how to manage high risk myeloma dr matthew jenner consultant haematologist southampton general...
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How to Manage High Risk Myeloma
Dr Matthew Jenner
Consultant Haematologist
Southampton General Hospital
UK Myeloma Forum Autumn Day
12 November 2014
Introduction
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Why define high risk myeloma?
• Patient expectationso Outcomes vary widely between different patientso Myeloma very heterogenous disease
• Aim for a risk stratified approach – one size may not fit allo Maximise treatment for those that need ito Minimise treatment and toxicities for those who may noto Acute leukaemia and lymphoma models
• Better define high risk diseaseo Subgroup analysis may lead to identification of common clinical and biological
features leading to more individualised treatments
Variables that impact prognosis in any malignancy including myeloma
• Patient factors
o Age
o Performance status (activity levels)
o Co-morbidities
o Medication
o Kidney function
• Tumour stage
o in myeloma, markers of disease bulk
o ISS based on albumin and beta 2 microglobulin
• Tumour biology
o Isotype
o Extramedullary myeloma and plasma cell leukaemia
o Genetic lesions detected by cytogenetics, gene expression or mutation analysis
o Response to treatment
High risk myeloma
Defining high risk myeloma
Individual drug therapies
Autologous transplantation
Clinical trials and future strategies
Smouldering myeloma
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Smouldering myelomaClassifiers of high risk status
• Degree of bone marrow infiltrationo IMWG criteria
• Imagingo PET-CTo Whole body CTo Whole body DW MRI
• Immunophenotypingo Aberrant vs normal plasma cells
• ?Cytogenetics
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Smouldering myelomaRole of high risk cytogenetics
• Data for cytogenetics in symptomatic myeloma is clear cut
• Adverse IgH translocations and copy number abnormalities well recognisedo 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 events
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MGUS and smouldering myeloma cytogenetics:Wessex myeloma database
IgH translocations
• Different patterns of progression from MGUS and SMM to myeloma• t(14;20) stable disease• MGUS
o 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
• SMMo t(4;14) 12/19 progressed and t(14;16) 2//4 progressed at median f/u of 33 to 78months from
diagnosis of SMMo 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 2010
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Smouldering myeloma
• No evidence to recommend treatment based on HR cytogenetics alone• Use standard CRAB criteria for commencing treatment +/- novel imaging• Close monitoring including imaging
• Rationale:o Potential role for homeostasis between sub clones
• Need for further studies to evaluate in face of new agentso Require OS as well as PFS data
Case 1
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Case 160 year old female
• 1996 o Right breast carcinoma treated with WLE and RT
• 2005o DCIS left breast with bilateral mastectomies and Arimidexo No evidence of relapse on follow-up
• May 2013o Generalised bone pain, weight losso IgG kappa paraprotein 15g/Lo Free KLC 551 mg/Lo BMA: 15% PCo FISH: t(14;16), del17p, del1p, gain 1qo ISS 2o SS: lytic lesions skull, humeri, collapse L2 and T12
• July 2013o Local RT L2 8Gy single fractiono Myeloma XI: CTD
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Case 1
• CTD x6 achieving VGPR:o paraprotein 0.7 g/Lo FKLC 140 mg/L
• BM: MRD positive 0.1% abnormal PC• HDM(200) ASCT 9/12/13• D100 11/3/14
o Paraprotein 1.6 g/L o FKLC 127 mg/Lo BM: no excess PCo MRD pos 0.1% abnormal PC
• April 2014 Randomised to lenalidomide and vorinostat maintenance• June 2014 progressive flank pain:
o Renal tract USS nego July 2014 PET-CT
Case 1PET-CT
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Case 1July 2014
• PET-CTo Widespread FDG avid lesions multiple vertebrae, sternum, ribs, pelviso Left paravertebral mass
• MRIo 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:o RT to paraspinal masso VRD-PACEo VRDo VRD-PACE
• Awaiting follow-up imaging
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Case 1Observations
• 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:o How important is depth of response in cytogenetically defined HRMM?o Does high dose mephalan improve outcome or promote progression?o What is the role of consolidation and maintenance and when should it start?
o Does recovery period post ASCT enable myeloma plasma cell recovery?o What is more important dose intensity or dose density?o What is the role of imaging?
