Minimal residual disease (MRD) assessment using
multiparameter flow cytometry (MFC) predicts outcome in
both intensively and nonintensively treated patients:
Results from the MRC Myeloma IX trial.
A Rawstron, R de Tute, A Child, F Davies, W
Gregory, S Bell, A Szubert, N NavarroCoy, M
Drayson, S Feyler, F Ross, G Cook, G Jackson, G
Morgan & R Owen.
Disclosures
· The trial was funded by the Medical Research Council (UK).
· Support for the linked scientific investigational studies was
received from BayerSchering, Celgene, Chugai, Novartis,
Pharmion, and Ortho Biotech in the form of unrestricted
educational grants.
· Dr RG Owen has received honoraria from Celgene and Ortho
Biotech.
1
MRC Myeloma IX-- Trial Design
N = 1,960
Intensive
Nonintensive
RANDOMISATION
RANDOMISATION
Clodronate
Zoledronic acid
Clodronate
Zoledronic acid
Clodronate
Zoledronic acid
Clodronate
Zoledronic acid
CVAD
CVAD
CTD
CTD
MP
MP
CTDa
CTDa
MEL200
Maximal
ASCT
Response
RANDOMISATION
RANDOMISATION
Thal
+Thal
Thal
+Thal
Flow cytometry in MM.
Minimum four colour method
Gating using CD38, CD138 and CD45
MRD+ defined by a minimum of 100 events (106 total events acquired
for a sensitivity of 0.01%)
Clonality assessment suboptimal for MRD due to the presence of
normal cells in post treatment samples
Aberrant phenotype defined by CD19 and CD56
Leeds CD138/CD38/CD45/CD19/CD56/CD27
2
MRD negativity: Superiority of CTD/CTDa.
CVAD
CTD
Post induction
8%
16%
P=0.0029
(n=774)
Day 100
38%
53%
P=0.0009
(n=526)
M & PCTDa
End of treatment
2%
13%
P=0.000007
(n=510)
PFS: Day 100 MRD assessment.
3
PFS according to end of induction and day 100
MRD.
Overall survival: Day 100 MRD status.
4
PFS: Nonintensive pathway (n=510).
OS: Nonintensive pathway.
5
Comparison of MRD and paraprotein responses at Day
100 post HDM.
120%
100%
80%
60%
MRD pos
MRD neg
40%
20%
0%
CR
no CR
MRD predicts outcome in patients in CR.
6
Outcome according to MRD status and
conventional response.
What about maintenance?
7
Maintenance or consolidation?
Become MRD-neg
Become MRD-pos
1
1
0.9
0.9
0.8
0.8
P=0.01
0.7
0.7
P=0.04
0.6
0.6
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0
0
No Thal
Thal
No Thal
Thal
N=158
Effect of cytogenetics.
8
Conclusions.
· MRD assessment by flow cytometry is highly
predictive of outcome
PFS and OS
intensive and nonintensive therapies
favourable and adverse cytogenetics
· Complimentary to conventional response
assessment
· Assessment of individual components of
multicomponent treatment schedules and
maintenance strategies
Acknowledgements
Chief Investigators
University of Birmingham
HMDS, Leeds
MRC Leukaemia Trial Steering
JA Child
MT Drayson
RG Owen
Committee
GJ Morgan
K Walker
AC Rawstron
MRC Leukaemia Data Monitoring and
GH Jackson
A Adkins
R de Tute
Ethics Committee
N Newnham
M Dewar
NCRI Haematological Oncology
CTRU, Leeds
S Denman
Clinical Studies Group
K Cocks
Wessex Regional Genetics
Laboratory, Salisbury
NIHR, through the National Cancer
W Gregory
ICR, London
Research Network
F Ross
A Szubert
FE Davies
L Chieccio
UK Myeloma Forum Clinical Trials
S Bell
M Jenner
Committee
N Navarro Coy
B Walker
LTHT, Leeds
F Heatley
D Johnson
Myeloma UK
G Cook
P Best
D Gonzalez
S Feyler
Funding
J Carder
N Dickens
D Bowen
Medical Research Council
M Matouk
K Boyd
Pharmion
D Emsell
P Leone
Novartis
A Davies
L Brito
Chugai Pharma
D Phillips
A Avridromou
Bayer Schering Pharma
A Gillman
OrthoBiotech
L Flanagan
Celgene
C Tyas and others
Kay Kendall Leukaemia Fund
9
Acknowledgements
Patients and staff from 121 participating institutions in the UK
Nottingham City Hospital
