Monoclonal gammopathy of
unknown significance
significance (MGUS):
a disease in progression
Ola Landgren, M.D.,
M.D., Ph.D.
Principal Investigator
Multiple Myeloma Section
Medical Oncology Branch
National Cancer Institute, NIH
Bethesda, Maryland

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Faculty disclosure information
Nothing to disclose

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Prevalence of MGUS from different
countries around the world
world
Subjects
Age
Prevalence
Study population
(n)
(yrs)
(%)
Ghana1
917
50-74
5.8
Olmsted County
County, MN2
MN
21 463
,
>50
>
32
3.2
Provincial Hospital, Italy3
35,005
11-75
2.9
Nagasaki City, Japan4
52,802
44-70
2.4
Finistere, France5
30,279
>50
1.7
New York, NY6
73,630
­
1.2
Varmland, Sweden7
6995
>25
0.9
Rangiora, New Zealand8
2192
>21
0.7
General Hospital, Italy9
102,000
­
0.7
1Landgren et al. 2007; 2Kyle et al, 2006; 3Aguzzi et al. 1992; 4Iwanaga et al. 2007; 5Saleun et al. 1982;
6Vladutiu et al. 1987; 7Axelsson et al. 1966; 8Carrell et al. 1971; 9Malacrida et al. 1987

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Myeloma incidence around the world
Males Females
Zimbabwe
AFRICA
USA, Puerto
Puer Rico
Rico
Uruguay
Argentina
France, Martinique
CENTRAL AND SOUTH AMERICA
Brazil
Ecuador
Costa Rica
Colombia
Cuba
USA, SEER Blacks
USA, California, LA, Angeles, Hispanic White
Canada
NORTH AMERICA
USA, SEER Whites
NORTH
USA, California, LA, Non-Hispanic White
Israel, All Jews
Israel, Non-Jews
China, Hong Kong
India
ASIA
Japan, Osaka
Korea, Seoul
Philippines, Manila
Thailand, Bangkok
Italy, Florence
Switzerland, Zurich
Ireland
Italy, NE Cancer Surveillance Network
France, Isere
The Netherlands
Sweden
Norway
Belgium
EUROPE
UK, England
Denmark
Spain,
p, Asturias
Germany, S
l
aar and
Finland
Austria, Tyrol
Slovakia
Poland, Lower Silesia
Croatia
Czech Republic
Lithuania
Estonia
Latvia
Belarus
Russia, St Petersburg
Age-adjusted
New Zealand
Graphed using data from
Australia, New South Wales
OCEANIA
Australia, Victoria
rates per 100,000
Australia, Queensland
Parkin et al., IARC , Cancer
person-years
Incidence in Five Continents,
Vol. VIII, 2002
10
5
0
5
10

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Nationwide MGUS/MM study
including 4 million
million U S
. . veterans*
veterans
Whites
African-Americans
non-
non-
Characteristics
MGUS
MGUS
MGUS
MGUS
Number of subjects
3,248,795
1,312
749,020
734
Years
Y
of follow-
follow up (mean) b
(mean)
10.0
4.2
10.0
4.4
Person years at risk b
32,347,635 5,557
7,519,478
3,226
Mean age at ascertainment of MGUS
68.3
66.2
Mean age at diagnosis of MM
68.2
69.5
66.5
67.5
Number f
o MM cases
2 217
,
105
1 150
,
74
* About 30 million U.S. veterans were eligible (Brown et al. Blood 2008). Study inclusion criteria were: >18 yrs old,
male sex, African American or white race, cancer-free and alive the first year, hospitalized at least once in a U.S.
Veterans Affairs (VA) hospital October 1, 1980 to September 30, 1996
b The first year of follow-up was censored
Landgren et al. Blood 2006

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Prevalence of MGUS by race
Age-adjusted
prevalence-ratf
te for MGUS
MGUS
3.0-fold (95%CI: 2.7-3.3) hig
)gher
in African Americans
than in whit
hites
Landgren et al. Blood 2006

