Blinder 2004 08 20 by HC120727023542

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									Monoclonal Gammopathies
      Morey A. Blinder, M.D.
      Associate Professor of Medicine
      and Pathology & Immunology




          Department of Internal Medicine
          Division of Hematology
Objectives


   Laboratory evaluation of gammopathies
   Diseases associated with gammopathies
   Common clinical syndromes
Properties of human immunoglobulins
        Heavy   Light    Molecular   Serum                      Half-life
Class   Chain   Chain    Weight      Concentration Subclasses   (days)

IgG             or    150,000     700-1450 mg/dl   IgG1        23
                                                      IgG2
                                                      IgG3
                                                      IgG4

IgA             or    170,000     70-370 mg/dl     IgA1         6
                                                      IgA2

IgM             or    900,000     30-210 mg/dl     None         5

IgD             or    185,000     0-14 mg/dl       None         2

IgE             or    200,000     <250 IU/ml       None         2
Clinical indications for the evaluation of
immunoglobulins


 Normochromic normocytic anemia
 Nephrotic syndrome in a non-diabetic patient
 Osteolytic lesions
 Lymphadenopathy
 Non-ischemic heart failure
 Elevated total serum protein
 Hypercalcemia
Lymphoproliferative Disorders Commonly
Associated with a Monoclonal Gammopathy


 Monoclonal gammopathy of undetermined significance
  (MGUS)
 Multiple myeloma
 Waldenstroms macroglobulinemia
 Amyloidosis
Monoclonal Gammopathy of
Undetermined Significance (MGUS)
   Commonly found on serum protein electrophoresis
   Occurs in ~2% of persons > 50 years of age
   Characteristics
    •   Low serum monoclonal protein concentration (<3 g/dl)
    •   Less than 5% plasma cells in bone marrow
    •   Little or no monoclonal protein in urine
    •   Absence of lytic bone lesions
    •   No anemia, hypercalcemia, or renal insufficiency
“Benign Monoclonal Gammopathy” Course of MGUS
in 241 Patients
                                                       Median follow-up
                                                          22 years
Group                      Description                  No.        %


1               No substantial increase of serum         46       19
                or urine monoclonal protein (benign)

2               Monoclonal protein = 3.0g.dl but         23       10
                no myeloma or related disease

3               Died of unrelated causes                 113      47

4               Development of myeloma,                  59       24
                amyloidosis or related disease

Total                                                    241      100

 Am J Med 1978; 64:814-26
 N Engl J Med 2002;346:564-9 (Updated)
Patterns of Monoclonal Protein Increase

                                Multiple myeloma
 Pattern                         No. patients (%)

 Stable with sudden increase          19 (25%)
 Stable with gradual increase          9 (12%)
 Gradual increase                      9 (12%)
 Sudden increase                      11 (15%)
 Stable                               10 (13%)
 Indeterminate                        17 (23%)

 N Engl J Med 2002:346; 564-9
    Summary:
    Monoclonal gammopathies of uncertain significance

   Monoclonal proteins rarely disappear spontaneously (<5%)
   MGUS is a risk factor for multiple myeloma and related
    disorders
   Risk of progression to multiple myeloma or related
    disorders is increased with higher initial monoclonal protein
    levels
   Risk of progression is ~1 % per year
Multiple Myeloma: Incidence and Etiology
 13,000 cases/year in USA
 Median age - 65 yrs.
 Incidence in African-Americans is two-fold other ethnic
  groups
 Familiar clusters are rare
 Environmental/occupational exposures have been
  implicated
Multiple Myeloma: Clinical Manifestations
 Bone pain/skeletal involvement
 Fatigue/anemia
 Renal insufficiency
 Hypercalcemia
 Neurologic symptoms
 Infections
Laboratory evaluation

   CBC with peripheral smear
   Chemistry panel (Include calcium and creatinine)
   SPEP/UPEP (immunofixation electrophoresis)
   Urinalysis/24 hr urine for protein
   Bone marrow exam
   Skeletal survey
   LDH and b2-microglobulin
   Serum viscosity
Peripheral smear: Plasma cell
Bone marrow aspirate: Plasma cell infiltrate
Diagnostic Criteria for Multiple Myeloma
    Major criteria
     I. Bone marrow plasmacytosis > 30%
     II. Histologic diagnosis of plasmacytoma
     III. Serum paraprotein IgG > 3.5 g/dl or IgA > 2.0 g/dl
    Minor criteria
     a. Bone marrow plasmacytosis 10-30%
     b. Serum paraprotein less than major criteria
     c. Osteolytic lesion
     d. Hypogammaglobulinemia

