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Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
Multiple   Myeloma Modified ,  Dr  Gamal  Abdul  Hamid
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Multiple Myeloma Modified , Dr Gamal Abdul Hamid

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Multiple myeloma

Multiple myeloma

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  • exposed to the radiation of nuclear warheads in World War II after a 20-year latency
  • (Only 2 to 3 percent of cases are reported in patients < 30 years)
  • Two thirds of patients complain of bone pain, frequently located in the back, long bones, skull and pelvis. Patients with multiple myeloma commonly present with lower back pain.
  • tubular damage associated with the excretion of light chains is almost always present. Normally, light chains are filtered, reabsorbed in the tubules, and catabolized. With the increase in the amount of light chains presented to the tubule, the tubular cells become overloaded with these proteins, and tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes . The earliest manifestation of this tubular damage is the adult Fanconi syndrome (a type 2 proximal renal tubular acidosis), with loss of glucose and amino acids, as well as defects in the ability of the kidney to acidify and concentrate the urine The proteinuria is not accompanied by hypertension, and the protein is nearly all light chains. Generally, very little albumin is in the urine because glomerular function is usually normal . When the glomeruli are involved, the proteinuria is nonselective Patients with myeloma also have a decreased anion gap [i.e., Na+– (Cl–+ HCO3–) because the M component is cationic, resulting in retention of chloride. This is often accompanied by hyponatremia that is felt to be artificial (pseudohyponatremia) because each volume of serum has less water as a result of the increased protein. Myeloma patients are susceptible to developing acute renal failure if they become dehydrated.
  • The serum M component will be IgG in 53% of patients, IgA in 25%, and IgD in 1%; 20% of patients will have only light chains in serum and urine. Dipsticks for detecting proteinuria are not reliable at identifying light chains, and the heat test for detecting Bence Jones protein is falsely negative in about 50% of patients with light chain myeloma.
  • Total-body tumor burden is estimated to be low (stage I, <0.6 x 1012 cells/m2), intermediate (stage II, 0.6 to 1.2 x 1012 cells/m2), or high (stage III, >1.2 x 1012 cells/m2), and the stages are further subdivided on the basis of renal function [A if serum creatinine <177 mol/L (<2 mg/dL), B if >177 (>2). Patients in stage IA have a median survival of more than 5 years and those in stage IIIB about 15 months. 2-Microglobulin is a protein of 11,000 mol wt with homologies with the constant region of immunoglobulins that is the light chain of the class I major histocompatibility antigens (HLA-A, -B, -C) on the surface of every cell. Patients with 2-microglobulin levels <0.004 g/L have a median survival of 43 months and those with levels >0.004 g/L only 12 months. IL-6 may be an autocrine and/or paracrine growth factor for myeloma cells; elevated levels are associated with more aggressive disease.
  • VMP DOR by Investigator: All responders 22.6 mo; CR = NE, PR = 16.2 months; MP: All responders 14.3 months; CR 16.7 months; PR 13.1 months VMP DOR by Investigator with 0.5 g/dL cut-off: All responders ??; CR = NE, PR = 22.4 months; MP: All responders ??: CR ??; PR ?? DOR p value 0.0012 for all responders, and 0.03 for patients with CR Progressive disease: 1% VMP vs 2% MP
  • Transcript

    • 1. Multiple Myeloma Gamal Abdul Hamid MD
    • 2. Definition
      • A malignant proliferation of plasma cells derived from a single clone involving more than 10 percent of the bone marrow
      • The multiple myeloma cell produces monoclonal immunoglobulins that may be identified on serum or urine protein electrophoresis .
    • 3. As a result !
      • Tumor, its products, and the patients response to it, result in a number of organ dysfunctions
        • Fracture/bone pain
        • Renal failure
        • Susceptibility to infection
        • Anemia
        • Hypercalcemia
        • Clotting abnormalities
        • Neurologic symptoms
        • Vascular manifestations of hyperviscosity
    • 4. Etiology
      • Cause not known !
