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medicine.myeloma.(dr.anwar shexa)

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  • I never had a problem in MM Dx but sometimes it can become an issue
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    • 1. PARAPROTEINEMIAS ha h eik S
    • 2. Professor Anwar Sheikha MD, FRCP, FRCPath., FCAP, FRCPA, FRCPI, FACPSenior Consultant Clinical & Lab. Hematologist Clinical Professor of HematologyUniversity of Mississippi Medical Center, Jackson, Mississippi Professor of Hematology, University of Salahaddin, Erbil, Kurdistan, IRAQ
    • 3. PARAPROTEINEMIAS kha S hei
    • 4. khaS hei
    • 5. MULTIPLE MYELOMA WALDENSTROM’S MACROGLOBULINEMIA PARA PROTEINEMIAS PRIMARY AMYLOIDOSIS HEAVY CHAIN DISEASES M-GUS a h h eik S
    • 6. ANEMIA BONE PAIN # VERTEBRAL COLLAPSE BLEEDING LYTIC BONE LESIONS INFECTION ORTHOPEDIC SURGEONNEURO- NEPHRO-LOGIST HEMATOLOGIST LOGISTS RENAL HYPERVISCOSITY FAILURE kha S hei
    • 7. 1% of All Cancers 2% of All Cancer Deaths MULTIPLE MYELOMA Average Age ~ 65 Black: White = 2:1
    • 8. MULTIPLEMYELOMA BONE MARROW INFILTRATION OSTEOLYTIC PARAPROTEINBONE LESIONS PRODUCTION ha h eik S
    • 9. ↓ PLATELET↓ WBC PANCYTOPENIA ANEMIA BONE MARROW INFILTRATIONMULTIPLEMYELOMA ha h eik S
    • 10. ha h eik S INFECTION BLEEDING ↓ PLATELET ↓ WBC PANCYTOPENIA ANEMIA IMMUNE BONE MARROW MULTIPLSUPPRESSION INFILTRATION E MYELOM A
    • 11.  Chemotherapy myelosuppression INFECTION  Steroid immunosuppression MULTIPLE MYELOMA ↓ WBC PANCYTOPENIA IMMUNE BONE MARROWSUPPRESSION INFILTRATION ha h eik S
    • 12. MULTIPLEMYELOMA ANEMIA BONE PAIN BONE OSTEOLYTIC # BONE LESIONS VERTEBRAL COLLAPSE ↑ Ca++ RENAL a FAILURE heikhS
    • 13. MULTIPLEMYELOMA ANEMIA HEMO- DILUTION PARAPROTEIN PRODUCTION HYPER VISCOSITY CNS SYMPTOMS ha h eik S
    • 14. MULTIPLEMYELOMA INTERFERENCE WITH CLOTTING BLEEDING FACTORS ANEMIA PARAPROTEIN COATING OF PRODUCTION PLATELETS ha h eik S
    • 15. MULTIPLEMYELOMA LIGHT CHAINS PARAPROTEIN PRODUCTION RENAL FAILURE AMYLOID a h h eik S
    • 16. ?RENALINFECTION PYELONEPHRITIS FAILURE LIGHT CHAINS ↑ Ca++ RENAL FAILURE MULTIPLE AMYLOID a h MYELOMA h eik S
    • 17. PARAPROTEIN ?BLEEDINGINTERFERENCEWITH CLOTTING FACTORS BONE MARROW INFILTRATION BLEEDING MULTIPLE MYELOMA PARAPROTEIN COATING OF ha PLATELETS h eik S
    • 18. MULTIPLEMYELOMA ?ANEMIA BLEEDING BONE MARROW INFILTRATION HEMO- DILUTION RENAL kha FAILURES hei
    • 19. a BONE MARROW heikh S INFILTRATION OSTEOLYTIC PARAPROTEIN BONE LESIONS PRODUCTION INFECTION RENAL BLEEDING FAILURE MULTIPLE BONE PAIN, MYELOMA HYPER- # & VERT.↑ Ca++ ANEMIA VISCOSITY COLLAPSE
    • 20. The cytoplasm of Myeloma Cells contains abundantEndoplasmic Reticulum (ER) , which may contain retained,condensed or crystallised cytoplasmic Ig producinga variety of morphologically distinctive findings, including:Multiple pale bluish-white, grape-like accumulation  Mott or Morula CellsCherry-red refractive round bodies  Russell BodiesVermilion staining glycogen-rich IgA  Flame CellsOverstuffed fibrils  Gaucher-like cells; thesaurocytes&Crystalline RodsTHESE CHANGES ARE NOT PATHOGNOMONIC FOR MMSINCE THEY MAY BE FOUND IN REACTIVE PLASMA CELLS
    • 21. ha IgG S h eik >50% MULTIPLE LightIgA MYELOMA Chain25% 20% Bi-clonal IgD rare Non- Secretory ? IgM
