1. MULTIPLE MYELOMA (MM)

2. 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

3. CASE STUDY – MULTIPLE MYELOMA
CBC with diff
WBC K/uL
RBC M/uL
Platelets K/uL
Hemoglobin g/dL
Hematocrit %
CMP
BUN mg/dL
Creatinine mg/dL
Total protein g/dL
Albumin g/dL
Urinalysis
Protein < mg/dL

9. CASE STUDY – MULTIPLE MYELOMA
Serum free light chains
Free kappa – mg/L
Free lambda – mg/L
Ratio – 1.7
Interpretation
Free lambda light chain monoclonal gammopathy
Radiology
Diffuse osteolytic lesions in thoracic and lumbar regions with several compression fracturres

11. 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 in biceps, triceps, left elbow and shoulder

12. 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

13. CASE STUDY – MULTIPLE MYELOMA
CBC with diff
WBC – K/uL
RBC – M/uL
Platelets – K/uL
Hemoglobin – g/dL
Hematocrit – %
CMP
BUN – mg/dL
Creatinine – mg/dL
Calcium – mg/dL
Total protein – g/dL
Urinalysis
Protein < mg/dL

18. CASE STUDY – MULTIPLE MYELOMA
Serum free light chains
Free kappa – mg/L
Free lambda , – mg/L
Ratio
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

21. MONOCLONAL GAMMOPATHIES (PLASMA CELL DISORDERS)
Diseases characterized by uncontrolled proliferation of a single clone of plasma cells
Multiple myeloma
Waldenstrom’s macroglobulinemia
AL amyloidosis
Heavy chain disease
Light chain disease
Plasmacytoma
Monoclonal gammopathy of undetermined significance (MGUS)

22. MULTIPLE MYELOMA (MM)
A neoplastic (malignant) proliferation of a single clone of plasma cells in bone marrow
Major laboratory diagnostic criteria
>10% 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

24. 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

25. 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

26. VARIANT FORMS OF MULTIPLE MYELOMA
Non-secretory multiple myeloma
No monoclonal protein detected
Myeloma cells unable to secrete M protein
Bone marrow plasma cells > 10%
Anemia, hypercalcemia, lytic bone lesions or renal insufficiency
Smoldering multiple myeloma (SMM)
M protein > 3.0 g/dL
No anemia, hypercalcemia, lytic bone lesion or renal insufficiency

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

28. 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 (< 1%)
IgD (<1%)
IgE (<1%)

29. 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

30. 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 IG’s
Characteristic of myeloma cells
Translocation of IG heavy chain gene (14) to proto-oncogenes (11, 16, 20)
Missing all or part of chromosome 13

31. 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 31

32. 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

33. 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 < 2.0 mg/dL (A)
Serum creatinine > 2.0 mg/dL (B)
International Staging System (ISS)
Beta-2-microglobulin (B2M) level
Albumin level

34. DURIE-SALMON STAGING SYSTEM
Stage I
Concentration of M proteins
IgG < 5 g/dL
IgA < 3 g/dL
BJP < 4g/24 hours
No bone lesions
Hemoglobin > 10.5 g/dL or Hematocrit > 32%
Normal calcium level
Stage II
Neither I nor III

35. DURIE-SALMON STAGING SYSTEM
Stage III
Concentration of M protein
IgG > 7 g/dL
IgA > 5 g/dL
BJP > 12 g/24 hours
> 3 lytic bone lesions
Hemoglobin < 8.5 g/dL or Hematocrit < 25%
Calcium > 12 mg/dL

36. INTERNATIONAL STAGING SYSTEM (ISS)
Stage I
Beta-2-microglobin (B2M) < 3.5 mg/L
Albumin > 3.5 g/dL
Stage II
B2M < 3.5 mg/L
Albumin < 3.5 g/dL OR
B2M of 3.5 to 5.5 mg/L with any albumin level
Stage III
Beta-2-microglobulin (B2M) > 5.5 mg/L

37. TREATMENT OF MULTIPLE MYELOMA
No cure for MM
Median survival time
Stage I
60 months
Stage II
45 months
Stage III
30 months

38. TREATMENT OPTIONS IN MULTIPLE MYELOMA
Chemotherapy
Melphalan (Alkeran)
Cyclophosphamide (Cytoxan)
Vincristin (Oncovin)
Doxorubicin (Adriamycin)
Immunotherapy
Thalidomide (Thalomid)
Lenalidomide (Revlumid)
Bortezomib (Velcade)

39. TREATMENT OPTIONS IN MULTIPLE MYELOMA
Corticosteroids
Prednizone
Stem cell transplantation
Autologous
Allogenic
Radiation therapy
Best initial therapy
Melphalan / Prednizone / Thalidomide (MPT)

40. 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

45. 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)

46. 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

48. 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

50. 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

51. URINE PROTEIN ELECTROPHORESIS (UPE / UPEP)
Screen for (detection of) protein abnormalities
Monoclonal gammopathy
Glomerular proteinuria
Selective or non-selective
Tubular proteinuria
Overflow proteinuria

52. 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

53. 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