      • More commonly than expected among
        • Low socioeconomic class
        • Farmers (DDT exposure)
        • Wood workers
        • Leather workers
        • Sheet metal workers
        • Nuclear industry workers
        • Those exposed to petroleum products (??benzene)
    • 5. Incidence
      • Increases with age
        • Ages from 45 up to 68 years
      • Males > Females (slightly)
      • Accounts for about
        • 1% of all malignancies in whites
        • 13% of all hematologic cancers in whites
    • 6. MULTIPLE MYELOMA: Pathophysiology
      • The pathological and clinical features of myeloma are due to:
      • 1. Tissue infiltration
      • 2. Production of large amount of paraprotein
      • 3. Impairment of immunity.
    • 7. Clinical Manifestations of Multiple Myeloma
      • Pain in the lower back, long bones or ribs
      • Generalized malaise
      • Infections
      • Fever
      • Bleeding
      • Symptoms of hypercalcemia
        • Nausea
        • Fatigue
        • Thirst
      • Symptoms of hyperviscosity
        • Headaches
        • Bruising
        • Ischemic neurologic symptoms
      • Other neurologic symptoms
        • Peripheral neuropathy
        • Meningitis
    • 8. Pathogenesis and Clinical Manifestations Bone Symptoms
      • Bone pain (most common symptom affecting 70% of patients )
        • Involves back , ribs , long bones, skull and pelvis
        • Precipitated by movement (unlike the pain of metastatic carcinoma, which often is worse at night)
        • If persistent & localized usually signifies a pathologic fracture
    • 9.  
    • 10.  
    • 11. Pathogenesis and Clinical Manifestations Susceptibility to bacterial infections
      • Recurrent infections are the presenting features in 25% of patients
      • Most common infections are
        • Pneumonias ( Streptococcus pneumoniae , Staphylococcus aureus , and Klebsiella pneumoniae )
        • Pyelonephritis ( Escherichia coli and other gram-negative organisms )
    • 12. Pathogenesis and Clinical Manifestations Renal failure / pathology
      • Failure occurs in nearly 25%
      • Some renal pathology is noted in > 50%
      • Factors contributing to renal dysfunction
        • Hypercalcemia ( most common cause of renal failure)
        • Glomerular deposits of amyloid
        • Hyperuricemia
        • Recurrent infections
        • Infiltration of the kidney by myeloma cells
        • Tubular damage associated with the excretion of light chains (almost always present )
    • 13. Pathogenesis and Clinical Manifestations Anemia
      • Occurs in 80% of myeloma patients
      • Types
        • Usually normocytic and normochromic
        • Can be megaloblastic due to either folate or vitamin B12 deficiency
      • Due to
        • Replacement of normal marrow by expanding tumor cells
        • Inhibition of hematopoiesis by factors made by the tumor
        • Mild hemolysis
    • 14. Diagnosis
      • 30% of new cases are diagnosed incidentally during evaluation for seemingly unrelated problems
      • In 30 % a pathologic fracture is the presenting feature
      • In 25% of patients recurrent infections are the presenting features
    • 15. Diagnosis
      • The classic triad of myeloma
        • Marrow plasmacytosis (>10%)
        • Lytic bone lesions
        • Serum and/or urine M component
      • The diagnosis may be made in the absence of bone lesions if the plasmacytosis is associated with a progressive increase in the M component over time or if extramedullary mass lesions develop
    • 16. Confirmation of 1 major and 1 minor criterion or 3 minor criteria in symptomatic patients Major Diagnostic Criteria Minor Diagnostic Criteria
      • Biopsy-proven plasmacytoma
      • Bone marrow sample = 10% to 30% plasma cells
      • Bone marrow sample = 30% plasma cells
      • Minor monoclonal immunoglobulin levels in blood or urine (< 3 g/dL)
      • Elevated monoclonal immunoglobulin levels in blood or urine
      • Osteopenia/lytic bone lesions (confirmed through imaging studies)
      • Abnormally low antibody levels (not associated with malignant cells) in the blood
    • 17. Myeloma classification Monoclonal Gammopathy of Undetermined Significance
      • Serum M-protein < 3 g/dL
      • Bone marrow plasma cells < 10%
      • Absence of anemia, renal failure, hypercalcemia, lytic bone lesions
      Asymptomatic Multiple Myeloma Smoldering Multiple Myeloma Indolent Multiple Myeloma
      • Serum M-protein > 3 g/dL and/or bone marrow plasma cells ≥ 10%
      • Bone marrow plasmacytosis
      • No anemia, renal failure, hypercalcemia, lytic bone lesions
      • Mild anemia or few small lytic bone lesions
      • Stable serum/urine M-protein
      • No symptoms
      • Presence of serum/urine M-protein
      Symptomatic Multiple Myeloma
      • Bone marrow plasmacytosis (> 10%)
      • Anemia, renal failure, hypercalcemia, or lytic bone lesions
    • 18. Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone
    • 19. Bone marrow biopsy demonstrating sheets of malignant plasma cells in multiple myeloma
    • 20. Clinical evaluation
      • Careful physical examination
        • Tender bones and masses
        • Enlargement of the spleen and lymph nodes, the physiologic sites of antibody production (minority)
        • Exudative macular detachment, retinal hemorrhage or &quot;cotton-wool&quot; spots
        • Amyloid deposition on the tongue, causing macroglossia
        • Cardiomegaly related to deposition of immunoglobulin.
