Multiple Myeloma

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Multiple Myeloma

• By Dr. Navinee Vongsupathai

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Multiple Myeloma

• Definition
• Causes and incidence
• Clinical feature
• Physical examination
• Diagnosis
• Classification and staging
• Threatment
• Prognosis

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Definition

• Multiple myeloma as myeloma or plasma cell
  myeloma
• cancer of the plasma cell
• Multiple myeloma
• excessive numbers of abnormal plasma cells in the
  bone marrow
• overproduction of intact monoclonal
  immunoglobulin (IgG, IgA, IgD, or IgE) or
  Bence-Jones protein (free monoclonal ? and ?
  light chains)

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Definition

• Normal Plasma Cell Function in the Immune System
• Stem cells can develop into B lymphocytes --
  gttravel to the lymph nodes, mature, and then
  travel throughout the body.
• When foreign substances (antigens) enter the body
  -- gtB cells develop into plasma cells that
  produce immunoglobulins Ig (antibodies) to help
  fight infection and disease.

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Figure legend In multiple myeloma, the B cell is
damaged and gives rise to too many plasma cells
(myeloma cells). These malignant cells do not
function properly and their increased numbers
produce excess immunoglobulins of a single type
that the body does not need along with reduced
amounts of normal immunoglobulins.
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Figure legend Bone marrow stromal cells and
myeloma cells produce cytokines that help myeloma
cells grow and survive. Myeloma cells also
produce growth factors that stimulate new blood
vessel formation through a process called
angiogenesis. New blood vessels provide nutrients
and oxygen to the tumor, allowing it to grow. The
natural immune response that attacks myeloma
cells is suppressed.
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Definition

• These myeloma cells travel through the
  bloodstream and collect in the bone marrow, where
  they cause permanent damage to healthy tissue.
• As tumors grow, they invade the hard outer part
  of the bone, the solid tissue.
• In most cases, the myeloma cells spread into the
  cavities of all the large bones of the body,
  forming multiple small lesions. This is why the
  disease is known as "multiple" myeloma.

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Incidence

• Multiple myeloma is the second most prevalent
  blood cancer after non-Hodgkin's lymphoma
• 1 of all cancers and 2 of all cancer deaths.
• Age 60-65 years most common
• Occurs in men gt women
• African Americans and Native Pacific Islanders
  have the highest reported incidence of this
  disease and Asians the lowest

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Causes

• Genetic causes
• Ongoing research is investigating whether HLA-Cw5
  or HLA-Cw2 may play a role in the pathogenesis of
  myeloma.
• Environmental or occupational causes
• significant exposures in the agriculture, food,
  silicon ,Benzene, Nikel and petrochemical
  industries
• Radiation
• Radiation has been linked to the development of
  myeloma.
• In 109,000 survivors of the bombing of Nagasaki,
  29 died from myeloma from 1950-1976 however,
  some recent studies do not confirm that these
  survivors have an increased risk of developing
  myeloma.

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Clinical features

• common tetrad of multiple myeloma is CRAB
• C Calcium (elevated)
• R Renal failure
• A Anemia
• B Bone lesions

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Clinical features

• Bone pain
• Myeloma bone disease -- gtproliferation of tumor
  cells and release of IL-6 ltosteoclast activating
  factor OAFgt-- gtstimulates osteoclasts to break
  down bone-- gt leading to hypercalcemia
• These bone lesions in plain radiographs-- gt
  "punched-out" / lytic bone lesion

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Clinical features

• Bone pain
• Myeloma bone pain -- gt involves the rib ,sternum,
  spine , clavicle , skull , humerus femur
• The lumbar vertebrae are one of the most common
  sites of pain -- gtmay lead to spinal cord
  compression.
• Persistent localized pain may indicate a
  pathological fracture.

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Clinical features
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Clinical features
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Clinical features
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Clinical features

• Hypercalcemia
• Pt. present with confusion, somnolence, bone
  pain, constipation, nausea, and thirst.
• Anemia
• The anemia normocytic and normochromic.
• It results from the replacement of normal bone
  marrow by infiltrating tumor cells and inhibition
  of normal red blood cell production
  (hematopoiesis) by cytokines.

