Update on
High Dose Therapy (HDT)
The MRC Studies
J A CHILD
MRC Studies Update Sydney 2005
MRC MYELOMA VII
Standard conventional-dose chemotherapy
versus
Treatment incorporating HDT + autologous
PBSCT
Previously untreated patients
Age less than 65 years
401 evaluable patients
Closed October 2000
MRC Studies Update Sydney 2005
Myeloma VII
ELIGIBLE PATIENTS UNDER 65 YEARS OF AGE
Chemotherapy Randomisation
C-VAMP
ABCM
or
C WEEKLY
HDM 140mg/m2
+ TBI
or
HDM 200mg/m2
to plateau
PBSCT (autograft)
(stop chemotherapy)
-IFN maintenance therapy
to progression
MRC Studies Update Sydney 2005
MYELOMA VII UPDATE
MRC Studies Update Sydney 2005
MYELOMA VII UPDATE
MRC Studies Update Sydney 2005
TREATMENT WITH HIGH DOSE THERAPY
(HDT) IN PREVIOUSLY UNTREATED PATIENTS
Published data meta-analysis
MRC Studies Update Sydney 2005
MRC MYELOMA VII
DEFINITION OF CR (EBMT CRITERIA)
· Absence of paraprotein by immunofixation
· Less than 5% plasma cells in bone marrow
· No increase in size /number of lytic lesions
· Disappearance of soft tissue plasmacytomas
MRC Studies Update Sydney 2005
MRC MYELOMA VII
MAXIMUM RESPONSE RATE
Standard
Intensive
Complete response
8.5%
44.5%
Partial response
40.5%
42.3%
Minimal response
17.5%
3.5%
No change
15%
2%
MRC Studies Update Sydney 2005
Survival by Response
· Kaplan-meier curves constructed to show
survival estimates for CR, PR and MR
patients within each treatment group.
· No formal statistical comparisons planned
or carried out.
· Trend observed in Intensive treatment
group for improved survival from MR
through to CR patients.
MRC Studies Update Sydney 2005
Overall survival: 2m >8mg/l
Median survival 41.9 months (95% CI 31.3 to 65.2) in the Intensive group
compared with 13.1 months (95% CI 9.2 to 23.9) in the Standard group.
MRC Studies Update Sydney 2005
MRC MYELOMA VII
SURVIVAL TRENDS
· For improved survival with increasing depth
of response from MR to PR to CR
· For greatest benefit from HDT (versus
conventional dose therapy) in higher m
2
stratum
MRC Studies Update Sydney 2005
ANALYSIS OF EARLIER MRC TRIALS
(MYELOMA IV, V, VI)
· Percentage fall in paraprotein failed to
correlate with duration of plateau or
survival
· Quick responders (time to plateau) had a
shorter survival than slow responders
· In terms of outcomes, the attainment and
stability of plateau was more important
than the serological response.
MRC Studies Update Sydney 2005
Treatment Approaches
Standard ABCM
ifn
Disease Bulk
ifn
Intensive cVAMP
HDM
Disease Bulk
MRC Studies Update Sydney 2005
MRC MYELOMA IX
· For newly diagnosed symptomatic
myeloma patients of all ages
· Two pathways ­ intensive and non-
intensive determined by patients in
discussion with the treating physician
MRC Studies Update Sydney 2005
MYELOMA IX
INTENSIVE PATHWAY
INITIAL "INDUCTION" TREATMENT
Is the (oral) combination CTD
(cyclophosphamide-thalidomide-dex)
as effective initial treatment as the
infusional CVAD regimen?
-
Response
-
Survival
-
Quality of life (QOL)
MRC Studies Update Sydney 2005
MYELOMA IX
INTENSIVE PATHWAY
INTENSIFICATION THERAPY
What is the role of low intensity
chemotherapy allogeneic transplantation
(mini-allograft)?
MRC Studies Update Sydney 2005
MYELOMA IX
NON-INTENSIVE PATHWAY
Is an attenuated version of CTD
(CTDa) superior to "standard"
melphalan plus prednisolone (MP)?
