medicine.myeloma.(dr.anwar shexa)

PARAPROTEINEMIAS

Sheikha

ProfessorAnwar SheikhaAnwar Sheikha

MD, FRCP, FRCPath., FCAP, FRCPA, FRCPI, FACP

Senior Consultant Clinical & Lab. Hematologist

Clinical Professor of HematologyUniversity of Mississippi Medical Center, Jackson,

Mississippi

Professor of Hematology, University of Salahaddin, Erbil, Kurdistan,

IRAQ

Sheikha

PARAPROTEINEMIAS

Sheikha

MULTIPLE MYELOMA

WALDENSTROM’S MACROGLOBULINEMIA

PRIMARY AMYLOIDOSIS

HEAVY CHAIN DISEASES

M-GUS

PARAPROTEINEMIAS

Sheikha

BONE PAIN#

VERTEBRAL COLLAPSELYTIC BONE LESIONS

ANEMIA

BLEEDING

INFECTION

HYPERVISCOSITY RENAL FAILURE

NEPHRO-LOGISTS

NEURO-LOGIST

ORTHOPEDIC SURGEON

HEMATOLOGIST

Sheikha

MULTIPLEMYELOMAMULTIPLEMYELOMA

1% of All Cancers 2% of All Cancer Deaths

Average Age ~ 65 Black: White = 2:1

PARAPROTEINPRODUCTION

OSTEOLYTICBONE LESIONS

BONE MARROWINFILTRATION

MULTIPLEMYELOMA

MULTIPLEMYELOMA

Sheikha


PANCYTOPENIA

↓ PLATELET

↓ WBC ANEMIA

MULTIPLEMYELOMA

MULTIPLEMYELOMA

Sheikha


PANCYTOPENIA

↓ PLATELET

↓ WBC ANEMIA

BLEEDING

INFECTION

IMMUNESUPPRESSION MULTIPLE

MYELOMA

MULTIPLEMYELOMA

Sheikha


PANCYTOPENIA↓ WBC

INFECTION

IMMUNESUPPRESSION

MULTIPLEMYELOMA

MULTIPLEMYELOMA

Chemotherapy myelosuppression

Steroid immunosuppression

Sheikha


BONE PAIN

VERTEBRALCOLLAPSE

BONE

#

↑ Ca++ RENAL FAILURE

ANEMIAMULTIPLEMYELOMA

MULTIPLEMYELOMA

Sheikha


ANEMIA

HYPERVISCOSITY

CNSSYMPTOMS

HEMO-DILUTION

MULTIPLEMYELOMA

MULTIPLEMYELOMA

Sheikha


BLEEDING

INTERFERENCEWITH CLOTTING

FACTORS

COATING OFPLATELETS

ANEMIA

MULTIPLEMYELOMA

MULTIPLEMYELOMA

Sheikha


RENAL FAILURE

AMYLOID

LIGHT CHAINS

MULTIPLEMYELOMA

MULTIPLEMYELOMA

Sheikha

RENAL FAILURE

AMYLOID

LIGHT CHAINS

?RENALFAILUREINFECTION PYELONEPHRITIS

↑ Ca++

MULTIPLEMYELOMA

MULTIPLEMYELOMA Sheikha

PARAPROTEININTERFERENCEWITH CLOTTING

FACTORS

PARAPROTEINCOATING OFPLATELETS

?BLEEDING

BONE MARROWINFILTRATION BLEEDING

MULTIPLEMYELOMA

MULTIPLEMYELOMA

Sheikha

RENAL FAILURE

?ANEMIA


BLEEDING

HEMO-DILUTION

MULTIPLEMYELOMA

MULTIPLEMYELOMA

Sheikha




MULTIPLEMYELOMA

MULTIPLEMYELOMAANEMIA

BLEEDINGINFECTION

RENALFAILURE

HYPER-VISCOSITY

↑ Ca++

BONE PAIN,# & VERT.COLLAPSE

Sheikha

The cytoplasm of Myeloma Cells contains abundant Endoplasmic 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 Cells