    • 22. Immunofixationperformed on serum IgG kfrom a patient with monoclonalimmunoglobulin Gk (IgGk) &a patient without amonoclonal protein normal
    • 23. OAF (IL-1/ TNF) OSTEOCLASTS PLASMA CELLSIL- 6 PDGF/ IL-6 BMSC ha h eik S “Bone Marrow Stromal Cells”
    • 24. Interleukin-6-mediated myeloma cell growth BMSC: bone marrow stromal cell IL: interleukin NF: nuclear factor TGF: transforming growth factor MM rely  on contact with BM Stromal Cells “BMSC”Adhesive interaction between MM cells & BMSC induce cells to secrete IL­6which then acts a paracrine growth factor promoting survival of MM cells & inhibiting apoptosis 
    • 25. IL-1 β Osteoclast  OSTEO- ActivationOAF TGF- β LYTIC BONE Osteoblast  LESIONS Other Suppression Cytokines
    • 26. STAGING OF MYELOMA ikh a S he 1 trillion PC (1012) = 1 Kg I II III < 1 > 1 to 2 Kg 2 Kg PC Kg PC PC HIGH LOW CELL CELL MASS MASS<0.6 x 1012/m2 >1.2 X 1012/m2
    • 27. Durie-Salmon Myeloma Staging System Stage I Stage II All of the following: Stage III Overall one or more of the following:Hemoglobin value >10 g/dL data minimally Hemoglobin value <8.5 g/LSerum calcium value normal(<12 mg/dL) abnormal Serum Ca value >12 mg/dL as shown Advanced lytic bone lesionsOn roentgenogram, for (scale 3) normal bone structure(scale) or solitary bone stage I High monoclonal component plasmacytoma only and no production rates SingleLow monoclonal component IgG value >70 g/L value production rates abnormal IgA value >50 g/LIgG value <50 g/L as defined Urine light chain monoclonalIgA value <30 g/L For component on electrophoresisUrine light chain monoclonal stage III >12 g/24 hcomponent onelectrophoresis <4 g/24 h Sh Subclassification: eik h a: Relatively normal renal function (serum creatinine value <2.0 mg/dL) a b: Abnormal renal function (serum creatinine >2.0 mg/dL)
    • 28. Durie-Salmon Myeloma Staging System Stage I Stage II All of the following: Stage III Overall one or more of the following:Hemoglobin value >10 g/dL data minimally Hemoglobin value <8.5 g/LSerum calcium value normal(<12 mg/dL) abnormal Serum Ca value >12 mg/dL 1 <On roentgenogram, as shown > Advanced lytic bone lesions normal bone structure to for (scale 3) 1(scale) or solitary bone stage I 2 plasmacytoma only 2 and no High monoclonal component Kg Single Kg production ratesLow monoclonal component Kg IgG value >7 g/dL PC production rates value PCIgG value <5 g/dL PC abnormal as defined IgA value >5 g/dL Urine light chain monoclonalIgA value <3 g/dL For component on electrophoresisUrine light chain monoclonal stage III >12 g/24 hcomponent onelectrophoresis <4 g/24 h Sh Subclassification: ei a: Relatively normal renal function (serum creatinine value <2.0 mg/dL) kh a b: Abnormal renal function (serum creatinine >2.0 mg/dL)
    • 29. Criteria for Diagnosis of Multiple MyelomaMajor criteria1. Plasmacytomas on tissue biopsy2. Bone marrow plasmacytosis (>30% plasma cells)3. Monoclonal immunoglobulin spike on serum electrophoresis: IgG >35 g/L or IgA >20g/L; κ or λ light-chain excretion >1.0 g/d on 24-h urine protein electrophoresisMinor criteriaa. Bone marrow plasmacytosis (10-30% plasma cells)b. Monoclonal immunoglobulin spike present but of lesser magnitude than in 3c. Lytic bone lesionsd. Normal IgM <0.50 g/L, IgA <1.00 g/L, or IgG <6.00 g/LAny of the following sets of criteria will confirm the diagnosis:Any two major criteriaMajor criterion 1 plus minor criterion b, c, or dMajor criterion 3 plus minor criterion a or cMinor criteria a, b, and c or a, b, and d ha h eik S