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Risk of myeloma after MGUS by race
100
)
African-Americans
%
Whites
(
80
Wilcoxon-test, p = 0.37
risk
60
ive
40
20
Cumulat
0
0
5
10
15
20
Years
Landgren et al. Blood 2006

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Prevalence of MGUS in Accra, Ghana
vs. Olmsted County
County, MN
MN
Accra, Ghana
Olmsted County, MN
Age group,
Total, MGUS,
Prevalence,
Total,
MGUS,
Prevalence,
yrs
n
n
95% CI*
n
n
95% CI*
50 54
­
244
13
53
5.3 (2
(2 5
. 82
­8. )
2)
2181
40
18(
1.8 1
(1 3
. 24
­2. )
4)
55­59
209
12
5.7 (2.6­8.9)
1857
42
2.3 (1.6­2.9)
60­64
166
9
5.4 (2.0­8.9)
1520
52
3.4 (2.5­4.3)
65 69
­
168
13
77
7.7 (3
(3 7
. 12)
­
1344
53
39(
3.9 2
(2 9
. 50
­5. )
0)
70­74
130
7
5.4 (1.5­9.3)
1094
56
5.1 (3.2­6.4)
Unadjusted
917
54
5.9 (4.4­7.4)
7996
243
3.0 (2.7­3.4)
Total
5.8 (4.3­7.4)
3.0 (2.6­3.3)
adjusted
*Per 100 persons.
Standardized to the world 2000 standard population: 50­74 yrs.
Landgren et al. Mayo Clin Proc 2007

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Myeloma develops at younger ages
in African Americans than whites
(SEER 17, 1974-2006)
ages 25-84 years
o
:white)
rati
ence
merican
d
A
Inci
(African
At
Age at myeloma di
diagnosis
Landgren et al. unpublished data

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Family members with MM or MGUS
Lynch et al. NEJM 2008

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Nationwide Swedish MGUS study
MGUS pts*
N = 4,488
1st
1 degree relatives
N = 14 689
,
Matched controls
N = 17,628
1st
1 degree relatives
N = 58,698
*Diagnosed 1967-2005
Landgren et al. Blood 2009

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Risk for MGUS and LP tumors among
1st
1 degree relatives of MGUS pts
Condition
Relatives of
Relatives of RR (95%CI)
MGUS pts, n controls, n
MGUS
22
31
2.8 (1.4­5.6)
MM
41
57
2.9 (1.9­4.3)
WM
8
8
4.0 (1.5­11)
CLL
23
46
2.0 (1.2­2.3)
Landgren et al. Blood 2009

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Support for susceptibility genes
Racial disparity and
familial aggregation patterns
support a role for susceptibility
susceptibility
genes
g
in MGUS and MM
Landgren et al. Blood 2006; Landgren et al. Mayo Clin Proc 2007;
Landgren et al. Blood 2009; Vachon et al. Blood 2009

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Environmental factors likely play
a role
role in
in the
the causation of
of MGUS!
MGUS!
Alexander et al. Int J Cancer 2007;
Brown et al. Blood 2008; Iwanaga et al. Blood 2009

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Multistep molecular pathogenesis
of monoclonal gammopathies
~50% of MGUS pts
have primary
translocations
involving the
immunoglobulin
heavy chain (IgH)
locus on chr. 14q32
~40% of MGUS pts
are associated with
hyperdiploidy
~50% of MGUS pts
have deletion of
chromosome 13
Bergsagel and Kuehl
Best Pract Research Clin Haemat 2007

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"Average risk" of MGUSMM
progression is ~1% per year...
Kyle et al. N Engl J Med 2002

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... but "individual risk" varies!
All 3 factors ab
l
norma
Risk factors
Any 2 factors abnormal
Serum M-spike > 1.5 g/dL
Any 1 factor abnormal
At 20 years
Non-IgG subtype
None abnormal
58%
Abnormal free light-chain ratio
60
Kappa/lambda < 0.26 or > 1.65
40
37%
(%)
21%
20
Patients
5%
0
0
5
10
15
20
25
30
Time (years)
Rajkumar et al. Blood 2005