-
Response
-
Survival
-QoL
MRC Studies Update Sydney 2005
MYELOMA IX
INTENSIVE AND NON-INTENSIVE
PATHWAY
MAINTENANCE TREATMENT
Does low dose thalidomide in the
maintenance setting prolong remission
and improve overall survival?
MRC Studies Update Sydney 2005
OSTEOLYTIC LESIONS
Plasma Cell
Stromal Cell
IL-6
IL-6
IL-1
TNF
Osteoclast
IL-6
Osteoclast
Precursor
Bone Resorption
MRC Studies Update Sydney 2005
MYELOMA IX
INTENSIVE AND NON-INTENSIVE
PATHWAY
BISPHOSPHONATE TREATMENT
· Is a third generation bisphosphonate
(zoledronate) superior to clodronate in
inhibiting progression of bone lesions?
· Is there a more powerful anti-tumour
effect which contributes to improvement
of PFS and OS?
MRC Studies Update Sydney 2005
Myeloma IX Intensive pathway
Bisphosphonate Randomisation
&
Chemotherapy Randomisation
Clodronate
Zoledronic acid
Clodronate
Zoledronic acid
&
&
&
&
CVAD
CVAD
CTD
CTD
HDM200/m2
Patients with potential
&
sibling donors will also
be offered a low intensity
PBSCT (autograft)
allogeneic procedure
Maintenance Randomisation
No Thalidomide
Thalidomide
MRC Studies Update Sydney 2005
Myeloma IX Non-Intensive pathway
Bisphosphonate Randomisation
&
Chemotherapy Randomisation
Sodium Clodronate
Zoledronic acid
Sodium Clodronate
Zoledronic acid
&
&
&
&
MP
MP
CTDa
CTDa
Maximal
Response
Maintenance Randomisation
No Thalidomide
Thalidomide
MRC Studies Update Sydney 2005
MYELOMA IX
Age by Treatment Pathway
Age in Years
PATHWAY
INTENSIVE
NON-INTENSIVE
N
423
303
Mean
57.92
73.67
Median
58.43
73.50
Std Deviation
7.46
5.76
Std Error
0.36
0.33
Maximum
73.75
89.30
Minimum
31.32
59.48
MRC Studies Update Sydney 2005
Myeloma IX Recruitment - Initial Randomisation
(overall)
55
1800
51
52
48
50
47
1600
45
Monthly Accrual
45
41 40
1400
39
39
l
l 40
37
37
a
38
a
35
u
u
Cumulative Accrual
1200
35
31
Target Accrual
2928
30
1000
accr
26
accr
23
ly 25
800
tive
th
726
la
n 20
u
o
600
m
13
M 15
12
u
Target recruitment = approx 523
400
C
10
77
Actual = 726
5
200
1
0
0
3
3
4
4
5
5
6
6
7
7
8
-0
03
-0
04
-0
04
-0
05
-0
05
-0
06
-0
06
-0
07
-0
07
-0
08
-0
y
g-
v
b-
y
g-
v
b-
y
g-
v
b-
y
g-
v
b-
y
g-
v
b-
y
u
e
u
e
u
e
u
e
u
e
Ma
A
No
F
Ma
A
No
F
Ma
A
No
F
Ma
A
No
F
Ma
A
No
F
Ma
MRC Studies Update Sydney 2005
Myeloma IX Recruitment - Initial Randomisation
(Intensive pathway)
40
1000
Monthly accrual
35
900
30
750
800
l
l
28
28
30
a
a
Cumulative accrual
u
26 26
26 26
700
24
24
ru
Target accrual
25
c
22
22
c
600
accr
19
19
a
18
20
y
500
16
1515
hl
423
tive
400
13
15
