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Multiple Myeloma
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Multiple Myeloma• Definition: Malignant proliferation of plasma cells
derived from a single clone• Etiology: radiation;mutations in oncogenes;
familial causes;role of IL 6• Incidence/Prevalence: 14,400 cases in 1996;
incidence 30/1,00,000• Incidence increases with age• Males> females ; Blacks > Whites
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Clinical Manifestations• Common
– bone pain and pathological fractures
– anemia and bone marrow failure
– infection due to immune-paresis and neutropenia
– renal impairment
• Less common– acute hypercalcemia
– symptomatic hyperviscosity
– neuropathy
– amyloidosis
– coagulopathy
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Clinical Manifestations• Bone Pain:
– 70%,Precipitated by movement
– Pathological fractures
– Activation of Osteoclasts by OAF produced by myeloma cells
• Susceptibility to infections:– Diffuse hypogammaglob. If the M spike is excluded
– Poor Antibody responses ,Neutrophil dysfunction
– Pneumococcus,S.aureus,GN aerobes-Pneumonia,Pyelonephrits
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Clinical Manifestations• Renal failure: 25%
– Multiple contributory factors
– Hypercalcemia,Hyperuricemia,recuurent Infections
– Tubular damage produced by Light chains
– type 2 proximal RTA,Non selective proteinuria
• Anemia: 80%– Normochromic/Normocytic
– Myelophthisis;Inhibition by cytokines produced by plasma cells.
– Leukopenia/thrombocytopenia only in advanced cases.
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Bone Disease
• Lytic Lesions – 60%
• Osteoporosis, Fx, Compression Fx – 20%
• Myeloma Cells Produce Cytokines that:– Stimulate Osteoclastic Activity– Inhibit Osteoblastic Activity
• Can be Detected by Plain Xray
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Lytic lesions(Punched out lesions) on X Ray.
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Vertebral collapse secondary to osteoporosis/pathological fracture
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Multiple myeloma: lesion in rib – Lab 11
Lesion
Normal bone
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Multiple myeloma: multiple lesions in skull – Lab 11
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Renal Disease
• Serum Cr Elevated in 50% and >2 in 20% at Diagnosis• Cast Nephropathy (Myeloma Kidney)
– Large, Waxy Casts in Distal Tubules composed of Precipitated Light Chains
• Not detected on Dipstick
– SSA Test – Positive detected as the degree of turbidity when SSA added to urine suggests presence of non-albumin proteins
• Hypercalcemia• Amyloidosis
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Case Report of Myeloma nephropathy
• Bone marrow biopsy: 70% cellularity, increased atypical plasma cells comprising 60% of cellularity, c/w multiple myeloma
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Epidemiology of Myeloma nephropathy
• In two large multiple myeloma studies, 43% (of 998 pts) had a creatinine > 1.5 and 22% (of 423 pts) had a Cr > 2.0
• The one-year survival was 80% in pts with Cr < 1.5 compared to 50% in pts with a Cr > 2.3
• Prognosis is especially poor in pts who require dialysis
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Causes of renal failure in MM
• Cast nephropathy
• Light chain deposition disease
• Primary amyloidosis
• Hypercalcemia
• Renal tubular dysfunction
• Volume depletion
• IV contrast dye, nephrotoxic meds
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Myeloma Kidney
• Two main pathogenetic mechanisms:– Intracellular cast formation
– Direct tubular toxicity by light chains
• Contributing factors to presence of renal failure due to multiple myeloma:– High rate of light chain excretion (tumor load)
– Biochemical characteristics of light chain
– Concurrent volume depletion
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Cast Nephropathy
• Most common pathological diagnosis on renal biopsy in multiple myeloma
• Due to light chains binding with Tamm-Horsfall mucoprotein, which is secreted by tubular cells in ascending loop of Henle, forming casts
• Multinucleated giant cells surround the casts• Dehydration worsens cast nephropathy due to
decreased flow in tubules, increased concentration of light chains
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Cast Nephropathy
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Cast Nephropathy
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Cast Nephropathy
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Minimal diagnostic criteria for myeloma
• >10% Plasma cells in bone marrow or plasmacytoma on biopsy
• Clinical features of myeloma
• Plus at least one of:– Serum M band (IgG >30 g/l; IgA >20 g/l)– Urine M band (Bence Jones proteinuria)– Osteolytic lesions on skeletal survey
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Initial Work-up
• CBC w/diff – peripheral smear– Normocytic, Normochromic Anemia most common– Rouleaux Formation >50% of patients
• Chemistry (ca, alb, cr, LD, CRP, B2M)• SPEP – Monoclonal Protein• Serum Viscosity (if M-protein conc. Is high, >5g/dL) or sx
of hyperviscosity are present• UA and UPEP• Metastatic bone Survey• Bone Marrow Biopsy
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Rouleaux formation