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Clinical features

• Bleeding
• bleeding resulting from thrombocytopenia.
• In some patients, monoclonal protein may absorb
  clotting factors and lead to bleeding, but this
  development is rare.
• Hyperviscosity
• high volume of monoclonal protein -- gt blood
  viscosity increases-- gtcomplications such as
  stroke, myocardial ischemia, or infarction.

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Clinical features

• Infection
• Organism polysaccharide encapsulated
  ltstrep.pneumoniae, H.influenzaegt
• Common pneumonia pathogens S pneumoniae, S
  aureus, and K pneumoniae
• Common pathogens causing pyelonephritis E coli
  and other gram-negative organisms.
• The increased risk of infection is due to immune
  deficiency resulting from diffuse
  hypogammaglobulinemia, which is due to decreased
  production and increased destruction of normal
  antibodies.

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Clinical features

• Renal failure
• Renal failure may develop both acutely and
  chronically.
• It is commonly due to hypercalcemia.
• It may also be due to tubular damage from
  excretion of light chains, which can manifest as
  the Fanconi syndrome (type II renal tubular
  acidosis).
• Other causes include glomerular deposition of
  amyloid, hyperuricemia, recurrent infections
  (pyelonephritis), and local infiltration of tumor
  cells.

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Clinical features

• Neurological symptoms
• Common problems are weakness, confusion and
  fatigue due to hypercalcemia.
• Headache, visual changes and retinopathy may be
  the result of hyperviscosity of the blood
  depending on the properties of the paraprotein.
• Finally, there may be radicular pain, loss of
  bowel or bladder control (due to involvement of
  spinal cord leading to cord compression) or
  carpal tunnel syndrome and other neuropathies
  (due to infiltration of peripheral nerves by
  amyloid).
• It may give rise to paraplegia in late presenting
  cases.

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Physical Examination

• Pallor anemia
• Ecchymoses or purpura thrombocytopenia
• Bone pain without tenderness is typical
• lytic destructive bone lesions or pathologic
  fracture.

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Physical Examination

• Neurologic findings
• Sensory level change (ie, loss of sensation below
  a dermatome corresponding to a spinal cord
  compression)
• Weakness
• Extramedullary plasmacytomas soft tissue masses
  of plasma cells, are not uncommon.

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Physical Examination

• Amyloidosis
• The shoulder pad sign is defined by bilateral
  swelling of the shoulder joints secondary to
  amyloid deposition-- gtswelling as hard and
  rubbery.
• Macroglossia is a common finding in patients with
  amyloidosis.

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Diagnosis

• Lab Studies
• CBC anemia, thrombocytopenia, leukopenia
• Peripheral blood smear rouleaux formation

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Rouleaux formation high plasma protein
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????????????????????????????????? plasma cells
??? ??????????????????????? ????? nucleus
????????????????????????????????? ?????????
nucleus ?????? chromatin ?????????????????????????
????????????????
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Diagnosis

• total protein, albumin and globulin, BUN,
  creatinine, and uric acid, which is high if the
  patient has high cell turnover or is dehydrated
• Serum protein electrophoresis, urine protein
  electrophoresis, and immunofixation
• Serum protein electrophoresis is used to
  determine the type of each protein present and
  may indicate a characteristic curve (ie, where
  the spike is observed).
• Urine protein electrophoresis is used to identify
  the presence of the Bence Jones protein in urine.
• Immunofixation is used to identify the subtype of
  protein (ie, IgA lambda).

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Diagnosis

• A 24-hour urine collection for the Bence Jones
  protein (ie, lambda light chains), protein, and
  creatinine
• Quantification of proteinuria is useful for
  diagnosis (gt1 g of protein in 24 h is a major
  criterion) and for monitoring the patient's
  response to therapy.
• Creatinine clearance can be useful for defining
  the severity of the patient's renal impairment.

