Multiple Myeloma. Definition: Malignant proliferation of plasma cells derived from a single clone...
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Transcript of Multiple Myeloma. Definition: Malignant proliferation of plasma cells derived from a single clone...
Multiple Myeloma
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
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
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
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.
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
Lytic lesions(Punched out lesions) on X Ray.
Vertebral collapse secondary to osteoporosis/pathological fracture
Multiple myeloma: lesion in rib – Lab 11
Lesion
Normal bone
Multiple myeloma: multiple lesions in skull – Lab 11
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
Case Report of Myeloma nephropathy
• Bone marrow biopsy: 70% cellularity, increased atypical plasma cells comprising 60% of cellularity, c/w multiple myeloma
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
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
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
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
Cast Nephropathy
Cast Nephropathy
Cast Nephropathy
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
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
Rouleaux formation
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
1.Normal Plasma 2.Polyclonal Hyperglobulinemia 3.Monoclonal Spike4.Bence Jones proteins in urine
Plasmapheresis in MM
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
Screening and Diagnosis
• Blood and urine tests
• X-rays
• Magnetic Resonance Imaging (MRI)
• Computerized Tomography (CT)
• Bone marrow examination
Normal Cell (5%)
Myeloma Cells (10%)
Plasma Cell
Bone Marrow Aspirate
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
Bone Marrow Biopsy
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
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
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.
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
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
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”)
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 ???
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
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
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
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