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Multiple myeloma


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MUltiple myeloma in learning curve

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Multiple myeloma

  1. 1. Multiple Myeloma Dr Harpreet Singh Bhatia DMCH, Ludhiana,Punjab
  2. 2. 2 Cancer of plasma cells. Malignanat B cell lymphoproliferative disorder of the marrow with plasma cell predominating. Most common primary malignancy of bone. Plasma cells come from B lymphocytes, and produce antibodies (immunoglobulins). Myeloma cells produce abnormal immunoglobulins. – Overproduce monoclonal protein or paraprotein. – Ineffective immunoglobulins. – Leads to decreased bone marrow function. – Destruction of bone tissue.
  3. 3. Incidence • Increases with age – Ages from 5th to 7th decade • Males > Females (2:1) • Any pt > 40 yrs with new bone tumor should include in d/d of MM and metastatic carcinoma, • Accounts for about – 1% of all malignancies in whites – 13% of all hematologic cancers in whites
  4. 4. RISK FACTORS • Age >60. • Exposure to pesticides ( DDT ). • Radiation • Wood,leather,sheet metal & nuclear industry worker • Exposure to ptroleum products (Benzene) • Kaposi’s sarcoma Herpes Virus(Presence of IL- 6 and HHV8 )
  5. 5. 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.
  6. 6. 8 Skull Spine Thoracic Lumbar Vertebrae Pelvis Long bones Spinal cord – compression can occur
  7. 7. Clinical Manifestations of Multiple Myeloma •BONE PAIN (Pain in the lower back, long bones or ribs) •Generalized malaise,Weight loss, •Anaemia,Thrombocytopenia (Bleeding) • Renal failure( Light chains and amyloid depostion) •Symptoms of hypercalcemia •Nausea •Fatigue •Thirst •Symptoms of hyperviscosity •Headaches •Bruising •Ischemic neurologic symptoms •Hyperuricemia •Infections •Other neurologic symptoms Peripheral neuropathy •Meningitis
  8. 8. Mechanism of disease • Plasma cell proliferation - > anemia, bone marrow suppression, infection risk • Osteoclasts - > bony lesions, fractures, vertebral collapse, spinal cord compression • Paraprotein, hypercalcemia -> renal failure • Hypercalcemia – polyuria, thirst, drowsiness, coma
  9. 9. • May be symptomatic or asymptomatic. • Symptomatic myeloma characterized by presence of ROTI and CRAB. • Myeloma Related Organ or Tissue Impairment. • Calcium levels increased • Renal failure • Anemia • Bone lesion
  10. 10. • FBC- normal or low. • ESR, CRP-almost always raised. • Blood film- Rouleaux formation, macrocytosis. • U&Es, Cr-renal failure • Serum B2 microglobulin >2.5mg/L. • Raised LDH • Serum calcium- normal or raised. • Serum ALP-normal • Total protein-normal or raised. • Serum albumin- normal or low. • SPE- monoclonal band. • Serum free light chain assay • Uric acid-normal or raised • 24-hour urine electrophoresis and immunofixation is used for assessment of light-chain excretion. • Bone marrow aspirate or trephine shows characteristic infiltration by plasma cells .Amyloid may be found.
  11. 11. 1) Xrayz - Multiple punched out sharply demarcated purely lytic lesion without any srrounding rective sclerosis. - Lack of reactive bone formation 2) Immunochistochemistry - +ve for CD 56 3)Monocolnal gammopathy
  12. 12. • 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 "spike" in the g, ß or a 2 regions
  13. 13. Histologically Small, round blue cells with clock face nuclei and abundant cytoplasm with perinuclear clearing halo
  14. 14. Cytogenetics
  15. 15. FISH
  16. 16. Stage International Staging System Criteria I β2-microglobulin < 3.5; albumin ≥ 3.5 II Neither stage I nor stage III values III β2-microglobulin > 5.5 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 β2- microglobulin
