Updated: 9/27/2020

Multiple Myeloma

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https://upload.orthobullets.com/topic/8024/images/Case A - femur - xray b - Parsons_moved.gif
https://upload.orthobullets.com/topic/8024/images/Case A - femur - MRI T1 - Parsons_moved.gif
https://upload.orthobullets.com/topic/8024/images/Histo 38c_moved.jpg
https://upload.orthobullets.com/topic/8024/images/Case B - femur - xray - Parsons_moved.jpg
https://upload.orthobullets.com/topic/8024/images/Case A - femur - MRI T1 and T2_moved.jpg
https://upload.orthobullets.com/topic/8024/images/Histology C - Parsons_moved.png
Introduction
  • Overview
    • multiple myeloma is a 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, lambda
          • aka Bence Jones proteins
      • 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
        • occurs in 3-4:100,000
      • accounts for 1% of all malignancies
    • demographics
      • patients > 40 years of age (median age is 60)
      • affects males > females
      • 2x more common in African Americans
  • Pathophysiology
    • results from osteoclastic stimulation by malignant cells
      • malignant cells bind bone marrow stromal cells to stimulate the production of receptor activator of nuclear factor-κ B ligand (RANKL) and other pro-osteoclastic mediators (macrophage colony-stimulating factor (M-CSF, IL-6, IL-11, TNF)
      • osteoprotegerin (OPG) synthesis is suppressed, resulting in further osteoclast activation
        • OPG competes with RANK to bind to RANKL as a decoy receptor
  • Prognosis
    • prognosis is variable
    • data suggests 5-year survival rate of 30% and 10-year survival rate 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 the best prognosis
Classification
  • Multiple myeloma 
    • most common form
    • diagnostic criteria
      • monoclonal plasma cells ≥10% on bone marrow biopsy or biopsy-proven bony/extramedullary plasmacytoma and ≥1 of the CRAB features and myeloma-defining events (MDEs)
        • CRAB features of end-organ damage
          • 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/min or serum creatinine >177µmol/L (>2mg/dL)
          • Anemia: hemoglobin >20g/L below the lowest limit of normal or hemoglobin <100g/L
          • Bone lesions: 1 osteolytic lesion on radiographs, CT, or PET/CT
            • if bone marrow has <10% clonal plasma cells, >1 bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
        • MDEs
          • 60% clonal plasma cells on bone marrow biopsy
          • serum involved:uninvolved free light chain ratio of 100
            • only applies if the absolute level of the involved light chain is at least 100mg/L
            • “involved” free light chain is the one that is above the normal range
            • “uninvolved” free light chain is the one that is typically at/below the normal range
          • ≥ 1 focal lesion on MRI that is 5mm in size
    • staging
Internation Staging System (ISS)
Stage
Criteria
Prognosis
I  • beta-2 microglobulin < 3.5 mg/L
 • serum albumin ≥ 3.5 g/dL
62 months
II  • beta-2 microglobulin 3.5-5.4 mg/L 44 months
III  • beta-2 microglobulin ≥ 5.5 mg/L 29 months
  • Solitary plasmacytoma
    • plasma cell tumor occurring in a single skeletal location and lacking appropriate criteria for diagnosis of multiple myeloma
    • sensitive to radiation
    • progresses 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)
    • obtain MRI and FDG-PET
      • additional lesions identified in 33% of patients
  • Osteosclerotic myeloma
    • rare syndrome characterized by POEMS
      • Polyneuropathy
        • often symmetric
        • begins distally and migrates proximally
        • usually does not improve
      • Organomegaly
      • Endocrinopathy
        • sclerotic bone lesions occur in both the axial and appendicular skeleton
      • M protein
      • Skin changes
        • characteristic
        • occurs predominantly in the trunk
          • up to 25-50% of skin lesions occur in the extremities
Presentation
  • Symptoms
    • usually presents with
      • localized bone pain (usually spine or ribs)
      • pathologic fracture 
    • fatigue secondary to anemia, renal insufficiency, hypercalcemia
Imaging
  • Radiographs
    • findings
      • multiple "punched-out" lytic lesions 
        • only visible once >50% destruction has occurred
        • lytic appearance
          • caused by osteoclastic bone resorption via RANKL, IL-6 and MIP-1alpha 
        • punched-out appearance
          • absence of slerotic border
          • results from the lack of osteoblastic activity in myeloma
    • obtain skeletal survey if there is a suspicion for multiple myeloma given that bone scans are cold in 30%
  • MRI
    • indications
      • more sensitive than XR for pelvis, spine
    • findings
      • dark on T1
      • bright on T2
  • Bone scans
    • cold in 30% so skeletal survey is recommended
      • 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
  • Fluorodeoxyglucose-positron emission tomography (FDG-PET)
    • 93% sensitivity
      • more sensitive than plain radiographs in diagnosing/screening for MM
    • may uncover additional sites in "solitary" plasmacytoma
    • uptake into cancer cells due to increased glucose metabolism in most types of tumors
Labs
  • 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)
    • beta-2 microglobulin
      • marker of prognosis/disease severity
  • Urine
    • proteinuria
    • UPEP (urine protein electrophoresis) 
      • may show Bence Jones proteins (secreted immunoglobulin kappa and lambda light chains)
Histology
  • 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
    • CD138+
Treatment (by treatment)
  • Nonoperative
    • annual surveillance
      • indications
        • monoglonal gammopathy of unknown significance, asymptomatic myeloma
    • external beam irradiation alone
      • indications
        • solitary plasmacytoma
    • multiagent chemotherapy +/- stem cell transplantation +/- bisphosphonates
      • indications
        • multiple myeloma
      • techniques
        • chemotherapy
          • non-transplant candidates 
            • melphalan + prednisone + thalidomide or bortezomib
            • lenalidomide + dexamethasone
            • thalidomide + dexamethasone
          • transplant candidates 
            • lenalidomide + dexamethasone
            • bortezomib + dexamethasone
            • bortezomib + lenalidomide + dexamethasone
            • bortezomib + thalidomide + dexamethasone
  • Operative
    • surgical stabilization and external beam radiation therapy 
      • indications
        • complete or impending fractures  
        • life expectancy >3 months
    • kyphoplasty
      •  indications
        • vertebral compression fractures with instability or neural compression resistant to radiation
Treatment (by disease type)
  • Monoglonal gammopathy of unknown significance, asymptomatic myeloma
    • nonoperative
      • annual surveillance
  • Multiple myeloma
    • nonoperative
      • multiagent chemotherapy +/- autologous and allogeneic stem cell transplantation
        • indications
          • chemotherapy alone for non-transplant candidates
            • multiple medical comorbidities
            • advanced age >65 years old
            • poor physical condition
          • induction chemotherapy and stem cell transplantation for transplant candidates
            • autologous and allogeneic stem cell transplantation isnot curative but increases disease free survival by 2-3 years
        • agents
          • non-transplant candidates 
            • melphalan + prednisone + thalidomide or bortezomib
            • lenalidomide + dexamethasone
            • thalidomide + dexamethasone
          • transplant candidates 
            • lenalidomide + dexamethasone
            • bortezomib + dexamethasone
            • bortezomib + lenalidomide + dexamethasone
            • bortezomib + thalidomide + dexamethasone
      • bisphosphonates 
        • helps reduce the number of skeletal events in multiple myeloma patients
    • operative
      • surgical stabilization and external beam radiation therapy
        • indications
          • complete or impending fractures  
          • life expectancy >3 months
          • vertebral compression fractures with instability or neural compression resistant to radiation
        • techniques
          • kyphoplasty/vertebroplasty
            • painful vertebral compression fractures 
          • currettage, PMMA and modified Harrington pins
            • periacetabular lesions with intact acetabular subchondral plate
          • complex THA with acetabular cage
            • periacetabular lesions where acetabular subchondral plate is violated
  • Solitary plasmacytoma
    • nonoperative
      • external beam irradiation (45-50 Gy)
        • indications
          • mainstay of treatment
    • operative
      • surgical stabilization
        • indications
          • complete or impending fractures
  • Osteosclerotic myeloma
    • nonoperative
      • chemotherapy, radiotherapy, and plasmapheresis
        • indications
          • 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)
Myeloma
 
