![Page 1: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/1.jpg)
in partnership with
Making the discoveries that defeat cancer
The Role of Cytogenetics in Elderly patients with MyelomaDr Faith DaviesCancer Research UK Senior Cancer FellowCentre for Myeloma ResearchDivisions of Molecular Pathology, Cancer Therapeutics and Clinical StudiesRoyal Marsden Hospital and The Institute of Cancer ResearchLondon
![Page 2: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/2.jpg)
Stages of Diseaseclinically and biologically
Morgan, Walker & Davies Nat Rev Cancer 2012 12:335
![Page 3: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/3.jpg)
Advances in technology have led to an increasing knowledge of myeloma genetics
1995
G band
FISH
Translocations of C14
![Page 4: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/4.jpg)
Conventional Cytogenetics G-banding
Wikipedia et al !!
![Page 5: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/5.jpg)
Chromosome 14 FISH - translocation
Centromere Telomere
Dual, Break Apart probe
c. 250 kb c. 900 kb
Constant seg Variable segmentsJ se
gsD
seg
s
IGH 3’ Flanking Probe IGHV Probe
14q32 regionImmunoglobulin heavy chain locus
Kindly provided by Dr Fiona Ross, Wessex Regional Cytogenetics Laboratory
![Page 6: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/6.jpg)
Translocations
Hyperdiploidy
• Translocations– t(4;14)– t(11;14)– t(6;14)– t(14;16)– t(16;20)
Early events
• Chromosome gain– 3, 5, 7, 9, 11, 15, 19, 21
Molecular classification of myeloma
Kuehl & Bergsagel 2005
![Page 7: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/7.jpg)
Normal Isotype Switching on Chromosome 14q32
VDJ S C S2 C2
VDJ
S S2
C2- Intervening DNA deleted- Hybrid switch formed
VDJ 2 2
switch region = 1-3kb long, tandem pentameric repeats)telomere
centromere
![Page 8: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/8.jpg)
Illegitimate switch recombination in Myeloma
VDJ 2 2
VDJ C2
VDJ Gene X Gene Y C2
Gene X Gene Y
![Page 9: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/9.jpg)
Translocations into 14q32• Various partner chromosomes are linked to 14q32, in cell line studies.
Some have also been identified in patients.
• Up to 70% of patients have a translocation - thought to be a primary event.
• t(11;14)(q13;q32) 30% cyclin D1• t(4;14)(p16:q32)15% FGFR3 and MMSET• t(6;14)(p25;q32)4% cyclin D3 and IRF4• t(14;16)(q32;q23) 5% cMAF (and WWOX)
• many other regions may be involved • often the partner is not identified.
![Page 10: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/10.jpg)
Advances in technology have led to an increasing knowledge of myeloma genetics
1995 2010
Global mappingGene expressionarrays
miRNAmethylation
G band
FISH
Translocations of C14
TC classification NGS
Translocations
Hyperdiploid
Translocationst(4;14)
t(11;14)
t(6;14)
t(14;16)
t(14;20)
Chromosome gain3, 5, 7, 9, 11, 15, 19, 21
Normal MGUS MM
2000 2005 2015
![Page 11: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/11.jpg)
11
1 2 3 4 5
6 7 8 9 10 11 12
13 14 15
19 20
16 17 18
21 22 X
Hyperdiploidy
Walker et al. Blood 2006
• Gain of chromosomes (between 48-74)• Mostly odd numbered chromosomes• 3, 5, 7, 9, 11, 15, 19, 21• gain of chromosomes 15, 9 and 19 are most frequent• mechanism of gain not understood
![Page 12: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/12.jpg)
Myeloma specific copy number variationDeletion-Deletion 1p (30%) CDKN2C, FAF1, FAM46C- Deletion 6q (33%)-Deletion 8p (25%)- Deletion 13 (45%) RB1, DIS3- Deletion 11q (7%) BIRC2/BIRC3- Deletion 14q (38%) TRAF3- Deletion 16q (35%) WWOX, CYLD- Deletion 17p (8%) TP53 - Deletion 20 (12%)- Deletion 22 (18%)- Deletion X (28%)
GainGain 1q (40%) CKS1B, ANP32E Gain 12p LTBR Gain 17p TACI Gain 17q NIK
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 202122 X
Boyd KD, et al. Leukemia. 2012;26:349-355. Walker BA, et al. Blood. 2010;116:e56-e65.