    • 30. Normal Ig Values g/L mg/dLIgM 0.5 – 1.5 50 - 150IgA 1.5 – 5.0 150 - 500IgG 5.0 – 15.0 500-1500
    • 31. PresentingFeatures Feature Incidence, %of Multiple Age >40 yr 98Myeloma Male 61 Bone pain 68 Anemia 62 Renal insufficiency 55 Hypercalcemia 30 Hepatomegaly 21 Splenomegaly 5 Proteinuria 88 Bence Jones proteinuria 49 Skeletal roentgenographic abnormalities 79 IEP: Spike on SEP 76 Immuno- Hypogammaglobulinemia on SEP 9 electro- phoresis; Minor or no abnormalities on SEP 15 Spike on urinary protein electrophoresis 75 SEP: Monoclonal heavy chain on serum IEP 83 Serum Monoclonal light chain on IEP 8 protein Nonsecretory 0.3 electro- Amyloidosis 7 phoresis
    • 32. Frequency of Different Types of Monoclonal Proteins Produced By Plasma Cell TumorsMonoclonal Protein Frequency, %IgG 52IgA 21IgD 2IgE <0.01IgM (Waldenströms) 12Light chain only 11Heavy chain only <12 or more 0.5None detected 1
    • 33. A. M-GUSMonoclonal Gammopathy of Unclear Significance1. Monoclonal component level: IgG <35 g/L IgA <20 g/L Bence Jones protein <1.0 g/24 h Classification2. Bone marrow plasma cells <10% of3. No bone lesions Monoclonal4. No symptoms GammopathiesB. Indolent myeloma (as in A except:)1. No bone lesions or only limited bone lesions (<3 lytic lesions); no compression fractures2. Monoclonal component levels a. IgG <70 g/L b. IgA <50 g/L C. Smoldering3. No symptoms or associated disease features myelomaa. Performance status >70% (as in B except:)b. Hemoglobin >10 g/dL 1. No bone lesionsc. Serum calcium normal 2. Bone marrowd. Serum creatinine <2.0 mg/dL plasma cells <30%e. No infections
    • 34. IMMUNOPHENOTYPING OF MYELOMA CELLS Myeloma cells typically express monotypic Cytoplasmic Ig & lack SmIg CD19+ CD56/58 - CD Most NORMAL PCMyeloma  38 Cells CD45 - Lack  Pan­B CD79a CD56/58 + CD19  CD19 - &  MYELOMA CELL CD20Markers CD 138 h eik ha S
    • 35. Prognostic Parameters in Multiple Myeloma Chromosome Β2- Microglobulin LDH 13 abnormalities Β2- Microglobulin Albumin MEDIAN SUVIVAL ug/mL g/L Months<6 Plus  > 30 55>6 Plus  > 30 19>6 Plus  < 30 4 ha h eik S
    • 36. MANAGEMENT OF MULTPLE MYELOMA ha h eik S
    • 37. VAD M2MP PROTOCOL Quicker Response Better control of symptoms Less Myelotoxic & Aggressive more convenient beforeSTANDARD Alkylating autologous Transplant REGIMEN Combination Good after MP relapse NO OTHER Better reserved REGIMEN for relapse after 4 day infusion isPRODUCED  autotransplant cumbersome & needBETTER OS failure & other central Line Special casesOS  > 3YRS Sh eik ha
    • 38. VAD M2 MP PROTOCOL Vincristine 0.4 mg/m2/dayMelphalan i.v. infusion over 4 days1 mg/kg Vincristine÷ 5 days Adriamycin 9 mg/m2/day CarmustineEach 5 weeks i.v. infusion over 4 daysTailor dose ~  CyclophosphamideANC nadir Dexamethasone 20 mg/m2 MelphalanPrednisolone p.o. on days60 mg/day 1-4, 9-12, & 17-20 PrednisoloneFor 5 days REPEAT COURSE ShEach 5 weeks eik EACH 28 DAYS ha
    • 39. Thalidomide Begin at 200 mg p.o. daily Thalidomide Increase by is  200 mg every NOT 2 weeks Myelotoxic for a goal of 800 mg p.o. daily Sh eikConstipation Neuropathy Somnolence ha
