Multiple myeloma - definition

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Multiple Myeloma and Amyloidosis
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Objectives

• To introduce the terminology used in describing
  
  the plasma cells neoplasm.
• To explain the physiology of the normal cells
  the pathological effects of their neoplastic
  growth.
• To describe the classification of plasma cells
  neoplasm.
• To discuss the relationship with amyloidosis and
  its pathology.

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Plasma cells

• Terminally differentiated B- Lymphocytes that
  are
• capable of producing immunoglobulins.
• Paraprotein
• Structurally identical homologous ig.of the
  same clone i.e monoclonal.
• Lymphoplasmacytic Neoplasm
• Neoplasm of the plasma cells producing excess
  paraprotein.

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Classification of plasma cell neoplasms

• Monoclonal gammopathy of undetermined
  significance.
• Multiple myeloma.
• Macroglobulinemia.

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Monoclonal gammopathy of undetermined
significance ( MGUS)

• M protein presence, stable
• levels of M protein IgG lt 3,5g IgA lt 2g
  LClt1g/day
• normal immunoglobulins - normal levels
• marrow plasmacytosis lt 5
• complete blood count - normal
• no lytic bone lesions
• no signs of disease

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Monoclonal gammopathy of undetermined
significance ( MGUS)

• M protein
• 3 of people gt 70 years
• 15 of people gt 90 years
• MGUS is diagnosed in 67 of patients with an M
  protein
• 10 of patients with MGUS develop multiple myeloma

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Macroglobulinemia

• Tumour of lymphoplasmacytoid cells producing
• Monoclonal ig most commonly ( Igm )
• Types - Essential macroglobulinemia.
• - waldenstrom macroglobulinemia.
• Clinical Features
• Weight loss, fatigue.
• Bleeding usually epistaxis.
• Bone marrow infiltration by the lymphoplasmcytic
  cells less mature than plasma cells presenting
  as anemia thrombocytopenia or leucopenia.

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Multiple Myeloma

• Definition
• B-cell malignancy characterised by
  abnormal proliferation of plasma cells able to
  produce a monoclonal immunoglobulin ( M protein
  )
• Incidence
• 3 - 9 cases per 100000 population / year
• more frequent in elderly
• modest male predominance

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Multiple Myeloma

• Clinical forms
• multiple myeloma
• solitary plasmacytoma
• plasma cell leukemia
• M protein
• - is seen in 99 of cases in serum and/or urine
• IgG gt 50, IgA 20-25, IgE i IgD 1-3
• light chain 20
• - 1 of cases are nonsecretory

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Multiple Myeloma

• Clinical manifestations are related to malignant
• behavior of plasma cells and abnormalities
  produced
• by M protein
• plasma cell proliferation
• multiple osteolytic bone lesions
• hypercalcemia
• bone marrow suppression ( pancytopenia )
• monoclonal M protein
• decreased level of normal immunoglobulins
• hyperviscosity

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Multiple Myeloma

• Clinical symptoms
• bone pains, pathologic fractures
• weakness and fatigue
• serious infection
• renal failure
• bleeding diathesis

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Multiple Myeloma

• Laboratory tests
• ESR gt 100
• anaemia, thrombocytopenia
• rouleaux in peripheral blood smears
• marrow plasmacytosis gt 10 -15
• hyperproteinemia
• hypercalcemia
• proteinuria
• azotemia

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Diagnostic Criteria for Multiple Myeloma

• Major criteria
• I. Plasmacytoma on tissue biopsy
• II. Bone marrow plasma cell gt 30
• III. Monoclonal M spike on electrophoresis IgG gt
  3,5g/dl,
• IgA gt 2g/dl, light chain gt 1g/dl in 24h urine
  sample
• Minor criteria
• a. Bone marrow plasma cells 10-30
• b. M spike but less than above
• c. Lytic bone lesions
• d. Normal IgM lt 50mg, IgA lt 100mg, IgG lt 600mg/dl

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Diagnostic Criteria for Multiple Myeloma

• Diagnosis
• I b, I c, I d
• II b, II c, II d
• III a, III c, I II d
• a b c, a b d

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Staging of Multiple Myeloma

• Clinical staging
• is based on level of haemoglobin, serum calcium,
  immunoglobulins and presence or not of lytic bone
  lesions
• correlates with myeloma burden and prognosis
• I. Low tumor mass
• II. Intermediate tumor mass
• III. High tumor mass
• subclassification
• A - creatinine lt 2mg/dl
• B - creatinine gt 2mg/dl

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Multiple Myeloma

• Poor prognosis factors
• cytogenetical abnormalities of 11 and 13
  chromosomes
• beta-2 microglobulines gt 2,5 ug/ml

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Treatment of Multiple Myeloma

• Patients lt 65 - 70 years
• high-dose therapy with autologous stem cell
  transplantation
• allogeneic stem cell transplantation (
  conventional and mini)
• Patients gt 65 years
• conventional chemotherapy
• non-myeloablative therapy with allogeneic
  transplantation (mini)

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Treatment of Multiple Myeloma

• Conventional chemotherapy
• Melphlan Prednisone
• M2 ( Vincristine, Melphalan, Cyclophosphamid,
  BCNU, Prednisone)
• VAD (Vincristin, Adriamycin, Dexamethasone)
• Response rate 50-60 patients
• Long term survival 5-10 patients

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Treatment of Multiple Myeloma

• Autologous transplantation
• patients lt 65-70 years
• treatment related mortality 10-20
• response rate 80
• long term survival 40-50
• Conventional allogeneic transplantation
• patients lt 45-50 years with HLA-identical donor
• treatment related mortality 40-50
• long term survival 20-30

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Treatment of Multiple Myeloma

• New method
• non-myeloablative therapy and allogeneic
  transplantation
• thalidomid

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Treatment of Multiple Myeloma

• Supportive treatment
• biphosphonates, calcitonin
• recombinant erythropoietin
• immunoglobulins
• plasma exchange
• radiation therapy

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Disorder Associated with Monoclonal Protein

• Neoplastic cell proliferation
• multiple myeloma
• solitary plasmacytoma
• Waldenstrom macroglobulinemia
• heavy chain disease
• primary amyloidosis
• Undetermined significance
• monoclonal gammopathy of undetermined
  significance (MGUS)
• Transient M protein
• viral infection
• post-valve replacement
• Malignacy
• bowel cancer, breast cancer
• Immune dysregulation
• AIDS, old age
• Chronic inflammation

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Amyloidosis

• Primary amyloidosis
• Deposition of light chain of Ig as in multiple
  myeloma sites Tongue, GIT, Heart, Connective
  tissue.
• Secondary Amyloidosis
• Deposition of amyloid -A- substance
• Sites Spleen, Liver, Kidney
• Familial Amyloidosis
• Due to genetic mutation
• Causing deposition of unmetalised prealbumin.