Dr Matthew Jenner Consultant Haematologist Southampton General Hospital UK Myeloma Forum Autumn Day 12 November 2014 Introduction Why define high risk myeloma 3 Patient expectations Outcomes vary widely between different patients ID: 405512
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Slide1
How to Manage High Risk Myeloma
Dr Matthew JennerConsultant HaematologistSouthampton General Hospital
UK Myeloma Forum Autumn Day
12 November 2014Slide2
IntroductionSlide3
Why define high risk myeloma?
3
Patient expectations
Outcomes vary widely between different patients
Myeloma very
heterogenous
disease
Aim for a risk stratified approach – one size may not fit all
Maximise treatment for those that need it
Minimise treatment and toxicities for those who may not
Acute leukaemia and lymphoma models
Better define high risk disease
Subgroup analysis may lead to identification of common clinical and biological features leading to more individualised treatmentsSlide4
Variables that impact prognosis in any malignancy including myeloma
Patient factors
Age
Performance status (activity levels)
Co-morbidities
Medication
Kidney function
Tumour stage
in myeloma, markers of disease bulk
ISS based on albumin and beta 2
microglobulin
Tumour
biology
Isotype
Extramedullary
myeloma and plasma cell leukaemia
Genetic lesions detected by
cytogenetics
, gene expression or mutation analysis
Response to treatment
Slide5
High risk myeloma
Defining high risk myeloma
Individual drug therapies
Autologous transplantation
Clinical trials and future strategiesSlide6
Smouldering myelomaSlide7
Smouldering myeloma
Classifiers of high risk status7
Degree of bone marrow infiltration
IMWG criteria
Imaging
PET-CT
Whole body CT
Whole body DW MRI
Immunophenotyping
Aberrant
vs
normal plasma cells
?
CytogeneticsSlide8
Smouldering myeloma
Role of high risk cytogenetics8
Data for cytogenetics in symptomatic myeloma is clear cut
Adverse
IgH
translocations and copy number abnormalities well recognised
t(4;14), t(14;16), t(14;20), del1p, del17p, gain 1q
Same abnormalities found in MGUS and smouldering myeloma
Case series of stable MGUS and SMM with apparent high risk abnormalities
IgH
translocations initiating
events
Copy number abnormalities ?progression eventsSlide9
MGUS and smouldering myeloma cytogenetics
:Wessex myeloma databaseIgH translocations
9
Different patterns of progression from MGUS and SMM to myeloma
t
(14;20) stable disease
MGUS
t(4;14) 1/5 progressed and t(14;16) 2/6 progressed at median f/u of 17-120 months from diagnosis of MGUS
SMM
t(4;14)
12/19 progressed and t(14;16
) 2
//4
progressed at median f/u of
33 to 78months
from diagnosis
of SMM
Evolving and non-evolving pattern of progression
MGUS
SMM
MM
t(4;14)
6/193 (3%)
19/148 (13%)
198/1830 (11%)
t(14;16)6/193 (3%)4/148 (3%)55/1830 (3%)t(14;20)9/192 (5%)1/149 (<1%)27/1830 (1.5%)
FM Ross, L
Chiecchio
et al,
Haematologica
2010Slide10
Smouldering myeloma
10
No evidence to recommend treatment based on HR cytogenetics alone
Use standard CRAB criteria for commencing treatment
+/- novel imaging
Close monitoring including
imaging
Rationale:
Potential
role for homeostasis between sub
clones
Need for further studies to evaluate in face of new agents
Require OS as well as PFS dataSlide11
Case 1Slide12
Case 1
60 year old female12
1996
Right breast carcinoma treated with WLE and RT
2005
DCIS left breast with bilateral mastectomies and
Arimidex
No evidence of relapse on follow-up
May 2013
Generalised bone pain, weight loss
IgG kappa paraprotein 15g/L
Free KLC 551 mg/L
BMA: 15% PC
FISH: t(14;16), del17p, del1p, gain 1q
ISS 2
SS: lytic lesions skull,
humeri
, collapse L2 and T12
July 2013
Local RT L2 8Gy single fraction
Myeloma XI: CTDSlide13
Case 1
13
CTD x6 achieving VGPR:
paraprotein 0.7 g/L
FKLC 140 mg/L
BM: MRD positive 0.1% abnormal PC
HDM(200) ASCT 9/12/13
D100 11/3/14
Paraprotein 1.6 g/L
FKLC 127 mg/L
BM: no excess PC
MRD pos 0.1% abnormal PC
April 2014 Randomised to lenalidomide and vorinostat maintenance
June 2014 progressive flank pain:
Renal tract USS
neg
July 2014 PET-CTSlide14
Case 1
PET-CTSlide15
Case 1
July 201415
PET-CT
Widespread FDG avid lesions multiple vertebrae, sternum, ribs, pelvis
Left
paravertebral
mass
MRI
T7 to T11/12 soft tissue mass with early cord compromise
Bone marrow approx 10% PC
Paraprotein 3.5 g/L
Free kappa light chains 77 mg/L
Treatment:
RT to
paraspinal
mass
VRD-PACE
VRD
VRD-PACE
Awaiting follow-up imagingSlide16
Case 1
Observations16
Cytogenetically defined high risk myeloma (HRMM)
Role of individual drugs cannot be ascertained from single case
Achieved VGPR. MRD positive.
