How to Manage High Risk Myeloma Dr Matthew Jenner Consultant Haematologist Southampton General Hospital UK Myeloma Forum Autumn Day 12 November 2014.

How to Manage High Risk Myeloma

Dr Matthew Jenner

Consultant Haematologist

Southampton General Hospital

UK Myeloma Forum Autumn Day

12 November 2014

Introduction

3

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

7

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

8

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

15

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

21

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

39

PFS

Mel 200 x2 vs. MPR Len maint vs. not

43

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%

17

Deletion 17p(n=74)

Adverse (n=144)

18

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