UKMF Spring Day Assessment of disease response CR and beyond Roger Owen St Jamess Institute of Oncology Leeds UK Myeloma trials the challenges What do we need Flow cytometry in MM ID: 198341
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MRD in myelomaUKMF Spring DayAssessment of disease response, CR and beyond.
Roger Owen
St James’s Institute of Oncology
Leeds, UKSlide2
Myeloma trials: the challengesSlide3
What do we need?Slide4
Flow cytometry in MM.
Minimum four colour method
Gating using CD38, CD138 and CD45
MRD+ defined by a minimum of 100 events (10
6
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
Applicability
~97%Slide5
Value of flow cytometry in the routine settingConfirmation of a diagnosis of myeloma - good practice c.f. acute leukaemia - immunohistochemistry on trephine sections only needed in limited situations - saves time and moneyDifferential diagnosis of MGUS and MMOutcome prediction – MGUS, smouldering MM and plasmacytomaAmyloidosis
Rare / difficult cases
Response assessmentSlide6
Flow
cytometry
in AL amyloidosis.
97% of patients have aberrant phenotype PCs
Paiva
B et al. Blood 2011;117:3613-3616Slide7
Perez-Persona, E. et al. Blood 2007;110:2586-2592
Updated BJ
Haem
epub
October 2009
Progression in MGUS (A) and SMM (B) – Salamanca data
Adverse risk defined by
>
95% aberrant phenotype plasma cells.Slide8
2002!Slide9Slide10
MRC Myeloma IX— Trial Design
Intensive
Clodronate
CVAD
Zoledronic acid
CVAD
Clodronate
CTD
Zoledronic acid
CTD
MEL-200ASCT–Thal
+Thal
Non-intensive
Clodronate
MP
Zoledronic acid
MP
Clodronate
CTDa
Zoledronic acid
CTDa
Maximal
Response
–Thal
+Thal
N = 1,960
RANDOMISATION
RANDOMISATION
RANDOMISATION
RANDOMISATIONSlide11Slide12Slide13
Effect of MRD according to cytogenetic risk profileSlide14
Paiva
B et al. Blood 2012;119:687-691Slide15Slide16
What about salvage Rx?
Ashcroft
et al,
ASH 2013
Paiva
et al,
Haematologica
.
2015;100
(2):e53-5. Slide17
Impact of therapy received
1
2
3
4
5
6
7
8
20
40
60
80
100
TIME (YEARS)
% PFS
MRD- CVAD n = 113
MRD+ CVAD n = 95
MRD- CTD n = 134
MRD+ CTD n = 55
2
3
= 24.30
P < .00001
de
Tute
et al,
submittedSlide18
de
Tute
et al,
submitted
Outcome determined by level of disease not treatment receivedSlide19Slide20
CR patients only?Slide21
MRD predicts outcome in CR patients.
Paiva
et al. Blood 2008;112:4017-4023Slide22
MRD and M protein response
Rawstron
et al,
2015Slide23
Bruno
Paiva
et al. Blood 2008;112:4017-4023
MRD and M protein responseSlide24
MRD and M protein response.Slide25
Multivariate
analysis.
Rawstron
et al,
2015Slide26Slide27Slide28
MRD: Comparison of induction regimens.CVAD
CTD
Post induction (n=252)
13%
25%
P=0.004
Day 100
(n=397)
54%
71%
P<0.0001Slide29
Ongoing role of ASCT?Rawstron et al, J Clin Oncol. 2013 ;31
(20):2540-7
Paiva
B et al. Blood 2008;112:4017-4023Slide30
MaintenanceSlide31
No change in conventional response with thalidomide maintenance but clear differences in neoplastic plasma cell levels“Using electrophoresis and immunofixation as a monitoring technique, there was no difference between the thalidomide maintenance and no maintenance arms in the percentage of patients that upgraded response status over time (
P
.19).
”
(1)
27.6
96
3.4
68.8
0
20
40
60
80
100
Become MRD negative
Remain MRD negative
Thalidomide maintenance
No maintenance
(2)
Morgan et al, Blood 2012, 119(1): 7-15
Rawstron
, JCO
2013; 31(20):2540-7
Slide32Slide33
1
2
3
4
5
6
7
8
9
10
0
0.2
0.4
0.6
0.8
1.0
0
Years from Diagnosis
Proportion free from disease progression
P=0.003
Normal phenotype
plasma cells
Neoplastic phenotype
plasma cells
Outcome prediction in SPB
Hill
et al,
Blood 2014
IMWG – “solitary
plasmacytoma
with minimal marrow involvement”
IDRIS study of Len-
Dex
in high-risk patientsSlide34
Conclusions.Slide35
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
MRC Leukaemia Trial Steering Committee
MRC Leukaemia Data Monitoring and Ethics Committee
NCRI Haematological Oncology Clinical Studies Group
NIHR, through the National Cancer Research Network
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
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
A Gillman
L Flanagan
C
Tyas
and others
AcknowledgementsSlide36