Multiple Myeloma and Related Myeloma Smolderimg Multiple Myeloma Plasma cell ... (SPEP/UPEP)...

download Multiple Myeloma and Related   Myeloma Smolderimg Multiple Myeloma Plasma cell ... (SPEP/UPEP) – Gamma-globulins • Polyclonal gammopathy:

If you can't read please download the document

  • date post

    04-May-2018
  • Category

    Documents

  • view

    213
  • download

    1

Embed Size (px)

Transcript of Multiple Myeloma and Related Myeloma Smolderimg Multiple Myeloma Plasma cell ... (SPEP/UPEP)...

  • Multiple

    Myeloma and

    Related

    Disorders

    Zsolt Nagy

  • Outline

    Biology

    Plasma Cell Dyscrasia

    MGUS

    Plasmacytoma

    Multiple myeloma

    Smoldering

    POEMS

    Waldenstroms Macroglobulinemia

    Amyloidosis

  • Classification of Monoclonal Gammopathies

    Monoclonal Gammopathy of Undetermined Significance "Benign"/idiopathic

    Associated with other diseases (autoimmune, infectious, non-heme cancer, etc)

    Plasma cell or lymphoid malignancy Waldenstrom's macroglobulinemia

    Other lymphoproliferative disorders

    Multiple Myeloma

    Smolderimg Multiple Myeloma

    Plasma cell leukemia

    IgD myeloma

    POEMS

    Plasmacytoma

    Heavy Chain disease

    Amyloidosis

  • The Continuum of Plasma Cell Disorders

    Normal MGUS Indolent Multiple

    Myeloma Myeloma

  • Myeloma, Malpas et al. 2004

  • The hallmark of plasma cell disorders is the

    presence of a paraprotein in the serum

    and/or urine.

  • Paraproteinemias

    Normal immunoglobulin pattern

    Polyclonal reflects progeny of different

    plasma cells

    Paraproteinemia

    Monoclonal immunoglobulin band in sera

    reflects synthesis from single plasma cell

    clone

  • SPEP

    Polyclonal

    Gammopathy

    Monoclonal

    Gammopathy

  • Normal Immunoelectrophoresis

  • Presentation of Plasma Cell Disorders

    Increased protein on a routine chemistry

    panel

    Anemia

    Bone pain

    Renal dysfunction

    Hypercalcemia

  • Pathophysiology: Monoclonal B-

    Cells/Plasma Cell Dyscrasia Marrow replacement

    Cytopenias

    Constitutional symptoms

    Decreased quantitative immunoglobulins

    Infections

    Lytic bone lesions

    Fractures

    Hypercalcemia

    Extramedullary involvement

    Plasmacytomas

    Organomegaly

  • Pathophysiology: Monoclonal

    Immunoglobulin Proteins Heavy chains or Light chains in serum, urine,

    kidney or other tissues

    Renal insufficiency

    Neurologic disease

    Hyperviscosity

    Cold Agglutinin disease

    AL Amyloidosis

    POEMS: Polyneuropathy, Organomegaly, Endocrine disturbances, M-protein, Skin changes

  • Solitary or extramedullary plasmacytoma

    3% (27)

    Chronic lymphocytic leukaemia 2% (21)

    Waldenstrms macroglobulinaemia 2% (20)

    MGUS 56% (578)

    Multiple Myeloma 18%

    (185)

    Lymphoma 5% (50)

    Amyloidosis (AL) 10%

    (106)

    Smouldering myeloma 4% (39)

    RA Kyle in: Myeloma Biology & Management, 1995

    M-protein at the Mayo Clinic

  • MGUS

    Diagnosis

    Serum M-protein

    Usually IgG or IgA, usually

  • Other diseases associated

    with M-protein

    Autoimmune diseases (RA, SLE, scleroderma)

    Skin diseases (pyoderma gangraenosum)

    Liver disease (cirrhosis)

    Infectious diseases (m.tuberculosis, Hep C,HIV)

    ..

  • NEJM 2002;346:564. Kyle ASH

    2002 #384.

    MGUS Progression

    1384 patients at Mayo

    MGUS: 1% per year progression

    Relative risk 25x (myeloma), 46x (Waldenstroms),

    8.4x (amyloid), 2.4x (lymphoma)

    IgM MGUS: 1.5% per year

    Predictors

    Size of M-spike (> 2.5 g/dL, 41% at 10 yr)

    Serum albumin

  • NEJM 2002;346:564

    MGUS Progression: 1% per Year

  • Diagnostic work-up MGUS

    LAB

    CBC

    Serum Ca/alb and creatinin

    Serum protein electrophoresis (EF) and immunofixation (IF)

    Quantification of immunoglobulins

    24-hour urine albumin, EF +IF

    Skeletal X rays

    Bm aspirate/biopsy if M-protein > 15 g/l

    IgA or IgM M-protein

    Abnormal free light chain ratio

    CT thorax/abdomen if IgM paraprotein (m.Waldenstrom)

  • MGUS: Management

    Testing

    CBC, calcium, creatinine, SPEP with immunofixation, quantitative immunoglobulins, 24-hour urine protein (with UPEP and immunofixation if positive)

    If M-protein 2-3 g/dl, add bone marrow and skeletal survey

    F/U

    SPEP/H&P repeated in 6 months, then annually

  • Multiple Myeloma and

    Related Disorders

    Definition:

    A group of diseases that involve

    malignant proliferation of Ig-secreting

    cells of B-cell lineage that are usually

    associated with paraproteinemia or

    paraproteinuria.

