Monoclonal Gammopathy
Gammopathy of
of Undetermined
Undetermined
Significance (MGUS)
and Smoldering
Smoldering Multiple Myeloma (SMM):
((SMM):
The Key
to Neoplasia
Robert A. Kyle, M.D.
XI International Myeloma Workshop
Kos,
Kos Greece
G
Greece
June 28, 2007
"Do not fear to repeat what has
already been said. Men need the
hd
truth
trut
i
di
d
nne into
i
their
i ears many
times and
aand from all sides
s
sides.
sides The
first rumor makes them prick up
their ears, the second registers,
and the
tthe third enters
eenters "
.
CP1222613-5
MGUS/SMM
· Prevalence of MGUS
· Follow-up of MGUS
Mayo Clinic
N = 241
SE Minnesota
N = 1384
· Sm
S o
m
Solde
dering mu
m lti
t ple mye
myeloma
m
MGUS:
Olmsted County, Minnesota
Results:
· Olmsted County Residents > 50 years:
28,038
· Serum samples obtained from
from population: 77%
Kyle et al., New Engl J Med, 2006, 354:1362
MGUS:
Olmsted County
C
County,
County Minnesota
M
Minnesota
M-protein
Age
No.
N
No.
%
50 ­ 59
83
8,
8 7
83 3
7
373
141
17
1.
1 7
60 ­ 69
6,019
178
3.0
70 ­ 79
7
4,508
4
205
4.6
80

25
2,
2 6
25 3
6
563
170
66
6.
6 6
To
T tal
o
21,463
2
694
3.2
70
7,071
375
5.3
5
CP1118008-35
Kyle et al., New Engl J Med, 2006, 354:1362
Prevalence of MGUS According to Age
Kyle et al., New Engl J Med, 2006, 354:1362
MGUS
OLMSTED COUNTY MN
Conclusions:
· Prevalence rate remained almost constant
throughout collection, suggesting that patients
who frequently
ffrequently seek medical care are
aare at little or
o
or no
n
no
greater risk for MGUS than those who do not.
· The prevalence was 4
4--fold
fold higher in persons >80
years of age than those age 50
50--59
59 years.
MGUS
OLMSTED COUNTY MN
Cl
Conclus
l
ions
i
(continued)
· The prevalence was 2
2--fold
fold higher than from the
literature in persons >50 years of age and almost
ti
tw
t i
w ce
i
th
tth t
a
i
prev
l
ous y
l report d
e in
i persons >70 years
of age.
· MGUS is one of the most common pre
pre--malignant
malignant
disorders in the general population >50 years of age.
Monoclonal Gammopathy of Undetermined
Significance
Natural History in 241 Cases
241 pati
t
en s i
w th
ith a
t
pro ein in th
the
th serum b t
u
initially no evidence of multiple myeloma,
macroglob linemia
u
, am loidosis
y
,
loidosis or l m
y phoma
m
mphoma
1956-1970 were followed up.
Am J Med 64:814, 1978
CP1118008-16
MGUS
Stat s
u at
at Follo
Follow-Up 1-39 Years ( 241 Cases)
Follow-up
Person-years
y
3,579
,
y,
Median
Group Description
No.
%
1
Nb
No sub
su
t
s
t
an i
ttia
ti l increase
i
14
6
of M-protein (benign)
2
Increase
I
M-protein
p
(
(
p( 3 g/dL
g
)
/dL
g)
25
10
3
Died of unrelated causes
138
57
4
Development of myeloma,
64
27
lbl
macrogl
macrog o
l b
o u
b i
lbllinem
li
ia,
i
amyloidosis, etc
Tot
To a
t l
a
241
100
Mayo Clinic Proceed 79:859, 2004, Kyle, et al.
CP1118008-17
MGUS
Development of
o
of Myeloma
M
Myeloma or
o
or Related
R
Related Disease in
64 Patients with MGUS
Interval to
disease (yr)
No.
%
Median
Range
Multiple myeloma
44*
4
69
10.6
1-32
Macroglobulinemia
7
11
1
10.3
4-16
4
Amyloidosis
8
12
9.0
6-19
6
Ly
L mphoproliferative
y
5
8
8.0
8
4-19
disease
To
T tal
o
64
100
10.4
1-32
*Dx of
o
of myeloma
m
myeloma made
m
made after
aafter 20
220-
20 yr F-
F Ui
U n
in 10
110 pt
p
pt
Mayo Clinic Proceed 79:859, 2004 Kyle et al.
