Le discrasie plasmacellulari

Discrasie plasmacellulari I:

• Gammopatia monoclonale di significato indeterminato (MGUS):• primitiva• secondaria

• Mieloma Multiplo• Smoldering myeloma• Plasma cell leukemia• Mieloma micromolecolare• Mieloma non-secernente• Mieloma osteosclerotico (POEMS: polineuropatia, organomegalia,

endocrinopatia, M protein, skin changes)

• Plasmocitoma solitario• osseo• extraosseo

Discrasie plasmacellulari II

• Macroglobulinemia di Waldenström

• Amiloidosi• primitiva (AL)• secondaria

• Malattia da catene pesanti (HCD)• HCD• HCD• HCD

• Crioglobulinemie

• Linfoma maligno

Presenza di componente monoclonale (M protein)

SP

Immunofixation

Immunoeletrophoresis

IgA MM

IgG MM

BJ MM

IgM WD

iper

normale

MGUS:

< 3 gr% M-protein< 10% BM PCno end-organ damageno AL

incidenza:1.5% > 50 anni3% > 70 anni10% > 80 anni

rischio di evoluzione:1% anno

SMM:

> 3 gr% M-protein> 10% BM PCno end-organ damageno AL

rischio di evoluzione:25% anno

(16% di tutti i MM all’esordio)

MM:

> 3 gr% M-protein> 10% BM PCend-organ damage

Active myeloma: end-organ damage

bone pain - often with loss of height

constitutional - weakness, fatigue and weight loss

anemia - responds to erythropoeitin

renal disease -renal tubular dysfunction

susceptibility to infections - neutropenia, hypogammaglobulinemia)

hypercalcemia - myeloma cells secrete osteoclast activating factors

hyperviscosity - 2 % with myeloma, 50 % with macroglobulinemia

neurologic dysfunction - spinal cord or nerve root compression

IRA/IRC

Myeloma staging systemcells x 1012 /sqm

MedianSurvival(months)

Stage I no anemia (Hb > 10gr%) >60 <0.6 no hypercalcemia

no more than one bony lesion low M protein (IgG < 5gr/dl; IgA < 3 gr/dl; BJ < 4 gr/24 ore)

Stage II between I and III 41 0.6-1.2

Stage III anemia (Hb < 8.5 gr%) 23 >1.2 hypercalcemia (Ca > 12 mg/dl) advanced lytic bone disease high M protein (IgG > 7gr/dl; IgA > 5 gr/dl; BJ > 12 gr/24 ore)

A/B A: creatininemia < 2; B: creatininemia > 2

Myeloma diagnostic work-up

MIDOLLO OSSEO• cellule emopoietiche• vasi• cellule stromali

adipocitifibroblastimacrofagimastociti

• matrice extracellulare

Il midollo osseo è un tessuto complesso

OSSO:• matrice ossea (trabecole)• osteoclasti• osteoblasti

B linfocitaCG

MGUSsmolderingmyeloma

symptomatic myelomaintramedullary

symptomatic myelomaextramedullary

Long-lived PC

Adapted from Nature Reviews - Cancer 2. 177-189, 2002

alterazioni geneticheinstabilita’ genetica

microambiente

• homing delle PC nel midollo

• paracrinia

sopravvivenza

differenziazione

proliferazione

• angiogenesi

• osteoclastogenesi

• inibizione osteogenesi

sistema immunitariointerazione direttainterazione indiretta

Mechanisms of disease progression:

ROLE OF MICROENVIRONMENT

ECM

T cells

VEGF

IL-6

2M

stromal cell

MHC class I+ cells

endothelial cell

PTX3

immune system

Causes of death in multiple myeloma

• Progressive myeloma 45%• Sepsis 25%• Renal failure 10%• Other (old age) 20%

Principles of treatment

• no evidence that early treatment prolongs survival• wait for symptoms, or evidence of disease progression to start

treatment• supportive measures are critically important

– drink 3 liters of fluids daily– treat infections promptly– prophylactic bisphosphonates reduce skeletal cmplications– anemia responds to erythropoeitin

Trattamenti utilizzati:

chemioterapia convenzionale

chemioterapia ad alte dosi con autotrapianto

alte dosi di steroidi (DEX)

interferone

talidomide

allotrapianto mieloablativo/non-mieloablativo

inibitori del proteasoma (Velcade)

Malattia di Waldenstrom

produzione di IgM da parte di B linfociti pre-switch

anomalie citogenetiche specifiche

familiarita’

interessamento midollo osseo, linfonodi, milza

midollo compatibile con linfoma plasmocitico • IgM+, CD19+, CD20+, CD79+, CD10-, CD23-, CD25+, CD27+

IgM con caratteristiche particolari• iperviscosita’• autoimmunita’• neuropatia• amiloidosi• crioglobulinemia

Malattia di Waldenstrom

Asintomatico Sintomatico

Hb < 10 gr%piastrine < 100,000/mmciperviscosita’neuropatia periferica sintomaticaamiloidosicrioglobulinemia sintomatica

TERAPIA

Malattia di Waldenstrom

iperviscosita’: non correlata ai livelli di IgM

sanguinamento mucose (nasale, gengivale)cefaleadisturbi visivi (alterazioni del fundus)disturbi neurologici (vertigini, acufeni, atassia)

viscosimetria

TERAPIA

Amiloidosi:

• disturbo della struttura secondaria delle proteine

• le proteine son prodotti in forma solubile dalle cellule

• diventano insolubili a livello extracellulare per - difetto strutturale della proteina stessa - effetto proteolitico a livello tessutale

• formano depositi a livello tessutale (fibrille)

• i depositi portano a disfunzione tessutale

rene cuore

Amyloid Protein Protein Precursor Clinical

AA SAA Reactive (secondary).Familial Mediterranean fever.Familial amyloid nephropathy with urticaria and deafness(Muckle-Wells' syndrome).

AL Immunoglobulin light chains Idiopathic (primary), myeloma or macroglobulinaemiassociated.

ATTR transthyretin (prealbumin) Familial amyloid polyneuropathy, Portuguese type;.familial amyloid cardiomyopathy, Danish type

AApoA1 apoA1 Familial amyloid polyneuropathy, Iowa type;Hereditary non-neuro pathic systemic amyloidosis

Agel Gelsolin Familial amyloidosis, Finnish type.

Acys Cystatin C Hereditary cerebral haemorrhage with amyloidosis,.Icelandic

Alys Lysozyme Hereditary non-neuropathic systemic amyloidosis (Ostertag-type).

Afib Fibrinogen Hereditary renal amyloidosis.Aß ß protein precursor Alzheimer's disease.

Down's syndrome.. Hereditary cerebral haemorrhage with amyloidosis, Dutch

Aß2M ß2-microglobulin Associated with chronic dialysis.

Ascr Scrapie protein precursor Creutzfeldt-Jakob disease, etc.Gerstmann-Straüssler-Scheinker syndrome.

Acal (Pro)calcitonin In medullary carcinomas of the thyroid

AANF Atrial natri-uretic factor solated atrial amyloid.

AAPP Islet amyloid polypeptide In islets of Langerhans, Diabetes type II, insulinoma.