Current European Experience with
Transplantation and Management of the
Newly Diagnosed Patient
Gareth J. Morgan, MD

Outline aim
Myeloma is a chronic disease which will require
multiple lines of treatment and the order these are
delivered is likely to be important
Responses to different lines of treatment are important
and will modify ongoing treatment decisions
Depth of response
Duration of response
Personalised medicine
Upfront stratification based on molecular features will
further refine our treatment strategies

Case Presentation 1
Male, aged 45, highly
articulate
IgG k pp 50g/l,
immunosuppression
Young apparently good
Performance status 1
risk patient for whom all
Blood count, biochemistry
treatment options are
normal
available
B2M low
Bone marrow plasma cells
40%
Skeletal survey normal
Cytogenetics/FISH normal
HLA compatible sibling

Treatment options
Standard non transplant treatment
Aim for plateau
Autologous transplant
Aim for minimal disease state
Double autograft
Allogeneic transplant
Aim for GVM but increased risk of GVHD
Not routinely offered

Standard initial treatment should
be HDM
MRC VII study shows
survival benefit for
HDM vs standard
treatment (NEJM 2003)
Meta-analysis of
comparable trials
confirms benefit

MAG group timing of HDM
Up-front versus relapse
70
HDM at relapse gives the
60
PBSCT (early)
same OS as if used up
PBSCT (late)
50
front
40
If used up front PFS is
30
better
Months
20
Consequently HDM is
10
treatment of choice up
front
0
Estimated median Median event free
TWISTT*
overall survival
survival
Fermand et al. Blood. 1998;92:3131.

Scheduled Tandem Autograft
Possible benefit for
double autograft
The benefit is seen late
on
Benefit only for a
minority of patients
Patient doesn't opt for
this

MRC VII:
Survival after HDM based on B2M
· Greatest benefit is in High B2M group
· Benefit seen in all groups
· Cannot use to make a treatment decision

Royal Marsden Experience:
50% complete responses after HDM
N=383
58 CR
195 PR
CVAMP
15%
51%
The majority of responders were in
PR post induction (51%) and the
administration of HDM was
associated with an 80% probability
of attaining a CR
HDM
140 CR
28 PR
50%
10%
Alvares et al. ASH 2004. Poster to be presented.

Royal Marsden Hospital experience:
Response to VAMP and response post HDM predict outcome
Fig. 3a Overall survival accordingtoresponse status at 3months after first highdose treatment
Fig.1a Overall survival according to maximum response to CVAMP
100
NonResponder
N = 68
O = 39
E = 26.7
CR
N = 111
O = 50 E = 62.8
Respponder
N = 214
O = 107 E = 119.3
100
REST
N = 149
O = 77 E = 64.2
HR = 0.61 95% CI (0.4 - 0.93)
HR = 1.51 95% CI (1.06 - 2.13)
Chis = 6.93
df = 1
P = 0.0085
Chis = 5.14
df = 1
P = 0.023
80
)
80
)
%(
(%
ival
ival
rv
60
CR
u
rv
60
s
REST
su
of
of
ility
40
ility
ab
40
b
ab
ro
bo
P
Pr
NonResponder
20
Responder
20
0
0
0
123
45
6789
10
11
12
13
14
15
16
17
01234
56789
10
11
12
13
14
15
16
17
Time since HDM (years)
Time since first highdose treatment +3 months (years)
Responders to VAMP have a
Complete response to HDM
better outcome
have a better outcome
Treatment Aim
Maximise complete responses
Alvares et al. ASH 2004.
Poster to be presented.

Treatment received
VAD
Discontinued
Thal/dex
Tolerated thalidomide poorly
Maximum response pre transplant Poor response
Paraprotein 20g/l, plasma cells 20%
Autograft 200mg/m2 melphalan
Maximum response at 3 months No response to HDM
Paraprotein 15g/l, plasma cells 15%
Puts him in a higher risk group - Management now ????

Treatment options
Nothing
Thalidomide
Velcade
Interesting option, different mechanism of action,
value in this setting uncertain
Second autologous transplant
Allogeneic transplant
Histocompatible sibling, potential high risk option

Thalidomide
Possible
Patients maintained up to 2 years on 100 mg daily
IFM data presented in abstract form suggests that this
may be beneficial
Significant improvement in PFS
Interesting therapeutic option
Expect a proportion 30%-50% thalidomide naive to respond
further
Patient refuses as he is intolerant
Revlimid
Not available at the time

Second autograft
Entirely possible to go for this as an option as he has
cells stored
IFM data suggests that patients who haven't had a CR
with first High Dose may benefit (NEJM 2003)
Despite this it is hard to escape the logical conclusion
that if it hasn't worked the first time why should a
second work and even if it did what would the expected
therapeutic benefit be in this setting ?

