Multiple Myeloma

Topic updated on 07/31/16 10:13pm
  • neoplastic proliferation of plasma cells that presents with skeletal lesions
    • neoplastic plasma cells produces immunoglobulins
      • heavy chains: IgG (52%), IgA (21%), IgM (12%)
      • light chains: kappa or lambda 
        • aka Bence Jones proteins
  • Disease forms 
    • disease takes multiple forms that vary in treatment and prognosis and includes
      • multiple myeloma (see below)
      • solitary plasmacytoma
      • osteosclerotic myeloma
  • Epidemiology
    • incidence
      • most common primary bone malignancy
    • demographics
      • patients > 40 years of age
      • affects males more than females
      • twice as common in African-americans
  • Prognosis
    • prognosis is variable
    • data suggests 5 year survival of 30% and 10 year survival of 11%
      • overall survival is related to stage of disease and secondary factors like renal failure or hypercalcemia
      • median survival is 3 years from diagnosis
      • shortest survival is seen in patients with renal failure
    • poor prognostic factors in multiple myeloma
      • chromosome 13 deletion or translocation (t4;14), 4(14;16)
      • circulating plasma cells
      • increased beta 2 microgloblulin (indicates elevated tumor burden)
      • decreased serum albumin
      • increased marrow microvessels
    • solitary plasmacytoma has best prognosis
  • Multiple Myeloma 
    • most common form
    • Clonal bone marrow plasma cells 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features and myeloma-defining events:
    • Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
      • HyperCalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL)
      • Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177µmol/L (>2mg/dL)
      • Anemia: hemoglobin valure of >20g/L below the lowest limit of normal, or a hemoglobin value <100g/L
      • Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT.  If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
    • Any one or more of the following biomarkers of malignancy (MDEs):
      • 60% or greater clonal plasma cells on bone marrow examination
      • Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100mg/L (a patient’s “involved” free light chain—either kappa or lambda—is the one that is above the normal reference range; the “uninvolved” free light chain is the one that is typically in, or below, the normal range)
      • More than one focal lesion on MRI that is at least 5mm or greater in size.
  • Solitary Plasmacytoma
    • plasma cell tumor occurring in a single skeletal location and lacking appropriate criteria for diagnosis of multiple myeloma
    • sensitive to radiation
    • progress to multiple myeloma in over 50% of patients
    • diagnostic criteria
      • solitary lesion on skeletal survey
      • histologic biopsy confirmation of plasmacytoma
      • negative bone marrow biopsy (i.e. no plasma cells in bone marrow)
  • Osteosclerotic Myeloma
    • a rare syndrome characterized by POEMS: Polyneuropathy,  Organomegaly, Endocrinopathy, M protein, Skin changes
    • neurologic symptoms are symmetric and begin distal and migrate proximally
      • sensory symptoms manifest first and then are followed by motor weakness
      • neurological symptoms usually do not improve
    • skin lesions are characteristic and occur predominantly in the trunk
      • up to 25-50% of skin lesions occur in the extremities
    • sclerotic bone lesions occur in both the axial and appendicular skeleton
  • Symptoms
    • usually present with localized bone pain (usually spine or ribs) or pathologic fracture 
    • fatigue secondary to anemia, renal insufficiency, hypercalcemia
  • Radiographic 
    • show multiple "punched-out" lytic lesions 
      • lytic lesions caused by osteoclastic bone resorption via RANKL, IL-6 and MIP-1alpha 
      • lack of osteoblastic activity in myeloma cause the "punched out lesions" on radiographs which lack a sclerotic border
    • skeletal survey
      • if there is a suspicion for multiple myeloma obtain a skeletal survey as bone scans are cold in 30%
  • MRI
    • shows multiple lesions that are bright on T2 and dark on T1 
  • Bone scans
    •  are cold in 30% so obtain a skeletal survey
    • bone scans are "hot" due to radio-tracer integration into the inorganic phase of bone caused by osteoblastic activity
    • multiple myeloma often lacks osteoblastic activity
  • Serum labs
    • anemia
    • elevated creatinine
    • hypercalcemia
      • present in 30% of patients due to excessive resorption of bone
    • ESR often elevated
    • SPEP (serum protein electrophoresis)
      • M spike present (50% IgG, 25% IgA)
  • Urine
    • proteinuria
    • UPEP (urine protein electrophoresis) 
      • may show Bence Jones proteins (secreted immunoglobulin kappa and lambda light chains)
  • Distinctive histology
    • round plasma cells with an eccentric nucleus, prominent nucleolus, and clock face organization of chromatin  
    • characteristic clear area (Hoffa clear zone) next to the nucleus represents the prominent Golgi apparatus involved in immunoglobulin (protein) production  
  • Bone marrow aspirate
    • percentage of plasma cells on bone marrow aspirate is one major criteria used to distinguish plasmacytoma (10-30% plasma cells) vs. multiple myeloma (>30% plasma cells) 
    • normal amount of plasma cells on bone marrow aspirate is < 2%
  • Immunohistochemical stains
    • CD38+
  • Multiple myeloma
    • nonoperative
      • multiagent chemotherapy
        • indications
          • is the mainstay of treatment
        • cytotoxic chemotherapy combined with steroids
      • bisphosphonates 
        • help reduce number of skeletal events in multiple myeloma patients
    • operative
      • surgical stabilization and irradiation 
        • indications
          • for complete or impending fractures
          • vertebral compression fractures with instability or neural compression resistant to radiation
        • technique
          • kyphoplasty an option for painful vertebral compression fractures
  • Solitary plasmacytoma
    • nonoperative
      • external beam irradiation alone (45 - 50 Gy)
        • indications
          • is the mainstay of treatment
    • operative
      • surgical stabilization
        • indications
          • for complete or impending fractures
  • Osteosclerotic myeloma
    • nonoperative
      • chemotherapy, radiotherapy, and plasmapheresis
        • indications
          • is the mainstay of treatment
        • outcomes
          • neurologic changes usually do not improve with treatment 

