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Updated: 1/2/2022

Multiple Myeloma

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Images
https://devupload.orthobullets.com/topic/8024/images/Case A - femur - xray b - Parsons_moved.gif
https://devupload.orthobullets.com/topic/8024/images/Case A - femur - MRI T1 - Parsons_moved.gif
https://devupload.orthobullets.com/topic/8024/images/Histo 38c_moved.jpg
https://devupload.orthobullets.com/topic/8024/images/Case B - femur - xray - Parsons_moved.jpg
https://devupload.orthobullets.com/topic/8024/images/Case A - femur - MRI T1 and T2_moved.jpg
https://devupload.orthobullets.com/topic/8024/images/Histology C - Parsons_moved.png
  • summary
    • Multiple Myeloma is neoplastic proliferation of plasma cells that commonly results in multiple skeletal lesions, hypercalcemia, renal insufficiency, and anemia. Patients typically present at ages > 40 with localized bone pain or a pathologic fracture. 
    • Diagnosis is made with a bone marrow biopsy showing monoclonal plasma cells ≥10%.
    • Treatment is usually chemotherapy and radiation. Surgical management is indicated for associated fractures.
  • 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
  • Etiology
    • Forms
      • 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
    • 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, )
        • osteoprotegerin (OPG) synthesis is suppressed, resulting in further osteoclast activation
          • OPG competes with RANK to bind to RANKL as a decoy receptor
      • osteoblastic differentiation may also be inhibited 
        • TNF and Dickkopf-1 (DKK-1) have been shown to down regulate osteoblast function
  • 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)
        • Criteria 
        • Prognosis
        • Stage I
        • Beta-2 microglobulin < 3.5 mg/L
        • Serum albumin≥ 3.5 g/dL
        • 62 months
        • Stage II
        • Beta-2 microglobulin 3.5-5.4 mg/L
        • 44 months
        • Stage 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+
  • Differential
      • Differential of Multiple Myeloma
      • Bone lesion in older patient
      • Multiple lesion in older patient
      • Benefits from Bisphosphonate therapy
      • Treatment is chemotherapy and radiotherapy
      • Myeloma
      • o
      • o
      • o
      • Metastatic bone disease
      • o
      • o
      • o
      • Lymphoma
      • o
      • o
      • o
      • Chondrosarcoma
      • o
      • MFH
      • o
      • Secondary sarcoma
      • o
      • Paget's disease
      • o
      • o
      • Fibrous dysplasia
      • o
      • Synovial sarcoma
      • Hyperparathyroidism
      • o
      • Glomus tumor
  • Treatment(by treatment type)
    • Nonoperative
      • annual surveillance
        • indications
          • monoclonal 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
  • 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
Flashcards (2)
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Questions (10)

(SBQ18SP.70) You are following a 62-year-old patient with metastatic disease. His most recent clinical radiograph is shown in Figure A. A previous biopsy specimen is displayed in Figure B. The patient was debating over the risks and benefits of prophylactic fixation of the right hip for progressively worsening functional groin pain. However two days after the visit, the patient presents to the emergency room where you see and diagnose him with a complete pathologic fracture of the right femoral neck. Which of the following is accurate of the pathology in this vignette?

QID: 211872
FIGURES:
1

A femoral prosthesis with a full-length press-fit stem is most appropriate to protect the entire bone

12%

(171/1462)

2

Lesions are poorly radiation or chemotherapy-sensitive

10%

(153/1462)

3

Pathologic fractures have a low chance of healing

33%

(487/1462)

4

Prophylactic fixation was indicated prior to fracture to avoid delay systemic therapy

39%

(572/1462)

5

Radionuclide bone scan is ideal for detection

4%

(59/1462)

L 5 A

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(OBQ18.142) A 60-year-old male patient with no recent falls or trauma is admitted due for severe lower back pain and inability to ambulate. Figure A is a lateral radiograph of the patient's lumbar spine. T2 weighted sequence MRI of the lumbar spine confirmed there to be fluid signal intensities at the affected level. The patient is discharged with NSAIDs and TLSO bracing. Outpatient DEXA scanning revealed a T score of 1.2. The patient returns 3 months later with worsening lower back pain. The patient is neurologically intact. Figure B is the follow-up radiograph and T2-weighted MRI in figure C. Figure D is a histologic slide from proximal humerus lesion that was biopsied 3 weeks ago. What is the most appropriate treatment?

QID: 213038
FIGURES:
1

L1 Corpectomy with strut grafting and posterior fusion from T10-L3

21%

(341/1595)

2

Teriparatide

2%

(28/1595)

3

External beam radiation

16%

(249/1595)

4

L1 Kyphoplasty

11%

(180/1595)

5

CT chest, abdomen, and pelvis

48%

(768/1595)

L 4 A

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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?

QID: 4550
FIGURES:
1

CT scan of head

1%

(36/3154)

2

Urine electrophoresis

44%

(1379/3154)

3

Lower extremity electromyelography

1%

(35/3154)

4

Lumbar puncture

1%

(30/3154)

5

Bone marrow aspiration and biopsy

53%

(1659/3154)

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?

QID: 3487
1

RANK ligand action on neoplastic cells

2%

(49/2805)

2

RANK action on neoplastic cells

1%

(18/2805)

3

Osteoprotegrin action on osteoclastic cells

2%

(47/2805)

4

RANK ligand action on osteoclastic cells

89%

(2488/2805)

5

RANK action on osteoclastic cells

7%

(196/2805)

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?

QID: 522
FIGURES:
1

Polyclonal heavy chain immunoglobins

1%

(16/1625)

2

Polyclonal light chain immunoglobins

3%

(41/1625)

3

Monoclonal heavy chain immunoglobin

16%

(254/1625)

4

Monoclonal light chain immunoglobin

80%

(1301/1625)

5

Decreased urine albumin

0%

(4/1625)

L 2 D

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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?

QID: 528
FIGURES:
1

Osteoblasts

2%

(23/1391)

2

Spindle Cells

1%

(10/1391)

3

Giant Cells

12%

(173/1391)

4

Plasma Cells

79%

(1104/1391)

5

Eosinophils

5%

(76/1391)

L 1 C

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