Commenced maintenance at approx 4 months post ASCT
Extramedullary
relapse
Questions:
How important is depth of response in cytogenetically defined HRMM?
Does high dose
mephalan
improve outcome or promote progression?
What is the role of consolidation and maintenance and when should it start?
Does recovery period post ASCT enable myeloma plasma cell recovery?
What is more important dose intensity or dose density?
What is the role of imaging?Slide17
Genomic landscape of high risk myelomaSlide18
Initiation and progression of myeloma
Morgan, Walker & Davies, Nature Reviews Cancer 2012Slide19
Clonal
dynamics in a patient with high-risk MM. The summarized results of 8 different FISH assays are shown to indicate the relative abundance of each clone defined by
aCGH
at the 5 time points studied.
Keats J
J
et al. Blood 2012;120:1067-1076
©2012 by American Society of
HematologySlide20
HRMM: ThalidomideSlide21
MRC Myeloma IX - Trial Design
Intensive
Clodronate
CVAD
Zoledronic acid
CVAD
Clodronate
C-TD
Zoledronic acid
C-TD
MEL-200
ASCT
–Thal
+Thal
Non-intensive
Clodronate
MP
Zoledronic acid
MP
Clodronate
C-TDa
Zoledronic acid
C-TDa
Max
Response
–Thal
+Thal
Primary endpoints:
PFS, OS, ORR
Secondary endpoints:
Time to first SRE, SRE incidence, Safety, and QoL
Zoledronic acid (4 mg IV q 3-4 wk); Clodronate (1,600 mg/d PO)
ISRCTN68454111
N = 1,960
RANDOMISATION
RANDOMISATION
RANDOMISATION
RANDOMISATION
Treatment continued until disease progression
21Slide22
12
24
36
48
60
0
Favourable iFISH
Adverse iFISH
0
12
24
36
48
60
OS (months)
0
20
40
60
80
100
Patients (%)
88
93
81
77
53
44
32
16
10
5
CTDa
MP
72
88
93
OS (months)
0
20
40
60
80
100
Patients (%)
60
55
43
44
23
17
8
8
3
6
CTDa
MP
60
55
CTDa
MP
P
< .001
Myeloma IX: Landmark analysis in patients with favourable and adverse
iFISH
In patients with favourable FISH there was a strong OS advantage for
CTDa
compared to MP.
This effect was not seen in patients with adverse
cytogenetics
:
t(4;14), t(14:16), +1q, del(17p)
CTDa
MP
P
= .41
A
B
GJ Morgan, FE
Davies et
al,
Blood 2011Slide23
Survival according to thalidomide maintenance therapy regimen (ITT population
):
(
A) PFS; and (B) OS; (C) OS in patients with
favorable
iFISH
profiles; (D) OS in patients with adverse
iFISH
profiles.
Morgan G J et al.
Clin
Cancer Res 2013;19:6030-6038
©2013 by American Association for Cancer ResearchSlide24
HRMM: bortezomibSlide25
Diagram of patient disposition and patient flow through protocol.
Harousseau
J et al. JCO 2010;28:4621-4629
©2010 by American Society of Clinical Oncology
IFM 2005-01
Bortezomib-Dex
vs.
