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Multiple myeloma

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multiple myeloma

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Multiple myeloma

  1. 1. Multiple myeloma DR.SWARNITA SAHU DNB RESIDENT RADIATION ONCOLOGY BATRA HOSPITAL AND MEDICAL RESEARCH CENTRE NEW DELHI
  2. 2. EPIDEMIOLOGY • PLASMA CELL NEOPLASMS- 22% OF ALL MATURE B CELL NEOPLASMS.  MULTIPLE MYELOMA - MAJORITY  SOLITARY PLASMACYTOMA - <6%  PLASMA CELL LEUKAEMIA - VERY RARELY
  3. 3. PLASMA CELL • ORIGINATE FROM TERMINALLY DIFFERENTIATED B CELL • BONE MARROW AND LYMPHOID TISSUE • PRODUCE AND SECRETE ALL CLASSES OF IMMUNOGLOBULINS • LIFE SPAN : 30 DAYS.
  4. 4. PLASMA CELL NEOPLASMS • SPECTRUM OF DISEASES • BENIGN :  SOLITARY PLASMACYTOMA  MONOCLONAL GAMMOPATHY OF UNKNOWN ORIGIN  CASTLEMAN’S DISEASE  ALPHA HEAVY CHAIN DISEASE  WALDENSTORM’S MACROGLUBULINAEMIA • MALIGNANT :  MYELOMA  LEUKEMIA
  5. 5. ETIOLOGY EXPOSURE TO - • Ionising Radiation (LOW DOSE). • Exposure to metals (NICKEL). • Agricultural chemicals ,Benzene and petroleum products. Hereditary and genetic factors (eg:HLA-Cw2 overexpression). MGUS (PREMALIGNANT CONDITION).
  6. 6. CLINICAL SPECTRUM OF MULTIPLE MYELOMA
  7. 7. MULTIPLE MYELOMA • ASYMTOMATIC Diagnosed in routine blood work. • HEMATOLOGIC DYSFUNCTION • BONE RELATED SYMPTOMS • INFECTIONS • ORGAN DYSFUNCTION  DIRECT BM INVOLVEMENT  EXTRAMEDULLARY PLASMACYTOMA  EFFECTS ON THE IMMUNE SYSTEM  PROTEINS PRODUCED BY THE TUMOR CELLS GET DEPOSITED IN VARIOUS ORGANS  CYTOKINES
  8. 8. ANAEMIA Normocytic normochromic • Tumor cells in the marrow • Inadequate erythropoietin responsiveness • Cytokines • Decreased renal function-----decreased erythropoiesis • Increased Igg levels---dilutional effects. • Fatigue • Weakness • Occasional shortness of breath Rx- ERYTHROPOIETIN ADMINISTRATION (IMP SUPPORTIVE CARE)
  9. 9. NEPHROPATHY LIGHT CHAIN TUBULAR CASTS ------ INTERSTITIAL NEPHRITIS (MYELOMA KIDNEY) ADDITIONAL FACTORS • Nsaids for pain control • Nephrotoxic chemotherapy drugs • Iv contrast for radiographic studies • Bisphosphonate therapy • Calcium deposition and stones in kidney HYPERCALCAEMIA • Osmotic diuresis • Volume depletion • Pre-renal azotemia Light chain deposition leading to decrease in GFR
  10. 10. HYPERCALCAEMIA AND BONE DISEASE • Osteoporosis • Lytic bone lesions • Mental changes • Lethargy • Constipation • Vomiting BM microenvironment myeloma cells—increased in osteoclast activatin factors(IL-1beta, TNF-beta, IL-6, MIP 1 alpha INCREASED OSTEOCLAST ACTIVITY DECREASED OSTEOBLAST ACTIVITY
  11. 11. NEUROLOGIC SYMPTOMS HYPERCALCAEMIA HYPERVISCOSITY THALLIDOMIDE BORTEZOMIB TUMOR MASS EFFECT WITH COMPRESSION OF spinal cord, cranial or spinal nerves.
  12. 12. HYPERVISCOSITY COAGULOPATHY • Increased production of immunoglobulins • Increased levels of paraproteins interfering normal coagulation • Thrombosis(d/t hyperviscosity) • Platelet dysfunction
  13. 13. EXTRAMEDULLARY DISEASE (advanced stage or relapse following allogenic transplantation) SKIN , SOFT TISSUE AND LIVER SUSPECTED IN: • INCREASED LDH • IMMUNOBLASTIC MORPHOLOGY • INCREASED TUMOR CELL LABELLING INDEX • COMPLEX KARYOTYPING FEATURES
  14. 14. SUspect MYELOMA IN: DIAGNOSIS DELAYED DUE TO NON SPECIFIC SYMPTOMS OLD PATIENT WITH UNEXPLAINED BONE PAIN, RECURRENT INFECTION, ANAEMIA , RENAL INSUFFIENCY. ADDITIONAL FEATURES:hyperproteinaemia, proteinuria, anaemia, hypoalbuminaemia, low immunoglobulin, marked elevation of ESR.
