MULTIPLE MYELOMA (MM)

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MULTIPLE MYELOMA (MM)
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CASE STUDY MULTIPLE MYELOMA

• 74 year old BF presents to ED
• Fatigue, pain in spinal column, less frequent
  urination with dark color, nausea, vomiting
• Laboratory
• CBC with diff
• Comprehensive metabolic panel (CMP)
• Urinalysis
• Serum and urine protein electrophoresis
• Serum free light chain assay
• Radiology
• MRI of spinal column

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CASE STUDY MULTIPLE MYELOMA

• CBC with diff
• WBC 5.9
  4.8-10.8 K/uL
• RBC 2.74
  4.0-5.4 M/uL
• Platelets 160
  145-499 K/uL
• Hemoglobin 8.7
  12.0-16.0 g/dL
• Hematocrit 25.6
  36.0-47.0
• CMP
• BUN 45
  7-18 mg/dL
• Creatinine 4.1
  0.5-1.2 mg/dL
• Total protein 11.0
  6.1-8.0 g/dL
• Albumin 2.2
  3.5-4.8 g/dL
• Urinalysis
• Protein 30.0
  lt 30.0 mg/dL

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CASE STUDY MULTIPLE MYELOMA

• Serum free light chains
• Free kappa 16.2
  3.3 19.4 mg/L
• Free lambda 3754.1
  5.7 26.3 mg/L
• Ratio
  0.0 0.3 1.7
• Interpretation
• Free lambda light chain monoclonal gammopathy
• Radiology
• Diffuse osteolytic lesions in thoracic and lumbar
  regions with several compression fracturres

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CASE STUDY MULTIPLE MYELOMA

• 59 year old WF presents to family internist
• Fatigue, pain in both right and left arms,
  nausea, vomiting, less frequent urination with
  dark color, constipation, depression, confusion
• Developed pain in right arm three weeks prior
• Worse with movement or change of position
• Worse in biceps, triceps and right shoulder
• Developed pain in left arm two weeks prior
• Worse with movement or change of position
• Worse in biceps, triceps, left elbow and shoulder

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CASE STUDY MULTIPLE MYELOMA

• Laboratory
• CBC with diff
• Comprehensive metabolic panel (CMP)
• Urinalysis
• Serum and urine protein electrophoresis
• Serum free light chain assay
• Radiology
• X-ray of right and left arms

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CASE STUDY MULTIPLE MYELOMA

• CBC with diff
• WBC 16.9
  4.8 10.8 K/uL
• RBC 3.65
  4.0 5.4 M/uL
• Platelets 117
  145 400 K/uL
• Hemoglobin 9.4
  12.0 16.0 g/dL
• Hematocrit 27.4
  36.0 47.0
• CMP
• BUN 57
  7 18 mg/dL
• Creatinine 6.5
  0.5 1.2 mg/dL
• Calcium 15.4
  8.5 10.5 mg/dL
• Total protein 7.3
  6.1 8.0 g/dL
• Urinalysis
• Protein 100
  lt 30.0 mg/dL

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CASE STUDY MULTIPLE MYELOMA

• Serum free light chains
• Free kappa 7.9
  3.3 19.4 mg/L
• Free lambda 12,224.0 5.7
  26.3 mg/L
• Ratio 0.0
• Interpretation
• Free lambda light chain monoclonal gammopathy
• Radiology
• Frontal images of right and left humerus show
• Destructive lytic lesions
• Pathologic fractures of proximal third of left
  humerus and middle third of right humerus

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MONOCLONAL GAMMOPATHIES(PLASMA CELL DISORDERS)

• Diseases characterized by uncontrolled
  proliferation of a single clone of plasma cells
• Multiple myeloma
• Waldenstroms macroglobulinemia
• AL amyloidosis
• Heavy chain disease
• Light chain disease
• Plasmacytoma
• Monoclonal gammopathy of undetermined
  significance(MGUS)

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MULTIPLE MYELOMA (MM)

• A neoplastic (malignant) proliferation of a
  single clone of plasma cells in bone marrow
• Major laboratory diagnostic criteria
• gt10 plasma cells in bone marrow
• Complete or incomplete monoclonal
  immunoglobulin(s) in serum and/or urine at
  elevated concentrations
• Monoclonal Immunoglobulins (Antibodies)
• Monoclonal proteins, M proteins or paraproteins
• Non-functional

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MULTIPLE MYELOMA

• Incidence in US for 2009 (NCI)
• 20,000
• Deaths in US for 2009 (NCI)
• 10,000
• Risk factors
• Age, ethnicity, occupational exposure, obesity,
  MGUS
• Median age at diagnosis is 65 years