![Page 13: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/13.jpg)
Myeloma Abnormalities
• Number of common abnormalities– Deletions
• 13q (45%) and 17p (8%)• Other regions – 1p, 1q (40%), 16q
– Translocations– Hyperdiploidy
• odd number chromosomes (3,7,9,11,17)
![Page 14: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/14.jpg)
14The Incidence of Abnormality Changes With Disease Progression
Ross et al. Haematologica 2010 95:1221Leone et al. Clinical Cancer Research 2008 14:6033Lopez-Corral et al. Clinical Cancer Research 2011 17:1692
Abnormality MGUS (%) SMM (%) MM (%)
t(11;14) 10 16 14
t(14;16) 3 3 3
t(14;20) 5 <1 1.5
del(13q) 24 37 45
del(17p) 3 1 8
1q+ 22 39 41
del(CDKN2C) 4 10 15
![Page 15: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/15.jpg)
15Myeloma Disease Progression and Genetic Events
Morgan, Walker & Davies Nat Rev Cancer 2012 12:335
![Page 16: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/16.jpg)
16
All t(4;14) have del(13)17p evenly distributed
t(4;14) t(11;14) 6 16 20? No Data HRD HRD+t(#;14) None
Inter relationship of abnormalities
Boyd KD, et al. Leukemia. 2012;26:349-355. Walker BA, et al. Blood. 2010;116:e56-e65.
![Page 17: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/17.jpg)
17
All t(4;14) have del(13)17p evenly distributed
t(4;14) t(11;14) 6 16 20? No Data HRD HRD+t(#;14) None
Inter relationship of abnormalities
Boyd KD, et al. Leukemia. 2012;26:349-355. Walker BA, et al. Blood. 2010;116:e56-e65.
![Page 18: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/18.jpg)
18
Myeloma IX trial: del(13) by FISH not associated with poor survival outcome*
n = 568ms 48.3 months
Patie
nts
(%)
Survival (months)
0
20
40
60
80
100
0 10 20 30 40 50 60 70
Survival according to del(13) by FISH
p = 0.024
n = 478ms 40.9 months
n = 283; ms not reached
Patie
nts
(%)
Survival (months)
0
20
40
60
80
100
0 10 20 30 40 50 60 70
Survival according to del(13) with “bad” IgH and del(17)(p53) removed
p < 0.001
n = 568ms 48.3 months
n = 191ms 27.7 months
* In the absence of other adverse prognostic features.
No del(13)del(13) onlyBad IgH or del(17p)
No del(13)del(13)
![Page 19: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/19.jpg)
19Inter-relationship of Adverse Lesions
Genetic abnormalities are not solitary eventsand can occur together
Strong positive association with adverse IGH and 1q+
-72% of IGH translocations with 1q+
Boyd et al. Leukemia 2011
Implicationsi. In order to understand the
prognosis of any lesion need to know if other lesions are present.
ii. Lesions may collaborate to mediate prognosis.
![Page 20: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/20.jpg)
Frequency in the Elderly
![Page 21: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/21.jpg)
Frequency of abnormalities with age
Ross et al Leukemia 2006
N = 228
![Page 22: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/22.jpg)
Frequency of abnormalities with age
Avet Loiseau et al 2013 JCO
N = 1890, median age 72, range 66-94
![Page 23: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/23.jpg)
Clinical and prognostic significance in the Elderly
![Page 24: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/24.jpg)
Myeloma IX trial: effect of “bad” IgH translocations on survival
n = 858ms 49.6 months
n = 170ms 25.8 months
Patie
nts
(%)
Survival (months)
0
20
40
60
80
100
0 10 20 30 40 50 60 70
Combined “bad” IgH translocations
p < 0.001
n = 495ms not reached
n = 170ms 36 months
Patie
nts
(%)
Survival (months)
0
20
40
60
80
100
0 10 20 30 40 50 60 70
Intensive arm
p < 0.001
n = 363ms 33.4 months
Patie
nts
(%)
Survival (months)
0
20
40
60
80
100
0 10 20 30 40 50 60
Non-intensive arm
p < 0.001
“Bad” IgHRest
n = 63ms 13.1 months
No “bad” IgH translocationsAny “bad” IgH translocation
ms = median survival.