Cherry-red refractive round bodies Russell Bodies

Vermilion staining glycogen-rich IgA Flame Cells

Overstuffed fibrils Gaucher-like cells; thesaurocytes

&

Crystalline Rods

THESE CHANGES ARE NOT PATHOGNOMONIC FOR MM SINCE THEY MAY BE FOUND IN REACTIVE PLASMA CELLS

MULTIPLE MYELOMA

IgG>50%

IgA25%

LightChain20%

IgDrare

Non-Secretory

Bi-clonal

?IgM

Sheikha

Immunofixation

performed on serum from a patient with monoclonal

immunoglobulin Gk (IgGk)

&

a patient without a monoclonal

protein

normal

IgG k

PLASMA CELLS OSTEOCLASTS

OAF(IL-1/ TNF)

PDGF/ IL-6

BMSC“Bone Marrow Stromal Cells”

IL- 6

Sheikha

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 IL-6which then acts a paracrine growth factor promoting survival of MM cells &

inhibiting apoptosis

OAF

IL-1 β

TGF- β

OtherCytokines

Osteoclast Activation

Osteoblast Suppression

OSTEO-LYTICBONE

LESIONS

I<1

KgPC

II1to2

KgPC

III>2

KgPC

1 trillion PC (1012) = 1 Kg

LOWCELLMASS

<0.6 x 1012/m2

HIGHCELLMASS

>1.2 X 1012/m2

STAGING OF MYELOMASheikha

Stage II Overall data

minimally abnormal as shown

for stage I and no Single value

abnormal as defined

For stage III

Stage IAll of the following:

Hemoglobin value >10 g/dL

Serum calcium value normal(<12 mg/dL)

On roentgenogram, normal bone structure (scale) or solitary bone plasmacytoma only

Low monoclonal component production rates

IgG value <50 g/L

IgA value <30 g/L

Urine light chain monoclonal component onelectrophoresis <4 g/24 h

Durie-Salmon Myeloma Staging System

Stage IIIone or more of the following:

Hemoglobin value <8.5 g/L

Serum Ca value >12 mg/dL

Advanced lytic bone lesions (scale 3)

High monoclonal component production rates

IgG value >70 g/L

IgA value >50 g/L

Urine light chain monoclonal component on electrophoresis >12 g/24 h

Subclassification:

a: Relatively normal renal function (serum creatinine value <2.0 mg/dL)

b: Abnormal renal function (serum creatinine >2.0 mg/dL)

Sheikha

Stage II Overall data

minimally abnormal as shown

for stage I and no Single value

abnormal as defined

For stage III

Stage IAll of the following:

Hemoglobin value >10 g/dL

Serum calcium value normal(<12 mg/dL)

On roentgenogram, normal bone structure (scale) or solitary bone plasmacytoma only

Low monoclonal component production rates

IgG value <5 g/dL

IgA value <3 g/dL

Urine light chain monoclonal component onelectrophoresis <4 g/24 h

Durie-Salmon Myeloma Staging System

Stage IIIone or more of the following:

Hemoglobin value <8.5 g/L

Serum Ca value >12 mg/dL

Advanced lytic bone lesions (scale 3)

High monoclonal component production rates

IgG value >7 g/dL

IgA value >5 g/dL

Urine light chain monoclonal component on electrophoresis >12 g/24 h

Subclassification:a: Relatively normal renal function (serum creatinine value <2.0 mg/dL)

b: Abnormal renal function (serum creatinine >2.0 mg/dL)

<1

KgPC

1to2

KgPC

>2

KgPC

Sheikha

Criteria for Diagnosis of Multiple Myeloma

Major criteria

1. Plasmacytomas on tissue biopsy

2. Bone marrow plasmacytosis (>30% plasma cells)

3. Monoclonal immunoglobulin spike on serum electrophoresis: IgG >35 g/L or IgA >20 g/L; or light-chain excretion >1.0 g/d on 24-h urine protein electrophoresis