     One major criteria and one minor criteria
     Minor criteria a + b and one other
Staging Classification for Multiple Myeloma
Stage        Criteria
I            All of the following:
                    Hemoglobin > 10 g/dl
                    Normal serum calcium
                    No generalized osteolytic lesions
                    Low paraprotein level
                             IgG < 5 g/dl
                             IgA < 3 g/dl
                    Urine light chains < 4g/24 hours
II           Intermediate between stage I and III
III          One or more of the following:
                    Hemoglobin < 8.5 g/dl
                    Serum calcium > 12 g/dl
                    Diffuse osteolytic lesions
                    High paraprotein level
                            IgG > 7 g/dl
                            IgA > 5 g/dl
                    Urine light chains > 12 g/dl
Smouldering Myeloma

   Criteria
     Presence of                   Absence of
       Plasmacytosis < 30%          Hemoglobin > 10 g/dl
       Serum paraprotein <5 g/dl    Normal renal function
                                    Normal serum calcium
                                    No osteolytic lesions
                                    Little or no urine paraprotein


   Median time to progression - 26 months

   No therapy indicated in asymptomatic patients
Treatment of Multiple Myeloma:
Principles of therapy
   Conventional treatment rarely results in complete
    remission

   Achieve disease stabilization

   Asymptomatic patients often need not be treated
Initial Treatment of Multiple Myeloma
Conventional-dose therapy




    Melphalan and prednisone

    VAD (Vincristine, adriamycin, and dexamethasone)

    High dose glucocorticoids (dexamethasone)
Adjunctive therapy in Multiple Myeloma

   Treatment of skeletal lytic lesions

   Treatment of anemia
Bisphosphonate therapy
   Backbone chemical structure:
                             OH      R1    OH

                            O=P–C–P=O

                             OH      R2    OH
   Pharmacokinetics
    • Plasma half-life 1-6 hours; skeletal half-life >100 days
    • Cleared by kidneys
   Mechanism of action
    • Inhibits development to mature osteoclasts
    • Inhibit osteoclast activity
Treatment of Multiple Myeloma
Treatment of skeletal events



  Pamidronate (Bisphosphonate)

         Inhibits osteoclastic activity

         Treatment of cancer-associated hypercalcemia,
         bone metastasis and multiple myeloma

         Dose: 90 mg IV over 4 hrs. monthly
N Engl J Med 1996:334;488-93
Zoledronic acid vs. Pamidronate in the Treatment of
Osteolytic Lesions of Multiple Myeloma


Proportion of Patients with any Skeletal-related Event at Month 13

                        No. of patients (%)

  Zoledronic acid                                 Pamidronate
(4mg IV over 15 min)                          (90mg IV over 4 hours)

   86/183 (47%)                                   82/167 (49%)


Cancer Journal 2001:7;377-87
Erythropoietin for the treatment of
anemia in multiple myeloma

   Erythropoietin 150U/kg sq tiw (40,000U sq q week)
    •   Decreased incidence of RBC transfusion
    •   Increased Hgb ~2 g/dl after 12 weeks of therapy
    •   Significant improvement in quality of life measures
    •   Improved performance status
    •   Well tolerated with rare adverse events
Newer approaches to the treatment of
multiple myeloma
   Thalidomide - A revival story
    • Possible mechanisms:
       – Direct anti-angiogenic effect
       – Direct effect on growth and survival of plasma cells or bone marrow
         stromal cells
       – Oxidative damage to tumor DNA mediated by free radicals (Teratogenic
         effect)
       – Decreased adhesion to or cytokines from bone marrow stromal cells
       – Inhibit vascular endothelial growth factor (VGEF)to block angiogenesis

    • Dose: 200-800 mg po qd
  Thalidomide for Relapsed Multiple Myeloma


                   Number              PR/stable       Overall
                   patients     CR     disease        response (%)

Singhal (1999)       84          2        25               33
Kneller (2000)       17          0        11               64
Juliusson (2000)     23          0        16               69

• Responses within 1-3 months
• Side effects: Constipation; weakness and fatigue; somnolence
New approaches to the Initial Treatment
of Multiple Myeloma
   Thalidomide + Dexamethasone
    • Reasonable alternative to VAD

   Chemotherapy + Thalidomide
    • Increased risk of venous thrombosis (~20% at 1 year)

   Chemotherapy + Autologous transplantation (10 studies)
    • Complete response rate     25-50%
    • Median event free survival 24-48 months
Experimental approaches for the
treatment of Multiple Myeloma
   Allogeneic transplantation (8 studies)
    • Complete response rate     26-51%
    • Median event free survival 12-36 months
   Revimid (CC-5013) Thalidomide derivative
    • Phase II study
   PS-341 Proteosome inhibitor - Cytotoxic to plasma cells
    • Phase II study
Waldenstroms Macroglobulinemia
Incidence and clinical features