Vincristine-Adriamicin-Dex
(VAD)
Newly diagnosed myeloma suitable for intensive chemotherapy and ASCT
A: VAD
B:
Vel
DexSlide26
IFM 2005-01: (A
) Event-free survival (EFS) and (B) overall survival (OS) in patients with t(4;14) treated with
bortezomib-dexamethasone
(
Vel
/
Dex
) induction (n = 106) or
vincristine
, doxorubicin, and
dexamethasone
(VAD) induction (n = 98; EFS and OS in years; P < .001
for EFS and OS
Avet-Loiseau
H et al. JCO 2010;28:4630-4634
©2010 by American Society of Clinical OncologySlide27
CONSORT diagram of 827 adult patients with multiple myeloma (MM) in the Dutch-Belgian
Hemato
-Oncology Group 65/German Multicenter Myeloma Group
HD4
(HOVON-65/GMMG-HD4)
Sonneveld
P et al. JCO 2012;30:2946-2955
©2012 by American Society of Clinical Oncology
A: VAD-thalidomide
B: PAD-
bortezomibSlide28
Phase III Trial of PAD
and bortezomib maintenance vs. VAD and thalidomide in Myeloma: Survival
Survival Outcome
HR
95% CI
P
Value
PFS
Overall
From last HDM
0.79
0.82
0.66-0.95
0.66-1.02
.01
.08
OS
0.73
0.56-0.96
.02
Sonneveld P, et al. ASH 2010. Abstract 40.
0
25
50
75
100
Cumulative %
Progression Free
0
12
24
36
48
VAD
PAD
373
371
n
243
215
F
VAD
PAD
Mos
HR: 0.79 (95% CI: 0.66-0.95;
P
= .01)
HOVONSlide29
Kaplan-Meier survival curves of progression-free survival (PFS) and overall survival (OS) according to treatment arm within subgroups according to
del(17p
).
Sonneveld
P et al. JCO 2012;30:2946-2955
©2012 by American Society of Clinical Oncology
Arm A VAD/
thal
Arm B PAD/
bort
Bortezomib
appears to overcome adverse effect of del(17p)
Perhaps related to adverse impact of thalidomide on del(17p) myeloma?Slide30
Kaplan-Meier
distribution curve (intent-to-treat analysis) for the key efficacy end point of progression-free survival
.
Forest plot of hazard ratios for progression-free survival, for the individual studies and the integrated analysis
Sonneveld
P et al. JCO 2013;31:3279-3287
©2013 by American Society of Clinical Oncology
Bortezomib
-Based Versus
Nonbortezomib
-Based Induction Treatment Before
Autologous
Stem-Cell Transplantation in Patients With Previously Untreated Multiple Myeloma: A Meta-Analysis of Phase III Randomized, Controlled TrialsSlide31
HRMM: Total therapySlide32
Total Therapy 3
Developed at MIRT, ArkansasMultidrug sequential treatment (V-DT-PACE)
Intensive chemotherapy
Tandem
autologous
transplantation
Consolidation
Maintenance
High risk myeloma defined by gene expression profiling
TT2 no
bortezomib
TT3 with
bortezomib
32Slide33
TP53
deletion is not an adverse feature in multiple myeloma treated with total therapy 3
British Journal of Haematology
Volume 147, Issue 3,
pages 347-351, 21 AUG 2009 DOI: 10.1111/j.1365-2141.2009.07864.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2009.07864.x/full#f1
OS
EFS
GEP low risk
GEP high riskSlide34
Identification of novel agents that improve the survival of patients with high-risk MM.
xy
plot of percent OS for the 2 arms of randomized controlled clinical trials for patients with different genetic lesions.
