in partnership with
The Impact of Thalidomide Maintenance Therapy
Varies According to Biological Risk Grouping
Annamaria Brioli
Fiona M Ross3, Martin Kaiser1, Charlotte Pawlyn1, Ping Wu1, Walter M Gregory4, Roger Owen5, Graham H Jackson6, Michele
Cavo2, Faith E Davies1, Gareth J Morgan1
1Haemato-Oncology
Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, London, UK; 2Seràgnoli Institute of Hematology,
Bologna University School of Medicine, Italy; 3Wessex Regional Genetics Laboratory, University of Southampton, Salisbury, UK; 4Clinical Trials
Research Unit, University of Leeds, Leeds, UK; 5St James's University Hospital, Leeds, UK; 6Haematology Department, University of Newcastle,
Newcastle-upon-Tyne, UK
UKMF Spring Day
13th March 2013
Abstract presented at the 54th ASH® Annual Meeting and Exposition
Atlanta, December 8-11 2012
Study Background
Maintenance therapy can modify residual disease behaviour
delaying or preventing relapses
decreasing post relapse survival
Induction
109
108
Presentation
PR
VGPR
CR
Tumour bulk
107
Maintenance
Relapse
Relapse
106
Time to progression
105
Time to progression
sCR
104
Relapse
103
102
Relapse
10
Cure
Clonal extinction and cure
Time
Study Background
The impact of maintenance may vary according to the underlying biology of the disease
Genetic alterations, such as t(4;14), del(17p) and +1q, can be used to define different
biological behaviours1, 2
The presence of co-segregating adverse FISH lesion defines a group of patients with more
aggressive disease3
PFS
OS
1. Avet-Loiseau H, et al. J Clin Oncol. 2012;30(16):1949-52.
2. Fonseca R, et al. Leukemia 2009;23(12):2210-21
3. Boyd K, et al. Leukemia 2012;26(2):349-55
Study Background
Thalidomide maintenance
Studies have shown conflicting results:

improvement of tumor response1-3 vs no improvement4

improvement of progression-free survival (PFS)1-2,5-6 vs no change3

survival benefit1,6-7 vs no advantage3,5

higher benefit in lower2,4 vs higher risk biological groups9

impaired quality of life10
Evaluate the impact of thalidomide maintenance on biological risk groups
defined by co-segregating FISH lesion
1.
2.
3.
4.
5.
Spencer A, et al. J Clin Oncol. 2009;27:1788-93.
Attal M, et al. Blood. 2006;108:3289-94
Sahebi F, et al. Bone Marrow Transplant. 2006;37:825-9
Morgan GJ, et al. Blood 2012: 119:7-15
Lockhorst HM, et al. Blood. 2010;115:1113-20
6.
7.
8.
9.
10.
Barlogie B, et al. N Engl J Med. 2006;354:1021-30
Brinker BT, et al. Cancer. 2006;106:2171-80
Barlogie B, et al. J Clin Oncol. 2010;28:1209-14
Barlogie B,et al. Blood 2008; 112:3115-3121
Hicks LK, et al. Cancer Treat Rev. 2008;34:442-52.
MRC Myeloma IX trial
Study Design
Induction1-3
Maintenance4
Older, less fit
MP
CTD
HDM
200 mg/m2
Younger, fitter
CVAD
•
Randomization
CTDa
Thalidomide
Maintenance
Median time on
maintenance treatment:
7 months
No
Maintenance
Thalidomide maintenance = 50 mg/day × 4 weeks, increasing thereafter to
100 mg/day if well tolerated, until disease progression
CTD, cyclophosphamide, thalidomide and dexamethasone; CTDa, CTD
attenuated (low-intensity); CVAD, vincristine, doxorubicin,
dexamethasone and cyclophosphamide; HDM, high-dose melphalan;
MP, melphalan and prednisone.
2.
1. Morgan GJ, et al. Lancet. 2010;376:1989-99.
Morgan GJ, et al. Haematologica. 2012: 97(3):442-50.
