MULTIPLE MYELOMA (MM)

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

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 < 30.0 mg/dL

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

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

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

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 < 30.0 mg/dL

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

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)

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

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

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

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• Bone marrow plasma cells > 10%• No anemia, hypercalcemia, lytic bone lesion or renal

insufficiency

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

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%)

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

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

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

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

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)• Three stages (I, II, III)

• Beta-2-microglobulin (B2M) level• Albumin level

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

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

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• Albumin < 3.5 g/dL

TREATMENT OF MULTIPLE MYELOMA

• No cure for MM

• Median survival time• Stage I

• 60 months• Stage II

• 45 months• Stage III

• 30 months

TREATMENT OPTIONS IN MULTIPLE MYELOMA

• Chemotherapy• Melphalan (Alkeran)• Cyclophosphamide (Cytoxan)• Vincristin (Oncovin)• Doxorubicin (Adriamycin)

• Immunotherapy• Thalidomide (Thalomid)• Lenalidomide (Revlumid)• Bortezomib (Velcade)

TREATMENT OPTIONS IN MULTIPLE MYELOMA

• Corticosteroids• Prednizone

• Stem cell transplantation• Autologous• Allogenic

• Radiation therapy

• Best initial therapy• Melphalan / Prednizone / Thalidomide (MPT)

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

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)

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

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

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

URINE PROTEIN ELECTROPHORESIS (UPE / UPEP)

• Screen for (detection of) protein abnormalities• Monoclonal gammopathy• Glomerular proteinuria

• Selective or non-selective

• Tubular proteinuria• Overflow proteinuria

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

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