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MULTIPLE MYELOMA

• Male to female ratio of 1
• Incidence per 100,000 in United States
• African Americans (10 cases)
• Caucasians (4 cases)
• Asians (1 case)
• Variant forms
• Smoldering
• Non-secretory

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VARIANT FORMS OF MULTIPLE MYELOMA

• Non-secretory multiple myeloma
• No monoclonal protein detected
• Myeloma cells unable to secrete M protein
• Bone marrow plasma cells gt 10
• Anemia, hypercalcemia, lytic bone lesions or
  renal insufficiency
• Smoldering multiple myeloma (SMM)
• M protein gt 3.0 g/dL
• Bone marrow plasma cells gt 10
• No anemia, hypercalcemia, lytic bone lesion or
  renal insufficiency

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MGUS AND SMM

• Monoclonal gammopathy of undetermined
  significance (MGUS)
• M protein lt 3.0 g/dL
• Bone marrow plasma cells lt 10
• No anemia, hypercalcemia, lytic bone lesions or
  renal insufficiency
• Smoldering multiple myeloma (SMM)
• M protein gt 3.0 g/dL
• Bone marrow plasma cells gt 10
• No anemia, hypercalcemia, lytic bone lesion or
  renal insufficiency
• Yearly progression to multiple myeloma
• 1 for MGUS
• 10 to 20 for SMM

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TYPES OF MONOCLONAL PROTEINS IN MULTIPLE MYELOMA

• Based on IG isotypes with frequency parallel to
  normal serum percentages
• IgG kappa (30) or lambda (18)
• IgA kappa (10) or lambda (6)
• Free kappa or lambda (15 to 20)
• Bence-Jones proteins
• IgM (lt 1)
• IgD (lt1)
• IgE (lt1)

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PATHOGENESIS OF MULTIPLE MYELOMA

• Transformation to malignant plasma cell involves
  multiple mutational events
• Malignant plasma cells have specific adhesion
  molecules for stromal cells of bone marrow
• Stromal cells produce cytokine interleukin-6
  (IL-6) which
• Stimulates growth of plasma cells
• Prevents apoptosis
• Stimulates osteoclast activity

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PATHOGENESIS OF MULTIPLE MYELOMA

• Malignant plasma cells produce
• Interleukin-6
• Angiogenesis cytokine
• Vascular endothelial growth factor (VEGF)
• Monoclonal protein (MP)
• Accelerates catabolism of functional polyclonal
  IGs
• Characteristic of myeloma cells
• Translocation of IG heavy chain gene (14) to
  proto-oncogenes (11, 16, 20)
• Missing all or part of chromosome 13

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DIRECT EFFECTS OF PLASMA CELL INFILTRATION INTO
BONE MARROW

• Osteoclast activation by IL-6
• Bone destruction and lytic lesions with resulting
  
• Bone pain, pathologic fractures, cord
  compression, symptomatic hypercalcemia and
  osteopenia
• Infiltration by plasma cells
• Panocytopenia, hypogammaglobulinemia,
  paraproteinemia resulting in
• Immunosupression and susceptibility to pneumonia
  (S. pneumoniae and S. aureus) and pyelonephritis
  (E. coli)
• Extra-osseous spread mainly to kidneys

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CLINICAL MANIFESTATION IN MULTIPLE MYELOMA

• Bone pain
• Spine, hip, rib cage and skull is common
• Weakness and fatigue
• Nausea, constipation, increased thirst and
  urination
• Recurrent bacterial infections
• Pneumonia and pyelonephritis
• Renal insufficiency

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STAGING OF MULTIPLE MYELOMA

• Durie-Salmon
• Three stages (I, II, III)
• Concentration of M protein
• Number of bone lesions
• Hemoglobin level
• Calcium level
• Stages further divided on renal function
• Serum creatinine lt 2.0 mg/dL (A)
• Serum creatinine gt 2.0 mg/dL (B)
• International Staging System (ISS)
• Three stages (I, II, III)
• Beta-2-microglobulin (B2M) level
• Albumin level

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DURIE-SALMON STAGING SYSTEM

• Stage I
• Concentration of M proteins
• IgG lt 5 g/dL
• IgA lt 3 g/dL
• BJP lt 4g/24 hours
• No bone lesions
• Hemoglobin gt 10.5 g/dL or Hematocrit gt 32
• Normal calcium level
• Stage II
• Neither I nor III