  17. 17. Staging • Salmon-Durie staging system for multiple myeloma • Stage I – Hemoglobin level greater than 10 g/dL – Calcium level less than 12 mg/dL – Radiograph showing normal bones or solitary plasmacytoma – Low M protein values (ie, IgG <5 g/dL, IgA <3 g/dL, urine <4 g/24 h) • Stage II – Findings that fit neither stage I nor stage III criteria • Stage III – Hemoglobin level less than 8.5 g/dL – Calcium level greater than 12 mg/dL – Radiograph showing advanced lytic bone disease – High M protein value (ie, IgG >7 g/dL, IgA >5 g/dL, urine >12 g/24 h) • Subclassification A involves a creatinine level less than 2 g/dL. • Subclassification B involves a creatinine level greater than 2 g/dL. • Median survival is as follows: – Stage I, >60 months – Stage II, 41 months – Stage III, 23 months
  18. 18. 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
  19. 19. 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
  20. 20. Slowly evolving cancer • MGUS Monoclonal Gammopathy of Unknown Significance • Asymptomatic myeloma • Symptomatic myeloma
  21. 21. 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
  22. 22. Disease Phases Asymptomatic Symptomatic MGUS or Smouldering Myeloma Active Myeloma Relapse Refractory relapse Plateau remission Therapy IIII IIII IIII MProteing/dL Go!
  23. 23. Bad prognosis if… • Raised B2-microglobulin >4. • Low serum albumin <3g/dl. • Cytogenetics –ch13 deletion, hypodiploidy, T(4:14) • Raised LDH, CRP, Cr. • Low platelet <150 and Hb<100. • Bone marrow plasma cell percentage ≥ 50% • Age >70.
  24. 24. Goals of MM Therapy  Goals of treatment  Address pain relief & other disease symptoms  Control disease activity  prevent further organ damage  Debulk tumor and use internal fixation augmented with methacrylate  Joint arthoplasty  Prolong overall survival  Preserve normal performance
  25. 25. 28 Conventional chemotherapy:  Melphalan  Doxorubicin  Cyclophosphamide • Radiation therapy • Stem cell transplantation: – Autologous – Allogenic • Novel therapeutics: – Thalidomide – Lenalidomide – Bortezomib Thalomid® Prescribing Information, Revlimid® Prescribing Information; Velcade® Prescribing Information • Steroid therapy: – Dexamethasone – Prednisone
  26. 26. • Radiotherapy • Surgery • Bone care – bisphosphonates • Transfusions • Growth factors • Treatment and prevention of infections • Monitoring, management and prevention of s/e Other treatment / Supportive care
  27. 27. Management of Complications • UREMIA: rehydratation, diuretics,steroids,antibiotics if renal infection is suspected, hemodialysis if these measures fail. • HYPERCALCEMIA: rehydratation, steroids, bisphosphonates, diuretics. • PARAPLEGIA: decompressive laminectomy, radiotherapy, chemotherapy. • BONE LESIONS: if painful and localised, chemo or local radio- therapy, analgetics, biphosphonates. • SEVERE ANEMIA: transfusions, erytropoetin • HYPERVISCOSITY SYNDROME: plasmapheresis, correction of hypercalcemia. • BLEEDING: platelet concentrates, fresh frozen plasma
  28. 28. Current Frontline Options •Examples of current Novel agent combinations: •Thalidomide based : TD, CTD, MPT •Bortezomib (Velcade) based: Vdex, VMP, CVD, PAD, VRD •Lenalidomide (Revlimid) based: LenDex, Lendex
  29. 29. Novel Therapies Bortezomib Thalidomide and analogues Trisenox (Arsenic Trioxide) Genasense (bcl-2 antisense) Farnesyl Transferase Inhibitors
  30. 30. 33 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 evidence1 1. Anderson et al. Leukemia 2008;22:231-9.
  31. 31. 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
  32. 32. Hope New drugs on the horizon • Carfilzomib • Pomalidomide • Panobinostat • Vorinostat • Elotuzumab Old drugs with new use • Bendamustine