![Page 25: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/25.jpg)
Myeloma IX trial: effect of deletion 17p53 on survival
n = 929ms 45.8 months
n = 87ms 22.2 months
Patie
nts
(%)
Survival (months)
0
20
40
60
80
100
0 10 20 30 40 50 60 70
Survival of patients with del(17)(p53)
p < 0.001
n = 545ms not reached
n = 48ms 40.9 months
Patie
nts
(%)
Survival (months)
0
20
40
60
80
100
0 10 20 30 40 50 60 70
del(17)(p53): intensive arm
p = 0.004
n = 384ms 32.6 months
Patie
nts
(%)
Survival (months)
0
20
40
60
80
100
0 10 20 30 40 50 60
del(17)(p53): non-intensive arm
p = 0.017n = 39
ms 19.2 months
del(17p)Rest
No del(17)(p53)del(17)(p53)
![Page 26: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/26.jpg)
26Prognostic Impact of Lesions
Avet Loiseau et al JCO 2013
N = 1890, median age 72, range 66-94
![Page 27: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/27.jpg)
Myeloma IX trial: effect of combined deletion 17p53 and “bad” IgH on survival
n = 754
Patie
nts
(%)
Survival (days)
0
20
40
60
80
100
0 500 1,000 1,500 2,000
Any bad IgH translocation + del(17)(p53)
p < 0.001
n = 214
n = 18
Rest
Bad IgH translocationBad IgH translocation + del(17p)
![Page 28: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/28.jpg)
28Impact of Combined Lesions
The number of adverse markers has an additive effect on overall survival
60 months40 months23.4 months9.1 months
Boyd et al. Leukemia 2011
![Page 29: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/29.jpg)
Defining high risk according to the ISS: “bad” IgH and del(17p)
Group 1 ISS1Group 2 ISS2Group 3 ISS3Group 4
bad IgH or del(17p)
bad IgH or del(17p)
Myeloma IX trial: effect of adverse prognostic features on survival
ISS + any bad IgH translocation + del(17)(p53)1 = 1 excluding bad IgH or del(17)(p53)2 = ditto + 1 including, etc.
n = 125
Patie
nts
(%)
Survival (days)
0
20
40
60
80
100
0 500 1,000 1,500 2,000
p < 0.001
n = 244
n = 269
n = 76
1234
ie having something bad doesn’t always mean it is! Boyd et al. Leukemia 2011
![Page 30: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/30.jpg)
Non-intensive pathway – chemotherapy regimens
Baseline assessment
Response assessment
Every 28 Days to maximal response. 6 - 9 cycles
Every 28 Days to maximal response. 6 - 9 cycles
CH
EM
OTH
ER
AP
Y R
AN
DO
MIS
ATION
Cyclophosphamide 500 mg po Days 1, 8, 15, 22
Thalidomide 50 - 200 mg po Daily
Da
examethasone
ttenuated
20 mg po Days 1- 4, 15- 18
elphalan 7 mg/m2 od po Days 1 - 4
Prednisolone 40 mg od po Days 1 - 4
Maximalresponse
THA
LIDO
MID
E R
AN
DO
MIS
ATION
M
Primary endpoints: PFS and OSSecondary endpoints: Response,
QoL and toxicity
Morgan et al Blood 2011
![Page 31: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/31.jpg)
Summary of patient characteristics at trial entry
MP(N=423)
CTDa(N=426)
Age (years) MedianRange
7357–89
7358–87
Gender(N (%))
MaleFemale
231 (54.6)192 (45.4)
242 (56.8)184 (43.2)
ISS (N (%)) IIIIIIMissing Data
64 (15.1)156 (36.9)165 (39.0)
38 (9.0)
46 (10.8)156 (36.6)168 (39.4)56 (13.1)
β2M (mg/l) MedianRange
4.90.3-40.4
5.00.4–64.0
![Page 32: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/32.jpg)
Summary of cytogenetics at trial entry
Trans-location
MP % CTDa % Total %
Favour-able
125 58.1 129 57.3 254 57.7
Adverse 90 41.9 96 42.7 186 42.3
Adverse group includes t(4;14), t(14;20) t(14,16), gain 1q and del 17p
Morgan et al Blood 2011
![Page 33: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/33.jpg)