Minor criteria

a. Bone marrow plasmacytosis (10-30% plasma cells)

b. Monoclonal immunoglobulin spike present but of lesser magnitude than in 3

c. Lytic bone lesions

d. Normal IgM <0.50 g/L, IgA <1.00 g/L, or IgG <6.00 g/L

Any of the following sets of criteria will confirm the diagnosis:

Any two major criteria

Major criterion 1 plus minor criterion b, c, or d

Major criterion 3 plus minor criterion a or c

Minor criteria a, b, and c or a, b, and dSheikha

g/L mg/dLIgM 0.5 – 1.5 50 - 150

IgA 1.5 – 5.0 150 - 500

IgG 5.0 – 15.0 500-1500

Normal Ig Values

Feature Incidence, %Age >40 yr 98

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

Spike on SEP 76

Hypogammaglobulinemia on SEP 9

Minor or no abnormalities on SEP 15

Spike on urinary protein electrophoresis 75

Monoclonal heavy chain on serum IEP 83

Monoclonal light chain on IEP 8

Nonsecretory 0.3

Amyloidosis 7

Presenting Features of Multiple Myeloma

IEP:Immuno-electro-phoresis;

SEP: Serumprotein electro-phoresis

Frequency of Different Types of Monoclonal Proteins Produced By Plasma Cell Tumors