        • Positive Tinel sign, Phalen sign for carpal tunnel compression due to amyloid deposition.
      • Imagings
        • Chest and bone radiographs ( lytic lesions or diffuse osteopenia )
        • MRI
          • To depict myeloma tumors
          • To document cord or root compression in patients with pain syndromes .
          • To assess efficacy of therapy (Radiographic improvement occurs in 30 % of treated patients )
    • 21. Clinical evaluation
      • Blood studies
        • CBC (anemia , pancytopenia ,)
        • ESR (elevated)
        • Ca, BUN , Cr and uric acid (elevated)
        • Serum alkaline phosphatase is usually normal (absence of osteoblastic activity)
        • Hypoalbuminemia
    • 22. Clinical evaluation Protein electrophoresis
      • In Monoclonal gammopathies & Myeloma the single clone of plasma cells produce a homogeneous monoclonal immunoglobulin ( M protein) characterized by the presence of a sharp, well-defined band with a single heavy chain and a similar band with a kappa or lambda light chain
      • The M protein is identified as a narrow peak or &quot;spike&quot; in the g, ß or a 2 regions
    • 23.  
    • 24. Staging: Durie-Salmon system: widely used since 1975 Stage based on M-protein levels, bone lesions, Hb values, serum calcium—many variables International Staging System Simplified staging based on serum β 2-microglobulin Stage International Staging System Criteria I β 2 -microglobulin < 3.5; albumin ≥ 3.5 II Neither stage I nor stage III values III β 2 -microglobulin > 5.5
    • 25. Staging
      • For predicting survival
      • Based on clinical and laboratory tests (unlike the anatomic staging systems for solid tumors)
        • Hemoglobin,
        • Calcium
        • M component
        • Degree of skeletal involvement
      • Stages(I , II , III ) further subdivided into A & B based on renal function
        • Stage IA (median survival > 5 years)
        • Stage IIIB about 15 months.
    • 26.
      • STAGE I (low cell mass, <0.6 x 10 12 cells/m 2 )
      • All of the following:
        • Haemoglobin value < 10 g/dL
        • Serum calcium value normal or < 10.5 mg/dL
        • Bone X-ray, normal bone structure (scale 0) or solitary bone plasmacytoma only
        • Low M-component production rates
          • IgG value < 5.0 g/dL
          • IgA value < 3.0 g/dL
        • Urine light chain M-component on electrophoresis < 4 g/24 hours
    • 27.
      • STAGE II (intermediate cell mass 600 - 1,200 x 10 12 cells/m 2 )
      • Fitting neither stage I nor stage III.
      • STAGE III (high cell mass > 1,200 x 10 12 cells/m 2 )
      • One or more of the following:
        • Haemoglobin value < 8.5 g/dL
        • Serum calcium value > 12 mg/dL
        • Advanced lytic bone lesions (scale 3)
        • High M-component production rates
          • IgG value > 7.0 g/dL
          • IgA value > 5.0 g/dL
        • Urine light chain M-component on electrophoresis >12 g/24 hours
    • 28. Disease Phases Asymptomatic Symptomatic MGUS or Smouldering Myeloma Active Myeloma Relapse Refractory relapse Plateau remission Therapy IIII IIII IIII M Protein g/dL Go!