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Prognosis of MGUS progression
·
Size of M protein
protein (>
( 1
> 5
. g/dL vs. 15g
1.5 /dL)
g/dL)
·
MGUS isotype (non-IgG vs. IgG)
·
Abnormal kappa-lambda free light chain (FLC) ratio
·
Bone marrow (BM)
() clonal plasma-cell
p
% (6-9
(
vs. <5%)
·
Presence of circulating plasma-cells
·
Suppression of uninvolved immunoglobulins
·
Higher relative proportion of aberrant BM plasma-cells
Cesana et al. JCO 2002; Rajkumar et al. Blood 2005;
Kumar et al. JCO 2005; Perez-Persona et al. Blood 2007

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Mayo Clinic risk-stratification model to
predict progression of MGUS
Risk group
gp
Patients
Relative
Absolute
(n)
risk
risk at
20 yrs (%)
Low-risk
449
1.0 (ref.)
5
(no abnormal factors)
Low-intermediate risk
420
5.4
21
(any 1 factor
factor abnormal)
High-intermediate risk
226
10.1
37
(any 2 factors abnormal)
High-risk
53
20.8
58
(all 3 factors abnormal)
Factors: Non-IgG MGUS, M-protein >1.5 g/dL, abnormal FLC-ratio (ref 0.26­1.65)
Rajkumar et al. Blood 2005

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Mayo Clinic risk-stratification model to
predict progression of MGUS
· Low-risk MGUS pts: rechecked in 6
months, and then once every two years
­ or only if symptoms
· All other subsets of MGUS pts:
rechecked in 6 months, and then yearly
thereafter
Rajkumar et al. Blood Reviews 2007

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Is MM always preceded by MGUS,
or does MM typically arise de
de novo?
??
MGUS
MM
Germinal-
center B-cell

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Nationwide prospective PLCO
Cancer Screening Tr
Trial
ial
Over 77,000 healthy
,y
men and women
Age 55­74 yrs
at study enrollment
Blood draw at baseline, repeated annually
(up to
to 6 years) together with screening protocol
protocol
Prospective
p
follow-up for cancer
Prorok et al. Clin Trials 2000;
Landgren et al. N Engl J Med 2009

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MM patients in the prospective PLCO
Cancer Screening Trial
Trial
Total
Total number*,n
, n
71
Age at diagnosis, mean (range)
70 (58­81)
Male sex (%)
50 (71)
Available annual samples, mean (range)
3 (1­6)
Months between blood draw and MM diagnosis,
median (range)
First pre-diagnosis blood draw
59 (29­118)
Last pre-diagnosis blood draw
32 (24­84)
*With available serum obtained 2 or more years prior to MM diagnosis
Landgren et al. Blood 2009

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Serum protein assays
· Electrophoresis performed on agarose gel
· All serum samples tested with immunofixation
· Serum kappa & lambda free light chain (FLC)
using `Freelite' assays
(The Binding Site, Birmingham, UK)
Kyle et al. ASM Press 2002;
Kyle et al. N Engl J Med 2006