Monoclonal Protein Frequency, %

IgG 52

IgA 21

IgD 2

IgE <0.01

IgM (Waldenström's) 12

Light chain only 11

Heavy chain only <1

2 or more 0.5

None detected 1

A. M-GUSMonoclonal Gammopathy of Unclear Significance

1. Monoclonal component level:

IgG <35 g/L IgA <20 g/L

Bence Jones protein <1.0 g/24 h

2. Bone marrow plasma cells <10%

3. No bone lesions

4. No symptoms

B. Indolent myeloma (as in A except:)

1. No bone lesions or only limited bone lesions (<3 lytic lesions); no compression fractures

2. Monoclonal component levels

a. IgG <70 g/L b. IgA <50 g/L

3. No symptoms or associated disease features

a. Performance status >70%

b. Hemoglobin >10 g/dL

c. Serum calcium normal

d. Serum creatinine <2.0 mg/dL

e. No infections

C. Smoldering myeloma (as in B except:)

1. No bone lesions

2. Bone marrow plasma cells <30%

Classification of

Monoclonal Gammopathies

IMMUNOPHENOTYPING OF MYELOMA CELLS

Sheikha

Myeloma cells typically express monotypic Cytoplasmic Ig & lack SmIg

MostMyeloma

CellsLack Pan-BCD19

& CD20

Markers

CD38

CD79a

NORMAL PC

MYELOMA CELL

CD19+

CD19 -

CD56/58 -

CD56/58 +

CD138

CD45 -

Prognostic Parameters in Multiple Myeloma

Sheikha

Β2-Microglobulin LDH

Chromosome13

abnormalities

Β2- Microglobulin

ug/mLug/mLAlbumiAlbumi

nn

g/Lg/L

MEDIAN SUVIVALMEDIAN SUVIVAL

MonthsMonths

<6 Plus <6 Plus > 30> 30 5555

>6 Plus >6 Plus > 30> 30 1919

>6 Plus >6 Plus < 30< 30 44

MANAGEMENT OF

MULTPLE MYELOMA

Sheikha

MPVAD

Quicker ResponseBetter control of symptoms

Less Myelotoxic & more convenient before autologous Transplant

Good after MP relapse

4 day infusion iscumbersome & need

central Line

M2PROTOCOL

AggressiveAlkylating

Combination

Better reservedfor relapse after

autotransplantfailure & otherSpecial cases

STANDARDREGIMEN

NO OTHERREGIMEN

PRODUCED BETTER OS

OS > 3YRSSheikha

MPVAD

Melphalan1 mg/kg

÷ 5 days Each 5 weeks

Tailor dose ~ ANC nadir

Prednisolone60 mg/dayFor 5 daysEach 5 weeks

Vincristine0.4 mg/m2/day

i.v. infusion over 4 days

Adriamycin9 mg/m2/day

i.v. infusion over 4 days

Dexamethasone20 mg/m2

p.o. on days1-4, 9-12, & 17-20

REPEAT COURSE EACH 28 DAYS

M2PROTOCOL

Vincristine

Carmustine

Cyclophosphamide

Melphalan

Prednisolone

Sheikha

Thalidomide

Begin at200 mg p.o. daily

Increase by200 mg every

2 weeksfor a goal

of 800 mg

p.o.daily

Constipation Neuropathy Somnolence

Thalidomideis

NOTMyelotoxic

Sheikha

Thalidomide

potential mechanisms of antimyeloma activity: (a) Direct effects (b) antiadhesive action (a)(c) GF inhibition (d) antiangiogenesis (a)(e) immunomodulation

bFGF: basic fibroblast growth factor TNF: tumor necrosis factor ICAM: intracellular adhesion molecule IFN: interferon IL: interleukin VEGF: vascular endothelial growth factor

Thalidomide

Begin at 200 mg p.o. daily

Increase by 200 mg every 2 weeks for a goal of 800 mg p.o. daily

Angio-genesis

Thalidomide

Dexamethasone

Described as the single most effective agent in Myeloma

Effective efficacy comparable to VAD in Primary Refractory Myeloma

Not Myelosuppressive and suits patients with severe marrow compromise

In Frail & Elderly patients start with a lower dose

Dexamethasone20 mg/m2 p.o. on days

1-4, 9-12, & 17-20

REPEAT COURSE EACH 28 to 42 DAYS

Sheikha

2006 ASH UPDATE

VAD

MP

DEXA THALID-OMIDE MDT

*MPT

VMP

Velcade“Bortezomib”

RMP

Revlimid“Lena-

lidomide”

ThalDD

Pegylated Ribosomal Doxorubicin

+Dexa

ThalidomideLenalidomide “Revlimid”Bortezomib “Velcade”Pegylated Ribosomal Doxorubicin

French randomized trial of conventional versus high-dose therapy

BONEMARROW

or

PERIPHERALSTEM CELL

TRANSPLANTATION

HIGH DOSE CHEMOTHERAPY

“VAD”

AutologousTransplant

ALLOGENEICTRANSPLANT

Ideal for YoungPatients with

HistocompatibleDonor Sibling

Sheikha

PBSCT, peripheral blood stem cell transplantation

Stem Cell Transplantation as Up-Front versus Rescue Treatment

Measure PBSCT Early PBSCT Late

Estimated median overall survival 64.6 mo 64.0 mo

Median event-free survival 39.0 mo 13.0 mo

Quality-adjusted time without symptoms or toxicity 27.8 mo 22.3 mo

ADJUVANT TREATMENTS IN MULTIPLE MYELOMA

BIS-PHOSPHONATES

PAMIDRONATEZOLEDRONATE

EPO

RADIATION

HEMO-DIALYSIS

INTERFERON

Pneumovax

Inhibit Bone Resorption

Reduces Bone #

Suppresses Hypercalcemia

Convenient 1 injection/monthSheikha

DC: dendritic cell IL: interleukin IMIDS: immunomodulatory drugs MM: multiple myeloma VEGF: vascular endothelial growth factor

Novel treatment approaches to Myeloma from the bench to the bedside

Thalidomide:

potential mechanisms of antimyeloma activity. (a)Direct effects; (b) antiadhesive action;

(b)(c) growth factor inhibition; (d) antiangiogenesis; (c)(e) immunomodulation. bFGF, basic fibroblast growth factor;