Differential & Groups
Bone lesion in older patient(1)
Multiple lesion in older patient(1)
Benefits from Bisphonate therapy
Treatment is chemotherapy and radiotherapy(2)
Metastatic bone disease
Secondary sarcoma
Pagets disease    
Fibrous dysplasia            
Synovial sarcoma                
Gomus tumor                  
ASSUMPTIONS: (1) Older patient is > 40 yrs; (2) assuming no impending fracture
B. Scan
Case A femur
Case B radius
Case B femur
Case C radius
Case D femur
Case E humerus
Case F spine
Case F skull



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Qbank (5 Questions)

(OBQ12.190) A 61-year-old male has a 6 month history of low back pain with increasing left sciatic leg pain for 5 weeks. On examination, he has bone tenderness in the lumbar and thoracic spine. Neurological examination shows 4/5 weakness in the L5 distribution in the left leg. MRI images of the thoracic and lumbar spine are shown in Figures A. Follow-up laboratory studies show anemia associated with the presence of a serum monoclonal protein. What would be the next most appropriate investigation in the diagnostic work-up of this patient? Topic Review Topic
FIGURES: A          

1. CT scan of head
2. Urine electrophoresis
3. Lower extremity electromyelography
4. Lumbar puncture
5. Bone marrow aspiration and biopsy

(OBQ11.64) Lytic bone lesions, commonly seen in metastatic bone disease or multiple myeloma, are due to which of the following mechanisms? Topic Review Topic

1. RANK ligand action on neoplastic cells
2. RANK action on neoplastic cells
3. Osteoprotegrin action on osteoclastic cells
4. RANK ligand action on osteoclastic cells
5. RANK action on osteoclastic cells

(OBQ08.136) A 55-year-old male with chronic low grade back pain, intermittent fevers, and anemia underwent a bone biopsy for a lytic lesion in the spine. The biopsy is seen in Figure A. A urine protein electrophoresis is likely to show which of the following? Topic Review Topic
FIGURES: A          

1. Polyclonal heavy chain immunoglobins
2. Polyclonal light chain immunoglobins
3. Monoclonal heavy chain immunoglobin
4. Monoclonal light chain immunoglobin
5. Decreased urine albumin

(OBQ08.142) A 55-year-old male has chronic thoracic back pain and undergoes a biopsy of a suspicious lesion in the T6 vertebral body seen in Figure A. The asterisk in Figure B represents what type of cell seen by the pathologist? Topic Review Topic
FIGURES: A   B        

1. Osteoblasts
2. Spindle Cells
3. Giant Cells
4. Plasma Cells
5. Eosinophils

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