Allogeneic - BMT
Graft versus myeloma is potentially important
Full Intensity Allogeneic Transplant
Possible but remains a high risk option for this
patient
Reduced Intensity Allogeneic Transplant
Reduced risks of Transplant Related Mortality but
relapse rate may be increased

Velcade
In vivo and in vitro data
24%
25%
suggests that Velcade has a
35%
novel mechanism of action
20%
18%
and may work when other
standard treatments have
15%
failed
Not myelosuppresive and
10%
doesn't damaged HSC
7%
6%
Interesting and feasible
4%
5%
therapeutic option
Aim to increase depth of
0%
CR IF -
CR IF +
PR
MR
SD
response
SUMMIT response data

Treated with Velcade
Single agent Velcade 1.3 mg/m2 d1, 4, 8, 11
Well-tolerated
4 cycles and reassessed
Paraprotein 15 g/l plasma cell 15%
Remains in a poor response
No response to Velcade !!!

Treatment options at this stage
Nothing
Heavily treated and poor response
Patient well and keen for further treatment at this
stage rather than delayed
Second autograft
Patient not keen on this option
Full allo high risk in this setting
Mini-allogeneic transplant

Tandem auto + mini allo
Combine cytoreduction achieved with high dose
autologous therapy and stable disease phase to
allow patient time to benefit from the graft versus
myeloma effects
Safer than a full intensity allograft
Relapse risk may be higher
Impact on survival not yet fully understood

UKMF experience:
Tandem auto mini-allo
HDM
Planned sib mini-allo at
3/12
Tandem "auto/mini
T depleted
allo"
DLI in escalating doses if
Feasible option
not full donor chimerism
Good responses
17 presenting patients entered
Safe no excess GVHD
Good responses
TRM acceptable
50% CR 50% PR
aGVHD not excessive

Patient opts for :-
Mini-allogeneic transplant
Effectively a tandem auto mini allo approach
Fludarabine, melphalan.
Campath not used
Discharged day +15
Assessed at 2 months post
Engafted, minor GVHD skin
Paraprotein unchanged
What to do now ????
Potential for DLI
Response can occur late
Watch and wait

Case Presentation 2
57-year-old female
Treated with an autograft in
1998
Good risk female patient
5 years in complete remission
who has a long response
Increasing tiredness and
aches and pains
to a first High Dose
Paraprotein gone up to 30g/l,
Melphalan Autograft
Hb 9.6, creatinine normal
What to do ?
Good performance status
No HLA compatible siblings
First relapse after HDM
Treatment options at this
stage ??

Treatment options
Dexamethasone
VAD
Alkylating agents - MP, cyclophosphamide
Velcade
Thal/Imids
Second HDM
MUD

Information to guide decision
- Relapse after standard Rx
Majority of data available is for patients
relapsing after standard dose chemotherapy not
high dose chemotherapy
Survival is dependent upon duration of first
response
How this relates to patients having initial high
dose chemotherapy is unknown

MRC experience:
Survival from relapse after standard
treatment vs duration of first response
Duration of first response
after standard treatment is
a pertinent prognostic
>3 yrs
factor at this disease stage
1-3 yrs
Patient is in an apparent
<1 yr
good risk group but
relapses after HDM
Survival from relapse for a response of
1 year, 1-3 years, > 3 years
Drayson et al. 2004 personal communication.

Royal Marsden Experience:
Survival from relapse after HDM split by
duration of response > 18 months
Fig. 3a Overall survival for patients receiving second HDM split by time to first relapse
100
<18months
N = 23 O = 20 E = 9.0
For patients with a > 18
>=18months N = 66 O = 41 E = 52.0
HR = 0.35 95% CI (0.17 - 0.72)
Chis = 15.62 df = 1 p = 0.0001
80
month response to a first
)
(%laiv
HDM autograft a second
rv 60
su
of
autograft is an excellent
y
ilitb 40
ab
<18months
treatent option
ro
>=18months
P
option
20
0
012
345
678
9
10
11
12
Time since second high dose (years)

Treatment
Second HDM
Induced with CVAMP
Tolerated HDM
Good engraftment
In remission 2 years following second procedure

Collaborators
MRC trial group
Institute of Cancer Research
Bud Flannagan Unit
JA Child
Royal Marsden Hospital
Royal Marsden Hospital
FE Davies
FE Davies
Nursing staff
CTRU
M Potter
Junior Doctors
K Hawkins
MEthell
S Bell
C Dearden
Haemato-Oncology
J Brown
J Treleavan
Diagnostic Laboratory
M Drayson
R Sasso
D Gonzalez de Castro
E Matutes
R Morilla
Colleagues in
C Alvares
A Morilla
regional hospitals
M Jenner
K Owusu
submitting
B Krishnan
V Brito-Bapapoule
patients
R Powles
A Dunlop
B Sirohi
H Rudenko

Document Outline