PFS and OS according to cytogenetics
PFS OSFavourable 14 months
95% CI 12-17 range 0-6537 months
95% CI 22-44 range 0-69
Adverse 12 months95% CI 10-13 range 0-67
24 months95% CI 20-28 range 0-68
Morgan et al Blood 2011
![Page 34: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/34.jpg)
OS according to treatment group in patients with favorable cytogenetics
MP
CTDaP=0.1041
Morgan et al Blood 2011
![Page 35: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/35.jpg)
OS in favorable cytogenetics according to treatment; landmark at 1.5 years
CTDamedian not reached
MP42 months
CTDa not reached vs 42 months Morgan et al Blood 2011
![Page 36: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/36.jpg)
Influence of cytogenetics on survival among patients achieving a CR
Favourable
Adverse
Morgan et al Blood 2011
![Page 37: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/37.jpg)
NGS results inform myeloma biology
Morgan GJ, Walker BA and Davies FE. Nature Reviews Cancer. Vol 12 May 335-348, 2012,
• No single mutation responsible for myeloma – hundreds of mutations identified.
• Deregulation of pathways is an important molecular mechanism.• Including NF-κB pathway,
histone modifying enzymes and RNA processing.
![Page 38: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/38.jpg)
Mutational landscape of myeloma
• Acute leukaemia– 8 non-synonymous variants per sample
• Myeloma– 35 non-synonymous variants per sample
• Solid tumours– 540 non-synonymous variants per sample
HallmarksOf
Myeloma
Morgan G, et al. Nat Rev Cancer. 2012;12:335-48.
![Page 39: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/39.jpg)
Comparative analysis of cancer evolutionary treesComparison across disease states and curability
Paediatric ALL Myeloma Solid cancer
![Page 40: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/40.jpg)
40Linear and branching models for myeloma evolution
Morgan, Walker and Davies Nature Reviews Cancer 2012
![Page 41: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/41.jpg)
41Linear and branching models for myeloma evolution
Morgan, Walker and Davies Nature Reviews Cancer 2012
![Page 42: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/42.jpg)
“Nothing in biology makes sense
except in the light of evolution”Theodosius Dobzhansky, 1973
![Page 43: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/43.jpg)
“Nothing in biology makes sense
except in the light of evolution”Theodosius Dobzhansky, 1973
Adaption and survival of the fittest
![Page 44: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/44.jpg)
Charles Darwin
“Applying the ideas developed initially by Darwin, to explain the origin of the species, can inform us of how cancer
develops and how best to treat it”
![Page 45: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/45.jpg)
Clonal evolution of myeloma
Adapted from Greaves MF, Malley CC. Nature. 2012;481:306-13.
Subclones with unique genotype/”driver” mutations
Ecosystem 1
Single founder cell (stem or progenitor)
Ecosystem 3 Ecosystem 5
Selective pressures Treatment
Ecosystem 4
PCLMMMGUS
Diffuse
Focal
Ecosystem 2
EMM
Adaption and survival of the fittest
![Page 46: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/46.jpg)
A Model of MM Disease ProgressionA model based on the random acquisition of genetic hits and Darwinian selection
Morgan G, et al. Nat Rev Cancer. 2012;12:335-48.