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Diagnosis

• Imaging Studies
• Skeletal series
• skull (a very common site ), the long bones ( for
  impending fractures), and the spine.
• Diffuse osteopenia may suggest myelomatous
  involvement before discrete lytic lesions are
  apparent.
• Do not use bone scans to evaluate myeloma
• MRI scan
• MRI to obtain a clear view of the spinal column
  and to assess the integrity of the spinal cord.

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Diagnosis

• Procedures
• bone marrow aspirate biopsy
• samples to calculate the percent of plasma cells
  in the aspirate (reference range, lt3) and to
  look for sheets or clusters of plasma cells in
  the biopsy specimen.

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• Bone marrow aspirate plasma cells of
  multiple myeloma.Note the blue cytoplasm,
  eccentric nucleus, and perinuclear pale zone (or
  halo).

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• Bone marrow biopsy sheets of malignant plasma
  cells in MM

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Diagnostic criteria

• Durie-Salmon criteria
• Dx 1 major 1 minor or 3 minor criteria
• Major criteria
• Plasmacytoma on tissure biopsy
• BM plasmacytosis with gt 30 plasma cell
• Monoclonal globulin spike on serum
  electrophoresis 3.5 g/dl for Ig G ,gt 2g/dl for
  IgA
• Or urine Bence Jones gt 1g/24 hr

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Diagnostic criteria

• Durie-Salmon criteria
• Minor criteria
• Marrow plasmacytosis 10-29
• Monoclonal globulin spike present ,but less than
  above
• Lytic bone lesion
• Normal Ig Mlt 0.05g/dl , IgA lt0.1g/dl , IgGlt0.6
  g/dl

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Staging

• Durie-Salmon staging system
• High tumor mass ltstage III gt one of following
  abnormalitie mus be present
• Hb lt8.5 g/dl, Hct lt 25
• Sr Ca gt 12 gm/dl
• Very high Sr or Urine myeloma protein production
  rate
  1. Ig G peak gt7 gm/dl
  2.
  IgA peak gt 5 gm/dl
  3. Bence Joneprotein
  gt 12 gm/ 24 hr
• gt 3 lytic bone lesion on bone survey

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Staging

• Durie-Salmon staging system
• 2. Low tumor mass ltstage Igt
• all of following must be present
• Hb gt 15 gm/dl, Hctgt 32
• Sr Ca normal
• Low Sr myeloma protein production rate 1. Ig G
  peaklt 5 gm/dl 2. IgA
  peak lt 3 gm/dl
  3. Bence Jone protien lt 4 g/ 24 hr
• No bone lesion or osteoporosis

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Staging

• Durie-Salmon staging system
• 3. Imtermediate tumor mass ltstage IIgt
• a. no renal failure ltCr lt 2 mg/dlgt
• b. Renal failure ltCr gt 2 mg/dlgt

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Staging

• The International Staging System (ISS)
• Stage I ß2-microglobulin (ß2M) lt 3.5 mg/L,
  albumin gt 3.5 g/dL
• Stage II ß2M lt 3.5 and albumin lt 3.5 or ß2M
  between 3.5 and 5.5
• Stage III ß2M gt 5.5

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Threatment

• Active care
• Chemotherapy
• Autologous / Allogenic stem cell transplamtation
• Drug Arsenic trioxide, Thalidomide
  Immunomodulator
• Interferon
• Supportive care
• Radiation therapy
• Bisphosphonate
• Kayphoplasty

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Threatment

• Radiation therapy ltpalliativegt
• Rx plasmacytoma post surgery
• Chemotherapy
• Melphalan Prednisolone
• VAD lt vincristine, adriamycin, dexamethasonegt
• VMCP lt vincristine , melphalan, cyclophosphamide,
  prednisolonegt

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Threatment

• Arsenic trioxide inhibit leukemic growth factor
  apoptosis
• Thalidomide Antiangiogenesis-- gtapoptosis of MM
  cell
• Bisphosphonate ltPamidronate,Zoledronic acidgt -- gt
  inhibit osteoclast

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Prognosis

• The International Staging System can help to
  predict survival
• Stage 1 62 months
• Stage 2 45 months
• Stage 3 29 months