Laboratory Examination

Transcription

1 Todd Zimmerman, M.D. 64 year old African American male presents to establish care with PCG. Meds: Norvasc 5 mg daily PMHx: HTN x 20 years, poorly controlled SHx: No tobacco, illicit; rare EtOH ROS: Negative Physical Examination:Unremarkable except for obesity; BP 158/92; +S4 1

2 Laboratory Examination CBC unremarkable Chemistry Panel: Glucose (fasting): 115 mg/dl Creatinine 1.8 mg/dl Total Protein 9.8 gm/dl Albumin 3.6 gm/dl Evaluation of elevated total protein Serum chemistry Total Protein 9.8 g/dl Albumin 3.6 g/dl 2

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4 Further laboratory examination SPEP reveals monoclonal protein measuring 2.3 gm/dl Immunofixation IgG/kappa Quantitative Immunoglobulins IgG 2,500 mg/dl IgA 130 gm/dl IgM 84 mg/dl Urinalysis: trace protein HgbA1C: 8.5 CRAB Criteria HyperCalcemia Renal insufficiency Anemia Bone disease CRABI Infections 4

5 MGUS Classification Characteristics Management Smoldering MM Symptomatic MM Serum M protein <3 g/dl Bone marrow plasma cells <10% if done Absence of anemia, renal failure, hypercalcemia, and lytic bone lesions Serum M protein >3 g/dl and/or Bone marrow plasma cells >10% if done Absence of anemia, renal failure, hypercalcemia, and lytic bone lesions Presence of serum/urine M protein Bone marrow plasmacytosis Anemia, renal failure, hypercalcemia, or lytic bone lesions Observation with treatment beginning at disease progression Observation, with treatment beginning at disease progression Immediate treatment BMBx: 9% kappa light chain restricted plasma cells: Cytogenetics normal male karyotype; FISH deletion 13 Skeletal Survey: No lytic lesions UPEP: 90 mg/24 hour, no monoclonal detected Serum Free Light Chains Kappa 3.2 mg/dl Lambda 2.8 mg/dl Ratio

6 M-spike 2.3 gm/dl Bone Marrow Biopsy 9% plasma cells Renal insufficiency Light chain nephropathy (Myeloma kidney) Tubular damage Light chains precipitate in distal tubule More common with lambda myeloma 6

7 Amyloid Kidney Glomerular damage Significant albuminuria; intact Immunoglobulin in urine Miscellaneous Medications (NSAIDs) Hypercalcemia Hyperuricemia Renal Evaluation Creatinine value 3 years ago 1.7 mg/dl MGUS Monoclonal Protein < 3 g/dl Bone Marrow Plasma Cells < 10% No MM related end-organ damage 7

8 Estimated 1-2% in US, Western European M>F (4.0% vs. 2.7%) More common in African Americans (2-3 fold higher) Increases with age >50 3.2% >70 5.3% >85 7.5% Definition M-protein < 3 g/dl < 10% plasma cells No end-organ damage Characteristics Reduction uninvolved Ig 38% Bence-Jones 31% IgD rare Kyle RA et al. NEJM

9 ,384 patients (11,009 p-years) Cumulative probability of progression Years Progression 10% 21% 26% Spontaneous regression 0.4% Relative Risk MM NHL AL WM CLL PC Kyle RA et al. Br J Haematol 2007 Prognostic Model M protein > 1.5 g/dl Non-IgG Abnormal sflc 20 year risk of progression #Risks % Cytogenetics Abnormalities common by FISH No prognostic information Years from diagnosis Rajkumar SV et al, Blood

10 40% 20% 0% 14-20% of MGUS 213 patients with IgM MGUS (1,567 person-years) 29% 38% 31% 16.5% Disease Obs Exp SIR 95% CI NHL AL % 0.50% WM CLL < Initial M-protein (g/dl) Total Kyle RA et al. Blood 2003 Multivariate Analysis Serum albumin (p=.03) Serum M-protein (p=.01) 10-year risk of progression >2.5 41% % % <0.5 14% 0% 10% 20% 30% 40% 50% Years from diagnosis Kyle RA e al. Blood

11 M-spike 2.3 gm/dl Bone Marrow Biopsy 9% plasma cells Renal insufficiency M-spike 2.3 gm/dl Bone Marrow Biopsy 11% plasma cells Renal insufficiency 11