3. Morgan GJ, et al. Blood. 2011;118:1231-8.
4. Morgan GJ, et al. Blood. 2012: 119:7-15.
MRC Myeloma IX trial
Thalidomide maintenance vs no maintenance
Study accrual
N° pts enrolled
N° entered maintenance
N° ® thalidomide
N° ® no maintenance
Cutoff date
2003-2007
1960
818
408
410
February 2012
Median follow-up
-from beginning of therapy
-from beginning of maintenance
5.9 years
5.4 years
MRC Myeloma IX trial
PFS and OS
according to maintenance randomization
PFS
OS
Median PFS:
23.0 m vs 15.3 m
Thal
maintenance
No
maintenance
Median OS:
59.1 m vs 57.6 m
p=0.397
survival
survival
p<0.001
Months from maintenance
randomization
Months from maintenance
randomization
Thal
maintenance
No
maintenance
Evaluable patients
881 patients entered
maintenance
369 patients with complete:
IgH@
del 17(p13)
+1(q32)
182
thalidomide maintenance
187
no maintenance
Median time from initiation of trial to maintenance randomization: 8.3 months
Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]
Patients’ characteristics
Age (years) median (IQR)
Thal maintenance (182)
No maintenance (187)
64 (57-69)
63 (56-70)
16%
27%
24%
34%
17%
28%
21%
34%
4.2 (3.1-6.1)
3.8 (3.0-6.5)
36 (31-39)
34 (30-39)
Stage ISS (%)
I
II
III
NA
2-M
(mg/L) median (IQR)
Albumin
(g/dL) median (IQR)
Creatinine
(µmol/L) median (IQR)
101 (84.7-129.2)
99(82-124)
Hb
(g/dL) median (IQR)
10.5 (9.5-12.0)
10.4 (9.1-11.9)
Plts
(x 109/mL) median (IQR)
217 (178-302)
239 (185-295)
41%
13.2%
1.1%
0.5%
8.8%
38.5%
44%
10%
3.7%
1.6%
4.8%
39%
Adverse genetic abnormalities by
FISH (%)
del13(q)
t(4;14)
t(14;16)
t(14;20)
del17(p13)
+1(q32)
Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]
Response rate pre maintenance
randomization
60% of patients in
each maintenance
arm had received
ASCT
50% of patients in
each maintenance
arm had received
Zoledronic acid
Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]
Presence of genetic alterations
Each lesion was considered whether present in isolation or plus an additional adverse lesion
(+(1)(q21) and del(17)(p13) for IGH translocations, +(1)(q21), del(17)(p13) and t(4;14) for
hyperdiploidy).
SR
HR
UHR
FISH based risk groups:
Standard risk: no adverse FISH lesion
High risk: presence of one of t(4;14), t(14;16), t(14;20), del17(p13), +1(q32)
Ultra high risk: presence of two or more between t(4;14), t(14;16), t(14;20), del17(p13),
+1(q32)
Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]
FISH based risk groups
PFS
High risk FISH
Standard risk FISH
Median PFS:
29.6 m vs 20.3 m
p=0.004
Thal
maintenance
No
maintenance
Median PFS:
11.3 m vs 13.4 m
Thal
maintenance
No
maintenance
survival
survival
p=0.840
Ultra-high risk FISH
Months from maintenance
randomization
Median PFS:
6.5 m vs 6.3 m
Thal
maintenance
No
maintenance
survival
p=0.475
Months from maintenance
randomization
Months from maintenance randomization
Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]
FISH based risk groups
OS
High risk FISH
Standard risk FISH
Median OS:
NR in both arms
Median PFS:
34.7 m vs NR
p=0.039
Thal
maintenance
No
maintenance
survival
survival
p=0.975
Thal
maintenance
No
maintenance
Months from maintenance
randomization
Ultra-high risk FISH
Median OS:
23.5 m vs 42.4 m
Thal
maintenance
No
maintenance
survival
p=0.431
Months from maintenance
randomization
Months from maintenance randomization
Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]
Translocation defined risk groups
PFS
No t(4;14)
No t(11;14)
Months from maintenance
randomization
Thal
maintenance
Median PFS:
18.9 m vs 18.8 m
No
maintenance
p=0.455
Months from maintenance
randomization
Thal
maintenance
No