     
   
Metastatic bone disease
 
     
 
 
Lymphoma
 
         
Chondrosarcoma
               
MFH
               
Secondary sarcoma
               
Pagets disease    
     
 
 
Fibrous dysplasia            
 
 
Synovial sarcoma                
 
Hyperparathyroidism    
           
Gomus tumor                  
ASSUMPTIONS: (1) Older patient is > 40 yrs; (2) assuming no impending fracture
 
IBank
  Location
Xray
Xray
CT
B. Scan
MRI
MRI
Histo(1)
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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(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? Tested Concept

QID: 4550
FIGURES:
1

CT scan of head

1%

(34/2964)

2

Urine electrophoresis

44%

(1308/2964)

3

Lower extremity electromyelography

1%

(32/2964)

4

Lumbar puncture

1%

(28/2964)

5

Bone marrow aspiration and biopsy

52%

(1548/2964)

L 4 C

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

QID: 3487
1

RANK ligand action on neoplastic cells

2%

(46/2663)

2

RANK action on neoplastic cells

1%

(16/2663)

3

Osteoprotegrin action on osteoclastic cells

2%

(40/2663)

4

RANK ligand action on osteoclastic cells

89%

(2370/2663)

5

RANK action on osteoclastic cells

7%

(183/2663)

L 1 C

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(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? Tested Concept

QID: 522
FIGURES:
1

Polyclonal heavy chain immunoglobins

1%

(14/1399)

2

Polyclonal light chain immunoglobins

3%

(35/1399)

3

Monoclonal heavy chain immunoglobin

16%

(219/1399)

4

Monoclonal light chain immunoglobin

80%

(1120/1399)

5

Decreased urine albumin

0%

(4/1399)

L 2 C

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(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? Tested Concept

QID: 528
FIGURES:
1

Osteoblasts

2%

(21/1192)

2

Spindle Cells

1%

(10/1192)

3

Giant Cells

11%

(137/1192)

4

Plasma Cells

80%

(959/1192)

5

Eosinophils

5%

(61/1192)

L 1 C

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