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13 64 year old African American male presents to establish care with PCG. Meds: Norvasc 5 mg daily PMHx: HTN x 20 years, poorly controlled SHx: No tobacco, illicit; rare EtOH ROS: Negative Physical Examination:Unremarkable except for obesity; BP 158/92; +S4 M-spike 2.3 gm/dl Bone Marrow Biopsy 40% plasma cells Renal insufficiency Multiple lytic lesions 13

14 Prevalence 50,000 Americans currently have MM Median age at diagnosis years 19,800 new diagnoses and 11,300 deaths expected in US in 2010 Population subgroups Incidence higher in African Americans Slightly more frequent in men than women Remains mostly incurable % 30 Percentage % 13% 10 8% 9% 7% 7% % 0.2% 1% 1% IgG IgG IgA IgA IgM IgM IgD IgD Free Free Biclonal Negative only only Type of Monoclonal Protein 2% 14

15 Environmental Factors: Petroleum/Benzene exposure Ionizing Radiation Host Factors History of auto-immune disease Rare myeloma families 15

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17 Immunoglogulin Suppression of polyclonal immunoglobulins Increased risk of sino-pulmonary infections Hyperviscosity Autoimmune 17

18 Elevated serum viscosity Symptomatic > 4.0 cp Clinical Syndrome Headache Neurologic deficits Epistaxis Bone Marrow Dysfunction Anemia: Direct marrow infiltration Chemotherapy damage Dilutional 2 nd volume expansion Thrombocytopenia (not common at diagnosis) Leukopenia (not common at diagnosis) 18

19 Bone Disease Lytic lesions Diffuse Osteopenia or Osteoporosis Mixed/Sclerotic Pathophysiology Increased Osteoclastic activity coupled with suppression of osteoblastic activity. 19

20 Hypercalcemia of Malignancy Increased osteoclastic activity Nausea/vomiting, anorexia, weakness/fatigue, somnolence and confusion Dehydration 20

21 Renal Failure Light chain nephropathy (myeloma kidney) Amyloid Kidney Miscellaneous: Hypercalcemia Drugs (NSAID s) Hyperuricemia Amorphous and homogeneous substance Non-branching rigid protein fibrils Congo-red > apple-green birefringence Component of multiple myeloma or Amyloidosis. 21

22 Cardiac Amyloid Restrictive cardiomyopathy Conduction abnormalities Echocardiography Granular, sparkling Thickened septum Renal Amyloid Glomerular damage Albuminuria Nephrotic range proteinuria Renal failure GI Intestinal Deposition Hepatic Muscle Invasion Macroglossia Deltoid Skin Peri-orbital purpura Nerves Peripheral Neuropathy Postural hypotension 22

23 M-protein Characterization SPEP/IEP Quantitative Immunoglobulin 24 hour UPEP/IEP Serum Free Light Chain Assay Complete Blood Count/Peripheral Smear Serum Chemistries BUN, Creatinine, Calcium LDH, Uric Acid Other blood tests C-reactive protein, β 2 -microglobulin 23

24 Radiographic analysis Skeletal Survey Bone scan not indicated MRI/PET Bone Marrow Biopsy/Cytogenetics Fat pad biopsy if indicated Stage I II III Hgb >10 <8.5 Ca Nl >12 mg/dl Xray Nl Adv. Lytic Lesions IgG <5 >7 g/dl IgA <3 >5 g/dl K/L <4 g/24hr >12g/24hr A=Nl Creat, B= Abnl Creat. 24

25 Stage Criteria Median Survival I Serum 2 M <3.5 g/dl Serum albumin 3.5 g/dl 62 mo II Serum 2 M <3.5 g/dl 44 mo Serum albumin <3.5 g/dl OR Serum 2 M 3.5 to <5.5 mg/dl* III Serum 2 M 5.5 g/dl 29 mo *Irrespective of serum albumin level Greipp PR et al. J Clin Oncol. 2005;23:3412 No specific chromosome changes in MM Often normal so FISH beneficial Poor Risk Del 13 (conv. cytogenetics) Del 17p t(4:14) t(14:16) Hypodiploid Good Risk Hyperdiploid t(11:14) 25

26 Plasma Cell Labeling Index (PCLI) IgA phenotype C-reactive protein Elevated LDH Gene Array Standard Chemotherapy Median Survival 3-5 years Response rate 70-90% Autologous Stem Cell Transplantation Median Survival 5-7 years Response Rates % 26

27 Myeloma specific agents Melphalan Corticosteroids Thalidomide Bortezomib (Velcade) Lenalidomide (Revlimid) Supportive Care: Bisphosphonate Erythropoietin Infection Prophylaxis 27