maintenance
p=0.813
Months from maintenance
randomization
t(11;14)
survival
survival
p=0.163
No
maintenance
Median PFS:
5.3 m vs 6.0 m
Months from maintenance
randomization
Months from maintenance
randomization
Median PFS:
22.1 m vs 14.7 m
p=0.280
Thal
maintenance
survival
No
maintenance
Median PFS:
24.6 m vs 7.1 m
t(4;14)+1
t(11;14)+1
Thal
maintenance
Median PFS:
11.7 m vs 12.1 m
No
maintenance
Thal
maintenance
No
maintenance
survival
p=0.069
Thal
maintenance
survival
survival
Median PFS:
22.1 m vs 16.1 m
t(4;14)
p=0.362
Months from maintenance
randomization
Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]
Translocation defined risk groups
OS
t(4;14)
Thal
maintenance
No
maintenance
survival
survival
Median OS:
54.6 m vs NR
t(4;14)+1
Median OS:
NR vs 36.1 m
Thal
maintenance
Median OS:
31.1 m vs 42.4 m
No
maintenance
Thal
maintenance
No
maintenance
p=0.987
p=0.762
survival
No t(4;14)
p=0.106
Months from maintenance
randomization
Median OS:
NR in both arm
No
maintenance
p=0.940
Thal
maintenance
No
maintenance
Median OS:
29..6 m vs NR
survival
Thal
maintenance
survival
survival
t(11;14)+1
t(11;14)
No t(11;14)
Median OS:
54.6 m vs NR
Months from maintenance
randomization
Months from maintenance
randomization
p=0.128
p=0.182
Months from maintenance
randomization
Months from maintenance
randomization
Months from maintenance
randomization
Thal
maintenance
No
maintenance
Hyperdiploidy defined risk groups
PFS
Hyperdiploidy alone
No Hyperdiploidy
Thal
maintenance
No
maintenance
Median PFS:
36.7 m vs 22.7 m
p=0.417
Thal
maintenance
No
maintenance
survival
p=0.003
Months from maintenance
randomization
Hyperdiploidy+1
Median PFS:
8.7 m vs 11.1 m
p=0.142
Months from maintenance
randomization
Thal
maintenance
No
maintenance
survival
survival
Median PFS:
14.0 m vs 13.3 m
Months from maintenance
randomization
Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]
Hyperdiploidy defined risk groups
OS
Hyperdiploidy alone
No Hyperdiploidy
Thal
maintenance
No
maintenance
Median OS:
NR in both arm
Thal
maintenance
No
maintenance
survival
survival
Median OS:
48.8 m vs NR
p=0.258
p=0.958
Months from maintenance
randomization
Hyperdiploidy+1
Median OS:
30.0 m vs 54.7 m
survival
p=0.056
Months from maintenance
randomization
Months from maintenance
randomization
Thal
maintenance
No
maintenance
Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]
Conclusions
The association of multiple FISH adverse genetic lesions
has an additive effect
 Maintenance thalidomide:
 prolongs PFS of both transplant eligible and non
eligible patients
prolongs PFS in patients with low biological risk
disease (hyperdiploidy and standard risk FISH)
Aknowledgments
Chief Investigators
JA Child
GJ Morgan
GH Jackson
CTRU, Leeds
K Cocks
W Gregory
A Szubert
S Bell
N Navarro Coy
F Heatley
P Best
J Carder
M Matouk
D Emsell
A Davies
D Phillips
University of Birmingham
MT Drayson
K Walker
A Adkins
N Newnham
Wessex Regional Genetics
Laboratory, Salisbury
F Ross
L Chieccio
LTHT, Leeds
G Cook
S Feyler
D Bowen
HMDS, Leeds
RG Owen
AC Rawstron
R de Tute
M Dewar
S Denman
ICR, London
FE Davies
M Jenner
B Walker
D Johnson
D Gonzalez
N Dickens
K Boyd
P Leone
L Brito
A Avridromou
C Pawlyn
M Kaiser
L Melchor
Everyone else from
the Morgan and
Davies Teams
MRC Leukaemia Trial Steering
Committee
MRC Leukaemia Data Monitoring and
Ethics Committee
NCRI Haematological Oncology Clinical
Studies Group
UK Myeloma Forum Clinical Trials
Committee
Myeloma UK
Funding
Medical Research Council
Pharmion
Novartis
Chugai Pharma
Bayer Schering Pharma
OrthoBiotech
Celgene
Kay Kendall Leukaemia Fund
Aknowledgments
