GAMMOPATIE MONOCLONALI
ACETATO DI CELLULOSA
ROSSO PONCEAU
ACETATO
CELLULOSA
AGAROSIO
STABLE
PROGRESSIVE
BENIGN MONOCLONAL GAMMOPATHY
DOES EXIST?
frequency
Percentage of neoplastic transformation
M. Boccadoro
www.mieloma.it
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
BENIGN MONOCLONAL GAMMOPATHY
M-COMPONENT
ASYMPTOMATIC
NO OSTEOLYTIC LESIONS
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MONOCLONAL GAMMOPATHIES
STABLE
MDD
PROGRESSIVE
NN
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Multistep cancerogenesis of myeloma
Normal
plasma cell
Monoclonal
gammopathy
Myeloma
Extramedullary
myeloma
Kariotipic instability
Chromosome
translocation
IgH switch region
K, N-ras, P53 mutations
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Incidence of Multiple Myeloma,
macroglobulinemia, amyloidosis after
recognition of M-component
Kyle R.A., Baillieres Clin Hematol, 1995
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
BENIGN MONOCLONAL GAMMOPATHY
MONOCLONAL GAMMOPATHY OF
UNDETERMINED SIGNIFICANCE
MGUS
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
FREQUENCY OF MONOCLONAL
GAMMOPATHIES
Related to the sensitivity
of the method
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MONOCLONAL GAMMOPATHIES
Detected by standard methods
1-2 % normal population
> 10 g/L
Detected by sensitive methods
~ 10 % normal population
< 5 g/L
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
OCCURRENCE OF MONOCLONAL GAMMOPATHIES
IN A GENERAL HOSPITAL
- Out-patients referred for routine laboratory tests
- Ospedale Evangelico Valdese, Torino
- Laboratorio analisi (Director: M. Saitta)
- routine agarose electrophoresis
(Hydrasis Ciampolini)
- period: Genuary- May 1998
- 3013 serum samples analysed
- 128 monoclonal gammopathies detected (4.2%)
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
FREQUENCY OF MONOCLONAL
GAMMOPATHY ACCORDING TO AGE
18
%16
14
12
10
8
6
4
2
0
<40
40-50
50-60
60-70
70-80
>80
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
DISTRIBUTION OF M-COMPONENT
CONCENTRATION (g/L)
11-20
4%
> 20 n.q.
2% 2%
5-10
14%
< 5 g/L
78%
Aguzzi et al, Eur J Haematol, 1992
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
DISTRIBUTION OF M-COMPONENT
CONCENTRATION (g/L)
Ospedale Evangelico Valdese, Torino
9%
2%
12%
g/L<10
>10 g/L <15
>15 g/L <30
g/L >30
77%
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MONOCLONAL GAMMOPATHY
PROBABILITY OF TRANSFORMATION
TO A MALIGNANT DISEASE
•Evaluated in patient series:
• Diagnosis 1960s - 70s
• Standard electrophoresis
• M-component at presentation >15 g/L
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MONOCLONAL GAMMOPATHY
PROBABILITY OF TRANSFORMATION FOR
PATIENTS WITH M-component > 15 <30 g/L
9%
2%
12%
77%
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MONOCLONAL GAMMOPATHY
Neoplastic transformation is related to
the M-component concentration
IgG > 50 g/L require chemotherapy
IgG > 30 g/L transformation within 1 year (Dimopoulos, 1993)
IgG > 15 < 30 g/L 26% transformation after 10 years
(Kyle, 1995)
IgG<15 g/L 1.3% transformation after 6 years (Baldini, 1996)
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
BENIGN MONOCLONAL GAMMOPATHY
A pre-neoplastic disorder?
- 5% frequency M-component
- incidence of myeloma 2-4/100.000/year
1 out of 1.000-2000 M-component is transformed
to myeloma every year
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
MONOCLONAL GAMMOPATHIES
TRANSFORMATION TO MYELOMA
Related to
M-component level
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
~ 70%
< 10 g/L
~ 4-6%
10-20 g/L
30 g/L
BENIGN MONOCLONAL
GAMMOPATHY
MONOCLONAL
GAMMOPATHY OF
UNDETERMINED
SIGNIFICANCE
MULTIPLE MYELOMA
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
BENIGN MONOCLONAL GAMMOPATHY
DOES EXIST?
PROBABLY YES
PROSPECTIVE LARGE STUDIES ON PATIENTS WITH
SMALL M-COMPONENTS ARE REQUIRED
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
The New England Journal of Medicine
A Long-Term Study of Prognosis in Monoclonal Gammopathy of
Undetermined 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 years
of 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 Clinic
from 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, IgM
lymphoma, primary amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma (relative risk of
progression, 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 patients
as compared with the white population of the Iowa Surveillance, Epidemiology, and End Results program. In 32 additional
patients, the monoclonal protein concentration increased to more than 3 g per deciliter or the percentage of plasma cells in
the bone marrow increased to more than 10 percent (smoldering multiple myeloma) but without progression to overt
myeloma or related disorders. The cumulative probability of progression was 12 percent at 10 years, 25 percent at 20 years,
The initial concentration of serum monoclonal protein was
a significant predictor of progression at 20 years.
and 30 percent at 25 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 at
[email protected].
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Multistep cancerogenesis of myeloma
Normal
plasma cell
Monoclonal
gammopathy
Myeloma
Extramedullary
myeloma
Kariotipic instability
Chromosome
translocation
IgH switch region
K, N-ras, P53 mutations
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
TRANSFORMATION
FROM
BENIGN
TO
PRE-NEOPLASTIC
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
DIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNI
TORINO, ITALY
Principal investigators
A. Palumbo
P. Omedè
M.Ladetto
A. Pileri
M. Massaia
B. Bruno
S. Battaglio
Investigators: S. Bringhen, A. Bertola, G. Aitoro, F. Cavallo,
P. Falco, L. Giaccone.
R. Ghignone, F. Giaretta, F. Morrone, M. Ruggeri
ITALIAN MULTIPLE MYELOMA STUDY GROUP