    • 40. ThalidomideBegin at 200 mg p.o. dailyIncrease by 200 mg every2 weeks for a goal of800 mg p.o. daily Angio­ genesisThalidomidepotential mechanisms of antimyeloma activity:(a) Direct effects (b) antiadhesive action(a)(c) GF inhibition (d) antiangiogenesis (a)(e) immunomodulationbFGF: basic fibroblast growth factor TNF: tumor necrosis factorICAM: intracellular adhesion molecule IFN: interferonIL: interleukin VEGF: vascular endothelial growth factor
    • 41. Thalidomide
    • 42. DexamethasoneDescribed as the single most effective agent in MyelomaEffective efficacy comparable to VAD in Primary Refractory MyelomaNot Myelosuppressive and suits patients with severe marrow compromiseIn Frail & Elderly patients start with a lower dose Dexamethasone 20 mg/m2 p.o. on days 1-4, 9-12, & 17-20 a heikh REPEAT COURSES EACH 28 to 42 DAYS
    • 43. 2006 ASH UPDATE MP VAD DEXA THALID- OMIDE MDT * MPTThalidomideLenalidomide “Revlimid” Thal RMPBortezomib “Velcade”Pegylated Ribosomal Doxorubicin DD VMP Revlimid Pegylated “Lena- Ribosomal Velcade lidomide” Doxorubicin + “Bortezomib” Dexa
    • 44. French randomized trial ofconventional versus high-dose therapy
    • 45. BONE MARROW or PERIPHERAL STEM CELLTRANSPLANTATION HIGH DOSE CHEMOTHERAPY ALLOGENEIC “VAD” TRANSPLANTAutologous Ideal for Young Patients withTransplant Histocompatible Donor Sibling ha eik Sh
    • 46. Stem Cell Transplantation as Up-Front versus Rescue TreatmentMeasure PBSCT Early PBSCT LateEstimated median overall survival 64.6 mo 64.0 moMedian event-free survival 39.0 mo 13.0 moQuality-adjusted time without symptoms or toxicity 27.8 mo 22.3 mo PBSCT, peripheral blood stem cell transplantation
    • 47. ADJUVANT TREATMENTS IN MULTIPLE MYELOMA BIS­ PHOSPHONATES INTERFERON PAMIDRONATE ZOLEDRONATE HEMO­ EPO DIALYSIS RADIATIONInhibit Bone ResorptionReduces Bone #Suppresses Hypercalcemia PneumovaxConvenient 1 injection/month ha h eik S
    • 48. Novel treatment approaches to Myeloma from the bench to the bedsideDC: dendritic cell IL: interleukin IMIDS: immunomodulatory drugs MM: multiple myeloma VEGF: vascular endothelial growth factor
    • 49. Angio- genesis Thalidomide:potential mechanisms of antimyeloma activity. • Direct effects; (b) antiadhesive action; • (c) growth factor inhibition; (d) antiangiogenesis; • (e) immunomodulation. bFGF, basic fibroblast growth factor; • ICAM, intracellular adhesion molecule; IFN, • interferon; IL, interleukin; TNF, tumor necrosis factor; • VEGF, vascular endothelial growth factor
    • 50. AMYLOIDOSIS ha h eik S
    • 51. PRIMARYAMYLOIDOSIS ha h eik S
    • 52. Primary Amyloidosis PC neoplasm that secretes an abnormal Ig, Which deposits in various tissues & forms aβ-pleated sheet structure that binds Congo Red dye with characteristic birefringence 80% of 15% of Diagnostic Rare Patients have Myeloma Biopsy Sites Monoclonal Ig have or Adult develop Abd. s.c. fat-pad Disease 20% have 10 Bone Marrow Myeloma Amyloidosis Rectum GUT NERVES HMG SensorimotorCHF N.S. Mal- neuropathy Absorp- Loss of Sphincter CRF tion control Macroglossia Sheikha