    • 29. Goals of MM Therapy
      • Goals of treatment
        • Address pain relief & other disease symptoms
        • Control disease activity
          • prevent further organ damage
        • Extend disease-free survival (DFS)
        • Prolong overall survival (OS)
        • Preserve normal performance and QOL for as long as possible
    • 30. Multiple Myeloma: Current Status
      • Relapsed Disease
      • Transient Response to Therapy
      • Survival 1-3 years
      • Diagnosis
      • Survival 3-5 yrs
      • Survival <12mo without therapy
      • Relapsed and Refractory
      • Resistant to all therapy
      • Universally fatal
      • Survival 6-9 months
      • First-Line:
      • VAD
      • MP
      • Transplant (depending on age)
      5-year Mortality: 75%; 10-year Mortality: 95-98%
      • Second Line:
      • VAD
      • Dexamethasone
      • Thalidomide
      • Transplant
      • Investigational Therapy
      • Refractory:
      • Supportive or palliative care
      • Investigational Therapy
      • Deaths 12,000/yr.
      50 - 75% Response Rate All patients relapse Unmet Medical Need Choice of therapy at relapse dependent on duration of response & previous therapies. Response rate & duration reduced with each sequential regimen
    • 31. 1960 1970 1980 1990 2000 Melphalan MP MEDIAN OS 3 years First reports on High-dose Treatment 1983 VAD 1984 ASCT 1996 Thalidomide 1999 Double ASCT > single 2003 Bortezomib 2004 Median OS Lenalidomide 2005 not reached at 7 years History Of MM Treatment
    • 32. Novel Therapies
      • Bortezomib
      • Thalidomide and analogues
      • Trisenox (Arsenic Trioxide)
      • Genasense (bcl-2 antisense)
      • Farnesyl Transferase Inhibitors
    • 33. Bortezomib Mechanism of Action
      • First in class
      • Novel mechanism of action
      • Reversibly inhibits the proteasome
      • One target, multiple downstream pathways:
            • The cell cycle
            • Apoptosis
            • Angiogenesis
            • Gene transcription
            • Interaction of cell with microenvironment
      Bortezomib [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid.
    • 34. Bortezomib - Indication
      • Bortezomib is approved as front-line treatment for multiple myeloma patients unsuitable for bone marrow transplantation in combination with melphalan and prednisone
      • Bortezomib is also indicated as
      • Monotherapy for the treatment
      • of progressive MM in patients who
      • have received at least one
      • prior treatment
    • 35. Recent Clinical Data: VISTA
      • VMP (Velcade+Melphalan+Prednisolone) significantly prolongs survival in the largest MP-based phase III study
        • Consistency of treatment effect
        • Rapid and durable responses with very high Complete Response rate (similar to transplantation)
        • Prolonged Time To Progression
      • VMP consistently superior across all prognostic subgroups including patients with poor prognostic characteristics
      • VMP well tolerated
      • Results establish VMP as a new standard of care for MM patients not eligible for HDT-ASCT, based on the highest level of evidence 1
      1. Anderson et al. Leukemia 2008;22:231-9.
    • 36.  
    • 37. VISTA : VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone San Miguel et al. ASH 07 VMP Cycles 1-4 Bortezomib 1.3 mg/m 2 IV: days 1,4,8,11,22,25,29,32 Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days 1-4 Cycles 5-9 Bortezomib 1.3 mg/m 2 IV: days 1,8,22,29 Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days 1-4 MP Cycles 1-9 Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days 1-4 9 x 6-week cycles (54 weeks) in both arms Primary endpoint: TTP Newly diagnosed MM patients; age >65 years
    • 38.  
    • 39. High CR rate with MPV VISTA : Response to Treatment MPV MP P CR + PR CR+VGPR 82% 45% 50% 10% <.0001 <.0001 CR (IF-) 35% 5% <.0001
    • 40. Thank you
    • 41. Thank you

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