Patients and staff from 121 participating institutions in the UK
Nottingham City Hospital
Leeds General Infirmary
Hull Royal Infirmary
Ninewells Hospital, Dundee
Addenbrooke’s Hospital, Cambridge
St James's University Hospital, Leeds
Christie Hospital, Manchester
Blackpool Victoria Hospital
Glan Clwyd Hospital
James Paget Hospital, Great Yarmouth
The Great Western Hospital, Swindon
New Cross Hospital, Wolverhampton
Eastbourne District General Hospital
Hillingdon Hospital, Uxbridge
Kings Mill Hospital, Sutton-in-Ashfield
University Hospital Aintree, Liverpool
Western Infirmary, Glasgow
Glasgow Royal Infirmary
Stepping Hill Hospital, Stockport
Good Hope Hospital, Sutton Coldfield
Darlington Memorial Hospital
Diana Princess of Wales Hospital, Grimsby
Bradford Royal Infirmary
Manchester Royal Infirmary
Stoke Mandeville Hospital, Aylesbury
Scarborough General Hospital
Hope Hospital, Manchester
Poole Hospital
Barnsley District Hospital
Royal Alexandra Hospital, Paisley
City Hospital, Birmingham
Pilgrim Hospital, Boston
Royal Surrey County Hospital
Southport and Formby District General Hospital
Grantham and District Hospital
Doncaster Royal Infirmary
Queen Mary's Hospital, Sidcup
Royal Bolton Hospital
Arrowe Park Hospital
Mid Staffordshire General Hospital
West Suffolk Hospitals NHS Trust
Western General Hospital, Edinburgh
Birmingham Heartlands Hospital
Royal Liverpool University Hospital
University Hospital of Wales, Cardiff
Aberdeen Royal Infirmary
Russells Hall Hospital, Dudley
Royal Cornwall Hospital, Truro
James Cook University Hospital
Medway Maritime Hospital, Gillingham
Royal United Hospital, Bath
Gloucestershire Royal Hospital
Ysbyty Gwynedd, Bangor
Sandwell General Hospital
Lincoln County Hospital
Queen Elizabeth Hospital, Kings Lynn
St Bartholomew’s Hospital, London
Southern General Hospital, Glasgow
Darent Valley Hospital
Trafford General Hospital, Manchester
St Richard’s Hospital, Chichester
Pembury Hospital
Warwick Hospital
Southend General Hospital
Whiston Hospital, Prescot
Queen Elizabeth Hospital, Gateshead
Countess of Chester Hospital
Victoria Infirmary, Glasgow
Princess Royal University Hospital
North Devon District Hospital
Borders General Hospital
King George Hospital, Ilford
Dorset County Hospital
University Hospital of North Tees
North Tyneside General Hospital
Harrogate District Hospital
Royal Marsden Hospital, Sutton
Prince Charles Hospital, Merthyr Tydfil
Central Middlesex Hospital
Ipswich Hospital
Mayday Hospital
Royal Devon and Exeter Hospital
Royal Hallamshire Hospital, Sheffield
Mid Yorkshire NHS Trust
Torbay Hospital, Torquay
Worcester Royal Infirmary
Derbyshire Royal Infirmary
Southampton General Hospital
Colchester General Hospital
Norfolk and Norwich University Hospital
St Helier Hospital, Carshalton
Singleton Hospital, Swansea
Monklands General Hospital, Airdrie
Wycombe General Hospital
Chesterfield & N Derbyshire Royal
Kent and Canterbury Hospital
Cheltenham General Hospital
Hereford County Hospital
Salisbury District Hospital
Bristol Haematology & Oncology Centre
Oldchurch Hospital, Romford
Taunton and Somerset Hospital
Walsgrave Hospital
The Royal Bournemouth Hospital
Derriford Hospital
Worthing Hospital
Royal Victoria Infirmary, Newcastle
Rotherham General Hospital
Milton Keynes General Hospital
Kingston Hospital
Queen Elizabeth Hospital, Birmingham
Conquest Hospital, St Leonard's on Sea
Southmead Hospital, Bristol
George Eliot Hospital
Epsom General Hospital
Basildon Hospital
Nevill Hall Hospital, Abergavenny
Prince Philip Hospital
Northwick Park Hospital, Harrow
South Tyneside District Hospital
Forth Valley