lau
ont
300
9
8
M 10
m
Target recruitment = approx 239
u
5
200
C
3
5
Actual = 423
1
100
0
0
3
3
4
4
5
5
6
6
7
7
8
-0
03
-0
04
-0
04
-0
05
-0
05
-0
06
-0
06
-0
07
-0
07
-0
08
-0
y
v
y
v
y
v
y
v
y
v
y
ug-
eb-
ug-
eb-
ug-
eb-
ug-
eb-
ug-
eb-
Ma
A
No
F
Ma
A
No
F
Ma
A
No
F
Ma
A
No
F
Ma
A
No
F
Ma
MRC Studies Update Sydney 2005
Myeloma IX Recruitment - Initial Randomisation
(Non-intensive pathway)
40
1000
Monthly accrual
35
850
900
800
l
Cumulative accrual
a
30
al
26
u
Target accrual
700
ruc
23
25
c
21
600
a
20
20
19
accr
e
18
20
500
17
ly
16
tiv
15
15
th
400
13
13
15
la
12
n
u
11
11
o
10 303
300
9
m
M 10
Target recruitment = approx 276
u
200
C
4 4 4
5
Actual = 303
2
100
0
0
0
3
3
4
4
4
5
5
5
6
6
6
7
7
7
8
8
-0
03
-0
-0
-0
04
-0
-0
-0
05
-0
-0
-0
06
-0
-0
-0
07
-0
-0
-0
y
v
b
y
v
b
y
v
b
y
v
b
y
v
b
y
ug-
ug-
ug-
ug-
ug-
Ma
A
No
Fe
Ma
A
No
Fe
Ma
A
No
Fe
Ma
A
No
Fe
Ma
A
No
Fe
Ma
MRC Studies Update Sydney 2005
Myeloma IX Recruitment
(Maintenance randomisation - overall)
40
900
35
Monthly accrual
762 800
700
30
l
l
a
a
Cumulative accrual
u
u
600
25
Target accrual
22
20
500
accr
20
accr 20
ve
17
ly
400
ti
th
la
n 15
13
u
o
11
300
10
M
m
9
10
10
u
88
7
Target recruitment = approx 150
200
C
6
168
4
Actual = 168
5 2
100
1
0
0
3
4
4
5
5
6
6
7
7
8
8
-0
04
04
-0
05
05
-0
06
06
-0
07
07
-0
08
08
-0
c
r-0
c
r-0
c
r-0
c
r-0
c
r-0
c
un-
ep-
un-
ep-
un-
ep-
un-
ep-
un-
ep-
De
Ma
J
S
De
Ma
J
S
De
Ma
J
S
De
Ma
J
S
De
Ma
J
S
De
MRC Studies Update Sydney 2005
MYELOMA IX
VENOUS THROMBOTIC EVENTS
As of 21st February 2005 689 patients in the trial. 70 VTE events reported in 69 patients
No of events
CVAD
CTD
MP
CTDa
(No of patients)
N=201
N=201 N=143 N=143
% of patients
with events
DVT
5.5%
5.0%
0%
6.3%
PE
2%
7.5%
0%
6.3%
Line related
5.5%
0.5%
0%
0%
TOTAL
13.0%
13.0%
0%
12.6%
MRC Studies Update Sydney 2005
MYELOMA IX STUDIES
Immunophenotypic characterisation of
plasma cells
· Pattern at diagnosis
· Assessment of response and MRD
· Longer term monitoring
MRC Studies Update Sydney 2005
Myeloma VII monitoring approach:
based on CD19/CD45/CD56 expression
Myeloma
MRD+
Normal
Non-myeloma patients post-autograft:
Plasma cells <10% CD19-
Normal bone marrow samples:
Plasma cells <30% CD19-
Sensitivity dependent on time-point and number of plasma cells
MRC Studies Update Sydney 2005
Identifying a disease-specific protein
expression profile
N
MGUS
MM
Use mRNA
microarray data to
identify candidate
antibodies. Test a
large panel of
antibodies on a small
series of cases.