Primary genetic eventsIgH translocationsHyperdiploidy Copy number abnormalities
DNA hypomethylationAcquired mutations
MGUS Smouldering myeloma Myeloma Plasma cell
leukaemia
Initiation Progression
Bone marrow Peripheral bloodGerminal centre
Post-GC B cell
Inherited variants
COMPETITION AND SELECTIVE PRESSURE MIGRATION AND FOUNDER EFFECT
Clonal advantage
Myeloma progenitor
cell
TUMOUR CELL DIVERSITYGENETIC LESIONS
Secondary genetic events
![Page 47: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/47.jpg)
A Darwinian View of Induction, maintenance and relapseClones can be eradicated - cured
Morgan GJ, Walker BA, Davies F. Nature Reviews Cancer, 2012
![Page 48: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/48.jpg)
Myeloma progenitor
cell
A Darwinian view of induction, maintenance and relapseClones can be eradicated - cured
Evolutionary / TreatmentBottleneck
Post treatment
Morgan GJ, Walker BA, Davies F. Nature Reviews Cancer, 2012
![Page 49: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/49.jpg)
Clones with a distinct pattern of mutations
Target
Intraclonal heterogeneity and targeted treatment
![Page 50: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/50.jpg)
Clones with a distinct pattern of mutations
Intraclonal heterogeneity and targeted treatment
Suboptimal response at 30%
![Page 51: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/51.jpg)
A Darwinian View of Induction, maintenance and relapseClones can be eradicated - cured
Morgan GJ, Walker BA, Davies F. Nature Reviews Cancer, 2012
![Page 52: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/52.jpg)
Myeloma progenitor
cell
A Darwinian view of induction, maintenance and relapseClones can be eradicated - cured
Evolutionary / TreatmentBottleneck
Post treatment
Morgan GJ, Walker BA, Davies F. Nature Reviews Cancer, 2012
![Page 53: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/53.jpg)
Myeloma progenitor
cell
Clonal Tides During Myeloma TreatmentRelapse can come from any one of a number of clones
Relapse
Morgan GJ, Walker BA, Davies F. Nature Reviews Cancer, 2012
Original clone – treatment resistant
treatment sensitiveDifferential sensitivity to treatment
![Page 54: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/54.jpg)
Clonal dynamics over multiple relapsesClinical evidence supports this - a t(4;14) case
Keats JJ, et al. Blood. 2012;120:1067-76.
![Page 55: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/55.jpg)
Conclusions
• Myeloma is biologically and genetically diverse. • Genetic complexity develops early before clinical symptoms develop.
• Linking biological data to clinical data is beginning to identify clinically distinct subgroups with different disease characteristics and outcomes.
• The frequency of the different subgroups differs with age, but the prognostic significance remains
• Darwinian style processes can describe the multistep pathogenesis of myeloma. • The impact of clonal heterogeneity needs to be considered when
making treatment choices
![Page 56: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/56.jpg)
Conclusion
• Knowledge of the patients genetic sub group is important regardless of the patients age
• This has been incorporated into the UKMF/BCSH guidelines
• C14 translocation, 17p, HRD, C1
![Page 57: The Role of Cytogenetics in Elderly patients with Myeloma](https://reader036.vdocuments.mx/reader036/viewer/2022062302/568166ee550346895ddb45a3/html5/thumbnails/57.jpg)
in partnership with
Centre for Myeloma Research, ICRDavies LabMike BrightLei ZhangLauren AronsonJade StroverJackie FokDaniel Izthak
Morgan LabBrian WalkerChris WardellDavid JohnsonLi NiDavid GonzalezPing WuFabio MirabellaLorenzo MelchorAnnaMaria BrioliCharlotte PawlynElileen BoyleMatthew JennerKevin BoydMartin Kaiser
LeedsRG OwenAC RawstronR de TuteM DewarS Denman
G Cook
S Feyler
D Bowen
BirminghamMT Drayson
K Walker
A Adkins
N Newnham
SalisburyF Ross
L Chieccio
MRC Leukaemia Trial Steering CommitteeMRC Leukaemia Data Monitoring and Ethics CommitteeNCRI Haematological Oncology Clinical Studies GroupUK Myeloma Forum Clinical Trials CommitteeMyeloma UK
FundingMedical Research CouncilPharmion Novartis Chugai Pharma Bayer Schering PharmaOrthoBiotech CelgeneKay Kendall Leukaemia Fund
Chief InvestigatorsJA ChildGJ MorganGH JacksonNH Russell
CTRU, LeedsK CocksW GregoryA SzubertS BellN Navarro CoyF HeatleyP BestJ CarderM MatoukD EmsellA DaviesD Phillips