Genomic landscape of high risk myeloma
Initiation and progression of myeloma
Morgan, Walker & Davies, Nature Reviews Cancer 2012
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 Hematology
HRMM: Thalidomide
MRC Myeloma IX - Trial DesignIntensive
ClodronateCVAD
Zoledronic acidCVAD
ClodronateC-TD
Zoledronic acidC-TD
MEL-200ASCT
–Thal +Thal
Non-intensive
ClodronateMP
Zoledronic acidMP
ClodronateC-TDa
Zoledronic acidC-TDa
MaxResponse
–Thal +Thal
Primary endpoints: PFS, OS, ORRSecondary endpoints: Time to first SRE, SRE incidence, Safety, and QoLZoledronic 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
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12 24 36 48 600
Favourable iFISH Adverse iFISH
0 12 24 36 48 60OS (months)
0
20
40
60
80
100
Patie
nts
(%)
8893
8177
5344
3216
105
CTDaMP
72
8893
OS (months)
0
20
40
60
80
100
Patie
nts
(%)
6055
4344
2317
88
36
CTDaMP
6055
CTDaMPP < .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)
CTDaMPP = .41
A B
GJ Morgan, FE Davies et al, Blood 2011
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 Research
HRMM: bortezomib
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 2005-01Bortezomib-Dex vs. Vincristine-Adriamicin-Dex (VAD)Newly diagnosed myeloma suitable for intensive chemotherapy and ASCT
A: VAD B: Vel Dex
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 Oncology
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-bortezomib
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
0.790.82
0.66-0.950.66-1.02
.01
.08
OS 0.73 0.56-0.96 .02
Sonneveld P, et al. ASH 2010. Abstract 40.
0
25
50
75
100
Cum
ulati
ve %
Pr
ogre
ssio
n Fr
ee
0 12 24 36 48
VADPAD
373371
n243215
FVAD
PAD
Mos
HR: 0.79 (95% CI: 0.66-0.95; P = .01)
HOVON
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/thalArm B PAD/bort
Bortezomib appears to overcome adverse effect of del(17p)Perhaps related to adverse impact of thalidomide on del(17p) myeloma?
(A) Kaplan-Meier distribution curve
(intent-to-treat analysis) for the key efficacy end
point of progression-free
survival.(B) 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 Trials
HRMM: Total therapy
Total Therapy 3
Developed at MIRT, Arkansas
Multidrug sequential treatment (V-DT-PACE)Intensive chemotherapy
Tandem autologous transplantation
ConsolidationMaintenance
High risk myeloma defined by gene expression profiling
TT2 no bortezomibTT3 with bortezomib
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TP53 deletion is not an adverse feature in multiple myeloma treated with total therapy 3
British Journal of HaematologyVolume 147, Issue 3, pages 347-351, 21 AUG 2009 DOI: 10.1111/j.1365-2141.2009.07864.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2009.07864.x/full#f1
OS EFS
GEP low risk
GEP high risk
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 Hematology
HRMM:Novel agent combinations
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VRD consolidationNooka et al Leukaemia 2014
• High-risk myeloma defined byo the presence of deletion of p53 (locus 17p13)o deletion of 1po (t(4;14) or t(14;16) by fluorescence in situ hybridization or by metaphase cytogeneticso presentation as PCL (20% circulating plasma cells in peripheral blood)
• 45 patients• Induction not specified, majority VTD or VRD• ASCT• Maintenance therapy
o lenalidomide (10 mg/day orally) on days 1–21 of a 28-day cycleo bortezomib (1.3 mg/m2 per week subcutaneously/intravenously)o low-dose dexamethasone (40 mg per week orally)o for up to 3 years, followed by single-agent lenalidomide maintenance thereafter
RVD consolidation
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Overall median PFS 32/12, 3 year OS 93%
ASCT and maintenance
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PFS
Mel 200 x2 vs. MPR Len maint vs. not
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Therapy of high risk myelomaPotential conclusions
• 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 evaluation
MUK9 Optimum study
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 maintenance
Cytogenetic inter-relationship
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Deletion 1p- (n=71)
Deletion 17p(n=74)
Adverse translocation(n=144)
6
2135
60
61
Number gained Frequency
1p- 10%
1q+ 34%
17p 9%
Adverse Translocation 21%
GEP 20%
Overall 25-35%
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Deletion 17p(n=74)
Adverse (n=144)
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65
71
48
180
Gain 1q(n=264)
20
18
14
EMC92
Cytogenetics
Myeloma IX data
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)
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.
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 arm
Pre-Screening
1200 newly diagnosed myeloma patients20-30% lost
20-30%High risk
70%Standard risk
15-20% t(11;14)
60 % Hyper
diploidyOther
High risk trial Other trials
Trial design
Registration phase: 1200 newly diagnosed patients
8 week turnaround time
Randomise 50 patients per armExpand by another 35 patients in best arm vs. ControlAim to open early 2015
New
ly d
iagn
osed
patie
nts
CTDCVDCRDVTD
InductionX2 cycles
Max
VDT-PACE X 2
CVRDd
CRD
SplitHDM-VASCT
HDM ASCT
Rd
Def
ine
high
ris
k st
atus VRDdX6
HDM ASCT
R
To progression
RdHDM-V ASCT
VRdX12
VRDdX6 VRdX12
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.
Follow-on from MUK9 Optimum study
Phase 2/3 expansion
National Phase 3 study: NCRI portfolio
Pick a winner concept
Define 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 studies
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Acknowledgements
• ICR/RMHo Gareth Morgano Faith Davieso Martin Kaisero Eileen Boyle
• Myeloma CTNo Eric Lowo Heather MacKinnono Jennifer Frasero Gordon Cooko Guy Pratt
• Leeds CTRU
o Sarah Browno Louise Flanagan
• Wessex Regional Genetics Labo Fiona Rosso Laura Chiecchio