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DURIE-SALMON STAGING SYSTEM

• Stage III
• Concentration of M protein
• IgG gt 7 g/dL
• IgA gt 5 g/dL
• BJP gt 12 g/24 hours
• gt 3 lytic bone lesions
• Hemoglobin lt 8.5 g/dL or Hematocrit lt 25
• Calcium gt 12 mg/dL

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INTERNATIONAL STAGING SYSTEM (ISS)

• Stage I
• Beta-2-microglobin (B2M) lt 3.5 mg/L
• Albumin gt 3.5 g/dL
• Stage II
• B2M lt 3.5 mg/L
• Albumin lt 3.5 g/dL
• OR
• B2M of 3.5 to 5.5 mg/L with any albumin level
• Stage III
• Beta-2-microglobulin (B2M) gt 5.5 mg/L
• Albumin lt 3.5 g/dL

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TREATMENT OF MULTIPLE MYELOMA

• No cure for MM
• Median survival time
• Stage I
• 60 months
• Stage II
• 45 months
• Stage III
• 30 months

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TREATMENT OPTIONS IN MULTIPLE MYELOMA

• Chemotherapy
• Melphalan (Alkeran)
• Cyclophosphamide (Cytoxan)
• Vincristin (Oncovin)
• Doxorubicin (Adriamycin)
• Immunotherapy
• Thalidomide (Thalomid)
• Lenalidomide (Revlumid)
• Bortezomib (Velcade)

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TREATMENT OPTIONS IN MULTIPLE MYELOMA

• Corticosteroids
• Prednizone
• Stem cell transplantation
• Autologous
• Allogenic
• Radiation therapy
• Best initial therapy
• Melphalan / Prednizone / Thalidomide (MPT)

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RADIOLOGY DIAGNOSIS OF MULTIPLE MYELOMA

• Skeletal bone X-ray series
• Skull, spine, ribs, arms, legs and pelvis
• Alternative procedures
• Magnetic resonance imaging (MRI)
• Computed tomography (CT)
• Computerized axial tomography (CAT)
• Lytic bone lesions and/or pathologic fractures

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LABORATORY DIAGNOSIS OF MULTIPLE MYELOMA

• Complete blood count (CBC) with differential
• Chemistry profile
• Comprehensive metabolic
• Basic metabolic
• Urinalysis
• C-reaction protein (CRP) or ESR
• Beta-2-microglobulin (B2M)

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LABORATORY DIAGNOSIS OF MULTIPLE MYELOMA

• Protein electrophoresis
• Screening
• Serum (SPEP) and
• Urine (UPEP) random or 24 hour specimen)
• Confirmation
• Immunofixation Electrophoresis (IFE)
• Free light chains (FLC) with ratio
• Serum by nephelometry or turbidimetry
• Histopathology of bone marrow aspiration or
  biopsy
• Percent plasma cells

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LABORATORY DIAGNOSIS OF MULTIPLE MYELOMA

• International Myeloma Working Group guidelines
  (2009)
• Screening
• Serum (SPEP) and
• Serum (FLC) assay
• Confirmation of positive SPEP
• Immunofixation Electrophoresis (IFE)
• AL amyloidosis
• Same as above plus
• Urine (24 hour) for UPEP and IFE

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SERUM PROTEIN ELECTROPHORESIS(SPE / SPEP)

• Screen for (detection of) protein abnormalities
• Monoclonal gammopathy
• Gammaglobulinemia (hyper or hypo)
• Polyclonal gammopathy
• Acute and chronic inflammation
• Diffuse hepatodegeneration or cirrhosis
• Anemia (iron deficiency or hemolytic)
• Protein losing disorders
• Malnutrition

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URINE PROTEIN ELECTROPHORESIS (UPE / UPEP)

• Screen for (detection of) protein abnormalities
• Monoclonal gammopathy
• Glomerular proteinuria
• Selective or non-selective
• Tubular proteinuria
• Overflow proteinuria

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PROTEIN ELECTROPHORESIS

• Separation of serum and urine proteins into 5
  major fractions by electrophoresis
• Separation based on charge at pH 9.2 using an
  agarose gel as support medium
• Separate proteins stained with amidoblack
• Densitometry quantitation of stained fractions
• Visual interpretation of electrophoregrams

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PROTEIN ELECTROPHORESIS IN MULTIPLE MYELOMA

• Detection of monoclonal protein(s)
• Serum and urine specimens
• Quantitation of MP by densitometry
• Initial quantitation
• Monitoring disease progression
• Confirmation and Identification of MP
• Immunofixation electrophoresis (IFE)
• Interpretation of pattern

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