    1,500 cases/year in USA
    Median age -, 63 yrs
    Presenting symptoms
      • Weakness and fatigue         44%
      • Hemorrhagic manifestations   44%
      • Weight loss                  23%
      • Neurologic symptoms          11%
      • Visual disturbances           8%
      • Raynauds phenomenon           3%
Waldenstroms Macroglobulinemia:
Clinical Features
   Tumor infiltration
    • Bone marrow                 90%
    • Splenomegaly                38%
    • Lymphadenopathy             30%
   Circulating IgM
    •   Hyperviscosity syndrome   15-20%
    •   Cryoglobulinemia          5-15%
    •   Cold agglutinin disease   5-10%
    •   Bleeding disorders        10%
   Tissue IgM
    • Neuropathy                  10-20%
    Waldenstroms Macroglobulinemia:
    Approach to Treatment
   Plasmapheresis for circulating IgM complications
   Alkylating-agent based therapy (50-70% response rate)
    •   Chlorambucil and prednisone
    •   Cyclophosphamide
    •   Melphalan
    •   CHOP (Cyclophosphomide, adriamycin, vincristine, prednisone)

   Nucleoside analogues (80-90% response rate)
    • Fludarabine
    • 2-Chloro-deoxyadenosine (2-CdA)
Amyloidosis: Classification and
Biochemical Composition
   Primary amyloidosis
    • Immunoglobulin light chain (AL)
   Secondary amyloidosis
    • Amyloid A protein (AA)
    • Synthesized by liver as an acute phase reactant
   Hereditary amyloidosis
    • Transthyretin-derived amyloid (ATTR)
Primary Amyloidosis: Clinical Features
   Nephropathy                  % involved
    • Renal function loss           80
    • Proteinuria                   75
   Cardiomyopathy
    • Heart failure                 40-50
   Neuropathy
    • Polyneuropathy                36
    • Orthostatic hypotension       26
    • Carpal tunnel syndrome        8
   Enteropathy
    • Hepatomegaly                  57
    • Macroglossia                  32
    • Diarrhea ± Malabsorption      8
Primary Amyloidosis: Histopathology
      Tongue
(Macroglossia)




                 H&E   Congo Red
Primary Amyloidosis: Conventional Therapy
   General measures
    • Delay target organ failure
    • Improve quality of life

   Specific interventions
    • Melphalan and Prednisone
Primary amyloidosis
Key points

1. Suspect amyloidosis when a patient has unexplained:
    Nephrotic range proteinuria with or without renal insufficiency
    Cardiomyopathy manifested by fatigue or CHF
    Peripheral neuropathy
    Hepatomegaly

2. Pursue diagnosis if:
    A monoclonal protein is detected in serum or urine

3. Confirm diagnosis with Congo red stain of:
    Bone marrow
    Subcutaneous fat
    Other affected tissue

4. Perform echocardiogram to assess prognosis

5. Begin systemic treatment
Common clinical syndromes
associated with monoclonal gammopathies

       Bleeding disorders

       Hyperviscosity

       Cryoglobulinemia

       Peripheral neuropathy
Hemostatic defects associated with
Monoclonal proteins

 Effect on hemostasis                  Assay

 Inhibition of platelet aggregation    Bleeding time

 Inhibition of fibrin polymerization   Thrombin time

 Acquired von Willebrand disease       VWF activity and antigen

 Acquired factor X deficiency          Factor X activity
Acquired factor X deficiency

     Low factor X levels (<50%)
     Severe bleeding with activity <10%
     Associated with amyloidosis
     Factor X binds to amyloid deposits in tissues
     Treatment
      • Underlying amyloidosis
      • Splenectomy
      • Large volumes of FFP/plasma exchange
Hyperviscosity syndrome

   Associated with Waldenstroms macroglobulinemia (15-20% of
    patients)
   Measure serum viscosity (normal <1.8)
   Clinical syndrome of hyperviscosity occurs >4.0
   Symptoms
    •   Headaches
    •   Other neurologic symptoms (dizziness, mental status changes
    •   Blurry vision
    •   Easy bleeding
Cryoglobulinemia
    Type I (monoclonal) cryoglobulin
    Associated with any lymphoproliferative disorder
     • Waldenstroms macroglobulinemia 10-20%
    Symptoms
     •   Raynaud phenomenon
     •   Purpura
     •   Renal insufficiency
     •   Arthralgia
    Blood handling is difficult
     •   Collect blood in 37° C tube
     •   Transport and centrifuge at 37° C
     •   Chill serum to 4° C for 48 hrs
     •   Assay for cryoglobulin
Peripheral smear: Cryoglobulinemia
Neuropathies associated with
monoclonal protein disorders
   Associated with any lymphoproliferative disease

   Target antigens are occasionally identified (MAG; myelin
    associated glycoprotein)

   Symmetric, distal, sensory or sensorimotor

   May simulate CIDP (Chronic inflammatory demyelinating
    polyneuropathy)

   Associated with any class of monoclonal protein
Summary

   Lymphoproliferative disorders associated with
    monoclonal proteins are common

   Diagnosis may be difficult

   Treatment requires identification of underlying
    disease and any associated clinical syndromes

								
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