GAMMOPATIE MONOCLONALI. ACETATO DI CELLULOSA ROSSO PONCEAU.

GAMMOPATIE MONOCLONALIGAMMOPATIE MONOCLONALI

ACETATO DI CELLULOSA

ROSSO PONCEAU

ACETATO

CELLULOSA

AGAROSIO

STABLE

PROGRESSIVE

BENIGN MONOCLONAL GAMMOPATHYBENIGN MONOCLONAL GAMMOPATHY

DOESDOES EXISTEXIST??

frequencyfrequency

Percentage of neoplastic transformationPercentage of neoplastic transformation

M. Boccadoro

www.mieloma.itDIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY

ASYMPTOMATICASYMPTOMATIC

NO OSTEOLYTIC LESIONSNO OSTEOLYTIC LESIONS

M-COMPONENTM-COMPONENT

BENIGN MONOCLONAL GAMMOPATHYBENIGN MONOCLONAL GAMMOPATHYBENIGN MONOCLONAL GAMMOPATHYBENIGN MONOCLONAL GAMMOPATHY

DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY

STABLESTABLE

PROGRESSIVEPROGRESSIVE

MONOCLONAL GAMMOPATHIESMONOCLONAL GAMMOPATHIESMONOCLONAL GAMMOPATHIESMONOCLONAL GAMMOPATHIES

MDD

NN


Multistep cancerogenesis of myelomaMultistep cancerogenesis of myeloma

NormalNormalplasma cellplasma cell

MonoclonalMonoclonalgammopathygammopathy

MyelomaMyeloma Extra-Extra-medullarymedullarymyelomamyeloma

ChromosomeChromosometranslocationtranslocation

IgH switch regionIgH switch region

Kariotipic instabilityKariotipic instability

K, N-ras, P53 mutationsK, N-ras, P53 mutations


Incidence of Multiple Myeloma, Incidence of Multiple Myeloma, macroglobulinemia, amyloidosis macroglobulinemia, amyloidosis after after

recognition of M-componentrecognition of M-component

Kyle R.A., Baillieres Clin Hematol, 1995 DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY

BENIGN MONOCLONAL GAMMOPATHYBENIGN MONOCLONAL GAMMOPATHYBENIGN MONOCLONAL GAMMOPATHYBENIGN MONOCLONAL GAMMOPATHY

MONOCLONAL GAMMOPATHY OFMONOCLONAL GAMMOPATHY OFUNDETERMINED SIGNIFICANCEUNDETERMINED SIGNIFICANCE

MGUSMGUS

MONOCLONAL GAMMOPATHY OFMONOCLONAL GAMMOPATHY OFUNDETERMINED SIGNIFICANCEUNDETERMINED SIGNIFICANCE

MGUSMGUS


FREQUENCY OF MONOCLONALFREQUENCY OF MONOCLONALGAMMOPATHIESGAMMOPATHIES

FREQUENCY OF MONOCLONALFREQUENCY OF MONOCLONALGAMMOPATHIESGAMMOPATHIES

Related to the sensitivityRelated to the sensitivityof the methodof the methodRelated to the sensitivityRelated to the sensitivityof the methodof the method


1-2 % normal population1-2 % normal population> 10 g/L> 10 g/L

Detected by standard methodsDetected by standard methods

Detected by sensitive methodsDetected by sensitive methods

~ 10 % normal population~ 10 % normal population< 5 g/L< 5 g/L

MONOCLONAL GAMMOPATHIESMONOCLONAL GAMMOPATHIES


- Out-patients referred for routine laboratory tests- Out-patients referred for routine laboratory tests

- Ospedale Evangelico Valdese, Torino- Ospedale Evangelico Valdese, Torino

- Laboratorio analisi (Director: M. Saitta)- Laboratorio analisi (Director: M. Saitta)

- routine agarose electrophoresis- routine agarose electrophoresis (Hydrasis Ciampolini)(Hydrasis Ciampolini)