(d)ICAM, intracellular adhesion molecule; IFN, (e)interferon; IL, interleukin; TNF, tumor necrosis factor;

(f)VEGF, vascular endothelial growth factor

Angio-genesis

AMYLOIDOSIS

Sheikha

PRIMARYAMYLOIDOSIS

Sheikha

Primary Amyloidosis

PC neoplasm that secretes an abnormal Ig,Which deposits in various tissues & forms a

β-pleated sheet structure that binds Congo Red dye with characteristic birefringence

RareAdult

Disease

80% of Patients have Monoclonal Ig

20% haveMyeloma

15% ofMyeloma have or develop

10

Amyloidosis

GUT

Mal-Absorp-

tion

CHFHMG

N.S.

CRF

Macroglossia

NERVESSensorimotorneuropathy

Loss of Sphinctercontrol

DiagnosticBiopsy Sites

Abd. s.c. fat-padBone Marrow

Rectum

Sheikha

Primary Amyloidosis

Deposition in organs ORGANOMEGALY

BLEEDINGIncreased vessel fragility

Coagulation factors binding

Amyloid is a fibrillary protein that causes organ failure

ALPrimary or

Ig- light chainAmyloidosis

(~ Myeloma)

AASecondary

~ inflammation

AFFamilial

β2 Micro-

globulin

~ Dialysis

Sheikha

SOP

Sheikha

SOP

SolitaryOsseous

Plasmacytoma

Sheikha

SOP

5% of PC neoplams

No other Lytic lesions should be detectedMarrow 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

35%CURED

55%MM

>10 years

10%Local Recurrennce

orAnother SOP

Treatment

RTIf Paraprotein +veit should disappear

after treatment

Sheikha

EXTRA-OSSEOUSPLASMACYTOMA

Sheikha

EOP

ExtraOsseous

Plasmacytoma

Sheikha

BMSC, 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

Role of

adhesion molecules

in disease

pathogenesis

EOPEXTRA

OSSEOUSEXTRA

MEDULLARY

5% of PC neoplasmsNo Lytic lesions or marrow plasmacytomaMedian Age: 55 yearsM/F ratio: 2:1

80%UPPER

RESPIRATORY TRACT

OropharynxNasopharynx

SinusesLarynx GIT

BLADDER CNS BREAST THYROID

TESTIS

PAROTIDL. N.SKIN

15 – 20% may have PARAPROTEINEMIATreatment RT15%MM

25%Recurrence

Sheikha

WALDENSTOROM’SMACROGLOBULINEMIA

Sheikha

M-GUS

MONOCLONAL GAMMOPATHYOF UNDETERMINATE SIGNIFICANCE

BENIGN MONOCLONAL GAMMOPATHY

Sheikha

Sheikha

HCD

HEAVYCHAIN

DISEASES

Sheikha

HCD

αμ γ

Sheikha

HCD

γGamma

HCD

αAlphaHCD

μmuHCD

A variant

of

LPCLymphoma

A variant

ofExtranodal

Margianl Zone

MALTLymphoma

A variant

of

CLL

Sheikha

αHeavy Chain Disease

IPSIDImmunoproliferative Small Intestinal Disaese

Mediterranean Lymphoma

~ H. pyloriSheikha

POEMSSYNDROME

POLYNEUROPATHY(Sensorimotor Demyelination)

SKIN CHANGES(Hyperpigmentation;

Hypertrichosis)MONOCLONAL GAMMOPATHY

ENDOCRINOPATHY(Diabetes;

Gynecomastia;Testicular Atrophy;

Impotence)

ORGANOMEGALY(Hepato-

Splenomegaly)

OSTEOSCLEROTICMYELOMA

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

BMSC, 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

Role of

adhesion molecules

in disease

pathogenesis

None 6

Health & Medicine

medicine.myeloma.(dr.anwar shexa)