  15. 15. 1STSTEP CONFIRM THE PRESENCE, TYPE & QUANTITY OF MONOCLONAL PROTEIN. DETECTION & QUANTIFICATION OF CLONAL PLASMA CELLS 2NDSTEP DIFFERENTIATE MGUS, SMM, SYMPTOMATIC MULTIPLE MYELOMA 3RDSTEP EVALUATION OF PROGNOSTIC VARIABLES • LAB: RFT,Calcium,Albumin, Uric acid, LDH, BETA- 2 Microglobulin,CRP • SKELETAL SURVEY • MRI AND STIR IMAGES • BONE DENSITOMETRY • CYTOGENETICS(metapha se karyotype & FISH) • SERUM B2 MICROGLOBULIN • Sr LDH • Sr ALBUMIN • Sr pr electrophoresis • Quantitative Igg • 24 hr urine: total pr & bence jones pr • Immunofixation of urine and serum • Sr free light chain and ratio  Bone marrow aspirate & biopsy- histology, clonality, flow cytometry,cytogenetics & FISH.
  16. 16. • 70% IgG • 20% IgA • 5-10% monoclonal light chains only • <1% - monoclonal IgD, IgE, IgM or nonsecretory myeloma.  No difference in therapeutic approach  IgA MYELOMA PTS HAS POOR PROGNOSIS
  17. 17. RADIOGRAPHIC EVALUATION • SKELETAL SURVEY:A skeletal survey is comprised of various x-rays of all the bones in the body. Typically, this procedure involves radiographs of the skull, spine, humeri, ribs, pelvis and femora.  Osteopenia in early stages  Lytic bone lesions in advanced disease  Osteosclerotic lesions in POEMS syndrome.(exception) • BONE SCAN: NOT USEFUL  Due to predominant osteoclastic acivity and OSTEOBLASTIC INACTIVITY. • DEXA SCAN: IMPORTANT TOOL  measurement of bone mineral density by dual energy X-ray absorptiometry detects osteopenia. • MRI:  Spine and pelvis-in all patients with solitary plasmacytoma and SMM( detect occult and progression)  Defines pattern of marrow inv-diffuse /focal  Cord compression • PET:  Detection of extraosseous soft tissue masses  Evaluation of ribs and appendicular bone lesions.
  18. 18. SKELETAL SURVEY: LYTIC BONE LESIONS (PUNCHED OUT LESIONS)
  19. 19. DIAGNOSTIC CRITERIA FOR MYELOMA AND ITS VARIANTS
  20. 20.  MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE • M protein in serum < 30g/dl. • Bone marrow plasma cells < 10% . • No evidence of other B cell proliferative disorders. • No myeloma related organ or tissue impairment.  NON SECRETORY MYELOMA • Bone marrow plasma cells > 10% • No M protein in serum or urine • No organ damage  ASYMPTOMATIC MYELOMA ( SMOLDERING MYELOMA) • M protein in serum >30% and/or • Bone marrow clonal plasma cells >/= 10%. • No related organ damage  SYMPTOMATIC MULIPLE MYELOMA • M protein in serum/urine. • Bone marrow clonal plasma cells or plasmacytoma > 10%. • Organ damage. • Flow cytometry: >90% plasma cells – neoplastic phenotype. MYELOMA RELATED ORGAN DAMAGE : • C-HYPERCALCAEMIA • R-RENAL INSUFFIENCY • A-ANAEMIA • B-BONE LESIONS
  21. 21. UPDATE (NCCN) Active multiple myeloma is no longer diagnosed using the CRAB criteria for end- organ damage. The current diagnostic criteria are as follows
  22. 22.  SOLITARY PLASMOCYTOMA OF BONE • Single area of bone destruction due to clonal plasma cells • M protein - ABSENT • Bone marrow • Skeletal survey NORMAL. • Organs  EXTRAMEDULLARY PLASMACYTOMA • Extramedullary tumor of clonal plasma cells.  MUTIPLE SOLITARY PLASMACYTOMA(+/- RECURRENT) • >1 area localized area of bone destruction or extramedullary tumor of clonal plasma cells (which may be recurrent). • M protein – ABSENT • Bone marrow • Skeletal survey NORMAL. • Organs
  23. 23. PROGNOSTIC VARIABLES
  24. 24.  TUMOR BURDEN RELATED FACTORS • Sr.Beta 2 macroglobulin • >3 lytic lesions • Hb • Sr calcium  TUMOR MICROENVIRONMENT RELATED • Bone marrow microvessel density • Sr syndecan-1 levels • MMP-9 levels • Soluble CD16  PATIENT RELATED FACTORS • Age • Albumin • Performance status • Comorbidities  TUMOR BIOLOGY RELATED FACTORS • Cytogenetics/FISH abnormality • Gene expression profile pattern • Plasma cell labelling index • Bartl grade • Mitotic activity • IgA myeloma • CRP • LDH • Soluble IL6 receptor • Renal failure  TUMOR RELATED FACTORS • Tandem transplant • Achieving complete or very good partial response.