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Multiple myeloma is consistently
preceded by MGUS
Years prior to
M-protein *
,
Abnormal FLC ratio
ratio,
MGUS §
Years prior to
MGUS,
MM diagnosis
n/N (%; 95% CI)
n/N (%; 95% CI)
n/N (%; 95% CI)
2
25/27 (93; 76­99)
23/27 (85; 66­96)
27/27 (100; 87­100)
3
54/58 (93; 83­98)
46/58 (79; 67­89)
57/58 (98; 91­100)
4
45/48 (94; 83­99)
29/46 (63; 48­77)
47/48 (98; 89­100)
5
34/37 (92; 78­98)
25/37 (68; 50­82)
35/37 (95; 82­99)
6
25/25 (100; 86­100)
19/25 (76; 55­91)
25/25 (100; 86­100)
7
14/15 (93; 68­100)
11
11/15
/15 (73;
(73; 45­92)
14/15 (93; 68­100)
> 8
13/17 (77; 50­93)
8/17 (47; 23­72)
14/17 (82; 57­96)
Based on
on all
all MM patients with
with available
available serum
serum obtained 2 yrs
yrs prior to MM diagnosis (n = 71).
*Detectable by electrophoresis, immunofixation, or both. Normal ref range: 0.26­1.65.
§Defined as having evidence of an M-protein, an abnormal FLC-ratio, or both.
Landgren et al. Blood 2009

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Median M-protein concentration (g/dL)
prior to
to MM
MM diagnosis
diagnosis
Years
Y
prior
prior
N
Median (range)
MM
concentration
1.8
diagnosis
1.6
1.4
2
24
16(
1.6 0
(0 4
. ­37
3. )
7)
12
1.2
1
347
1.3 (0.5­3.1)
g/dL 0.8
0.6
4
37
1.1 (0.5
(0.5­3.9)
0.4
3.9)
0.2
526
1.2 (0.6­3.8)
0
8+
765432
620
1.2 (0.6­3.6)
Years
Y
prior MM diagnosis
711
1.3 (0.7­3.5)
Ptrend = 0.025
8+
10
0.9 (0.5­1.8)
Landgren et al. Blood 2009

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M-protein concentration year-by-year
prior to
to MM
MM diagnosis
diagnosis in
in individual
individual pts
M-protein level
Stable abnormal M-protein level
increase
4.0
3.5
no
3.0
2.5
centrati
)
n
L 2.0
co
(g/d 1.5
rotein
10
1.0
M-p
0.5
0
8
7
6
5
4
3
2
Years before MM diagnosis
Landgren et al. Blood 2009

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In summary ­ future directions
·
GS
MGUS prevalence varies around the
world. There is support for both
genetic and environmental factors in
the causation of
of MGUS
MGUS

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In summary ­ future directions (cont.)
· MM is consistently preceded by MGUS.
Individual MGUSMM risk varies.
We need better molecular markers!!
· Do the different
different M spike
-
trajectories
trajectories
represent separate MGUS/MM entities?

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Collaborators
National Cancer Institute, NIH
Walter Reed
Malmö University Hospital
Mayo Clinic
Mike Kuehl
Brendan Weiss
Ingemar Turesson
Vincent Rajkumar
Wyndham Wilson
Tina Annunziata
Jerry Katzmann
Kieron Dunleavy
Al
Angela Di
Dispenzi i
er
Lou Staudt
Dirk Larson
Neil Caporaso
Eric Engels
Celine Vachon
Lynn Goldin
U.S. Food and Drug
Joseph Melton
Gloria Gridley
Administration
Robert Kyle
y
Richard Hayes
Ui
Universitity f
o Gh
Ghana
Gerald Marti
Robert Hoover
Andrew Adjei
Fatima Abbasi
Ann Hsing
Richard Biritwum
Martha Linet
Mary McMaster
Yao Tettey
Ruth Pfeiffer
Karolinska
Edward Yeboah
Joshua Rapkin
Si
Sigurdur Kristinsson
Huei-Ting Tsai
Magnus Björkholm
Nichols Institute
Paul Dickman
Quest Diagnostics
Maher Albitar
Wa
W nlong
a
Ma
Sahlgrenska University Hospital
San Raffaele
Ulf-Henrik Mellquist
Umeå University Hospital
University
Cecilie Blimark
Anders Wahlin
Paolo Ghia

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-Thank you for your attention!
Multiple Myeloma Section
Section
Medical Oncology Branch
National Cancer Institute, NIH
www.cancer.gov
landgreo@mail.nih.gov

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Qt
Ques i
ti
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ons

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