Western General Hospital, Edinburgh
Royal Devon and Exeter Hospital
Leeds General Infirmary
Birmingham Heartlands Hospital
Royal Hallamshire Hospital, Sheffield
Hull Royal Infirmary
Royal Liverpool University Hospital
Mid Yorkshire NHS Trust
Ninewells Hospital, Dundee
University Hospital of Wales, Cardiff
Torbay Hospital, Torquay
Addenbrooke's Hospital, Cambridge
Aberdeen Royal Infirmary
Worcester Royal Infirmary
St James's University Hospital, Leeds
Russells Hall Hospital, Dudley
Derbyshire Royal Infirmary
Christie Hospital, Manchester
Royal Cornwall Hospital, Truro
Southampton General Hospital
Blackpool Victoria Hospital
James Cook University Hospital
Colchester General Hospital
Glan Clwyd Hospital
Medway Maritime Hospital, Gillingham
Norfolk and Norwich University Hospital
James Paget Hospital, Great Yarmouth
Royal United Hospital, Bath
St Helier Hospital, Carshalton
The Great Western Hospital, Swindon
Gloucestershire Royal Hospital
Singleton Hospital, Swansea
New Cross Hospital, Wolverhampton
Ysbyty Gwynedd, Bangor
Monklands General Hospital, Airdrie
Eastbourne District General Hospital
Sandwell General Hospital
Wycombe General Hospital
Hillingdon Hospital, Uxbridge
Lincoln County Hospital
Chesterfield & N Derbyshire Royal
Kings Mill Hospital, Sutton-in-Ashfield
Queen Elizabeth Hospital, Kings Lynn
Kent and Canterbury Hospital
University Hospital Aintree, Liverpool
St Bartholomew's Hospital, London
Cheltenham General Hospital
Western Infirmary, Glasgow
Southern General Hospital, Glasgow
Hereford County Hospital
Glasgow Royal Infirmary
Darent Valley Hospital
Salisbury District Hospital
Stepping Hill Hospital, Stockport
Trafford General Hospital, Manchester
Bristol Haematology & Oncology Centre
Good Hope Hospital, Sutton Coldfield
St Richard's Hospital, Chichester
Oldchurch Hospital, Romford
Darlington Memorial Hospital
Pembury Hospital
Taunton and Somerset Hospital
Diana Princess of Wales Hospital, Grimsby
Warwick Hospital
Walsgrave Hospital
Bradford Royal Infirmary
Southend General Hospital
The Royal Bournemouth Hospital
Manchester Royal Infirmary
Whiston Hospital, Prescot
Derriford Hospital
Stoke Mandeville Hospital, Aylesbury
Queen Elizabeth Hospital, Gateshead
Worthing Hospital
Scarborough General Hospital
Countess of Chester Hospital
Royal Victoria Infirmary, Newcastle
Hope Hospital, Manchester
Victoria Infirmary, Glasgow
Rotherham General Hospital
Poole Hospital
Princess Royal University Hospital
Milton Keynes General Hospital
Barnsley District Hospital
North Devon District Hospital
Kingston Hospital
Royal Alexandra Hospital, Paisley
Borders General Hospital
Queen Elizabeth Hospital, Birmingham
City Hospital, Birmingham
King George Hospital, Ilford
Conquest Hospital, St Leonard's on Sea
Pilgrim Hospital, Boston
Dorset County Hospital
Southmead Hospital, Bristol
Royal Surrey County Hospital
University Hospital of North Tees
George Eliot Hospital
Southport and Formby District General Hospital
North Tyneside General Hospital
Epsom General Hospital
Grantham and District Hospital
Harrogate District Hospital
Basildon Hospital
Doncaster Royal Infirmary
Royal Marsden Hospital, Sutton
Nevill Hall Hospital, Abergavenny
Queen Mary's Hospital, Sidcup
Prince Charles Hospital, Merthyr Tydfil
Prince Philip Hospital
Royal Bolton Hospital
Central Middlesex Hospital
Northwick Park Hospital, Harrow
Arrowe Park Hospital
Ipswich Hospital
South Tyneside District Hospital
Mid Staffordshire General Hospital
Mayday Hospital
Forth Valley
West Suffolk Hospitals NHS Trust
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