- period: Genuary- May 1998- period: Genuary- May 1998

- 3013 serum samples analysed- 3013 serum samples analysed

- 128 monoclonal gammopathies detected (4.2%)- 128 monoclonal gammopathies detected (4.2%)

OCCURRENCE OF MONOCLONAL GAMMOPATHIESOCCURRENCE OF MONOCLONAL GAMMOPATHIESIN A GENERAL HOSPITALIN A GENERAL HOSPITAL


FREQUENCY OF MONOCLONAL FREQUENCY OF MONOCLONAL GAMMOPATHY ACCORDING TO AGEGAMMOPATHY ACCORDING TO AGE

0

2

4

6

8

10

12

14

16

18

<40 40-50 50-60 60-70 70-80 >80

%%


> 202%

5-1014%

11-204%

< 5 g/L78%

n.q.2%

DISTRIBUTION OF M-COMPONENT CONCENTRATION (g/L)

Aguzzi et al, Eur J Haematol, 1992DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY



77%

12%9% 2%

g/L<10

>10 g/L <15

>15 g/L <30

g/L >30


Ospedale Evangelico Valdese, TorinoOspedale Evangelico Valdese, Torino

MONOCLONAL GAMMOPATHYMONOCLONAL GAMMOPATHY

PROBABILITY OF TRANSFORMATION TO A MALIGNANT DISEASEPROBABILITY OF TRANSFORMATION TO A MALIGNANT DISEASE

•Evaluated in patient series:•Evaluated in patient series:• Diagnosis 1960s - 70s• Diagnosis 1960s - 70s

• Standard electrophoresis• Standard electrophoresis

• M-component at presentation >15 g/L• M-component at presentation >15 g/L


MONOCLONAL GAMMOPATHYMONOCLONAL GAMMOPATHYPROBABILITY OF TRANSFORMATION FOR PROBABILITY OF TRANSFORMATION FOR PATIENTS WITH M-component > 15 <30 g/LPATIENTS WITH M-component > 15 <30 g/LPROBABILITY OF TRANSFORMATION FOR PROBABILITY OF TRANSFORMATION FOR PATIENTS WITH M-component > 15 <30 g/LPATIENTS WITH M-component > 15 <30 g/L

77%

12%

9%2%


Neoplastic transformation is related to Neoplastic transformation is related to the M-component concentrationthe M-component concentration

MONOCLONAL GAMMOPATHYMONOCLONAL GAMMOPATHY

IgGIgG<15 g/L 1.3% transformation after 6 years <15 g/L 1.3% transformation after 6 years (Baldini, 1996)(Baldini, 1996)

IgG > 50 g/L require chemotherapyIgG > 50 g/L require chemotherapy

IgG > 30 g/L transformation within 1 year IgG > 30 g/L transformation within 1 year (Dimopoulos, 1993)(Dimopoulos, 1993)

IgG > 15 < 30 g/L 26% transformation after 10 years IgG > 15 < 30 g/L 26% transformation after 10 years (Kyle, 1995)(Kyle, 1995)



A pre-neoplastic disorder?A pre-neoplastic disorder?

- 5% frequency M-component - 5% frequency M-component

- incidence of myeloma 2-4/100.000/year- incidence of myeloma 2-4/100.000/year

1 out of 1.000-2000 M-component1 out of 1.000-2000 M-component is transformed is transformedto myeloma every yearto myeloma every year


MONOCLONAL GAMMOPATHIESMONOCLONAL GAMMOPATHIESMONOCLONAL GAMMOPATHIESMONOCLONAL GAMMOPATHIES

Related to Related to M-component levelM-component levelRelated to Related to M-component levelM-component level


TRANSFORMATION TO MYELOMATRANSFORMATION TO MYELOMA


MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE

MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE

MULTIPLE MYELOMAMULTIPLE MYELOMA

~ 70%< 10 g/L

~ 4-6%10-20 g/L

30 g/L



DOES EXIST?DOES EXIST?