  • Multiple Myeloma

    US Incidence: 15,000 new cases/year

    1% of malignancies

    US Prevalence: 65,000 cases/year

    Double incidence rate in African Americans

    Median age 65

    3%

  • Etiology

    Etiology is not known.

    Risk factors: Race, sex.

    Increased risk with ionizing radiation and

    exposure to pesticides like Dioxin.

    Recently viruses like HHV-8 and SV-40,

    have been linked to myeloma development.

  • Pathogenesis

    Bone marrow microenvironment very important

    for proliferation and chemotherapy resistance.

    BM stromal cells produce IL-6, responsible for

    pathogenesis and progression.

    IL-6 inhibits apoptosis of plasma cells.

    IL-6 contributes to bone loss by stimulating

    osteoclasts and inhibiting bone formation.

    Interaction with extracellular matrix proteins

    protect cells from chemo and radiation.

  • MM: Clinical Features

    Disease of the elderly (7th decade)

    Bone pain

    most commonly vertebra and long bones

    lytic lesions

    fractures

  • Myeloma: Clinical Features

    Bone pain: often with loss of height

    Constitutional: weakness, fatigue, and weight loss

    Anemia

    Renal disease: renal tubular dysfunction

    Infections: neutropenia/hypogammaglobulinemia

    Hypercalcemia: myeloma cells secrete osteoclast-activating

    factors

    Hyperviscosity: 2% with myeloma; 50% with

    macroglobulinemia

    Neurologic dysfunction: spinal cord or nerve root compression

  • Major Symptoms at Diagnosis

    Bone pain: 58%

    Fatigue: 32%

    Weight loss: 24%

    Paresthesias: 5%

    Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.

    11% of patients are asymptomatic or have only mild symptoms at diagnosis

  • Multiple Myeloma

    Typical Punched Out Lesions

  • Multiple Myeloma

  • Diagnostic Criteria for Myeloma

    1. IMWG. Br J Haematol. 2003;121:749-757. 2. Kyle RA, et al. N Engl J Med. 2002;346:564-569.3. Durie BG, et al. Hematol J. 2003;4:379-398.

    Patient Criteria MGUS[1,2] Smoldering

    Myeloma[1]Active Myeloma

    M protein < 3 g/dL spike 3 g/dL spike

    and/or

    In serum

    and/or urine[2]

    Monoclonal

    plasma cells in

    bone marrow, %

    < 10 10 10[2]

    End-organ

    damage

    None None 1 CRAB*

    feature[3]

    *C: Calcium elevation (> 11.5 mg/L or ULN)R: Renal dysfunction (serum creatinine > 2 mg/dL)A: Anemia (Hb < 10 g/dL or 2 g < normal)B: Bone disease (lytic lesions or osteoporosis)

    Only patients with symptomatic MM should be treated

  • Multiple Myeloma Diagnosis(1 major+1 minor or 3 minor)

    Major Criteria

    Plasmacytoma on

    tissue biopsy

    30% Marrow

    plasmacytosis

    M-protein

    3.5 g/dL IgG

    2 g/dL IgA

    1g/24 hr urine Bence

    Jones

    Minor Criteria

    10-29% Marrow

    plasmacytosis

    M-protein

    Less than major

    Lytic bone lesions

    Low immunoglobuins

    IgM

  • Kyle, Mayo Clin Proc, 2003.

    Newly Diagnosed Multiple

    Myeloma: 1985-1998

    N=1027

    Median age: 66 years

    Median survival: 33 months

    Did not improve 1985 through 1998

    Multivariate analysis

    Age, plasma cell labeling index, thrombocytopenia, serum albumin, creatinine (log value)

  • Kyle, Mayo Clin Proc, 2003.

    Newly Diagnosed Multiple

    Myeloma: 1985-1998

    0%

    10%

    20%

    30%

    40%

    50%

    60%

    70%

    80%

    90%

    100%

    Ca Cr >2 Anemia Skel Surv UPEP SPEP

  • Myeloma Diagnostic Work-Up

    SPEP and UPEP (24 collection) with immunofixation

    3% nonsecretory: check serum free light chains

    Skeletal survey (not a bone scan)

    Quantitative serum immunoglobulins (IgA, IgG, IgM)

    Bone Marrow Aspirate and Biopsy

    Other tests (calcium, creatinine, beta-2 microglobulin, CRP, albumin, plasma cell labeling index, etc, etc) are only for staging/prognosis

  • M-Protein Tests

    Urine Dipstick not sensitive to Bence Jones proteins, need sulfosalicylic acid (SSA)

    Screening (SPEP/UPEP)

    Gamma-globulins

    Polyclonal gammopathy: liver disease, connective tissue disease, chronic infection, others

    Hypogammaglobulinemia: Immunodeficiency, nephrotic syndrome (amyloidosis), myeloma/CLL

    Monoclonality

    Immunofixation with monospecific antibodies

    Immunoelectrophoresis

    Immunoassay for serum free light chains (Mayo Clinic)

  • Myeloma Prognostic Work-Up

    Hemoglobin

    Calcium

    Serum creatinine

    Beta-2 microglobulin

    Albumin

    B