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 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 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 31

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) 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

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