    • 53. Primary Amyloidosis Deposition in organs  BLEEDING Increased vessel fragility ORGANOMEGALY Coagulation factors bindingAmyloid is a fibrillary protein that causes organ failure AL AA β2 Primary or Secondary AF Micro-Ig- light chain globulin Amyloidosis ~ Familial inflammation ~ Dialysis(~ Myeloma) Sheikha
    • 54. SOP ha h eik S
    • 55. SOP Solitary OsseousPlasmacytoma ha h eik S
    • 56. SOP a heikh S 5% of PC neoplams No other Lytic lesions should be detected Marrow away from the lesion should not have plasmacytosis Site depends on marrow activity In order of frequency sites are: Vertebrae  Ribs  Skull  Pelvis  Femur  Clavicle  Scapula Treatment RT 35% CUREDIf Paraprotein +veit should disappear after treatment 10% 55% >10 Local Recurrennce MM years or Another SOP
    • 57. EXTRA-OSSEOUS PLASMACYTOMA ha h eik S
    • 58. EOP Extra OsseousPlasmacytoma ha h eik S
    • 59. Role of adhesion molecules in disease pathogenesisBMSC, bone marrow stromal cell ECM, extracellular matrix ICAM, intracellular adhesion molecule IL, interleukin LFA, lymphocyte function-associated antigen MM, multiple myeloma VCAM, vascular cell adhesion molecule VLA, very late antigen
    • 60. EOP ha h eik S EXTRA EXTRA OSSEOUS MEDULLARY 5% of PC neoplasms No Lytic lesions or marrow plasmacytoma 80% Median Age: 55 years UPPER RESPIRATORY M/F ratio: 2:1 TRACT L. N. PAROTID SKIN Oropharynx TESTIS Nasopharynx Sinuses Larynx GIT BLADDER CNS BREAST THYROID15% 25%MM Treatment RT Recurrence 15 – 20% may have PARAPROTEINEMIA
    • 61. WALDENSTOROM’SMACROGLOBULINEMIA ha h eik S
    • 62. MONOCLONAL GAMMOPATHYOF UNDETERMINATE SIGNIFICANCE M-GUSBENIGN MONOCLONAL GAMMOPATHY ha h eik S
    • 63. ha h eikS
    • 64. HCD HEAVY CHAINDISEASES ha h eik S
    • 65. αμ γ HCD ha h eik S
    • 66. HCD γ α μGamma Alpha mu HCD HCD HCD A variant A A of variant variant of LPC of Extranodal CLLLymphoma Margianl Zone MALT ha Lymphoma h eik S
    • 67. α Heavy Chain Disease IPSIDImmunoproliferative Small Intestinal Disaese Mediterranean Lymphoma ~ H. pylori kha S hei
    • 68. OSTEOSCLEROTICPOLYNEUROPATHY MYELOMA ORGANOMEGALY (Sensorimotor (Hepato- Demyelination) Splenomegaly) POEMS SYNDROME ENDOCRINOPATHY SKIN CHANGES (Diabetes;(Hyperpigmentation; Gynecomastia; Hypertrichosis) MONOCLONAL Testicular Atrophy; GAMMOPATHY Impotence)Marrow infiltrated by PC & bone trabeculae thickenedRare: 1 to 2% of PC dyscrasias Median Age: 50 years
    • 69. Cellular origin of myeloma:genetic and cellular events in disease pathogenesis
    • 70. Interleukin-6-mediated myeloma cell growth. BMSC, bone marrow stromal cell; IL, interleukin;NF, nuclear factor; TGF, transforming growth factor
    • 71. Apoptosis signaling cascades in myeloma cells.IL, interleukin; JNK, c-jun N-terminal kinase;PYK, proline-rich tyrosine kinase; RAFTK, related adhesion focal tyrosine kinase;SAPK, stress-activated protein kinase
    • 72. Interleukin-6 growth and antiapoptotic cascades in myeloma cells. MAP, mitogen-activated protein; RAFTK,related adhesion focal tyrosine kinase;SHP, Src homology protein tyrosine phosphatase
    • 73. Role of adhesion molecules in disease pathogenesisBMSC, bone marrow stromal cell ECM, extracellular matrix ICAM, intracellular adhesion molecule IL, interleukin LFA, lymphocyte function-associated antigen MM, multiple myeloma VCAM, vascular cell adhesion molecule VLA, very late antigen
    • 74. None 6