How to Manage High Risk Myeloma
UK Myeloma Forum Autumn Day
12 November 2014
Dr Matthew Jenner
Consultant Haematologist
Southampton General Hospital
Introduction
Why define high risk myeloma?
•
Patient expectations
o Outcomes vary widely between different patients
o Myeloma very heterogenous disease
•
Aim for a risk stratified approach – one size may not fit all
o Maximise treatment for those that need it
o Minimise treatment and toxicities for those who may not
o Acute leukaemia and lymphoma models
•
Better define high risk disease
o Subgroup analysis may lead to identification of common clinical and biological
features leading to more individualised treatments
3
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
Smouldering myeloma
Classifiers of high risk status
•
Degree of bone marrow infiltration
o IMWG criteria
•
Imaging
o PET-CT
o Whole body CT
o Whole body DW MRI
•
Immunophenotyping
o Aberrant vs normal plasma cells
•
7
?Cytogenetics
Smouldering myeloma
Role of high risk cytogenetics
•
Data for cytogenetics in symptomatic myeloma is clear cut
•
Adverse IgH translocations and copy number abnormalities well recognised
o 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
8
MGUS and smouldering myeloma cytogenetics:
Wessex myeloma database
IgH translocations
•
•
•
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%)
Different patterns of progression from MGUS and SMM to myeloma
t(14;20) stable disease
MGUS
o
•
SMM
o
o
9
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
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
FM Ross, L Chiecchio et al, Haematologica 2010
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 agents
o Require OS as well as PFS data
10
Case 1
Case 1
60 year old female
•
1996
o
•
2005
o
o
•
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
o
o
12
DCIS left breast with bilateral mastectomies and Arimidex
No evidence of relapse on follow-up
May 2013
o
o
o
o
o
o
o
•
Right breast carcinoma treated with WLE and RT
Local RT L2 8Gy single fraction
Myeloma XI: CTD
Case 1
•
CTD x6 achieving VGPR:
o
o
•
•
•
BM: MRD positive 0.1% abnormal PC
HDM(200) ASCT 9/12/13
D100 11/3/14
o
o
o
o
•
•
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:
o
o
13
paraprotein 0.7 g/L
FKLC 140 mg/L
Renal tract USS neg
July 2014 PET-CT
Case 1
PET-CT
Case 1
July 2014
•
PET-CT
o
o
•
Widespread FDG avid lesions multiple vertebrae, sternum, ribs, pelvis
Left paravertebral mass
MRI
o
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
o
o
o
•
15
RT to paraspinal mass
VRD-PACE
VRD
VRD-PACE
Awaiting follow-up imaging
Case 1
Observations
•
•
•
•
•
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
o
o
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?
o Does recovery period post ASCT enable myeloma plasma cell recovery?
o
o
16
What is more important dose intensity or dose density?
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.
©2012 by American Society of Hematology
Keats J J et al. Blood 2012;120:1067-1076
HRMM: Thalidomide
MRC Myeloma IX - Trial Design
Intensive
N = 1,960
RANDOMISATION
Clodronate
CVAD
Zoledronic acid
CVAD
Clodronate
C-TD
Non-intensive
RANDOMISATION
Zoledronic acid
C-TD
Clodronate
MP
Zoledronic acid
MP
Clodronate
C-TDa
MEL-200
ASCT
Max
Response
RANDOMISATION
RANDOMISATION
–Thal
+Thal
–Thal
Zoledronic acid
C-TDa
+Thal
Treatment continued until disease progression
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
21
Myeloma IX: Landmark analysis in patients with
favourable and adverse iFISH
Favourable iFISH
Adverse iFISH
B
100
100
80
80
60
Patients (%)
Patients (%)
A
40
CTDa
MP
P < .001
20
0
88
93
0
CTDa
MP
88
93
12
60
40
CTDa
MP
P = .41
20
0
32
81
53
16
77
44
24
36
48
OS (months)
10
5
60
CTDa
MP
72
60
55
0
60
55
12
43
44
24
23
17
36
8
8
48
3
6
60
OS (months)
•
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)
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
IFM 2005-01
Bortezomib-Dex
vs. VincristineAdriamicin-Dex
(VAD)
Newly diagnosed
myeloma suitable
for intensive
chemotherapy
and ASCT
A: VAD
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
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)
A: VADthalidomide
Sonneveld P et al. JCO 2012;30:2946-2955
©2012 by American Society of Clinical Oncology
B: PADbortezomib
HOVON
Phase III Trial of PAD and bortezomib maintenance vs. VAD and
thalidomide in Myeloma: Survival
Cumulative %
Progression Free
100
HR: 0.79 (95% CI: 0.66-0.95; P = .01)
75
PAD
50
25
VAD
PAD
0
n
373
371
0
12
VAD
F
243
215
24
Mos
36
48
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.
Kaplan-Meier survival curves of progression-free survival (PFS) and overall survival (OS) according to
treatment arm within subgroups according to del(17p).
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?
Sonneveld P et al. JCO 2012;30:2946-2955
©2012 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
(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
HRMM: Total therapy
Total Therapy 3
Developed at MIRT,
Arkansas
Multidrug 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
32
TP53 deletion is not an adverse feature in multiple myeloma treated with total therapy 3
GEP low
risk
GEP high
risk
OS
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
EFS
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
VRD consolidation
Nooka et al Leukaemia 2014
•
High-risk myeloma defined by
o
o
o
o
•
•
•
•
45 patients
Induction not specified, majority VTD or VRD
ASCT
Maintenance therapy
o
o
o
o
36
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)
lenalidomide (10 mg/day orally) on days 1–21 of a 28-day cycle
bortezomib (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 thereafter
RVD consolidation
Overall median PFS 32/12, 3 year OS 93%
37
ASCT and maintenance
39
PFS
Mel 200 x2 vs. MPR
Len maint vs. not
Therapy of high risk myeloma
Potential 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
•
•
•
43
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
Adverse translocation
(n=144)
Deletion 1p(n=71)
135
Number gained
Frequency
1p-
10%
1q+
34%
17p
9%
Adverse
Translocation
21%
GEP
20%
Overall
25-35%
2
61
6
1
7
60
Deletion 17p
(n=74)
Gain 1q
(n=264)
EMC92
180
65
71
Adverse
(n=144)
14
18
1
7
18
48
Deletion 17p
(n=74)
20
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. Multiagent non-DNA damaging agents
• Arm C: standard arm
Pre-Screening
1200 newly diagnosed myeloma patients
20-30%
High risk
70%
Standard risk
15-20%
t(11;14)
High risk trial
60 %
Hyper
diploidy
Other trials
Other
20-30% lost
CTD
CVD
CRD
VTD
Induction
X2 cycles
Max
Define high risk status
Newly diagnosed
patients
Trial design
To progression
Split
HDM-V
HDM-V
ASCT
ASCT
VRDdX6 VRdX12
Rd
CVRDd
HDM
ASCT
VRDdX6 VRdX12
Rd
CRD
HDM
ASCT
VDT-PACE X 2
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
R
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
Acknowledgements
•
ICR/RMH
o
o
o
o
•
o Sarah Brown
o Louise Flanagan
Gareth Morgan
Faith Davies
Martin Kaiser
Eileen Boyle
•
•
Myeloma CTN
o
o
o
o
o
54
Eric Low
Heather MacKinnon
Jennifer Fraser
Gordon Cook
Guy Pratt
Leeds CTRU
Wessex Regional Genetics Lab
o Fiona Ross
o Laura Chiecchio