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M protein• Amount of the M protein -marker of tumor load• Nature variable:
– May be an intact molecule or a fragment– Extramedullary / Solitary plasmacytomas <1/3
have M spike– 20% of Myelomas _ only Light Chains
produced– Non Secretory Myelomas_rare– frequency of myelomas : Ig G> IgA > IgD
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1.Normal Plasma 2.Polyclonal Hyperglobulinemia 3.Monoclonal Spike4.Bence Jones proteins in urine
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Plasmapheresis in MM
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Diagnostic Criteria
• Presence of an M-Protein in serum and/or urine
• Presence of clonal bone marrow plasma cells or plasmacytoma
• Presence of Related Organ/Tissue involvement– Hypercalcemia, renal insufficiency, anemia,
lytic bone lesions
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Screening and Diagnosis
• Blood and urine tests
• X-rays
• Magnetic Resonance Imaging (MRI)
• Computerized Tomography (CT)
• Bone marrow examination
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Normal Cell (5%)
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Myeloma Cells (10%)
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Plasma Cell
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Bone Marrow Aspirate
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Bone Marrow Aspirate
• Usually >10% plasma Cells, but can be from 5-100% – ≥ 50% involvement – worse prognosis
• Immunoperoxidase staining detects either kappa or lambda light chains, NOT both (confirming proliferation is monoclonal)
• Immunophenotyping – Malignant Plasma Cells stain positive for CD38, CD56, and CD138
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Bone Marrow Biopsy
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Staging
• Stage 1 – Low amount of myeloma
• Stage 2– Medium amount of myeloma
• Stage 3 – High amount of myeloma
• A– Normal kidney function
• B– Abnormal kidney function
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International Staging System
• Stage I – B2M <3.5 mg/L and serum alb ≥ 3.5 g/dL
• Stage II – neither stage I nor Stage III
• Stage III – B2M ≥ 5.5 mg/L
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Staging 1.• Hb/Serum Ca/M component level/radiology
– Stage I: Hb >10;Serum Ca < 12;Normal Bone survey;Low M component levels
– Stage III: HB < 8.5, Serum Ca >12;Lytic lesions+;High M component levels
– Stage II : Intermediate
• Divided into A or B depending on Serum Creatinine level < or > than 2 mg/dl.
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Staging 2 • Serum b2 microglobulin levels.
• If < 0.004 g/L : Stage 1; Median survival 43 months
• If >0.004 g/L: Stage II; Median survival 12 months
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Prognostic Factors
• Performance status 3 0r 4• Serum albumin < 3 g/dL• Serum Cr ≥ 2.0 mg/dL• Platelet Count <150,000• Age ≥ 70 years• Beta-2-microglobulin >4 mg/L• Serum Calcium ≥ 11 mg/dL• Hemoglobin <10 g/dL
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Treatment • Options:
– melphalan with or without prednisone– Infusional chemotherapy - vincristine and
adriamycin infusion plus either dexamethasone all methylprednisolone
– combination therapy - for example, adriamycin, carmustine, cyclophosphamide, and melphalan
– weekly cyclophosphamide (“C weekly”)
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Treatment• Prompt reduction in bone
pain,anemia,hypercalcemia.• M component lags behind -4-6 weeks to fall• 60% of patients will acieve a 75% reduction in
tumor mass.• Treat q 4-6 weeks for 1-2 years.• Leads to a plateau phase- relapse within a year.• Maintenance: alpha Interferon ???
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Treatment• Supportive therapy
– analgesia– rehydration– treatment and any hypercalcemia– treatment of any renal impairment– treatment of any infection– local radiotherapy if required– chemotherapy– prevention of further bone damage
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Treatment• Melphalan and Prednisone (Oral)
– Preferred Tx in pts NOT going for BMT– 7 day course repeated q 6weeks (x 3)– Objective response in 50-60%, MS of 2-3 yrs
• Melphalan, prednisone, and Thalidomide– RR of 93% with 26% CR– When compared to above regimen, had better CR and
RR; however, more toxicity• Thalidomide with or w/o Dexamethasone
– Preferred in Candidates for BMT– For pts with Relapsed or Resistent Disease
• VAD (Vincristine, Dex, and Adriamycin)• Radiation – Reserved for pts with focal process that
has not responded to chemo
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Treatment Outcomes
• Cure – Not yet been Achieved• Molecular Complete Response
– No evidence of Disease
• Complete Response– No detectable M protein AND nml % of Plasma cells
in Bone Marrow
• Progressive Disease– >25% increase in M Protein, new bony lesions, or a
new plasmacytoma
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MGUS: Monoclonal gammopathy of undetermined significance
• No explained symptoms suggestive of myeloma• Serum M protein concentration < 30 g/l• < 5 percent plasma cells in bone marrow• Little or no M protein in urine• No bone lesions• No anemia, hypercalcemia, or renal impairment• M protein concentration and other results stable on
prolonged observation