PROSPECTIVE LARGE STUDIES ON PATIENTS WITHPROSPECTIVE LARGE STUDIES ON PATIENTS WITHSMALL M-COMPONENTS ARE REQUIREDSMALL M-COMPONENTS ARE REQUIRED

PROBABLY YESPROBABLY YES


A Long-Term Study of Prognosis in Monoclonal Gammopathy ofUndetermined Significance

Volume 346:564-569 February 21, 2002 Number 8

Robert A. Kyle, M.D., Terry M. Therneau, Ph.D., S. Vincent Rajkumar, M.D., Janice R. Offord, B.S., Dirk R. Larson,M.S., Matthew F. Plevak, B.S., and L. Joseph Melton, III, M.D.

Background A monoclonal gammopathy of undetermined significance (MGUS) occurs in up to 2 percent of persons 50 yearsof age or older. Reliable predictors of progression have not been identified, and information on prognosis is limited.

Methods We identified 1384 patients residing in southeastern Minnesota in whom MGUS was diagnosed at the Mayo Clinicfrom 1960 through 1994. The primary end point was progression to multiple myeloma or another plasma-cell cancer.

Results During 11,009 person-years of follow-up, MGUS progressed in 115 of the 1384 patients to multiple myeloma, IgMlymphoma, primary amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma (relative risk ofprogression, 25.0, 2.4, 8.4, 46.0, 0.9, and 8.5, respectively). The overall relative risk of progression was 7.3 in these patientsas compared with the white population of the Iowa Surveillance, Epidemiology, and End Results program. In 32 additionalpatients, the monoclonal protein concentration increased to more than 3 g per deciliter or the percentage of plasma cells inthe bone marrow increased to more than 10 percent (smoldering multiple myeloma) but without progression to overtmyeloma or related disorders. The cumulative probability of progression was 12 percent at 10 years, 25 percent at 20 years,

and 30 percent at 25 years. The initial concentration of serum monoclonal protein wasa significant predictor of progression at 20 years.

Conclusions The risk of progression of MGUS to multiple myeloma or related disorders is about 1 percent per year.

Address reprint requests to Dr. Kyle at the Mayo Clinic, 200 First St. SW, Rochester, MN 55905, or [email protected].

The New England Journal of Medicine


Multistep cancerogenesis of myelomaMultistep cancerogenesis of myeloma

NormalNormalplasma cellplasma cell

MonoclonalMonoclonalgammopathygammopathy

MyelomaMyeloma Extra-Extra-medullarymedullarymyelomamyeloma

ChromosomeChromosometranslocationtranslocation

IgH switch regionIgH switch region

Kariotipic instabilityKariotipic instability

K, N-ras, P53 mutationsK, N-ras, P53 mutations


DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY

TRANSFORMATIONTRANSFORMATION

BENIGN BENIGN PRE-NEOPLASTICPRE-NEOPLASTICFROMFROM TOTO

ITALIAN MULTIPLE MYELOMA STUDY GROUPITALIAN MULTIPLE MYELOMA STUDY GROUPITALIAN MULTIPLE MYELOMA STUDY GROUPITALIAN MULTIPLE MYELOMA STUDY GROUP

A. PileriPrincipal investigatorsPrincipal investigators

A. PalumboA. PalumboP. OmedèP. OmedèM.LadettoM.Ladetto

M. MassaiaM. MassaiaB. BrunoB. BrunoS. BattaglioS. Battaglio

Investigators: S. Bringhen, A. Bertola, G. Aitoro, F. Cavallo,Investigators: S. Bringhen, A. Bertola, G. Aitoro, F. Cavallo,P. Falco, L. Giaccone. P. Falco, L. Giaccone.

R. Ghignone, F. Giaretta, F. Morrone, M. Ruggeri


GAMMOPATIE MONOCLONALI. ACETATO DI CELLULOSA ROSSO PONCEAU.

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