RESPONSE BY sFLC AND MARROW FLOW
CYTOMETRY IN
IIN MRC
M
MRC MYELOMA IX
IIX.
IX
RG Owen, AC Rawstron, FE Davies, S Bell,
K Cocks, G Cook, AJ Ashcroft, G Jackson,
GJ Morgan,
M
JA
JA Child
Child & MT
M
MT Drayson.
D
Myeloma
IX
Myeloma
Intensive pathway.
IX
Randomisation
CVAD
CVAD
CTD
CTD
Cl d
o ronate
Zl
Zol d
e ronic i
ac d
id
Cl d
o ronate
Zl
Zol d
e ronic i
ac d
id
HDM 200mg/m2
Randomisation
Thalidomide
No Thalidomide
Myeloma IX Recruitment - Initial Randomisation
(I
( n
I ten
t
sive
si
pa
path
t way)
y)
38
40
1200
37
37
3
35
1114 1080
35
32
31
1000
30
29
l
28
28
30
al
26 26
26 26
26 26
25 25
25
2525
25 25
ru
24
24
24
2424
rua
800
2424
r
c
24
25
c
22
22
2222
c
20
ac
19
19
19
a
18
18
20
600
17
ly
16
1515
15
tive
th 15
la
n
400
u
9
9
Mo 10
m
8
5
200
Cu
3
5 1
0
0
3
3
4
4
5
5
6
6
7
7
-03
04
05
06
07
08
-0
-0
-04
-0
-0
-05
-0
-0
-06
-0
-0
-07
-0
-0
-08
g
v
v
v
v
v
eb-
g
eb-
g
eb-
g
eb-
g
eb-
May
Au
No
F
May
Au
No
F
May
Au
No
F
May
Au
No
F
May
Au
No
F
May
Thalidomide randomisation = 405 patients
Myeloma
IX
Non
Non--intensive
intensive pathway.
Randomisation
MP
MP
CTDa
CTDa
Cl d
o ronate
Zl
Zol d
e ronic i
ac d
id
Cl d
o ronate
Zl
Zol d
e ronic i
ac d
id
Maximal response
Randomisation
Thalidomide
No Thalidomide
Myeloma IX Recruitment
(In
(I it
i ial
tial ra
r ndomi
ndom sat
isa i
t o
i n - No
Non i
- n
inte
t nsiv
ive pat
a h
t way)
40
1000
900
35
850
790
800
l
30
a
al
26
26
700
25 24
24
ru 25
23
23 23
cru
c
600
c
21
21
21
21
c
20
20
a
19
19
19
a 20
18
18
18
1818
500
e
17
17
16
16
16 16
16
16
iv
15
15
15
hly
14
15
400
13
13
13
nt
lat
12
12
12
11
o
u
o
11
10
300
9
m
M 10
6
200
Cu
4 4 4
5
2
100
0
0
0
3
3
4
4
4
5
5
5
6
6
6
7
7
7
8
-03
-04
-05
-06
-07
-08
y
-0
-0
-0
-0
-0
-0
-0
-0
-0
-0
-0
-0
-0
-0
-0
g
v
b
y
g
v
b
y
g
v
b
y
g
v
b
y
g
v
b
y
Ma
Au
No
Fe
Ma
Au
No
Fe
Ma
Au
No
Fe
Ma
Au
No
Fe
Ma
Au
No
Fe
Ma
Thalidomide randomisation = 265 patients
Question
Do MRD flow cy
c tometr
y
y
yy and sFLC assessment
provide a better means of assessing response
(compared to conventional paraprotein
)i
measurements)
measurements in
i patients
i
i
rece v
i ing
i
sequent a
i l
therapies?
Central evaluation
- paraprotein and
and sFLC (Birmingham)
- MRD
MRD flow cytometry (HMDS, Leeds)
Applicability.
Flow cytometry
- informative/aberrant
informative/aberrant phenotype in 97%
- "normal"
"normal" phenotype in 0.4%
- low
low level marrow disease in 2.8%
sFLC
- >95%
>95% of patients informative
- li ht
g cha
h in
l
on y ­ 100%
- non
non--secretory
secretory ­ 70%
Results.....caution!
Post
Day 100
induction
post HDM
(n=129)
(n=159)
ORR 83
883.
83 4%
44% ORR 94
994.
94 8%
88%
CVAD
CV
CR 11.7%
CR 41.0%
ORR 95.7% ORR 98.7%
CTD
CR 20.
20 3%
CR 58.
58 2%
Conventional paraprotein response
100%
80%
60%
NR
PR
40%
VPR
CR
20%
0%
Induction:
Induction:
Day 100:
Day 100:
CVAD
CTD
CVAD
CTD
Results: sFLC and MRD
MRD flow.
