Multiple Myeloma

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  • 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)
    • do MRI and FDG-PET 
      • additional lesions identified in one third of patients
  • 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 
    • more sensitive than XR for pelvis, spine
  • 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
    • sensitivity 93%, more sensitive than plain radiographs in diagnosing/screening for MM
    • may uncover additional sites in "solitary" plasmacytoma
  • 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+
  • Monoglonal gammopathy of unknown significant or asymptomatic myeloma
    • annual surveillance
  • Multiple myeloma
    • nonoperative
      • multiagent chemotherapy
        • indications
          • is the mainstay of treatment
          • used alone for nontransplant candidates
            • advanced age >65y
            • poor physical condition
        • cytotoxic chemotherapy combined with steroids
          • melphalan + prednisone + thalidomide or bortezomib
          • lenalidomide + dexamethasone
          • thalidomide + dexamethasone
      • autologous and allogeneic stem cell transplantation
        • not curative but increases disease free survival by 2-3y
        • induction
          • dexamethasone + lenalidomide 
          • bortezomib + dexamethasone
          • bortezomib + lenalidomide + dexamethasone
          • bortezomib + thalidomide + dexamethasone
      • bisphosphonates 
        • help reduce number of skeletal events in multiple myeloma patients
    • operative
      • surgical stabilization and irradiation 
        • indications
          • for complete or impending fractures
          • when life expectancy >3mths
          • vertebral compression fractures with instability or neural compression resistant to radiation
        • technique
          • kyphoplasty / vertebroplasty an option for 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 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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(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? Review Topic


CT scan of head




Urine electrophoresis




Lower extremity electromyelography




Lumbar puncture




Bone marrow aspiration and biopsy



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The patient's clinical history, imaging, and lab values are indicative of multiple myeloma. The next most appropriate investigation for the diagnosis of multiple myeloma would be bone marrow aspiration and biopsy.

A diagnosis of multiple myeloma may be based on the Durie and Salmon criteria. The criterion considers findings of plasmacytomas on tissue biopsy, plasmacytosis in bone marrow, monoclonal immunoglobulin spike on serum or urine electrophoresis, and radiographic evidence of lytic bone lesions (commonly in the spine, long bones and skull).

Walker et al. looked at the effectiveness of MRI on the clinical diagnosis of multiple myeloma. They showed that MRI detected focal lesions in 74% of cases, compared to 56% with standard metastatic bone surveys (e.g. radiographs) of imaged anatomic sites.

Palumbo et al. reviewed multiple myeloma. They state that bony lesions are evident on MRI in 80% of patients with newly diagnosed disease. Anemia, which is present in about 73% of patients at diagnosis, is related to bone marrow infiltration and/or renal dysfunction.

Figures A shows T2 MRI images of the thoracic and lumbar spine with diffuse lucencies throughout. Illustration A and B demonstrate a sheet of round plasma cells consistent with the histology of multiple myeloma. There is an eccentric nucleus, prominent nucleolus, and clock-face organization of chromatin. Illustration C shows the most common sites of multiple myeloma in the body.

Incorrect Answers:
Answer 1: A CT head is not necessary. Bony lesions in the skull can typically be detected on radiographs.
Answer 2: Urine electrophoresis would not be needed as there was presence of a serum monoclonal protein.
Answer 3: Electromyelography technique is used to evaluate the electrical activity produced by skeletal muscles, which can help diagnose peripheral nerve damage. This would not be used for the diagnostic work-up of multiple myeloma, however it may be used as adjunctive test for the investigation of his left leg sciatica.
Answer 4: There is no evidence to suggest lumbar puncture is indicated for the diagnosis of multiple myeloma.


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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? Review Topic


RANK ligand action on neoplastic cells




RANK action on neoplastic cells




Osteoprotegrin action on osteoclastic cells




RANK ligand action on osteoclastic cells




RANK action on osteoclastic cells



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Tumor induced osteolysis, commonly seen in metastatic bone disease, is caused by increased osteoclastic bone resorption. This cascade is caused by tumor induced cytokine signaling through the RANK to RANK ligand pathway which activates the osteoclast and encourage local bone resorption (Illustration A). Medical blockade of this pathway through the use of bisphosphonates or deactivators of the RANK/RANK ligand pathway like denosumab are an active area of current research (Illustration B). Illustration C shows a video that illustrates bone remodeling and regulation involving osteoprotegrin, RANK, RANK-ligand.

In these images, RANK is a cell surface receptor which is NOT secreted. RANK ligand is the "ligand" which is secreted by osteoblasts and binds and activates RANK receptor. Osteoprotegrin is the "decoy" receptor which blocks the action of RANK ligand binding RANK.

Nannuru et al used animal model to evaluate the regulation of RANKL expression and its functional significance in tumor-induced osteolysis. They found that increased RANK ligand expression potentiates tumor-induced osteolysis and blockade of this pathway prevents bone lysis.

In a related publication, Anastasilakis et al review the inhibition of this same cell signaling cascade and its role in the clincal treatment and prevention of complications related to metastatic bone disease such as pain and pathologic fracture.

Taranta et al report on the decreased bone mineral density associated with celiac disease. They propose a "cytokine imbalance" in the RANK, RANK ligand, Osteoprotegrin (OPG) signaling pathway as the likely cause of low bone mineral density.


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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? Review Topic


Polyclonal heavy chain immunoglobins




Polyclonal light chain immunoglobins




Monoclonal heavy chain immunoglobin




Monoclonal light chain immunoglobin




Decreased urine albumin



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The answer is Monoclonal light chain immunoglobin.

Figure A shows multiple plasma cells suggestive of multiple myeloma. Multiple myeloma is a neoplastic process involving the proliferation of plasma cells. It is often associated with anemia, chronic pain, low-grade fevers, and skeletal lesions that are often "cold" on bone scans. Affected B-cells produce a single, non-functional antibody (ie “monoclonal”, and this can either be the light chain or the heavy chain, most commonly part of an IgG protein) which becomes the predominant antibody (nonfunctional) produced as the disease progresses. Quantitative measurements by urine electrophoresis can be used to diagnose and monitor the disease. Alternatively serum electrophoresis can be used to detect monoclonal heavy chain immunoglobins as monoclonal light chains are preferentially excreted by the kidneys.

Additional findings include: hypercalemia (when osteoclasts are breaking down bone, releasing calcium into the bloodstream), raised serum creatinine due to reduced renal function, which may be due to light chain deposition in the kidney.

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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? Review Topic






Spindle Cells




Giant Cells




Plasma Cells







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Figure A shows a lytic destructive lesion in the vertebral body. Figure B shows multiple plasma cells. Multiple myeloma is a neoplastic process involving the proliferation of plasma cells. It is often associated with anemia, chronic pain, low-grade fevers, and skeletal lesions that are often "cold" on bone scans.

Weber showed that the main differential diagnosis for a patient older than 40 with a destructive bone lesion should include metastatic bone disease, multiple myeloma, lymphoma, and, less commonly, primary bone tumors.

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