medicine.myeloma.(dr.anwar shexa)

PARAPROTEINEMIAS ha h eik S

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

PARAPROTEINEMIAS kha S hei

khaS hei

MULTIPLE MYELOMA WALDENSTROM’S MACROGLOBULINEMIA PARA PROTEINEMIAS PRIMARY AMYLOIDOSIS HEAVY CHAIN DISEASES M-GUS a h h eik S

ANEMIA BONE PAIN # VERTEBRAL COLLAPSE BLEEDING LYTIC BONE LESIONS INFECTION ORTHOPEDIC SURGEONNEURO- NEPHRO-LOGIST HEMATOLOGIST LOGISTS RENAL HYPERVISCOSITY FAILURE kha S hei

1% of All Cancers 2% of All Cancer Deaths MULTIPLE MYELOMA Average Age ~ 65 Black: White = 2:1

MULTIPLEMYELOMA BONE MARROW INFILTRATION OSTEOLYTIC PARAPROTEINBONE LESIONS PRODUCTION ha h eik S

↓ PLATELET↓ WBC PANCYTOPENIA ANEMIA BONE MARROW INFILTRATIONMULTIPLEMYELOMA ha h eik S

ha h eik S INFECTION BLEEDING ↓ PLATELET ↓ WBC PANCYTOPENIA ANEMIA IMMUNE BONE MARROW MULTIPLSUPPRESSION INFILTRATION E MYELOM A

 Chemotherapy myelosuppression INFECTION  Steroid immunosuppression MULTIPLE MYELOMA ↓ WBC PANCYTOPENIA IMMUNE BONE MARROWSUPPRESSION INFILTRATION ha h eik S

MULTIPLEMYELOMA ANEMIA BONE PAIN BONE OSTEOLYTIC # BONE LESIONS VERTEBRAL COLLAPSE ↑ Ca++ RENAL a FAILURE heikhS

MULTIPLEMYELOMA ANEMIA HEMO- DILUTION PARAPROTEIN PRODUCTION HYPER VISCOSITY CNS SYMPTOMS ha h eik S

MULTIPLEMYELOMA INTERFERENCE WITH CLOTTING BLEEDING FACTORS ANEMIA PARAPROTEIN COATING OF PRODUCTION PLATELETS ha h eik S

MULTIPLEMYELOMA LIGHT CHAINS PARAPROTEIN PRODUCTION RENAL FAILURE AMYLOID a h h eik S

?RENALINFECTION PYELONEPHRITIS FAILURE LIGHT CHAINS ↑ Ca++ RENAL FAILURE MULTIPLE AMYLOID a h MYELOMA h eik S

PARAPROTEIN ?BLEEDINGINTERFERENCEWITH CLOTTING FACTORS BONE MARROW INFILTRATION BLEEDING MULTIPLE MYELOMA PARAPROTEIN COATING OF ha PLATELETS h eik S

MULTIPLEMYELOMA ?ANEMIA BLEEDING BONE MARROW INFILTRATION HEMO- DILUTION RENAL kha FAILURES hei

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

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

ha IgG S h eik >50% MULTIPLE LightIgA MYELOMA Chain25% 20% Bi-clonal IgD rare Non- Secretory ? IgM

Immunofixationperformed on serum IgG kfrom a patient with monoclonalimmunoglobulin Gk (IgGk) &a patient without amonoclonal protein normal

OAF (IL-1/ TNF) OSTEOCLASTS PLASMA CELLSIL- 6 PDGF/ IL-6 BMSC ha h eik S “Bone Marrow Stromal Cells”

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

IL-1 β Osteoclast OSTEO- ActivationOAF TGF- β LYTIC BONE Osteoblast LESIONS Other Suppression Cytokines

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

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)

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)

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

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

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 electrophoresis; 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

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

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

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

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

MANAGEMENT OF MULTPLE MYELOMA ha h eik S

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

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

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

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

Thalidomide

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

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

French randomized trial ofconventional versus high-dose therapy

BONE MARROW or PERIPHERAL STEM CELLTRANSPLANTATION HIGH DOSE CHEMOTHERAPY ALLOGENEIC “VAD” TRANSPLANTAutologous Ideal for Young Patients withTransplant Histocompatible Donor Sibling ha eik Sh

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

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

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

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

AMYLOIDOSIS ha h eik S

PRIMARYAMYLOIDOSIS ha h eik S

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

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

SOP ha h eik S

SOP Solitary OsseousPlasmacytoma ha h eik S

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

EXTRA-OSSEOUS PLASMACYTOMA ha h eik S

EOP Extra OsseousPlasmacytoma ha h eik S

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

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

WALDENSTOROM’SMACROGLOBULINEMIA ha h eik S

MONOCLONAL GAMMOPATHYOF UNDETERMINATE SIGNIFICANCE M-GUSBENIGN MONOCLONAL GAMMOPATHY ha h eik S

ha h eikS

HCD HEAVY CHAINDISEASES ha h eik S

αμ γ HCD ha h eik S

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

α Heavy Chain Disease IPSIDImmunoproliferative Small Intestinal Disaese Mediterranean Lymphoma ~ H. pylori kha S hei

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

Cellular origin of myeloma:genetic and cellular events in disease pathogenesis

Interleukin-6-mediated myeloma cell growth. BMSC, bone marrow stromal cell; IL, interleukin;NF, nuclear factor; TGF, transforming growth factor

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

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

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

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medicine.myeloma.(dr.anwar shexa)

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