  25. 25. DURIE AND SALMON STAGING: predictive for clinical outcomes after standard dose chemotherapy NOT FOR HIGH DOSE OR NOVEL BASED CHEMOTHERAPY. NO LONGER USED CLINICALLY 62 months 44 months 29 months
  26. 26. TREATMENT
  27. 27. STAGE RECOMMENDED TREATMENT I or systemic smoldering Observe or systemic therapy II OR III • 2 or 3 agent combination of either alkylators, proteasome inhibitors, immunomodulatory agents, histone deacetylase inhibitors or newer monoclonal antibodies + bisphosphonate for bone disease. • Consider high dose therapy followed by stem cell transplant. • RT to be considered for palliation • New MM with cord compression and organ damage- steroids + bortezomib with RT to spine.(hold lenalidomide until after RT) • Surgical consideration for impending fractures. TREATMENT RECOMMENDATIONS FOR MULTIPLE MYELOMA
  28. 28. STEM CELL TRANSPLANTATION • Myeloma and normal cells are killed by high dose chemotherapy ( Melphalan) • Stem cells are bone marrow like cells harvested from the peripheral blood • Sources of stem cells: AUTOLOGOUS: • from the patient • Standard of care for eligible candidates • Treatment related mortality <2% • Outpatient procedure • Melphalan (200mg/m2 ) most commonly used (reduced use in elderly or renal insuffiency). ALLOGENIC: • from a donor • VERY LIMITED USE • d/t lack of donors, age restriction, high treatment related mortality and graft versus host disease.
  29. 29. TANDEM TRANSPLANTATION • Tandem/second transplant : planned second ASCT • Tandem vs single transplant : overall survival better with tandem. • To be considered in patients with suboptimal response to the first ASCT.
  30. 30. RELAPSE AFTER ASCT CONVENTIONAL THERAPY: • Repeated course of alkylator based therapy(melphalan). • Cyclophosphamide and steroids TRANSPLANTATION: • Second autologous stem cell transplant HIGH DOSE CHEMOTHERAPY: • High dose cyclophosphamide • DTPACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) NOVEL AGENTS: • Thalidomide • Bortezomib • Lenalidomide COMBINATION OF CONVENTIONAL & NOVEL AGENT.
  31. 31. RADIATION THERAPY IN MULTIPLE MYELOMA
  32. 32. • Considered mainstay of treatment prior to chemotherapeutic options. • NOW – VERY LIMITED ROLE in multiple myeloma. • Definitive role – solitary bone and extramedullary plasmacytoma.
  33. 33. TOTAL BODY IRRADIATION • TBI + HIGH DOSE CHEMOTHERAPY as conditioning regimen. • Toxicity concerns - mucosal and hematological d/t TBI • IFM 9502: 282 pts with MM undergoing conditioning regimen before autologous stem cell transfusion MELPHALAN (200mg/m2) MELPHALAN (140mg/m2) + TBI(8Gy/4#) Increased gr 3 & 4 toxicity. Heavier transfusion requirement & longer hospital stay. Decreased OS.
  34. 34. HEMIBODY IRRADIATION • Palliation of diffuse bone pain. • 5-8Gy in single #. • UNIRRADIATED MARROW: serves as stem cells which repopulated the irradiated marrow after treatment. • RARELY USED NOW. • Remain useful for palliation of advanced disease in chemotherapy refractory patients.
  35. 35. LOCAL EBRT FOR PALLIATION: • Most common use of radiotherapy. • Relief of compression of spinal / cranial / peripheral nerves. • Reduces incidence of impending fractures. ROLE UNCLEAR High risk lesions - referred for surgical stabilization. RT preferred for RESIDUAL disease ,post surgery. • Bone lesions- treat entire bone except for long bones and pelvis (to decrease the dose in bone marrow) • Vertebrae- treat 1-2 vertebrae above and below the diseased vertebrae • PAIN- 10-20Gy/5-10# - pain relief is often partial. • SPINAL CORD COMPRESSION- Motor improvement in 50% of the patients. (30Gy/10# better neurologic response than 20Gy/5# or 8Gy/1#)
  36. 36. RADIOIMMUNOTHERAPY APPROACHES (TARGETED RADIATION THERAPY) • SAMARIUM • HOLIUM • Emits gamma rays- permitting scanning to locate areas of uptake • Agents used for palliation • Higher doses than TBI can be given • 30-60Gy (sparing dose limiting normal tissues-lung, mucosa, kidneys)
  37. 37. SUPPORTIVE CARE • Erythropoietic agents. • Bisphosphonates (even has an effect on overall survival). • Local RT. • Newer surgical techniques: vertebroplasty & kyphoplasty.

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