Final Panel:
Test the most
Gated plasma cells:
specific antibody
CD19
CD56
CD45
CD19
CD39
CD31
combinations on
CD19
CD117
CD81
increasingly
CD19
CD63
CD40
CD19
CD27
CD20
larger series of
+ gating controls
cases
MRC Studies Update Sydney 2005
Myeloma IX monitoring approach:
based on disease-specific phenotype
Myeloma
MRD+
Normal
Non-myeloma patients post-autograft:
Plasma cells <5% abnormal
Normal bone marrow samples:
Plasma cells <5% abnormal
Sensitivity NOT dependent on time-point and number of plasma cells
MRC Studies Update Sydney 2005
MRD panel for Myeloma IX
Dilution studies indicate reproducible detection of
neoplastic plasma cells at the 0.01% level
10
cells
Example reports:
1
plasma
·Plasma cells = 0.3% of
leucocytes, of which 40% have
0.1
an abnormal phenotype CD19-
CD27-CD117+
neoplastic
0.01
of
R2 = 0.9979
·Plasma cells = 1.1% of
%
y = 0.944x
0.001
leucocytes; all have a normal
0.001
0.01
0.1
1
10
phenotype
Actual
Observed % of neoplastic plasma cells
MRC Studies Update Sydney 2005
MYELOMA IX STUDIES
Cytogenetics and FISH
· Cytogenetics and FISH on
all available samples
· Del 13 ­ Cytogenetics and
FISH
· 14 translocations
­ FISH: split IgH, t(4;14),
t(6;14), t(11;14), t(14;16),
t(14;20).
­ PCR to identify unknown
partners t(x;14)
· 17p - FISH
· ploidy ­FISH and flow
cytometry
MRC Studies Update Sydney 2005
MYELOMA IX STUDIES
Serum free light chain (flc)
Retrospective studies from previous trials
Serum flc levels of value in assessing and
monitoring:
- 19/28 non-secretary myeloma
(Blood 2001 97:9,2900)
- 224/224 Bence Jones Myeloma
(Lancet 2003 361,489)
- 96% of 493 intact immunoglobulin
paraproteinaemia
(Brit.J.Haem 2004 126,348)
MRC Studies Update Sydney 2005
MYELOMA IX STUDIES
Serum free light chain (flc)
Prospective studies in MRC Myeloma IX
· Evaluation of sensitivity of serum flc in
comparison with other measures in
assessing remission status/depth of
response
· Investigation of serum flc as an early
indicator of response to therapy (possible
because of the short half life)
MRC Studies Update Sydney 2005
MRC MYELOMA IX
linked studies of
bone disease
· SRE's and height in all treatment arms
· Serum and urine markers of bone turnover
(P1NP, CTX, urinary NTX)
· Molecular and serum analysis of cytokines
influencing
bone
turnover
(including
amongst others, RANKL, OPG, DKK1,
sFRP3)
MRC Studies Update Sydney 2005
Future Trials
(MRC/UKMF/NCRI)
· Peri-HDT strategies
· Enhancement of induction therapy
for sub-optimal responders
· Relapse regimens (± HDT)
· Selective approaches for good and
poor prognosis subsets
MRC Studies Update Sydney 2005
MRC MYELOMA IX
INTENSIVE PATHWAY AMENDMENT
CVAD/CTD
Early evaluation
at course 3 (Serological)
Responders
Non-responders
CVAD/CTD
BORTEZOMIB +
To total 4-6 courses
DEXAMETHASONE
for 3 courses
HDT
MRC Studies Update Sydney 2005
MRC MYELOMA IX
PERSONALIA
Chief Investigators
Tony Child, Graham Jackson, Gareth
Morgan
Principal Co-
Faith Davies, Mark Drayson, Fiona Ross,
investigators
Roger Owen, Andy Rawstron, Cathy
(Linked studies)
Williams, Gordon Cook, Eugene McClosky
and John Ashcroft.
Clinical Trials Research
Kim Hawkins, Sue Bell, Alex Smith and
Unit Team
Julia Brown
Quality of life studies
Galina Velikova, Kim Hawkins and Zoe
Bennett
Liaison pharmacist
David Thompson
NCRI, Adult Leukaemia
Alan Burnett, Steve Schey, Jamie Cavanagh,
Working Party and
Charles Singer, Alastair Smith, Nigel
UKMF linkage
Russell, Tim Littlewood and Judith Behrens

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