelet function and clotting factors).
    • Lymphadenopathy (LAD) & Hepatosplenomegaly (HSM) (present in ~20–30%; distinguishes from Multiple Myeloma).
    • Other Findings: Sensorimotor peripheral neuropathy, cold agglutinin disease / cryoglobulinemia (Raynaud, livedo reticularis), B-symptoms (fever, night sweats, weight loss), normocytic anemia.
    • Key Negative: No osteolytic bone lesions and no hypercalcemia (unlike Multiple Myeloma).
  • Diagnosis:
    • Initial: SPEP + Immunofixation (IFE) revealing monoclonal IgM M-spike.
    • Peripheral Blood Smear: Rouleaux formation.
    • Confirmatory (Gold Standard): Bone marrow biopsy demonstrating ≥10% clonal lymphoplasmacytic infiltration.
  • Key Differentials:
    • Multiple Myeloma (MM): CRAB criteria (HyperCalcemia, Renal failure, Anemia, Bone lytic lesions), IgG/IgA spike (rarely IgM), pure plasma cells on BM, no LAD/HSM.
    • IgM MGUS: Asymptomatic, IgM <3 g/dL, BM clonal cells <10%, no hyperviscosity or end-organ damage.
  • Management:
    • Asymptomatic: Observation / Watch-and-wait.
    • Acute Hyperviscosity (Emergency): Emergent Plasmapheresis (PLEX) to rapidly decrease intravascular IgM.
      • Caution: Do not transfuse packed RBCs before PLEX (increases blood viscosity and worsens symptoms).
    • First-line Systemic Therapy:
      • Rituximab-based regimens (e.g., Rituximab + Bendamustine). Must perform PLEX before Rituximab if IgM is markedly elevated to prevent a fatal “IgM flare”.
      • BTK inhibitors (e.g., Ibrutinib, Zanubrutinib).

Treatment

Complications

  • Myeloma cast nephropathy (i.e., myeloma kidney): most common cause of renal injury and renal failure in patients with multiple myeloma
    • Clinical features: oliguria, peripheral edema, dyspnea
    • Pathophysiology: excessive production and filtration of light chains into the urine → precipitation of light chains in renal tubules → tubular obstruction
    • Diagnosis: markedly positive urine sulfosalicylic acid test and/or urine protein electrophoresis
      • On light microscopy, numerous large, glassy eosinophilic casts are seen.
    • May progress to end-stage renal disease (ESRD)
  • AL amyloidosis: Light chains can accumulate as amyloids and may lead to restrictive cardiomyopathy, renal insufficiency, macroglossia, and malabsorption syndromes.
  • Infections
  • Secondary plasma cell leukemia

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