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)
ixation
trophoresis
P


normale
iper
IgA MM
BJ MM
IgG MM
IgM WD
MGUS:
SMM:
MM:
< 3 gr% M-protein
< 10% BM PC
no end-organ damage
no AL
> 3 gr% M-protein
> 10% BM PC
no end-organ damage
no AL
> 3 gr% M-protein
> 10% BM PC
end-organ damage
incidenza:
1.5% > 50 anni
3% > 70 anni
10% > 80 anni
rischio di evoluzione:
25% anno
rischio di evoluzione:
1% anno
(16% di tutti i MM all’esordio)
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
Median
Survival
(months)
Myeloma staging system
cells x 1012 /sqm
Stage I no anemia (Hb > 10gr%)
>60
no hypercalcemia
no more than one bony lesion
low M protein
(IgG < 5gr/dl; IgA < 3 gr/dl; BJ < 4 gr/24 ore)
<0.6
Stage II between I and III
0.6-1.2
41
Stage III anemia (Hb < 8.5 gr%)
23
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
>1.2
Myeloma diagnostic work-up
Il midollo osseo è un tessuto complesso
OSSO:
• matrice ossea (trabecole)
• osteoclasti
• osteoblasti
MIDOLLO OSSEO
• cellule emopoietiche
• vasi
• cellule stromali
adipociti
fibroblasti
macrofagi
mastociti
• matrice extracellulare
B linfocita
CG
Long-lived PC
MGUS
instabilita’ genetica
smoldering
myeloma
symptomatic
myeloma
intramedullary
symptomatic
myeloma
extramedullary
alterazioni genetiche
• homing delle PC nel midollo
• paracrinia
sopravvivenza
differenziazione
microambiente
proliferazione
• angiogenesi
• osteoclastogenesi
• inibizione osteogenesi
sistema immunitario
interazione diretta
interazione indiretta
Adapted from Nature Reviews - Cancer 2. 177-189, 2002
Mechanisms of disease progression:
ROLE OF MICROENVIRONMENT
ECM
stromal cell
endothelial cell
VEGF
PTX3
immune
T cells
system
IL-6
2M
MHC class I+ cells
Causes of death in multiple myeloma
•
•
•
•
Progressive myeloma
Sepsis
Renal failure
Other (old age)
45%
25%
10%
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/mmc
iperviscosita’
neuropatia periferica sintomatica
amiloidosi
crioglobulinemia sintomatica
TERAPIA
Malattia di Waldenstrom
iperviscosita’: non correlata ai livelli di IgM
sanguinamento mucose (nasale, gengivale)
cefalea
disturbi 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(MuckleWells' syndrome).
AL
Immunoglobulin light chains
Idiopathic (primary), myeloma or macroglobulinaemi
associated.
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
.
Aß
Fibrinogen
Hereditary renal amyloidosis
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.
.