CP1118008-18
MGUS
SE MINNESOTA
N = 1 384
,
Duration of Follow
Follow--up
up
Person Years
11,009
Range
0 35
-
years
Median
15.4 years
y
Deaths
963 (70%)
MGUS
SE MINNESOTA
Relative Risk of Progression
Obs
Exp*
Exp*
RR
Multiple Myeloma
75
75
3325
25
Lymphoma
19
19
7.8
2.4
2.4
Amyloidosis
10
1.2
8.4
8.4
Ml
Macrogl b
o
l
u illinem
li
ia
i
7
02
0.2
.
46
CLL
333.5
3.5
0.9
0.9
Plasmacytoma
1
01
0.1
.
85
8.5
.
Total
115
15.8
7.3
7.3
* Iowa SEER Registry
Kyle, et al., New Engl J Med, 346:564, 2002
MGUS SE Minnesota
1960-1994
30
n=1,384
30%
25%
(%)
25
26%
20
First progression
abilityb
21%
pro
15
12%
Full progression
ative
10
5
10%
Cumul
0
Years
Y
0
5
10
15
20
25
Patients 1,384
at risk
867
423
177
56
17
(no.)
CP1022686-6
Kyle, et al., New Engl J Med, 346:564, 2002
Full Progression or Death
100
)
Progression
%( 80
Death
76%
72%
ence
60
53%
40
veincid
20
mulatiu
10%
11%
11
u
6%
C
0
0
5
10
15
20
25
Years
Y
Kyle, et al., New Engl J Med, 346:564, 2002
CP971723- 6
MGUS and Free
Free Light
Light Chain (FLC)
RR
Risk of Prog
N
95% CI
20 yr
%
Absolute
Competing
risk
M
M--protein
protein < 1.5 g/dl,
449
115522
IgG, Normal FLC
1 risk factor,
factor abn
420
5.4
21
21
10
2 risk factors, abn
226
10.1
37
37
18
3 risk factors, abn
53
53
20.8
58
58
27
Rajkumar,
Rajkumar et al., Blood; 106:1148,
106:1
2005
Smoldering Multiple Myeloma
Mayo Clinic
1970 ­ 1994
N
%
Serum M
M--protein
protein 3 g/dl
and
106
38
Bone marrow plasma cells 10%
Serum M
M--protein
p
< 3 g/dl
g
pg
and
143
52
Bone marrow plasma cells 10%
SM
Serum M-
ti
-prot
pro e
t i
e n
i 3/
3 g dl
d
/dl
and
27
10
Bone marrow plasma cells < 10%
TOTAL
276
100
Smoldering Multip
gple Myeloma
Progression
N
N%
%
Expected
Expected R.R.
No. Pts
Pts
Multiple myeloma
157
57
0.3
522
Primary amyloid
aamyloid (AL)
5
2
01
0.
0 1
.
50
Total
162
59
Smoldering Multip
gple Myeloma
Time to progression
Median years
Serum M-
M spike 3
Bone marrow plasma
2
cells 10
Serum M
M--spike
spike < 3
Bone marrow plasma
8
cells 10
Serum M
M--spike
spike 3
Bone marrow plasma
p
19
19
cells < 10
Total (N = 276) p= <0.001
5
Progression to Multiple Myeloma or Amyloid
100
80
78%
73%
66%
60
51%
percent
40
20
0
0
5
10
15
20
25
years from diagnosis
Progression to MM or AL
100
M-spike>=3 & BMPC>=10
88%
87%
78%
77%
80
70%
70%
70%
69%
63%
M-spike< 3 & BMPC>=10
63%
64%
60
54%
M-spike>=3 & BMPC<10
percent
43%
39%
40
32%
33%
21%
MGUS
20
14%
16%
14%
15%
10%
4%
0
0
5
10
15
20
25
years
y
from diagnosis
MGUS and SMM
ASH
ASH--FDA
FDA EndPoints
Therapy justified only if
preventative strategy
li
prol
pro ongs
l
survi
surv va
i l
di
and
an is
i safe
f