Bergsagel
P L et al. Blood 2013;121:884-892
©2013 by American Society of HematologySlide35
HRMM:
Novel agent combinationsSlide36
VRD consolidation
Nooka et al Leukaemia 2014
36
High-risk myeloma defined by
the
presence of deletion of
p53
(locus
17p13
)
deletion
of
1p
(t(4;14
) or t(14;16
)
by fluorescence
in situ
hybridization or by metaphase
cytogenetics
presentation
as PCL (20% circulating plasma cells in peripheral blood
)
45 patients
Induction not specified, majority VTD or VRD
ASCTMaintenance therapylenalidomide (10 mg/day orally) on days 1–21 of a 28-day cyclebortezomib (1.3 mg/m2 per week subcutaneously/intravenously)low-dose dexamethasone (40 mg per week orally)for up to 3 years, followed by single-agent lenalidomide maintenance thereafterSlide37
RVD consolidation
37
Overall median PFS 32/12, 3 year OS 93%Slide38
ASCT and maintenanceSlide39
39Slide40Slide41Slide42
PFS
Mel 200 x2 vs. MPR
Len
maint
vs. notSlide43
Therapy of high risk myeloma
Potential conclusions43
Thalidomide minimal benefit during induction
Thalidomide adverse as maintenance
Bortezomib
partially overcomes adverse risk associated with t(4;14) myeloma
Bortezomib
may overcome adverse risk associated with del17p myeloma
Impact on GEP defined high risk myeloma unclear
Tandem
autologous
transplant superior to MPR consolidation in high risk myeloma
Lenalidomide
maintenance unclear in high risk myeloma
All needs formal randomised evaluationSlide44
MUK9 Optimum studySlide45
Introduction:
High risk myeloma accounts for 20-30% of presenting cases
This subset of patients do not benefit from current treatment approaches
There is a need for this population to develop both
Good diagnostic tools
to identify these patients
New treatment strategies
The high risk trial
is a specific trial geared towards fit newly diagnosed high risk patients
Registration phase: identify high risk patients
Treatment phase: investigate 2 new treatment approaches
Evaluate alongside anticipated best treatment including maintenanceSlide46
Cytogenetic inter-relationship
1
7
Deletion 1p-
(n=71)
Deletion 17p
(n=74)
Adverse translocation
(n=144)
6
2
135
60
61
Number gained
Frequency
1p-
10%
1q+
34%
17p
9%
Adverse Translocation
21%
GEP
20%
Overall
25-35%
1
7
Deletion 17p
(n=74)
Adverse
(n=144)
18
65
71
48
180
Gain 1q
(n=264)
20
18
14
EMC92
Cytogenetics
Myeloma IX dataSlide47
Diagnosing high risk myeloma
Our current definition of high risk is based on: a full blood-count to identify Plasma cell leukaemia A PCR based expression assay to identify translocations
MLPA to identify copy number changes such as 1q+, 1p- and 17q
Gene expression profile for High risk profile (EMC92 score)
Kuiper
et al (2009)
Kaiser et al (2013)Slide48
Daratumumab
Daratumumab is monoclonal antibody
Targets CD38 and has multiple mechanisms of action against CD38+ MM cells including
ADCC (antibody dependant cytotoxicity)
ADCP (antibody dependant cell phagocytosis)
Apoptosis
Modulating the enzymatic activity of CD38 (Cell adhesion)
Demonstrated activity in MM
Enhances the potency of other MM drugs such as Lenalidomide offering an interesting alternative to chemotherapy in myeloma.Slide49
MUK9 Optimum study concepts
Arm A: intensive, chemotherapy-rich, DNA damaging. Hit multiple sub-clones
Arm B: Alkylator light to minimise secondary genetic events. Multi-agent non-DNA damaging agents
Arm C: standard armSlide50
Pre-Screening
1200 newly diagnosed myeloma patients
20-30% lost
20-30%
High risk
70%
Standard risk
15-20% t(11;14)
60 %
Hyper
diploidy
Other
High risk trial
Other trialsSlide51
Trial design
Registration phase: 1200 newly diagnosed patients
8 week turnaround time
Randomise 50
patients per
arm
Expand by another 35 patients in best arm vs. Control
Aim to open early 2015
Newly diagnosed
patients
CTD
CVD
CRD
VTD
Induction
X2 cycles
Max
VDT-PACE X 2
CVRDd
CRD
Split
HDM-V
ASCT
HDM
ASCT
Rd
Define high risk status
VRDdX6
HDM
ASCT
R
To progression
Rd
HDM-V
ASCT
VRdX12
VRDdX6
VRdX12Slide52
Endpoints:
Primary phase II: PFS
Abilility to turn around risk-defining investigations within 8 weeks
Secondary
Overall survival
Deliverability of treatment
Clinical benefit rate
Maximum overall response
Time to progression
Time to maximum response
Response at first relapse
Safety
Toxicity
Recruitment rate
Exploratory
: To evaluate the potential to reduce genome instability by altering treatment strategies avoiding excessive alkylating agent exposure. Slide53
Follow-on from MUK9 Optimum study
Phase 2/3 expansionNational Phase 3 study: NCRI portfolioPick a winner conceptDefine best arm to evaluate against standard arm
Potential to establish a high risk “backbone” on to which newer agents can be added
Added benefit of providing baseline risk-based classification that may feed in to other studiesSlide54
Acknowledgements
54
ICR/RMH
Gareth Morgan
Faith Davies
Martin Kaiser
Eileen Boyle
Myeloma CTN
Eric Low
Heather MacKinnon
Jennifer Fraser
Gordon Cook
Guy Pratt
Leeds CTRU
Sarah Brown
Louise Flanagan
Wessex Regional Genetics Lab
Fiona Ross
Laura
Chiecchio