Post
P
indu
d ct
u i
ct onnD
o
ay
Day
a 100 post HDM
H
(n=129)
(n=159)
MRD neg 6.4%
MRD neg 37.7%
CVAD
CV
Normal
m sFLC 38.3% Nor
Normal
mal sFLC 72.4%
MRD neg 15.4%
MRD
MRD neg 58.6%
CTD
Normal
m sFLC 52.2% Nor
Normal
mal sFLC 84.6%
LC myeloma ­
Paraprotein vs sFCL
urine CR but
SFLC+
21% of all
100%
patients have
abnormal sFLC at
D1
Day 00
100
80%
60%
NR
40%
PR
VPR
CR
20%
0%
58% of pts with
CR
no CR
CR
no CR
persistent pp at Day
100 have normal
Post
Post Induction
Day 100
100
C
sFL
Conventional paraprotein response at Day 100 according to
induction sFLC response
100%
90%
80%
0%
7
60%
NR
70%
PR
50%
VPR
40%
CR
30%
35%
20%
10%
0%
Normal
Abnormal
Normal sFLC
Abnormal sFLC
post induction
post induction
MRD flow at Day 100 according to end
of inductition sFLC
100%
80%
60%
66%
POS
NEG
40%
42%
20%
0%
Norm
No al
a
Abnormal
a
Paraprotein vs MRD Flow
30% of CR pts
are MRD+
Mi
Most pts in a
conventional CR 100%
post induction are 90%
MRD+
80%
70%
49% of all pts are
MRD+ at Day 100
60%
50%
40%
POS
NEG
NE
30%
20%
10%
MRD neg
neg but
0%
persisting pp ­
CR
no CR
CR
no CR
mainly IgG
Post induction
Day 100
100
Conclusions: sFLC.
Informative in
in >95%
>95% of patients
Possible to provide a national service and hence a central
assessment of response
Value in light chain only disease ­ better
better definition of CR
sFLC response at the induction predicts response at Day 100
21% of
oof patients
ppatients at Day 100
100 have abnormal sFLC
sFLC
- ?high
?high risk pts
- ?applicability
?applicability of consolidation / maintenance strategies
Norma
N
l sFLC not
i
equ valent to
i
convent onal CR
C
CR
Conclusions ­­MRD
MRD flow.
flow.
Direct measure of residual tumour cells
Applicable to 97% pts (cf PCR)
Sensitive (0
((0.
(0 01%) and
aand quantitative
Can be performed on a large scale in real time
49% of patients have detectable MRD at Day
Da
py 100
30% of patients in conventional CR at Day 100 have detectable MRD
Is MRD flow the best way to define "CR"?
- most relevant for pts
pts receiving additional therapy before
before potentially
achieving their maximum paraprotein response.
Can we use MRD flow to identify and monitor those pts who should receive
consolidation /
i
ma ntenance
i
h
t erapi ?
es
Poster #843 tomorrow.
Myeloma
IX
Acknowledgements.
Nottingham City Hospital
112
Russells Hall Hospital, Dudley
27
Ld
Leeds Teachi
hing Hospit
it l
a s
78
St
Sou h
th
t
amp on Gene l
ra Hospit
it l
a
27
Western General Hospital, Edinburgh
72
Glan Clwyd Hospital
26
Royal Devon and Exeter Hospital
59
James Cook University Hospital
26
Birmingham Heartlands Hospital
40
James Paget Hospital, Great Yarmouth
26
Royal Hallamshire Hospital, Sheffield
40
Norfolk and Norwich University Hospital
26
Hull Royal Infirmary
39
St Helier Hospital, Carshalton
26
Royal Liverpool University Hospital
38
Blackpool Victoria Hospital
25
Ninewells Hospital, Dundee
34
Colchester General Hospital
25
Torbay Hospital, Torquay
34
Medway Maritime Hospital, Gillingham
25
Mid Yorkshire NHS Trust
33
Singleton Hospital, Swansea
24
Addenbrooke's Hospital, Cambridge
32
Gloucestershire Royal Hospital
23
University Hospital of Wales, Cardiff
32
Royal United Hospital, Bath
23
Aberdeen Royal Infirmary
29
The Great Western Hospital, Swindon
23
Christie Hospital, Manchester
29
Monklands General Hospital, Airdrie
22
Derbyshire Royal Infirmary
29
Eastbourne District General Hospital
21
Worcester Royal Infirmary
29
New Cross Hospital, Wolverhampton
21
Royal Cornwall Hospital, Truro
28
Wycombe General Hospital
20
Acknowledgements.
Chief investigators ­ JA
JA Child, GJ Morgan and G
Jackson.
Birmingham ­ MT
MT Drayson
Leeds (HMDS
(
)
() ­ AC
A Rawstron,
Rawstron,, R de Tute
Leeds (CTRU) ­ S Bell, K Cocks, A Szubert
London ­­FE
FE Davies
Davies
Salisbury ­ F Ross
Medical Research
Research Council
Council
Pharmion, Novartis, Chugai Pharma, Schering
Healthcare
Myeloma
IX