Black Swan Research Initiative®
Brian GM Durie
Saturday August 22, 2015
1
Black Swan Research Initiative (BSRI)
Purpose
• The Black Swan Research Initiative (BSRI) is a global
collaborative approach
• Which uses the most precise MRD testing
• To track myeloma at the lowest levels
• As a basis for treatment decisions
• To achieve a cure
International Myeloma Foundation
2
Black Swan Research Initiative
Where are we?
…What are the next steps?
International Myeloma Foundation
3
Key Elements of BSRI
3. Clinical Trials
2. MRD Assessment of
Response
1. Early Diagnosis
International Myeloma Foundation
4
Step 1: Early Diagnosis
BLACK SWAN RESEARCH INITIATIVE
International Myeloma Foundation
5
Key New Publication
“recommends the
implementation of
these criteria in
routine practice”
International Myeloma Foundation
6
New Criteria for Active Myeloma
•
•
•
•
CRAB Criteria
Calcium
Renal
Anemia
Bone
and/or
Myeloma Defining Events
International Myeloma Foundation
7
New Criteria for Active Myeloma
Myeloma-Defining Events
Creatinine clearance
< 40 ml/min
Bone marrow plasma cells ≥ 60%
Serum Freelite ratio
≥ 100
Imaging evidence of active disease
MDE
International Myeloma Foundation
• >1 focal lesion on MRI
New • Positive PET/CT
CRAB • Lesions >5mm on WBLD CT
8
Step 2: Next Generation MRD Testing
BLACK SWAN RESEARCH INITIATIVE
International Myeloma Foundation
9
Going beyond the CR criteria with MRD monitoring
< 5% PCs in
bone marrow
Cellular clonality
• Immunohistochemistry
• ASO-PCR
• Next Generation
Sequencing (NGS)
• Next Generation Flow
(NGF)
Negative IFE of
serum and urine
Cellular production
• sFLC
• Hevylite
• Sensitive M-spike
measurement
Disappearance of soft
tissue plasmacytomas
Cellular spread
• PET/CT
• WB-MRI
International Myeloma Foundation
10
MRD monitoring in multiple myeloma using NGS
Commercial
Home-made
1. Extraction and
quantification of
gDNA (qPCR)
2. VDJ, DJ,KDEL
etc. PCR
amplification with
Biomed 2 primers
3. Ligation with
barcodes
4. Sequencing,
Ion Proton
Platform
Martinez-Lopez J, et al.
International Myeloma Foundation
11
IMF/ EuroFlow Consortium
Develop more sensitive and standardized flow
method: Next Generation Flow (NGF)
• Ideal antibody cocktails: now sensitive at ≤ 10-6
• 8 and 10-color cross panel validation
• Multi-dimensional analysis software: now 12 minutes!
International Myeloma Foundation
12
NGF Antibody Panels
Panel
Tube
8color
1
10-color
1
BV421 BV510 BV605
FITC
PE
PerCP
Cy5.5
PE
Cy7
CD138
CD27
CD38
CD56
CD45
CD19
CD138
CD27
CD38
CD56
CD45
CD19
2
CyIgl
APC
APC
A700
APC
C750
CD117
CD81
CyIgk
CyIgl
CD117
CyIgk
CD81
International Myeloma Foundation
13
Current Use of NGF: 8 Colour “Gold Standard”
U.S.
MAYO
MDAH
UAMS (MIRT)
U of Chicago
Columbia (NY)
Mount Sinai (NY)
Carolinas
Roswell Park
Europe
Spain
France (IFM)
Italy (Palumbo)
Netherlands (Hovon)
Germany
Turkey
Latin America
Brazil
Japan
Singapore
Tokyo
National University
China
Beijing, Tianjin,
Shanghai
Melbourne
Australia
International Myeloma Foundation
14
MRD monitoring in MM using NGF: ultra-sensitivity
Next-generation flow
NGS
-
+
Total
-
9/14 (64%)
2/14 (14%)* 11/14 (78%)
+
0/14 (0%)
3/14 (22%)
Total
9/14 (64%)
5/14 (36%)
3/14 (22%)
NGS was applicable in 14/16 (88%) of MM cases
International Myeloma Foundation
15
Current Use of NGF: 8 Color “Gold Standard”
International Myeloma Foundation
NGF for MRD monitoring in MM: GEM2012MENOS65 (>400 tests)
CR and MRD-negative
49%
MRD-positive ≤10-4
20%
MRD-positive 10-5
22%
MRD-positive 10-6
8%
MRD positive @ ≤ 10-7
<1%
– 49%
+ 51%
International Myeloma Foundation
17
Iceberg Effect
49%
22%
10 -4
20%
51%
10 -5
10 -6
International Myeloma Foundation
8%
1%
NGF for MRD monitoring in MM: ultra-sensitivity
10
Patient 434
1
10% clonal PCs
0.1
0.0005%
MRD
0.0008%
MRD
0.0003%
MRD
0.0002%
MRD
0.01
0.001
0.0001
Diagnosis
CR
HDT/ASCT
Induction
Consolidation
International Myeloma Foundation
19
Steps to Assess and Treat MRD
Develop
specific Rx
Monitor
or
MoAb Studies
Maintain
If negative
If positive
MRD Assessment
Study Residual
MRD
Assess
Relapse/
Resistant
Disease
Car/Rev/Pom/
+ Elo or DARA
Alternate Rx
International Myeloma Foundation
20
Newly-diagnosed symptomatic MM patients with an MGUS-like
profile by Flow and GEP
Phenotypic MGUS-like profile
Molecular MGUS-like profile
Symptomatic
MM
MGUS-like symptomatic MM
(~10%)
Paiva B, et al. Leukemia. 2013;27(10):2056-2061.
Zhan et al. Blood. 2007;109:1692-1700
International Myeloma Foundation
21
Survival for MGUS-like MM patients is independent of CR
Less than CR should not be considered a sub-optimal response
TTP
TTP
100
100
80
Median: NR
59%@10y
80
60
60
40
40
20
Median: 44 months
14%@10y
20
0
HR: 3.27 ; P < 10-6
0
0
20
40
60
80
100
120
140
Time from diagnosis (months)
MGUS-like profile (n=59)
MM-like profile (n=639)
Median: NR
Median: NR
P = .812
0
20
40
60
80
100
120
140
Time from diagnosis (months)
CR (n=26)
< CR (n=33)
Paiva B, et al. Leukemia. 2013;27(10):2056-2061.
22
MRD clonal PCs show de-regulated GEP compared to baseline clonal PCs
B
A
S
E
L
I
N
E
M
R
D
Paiva B, et al. Blood 2013;122(21): abstract 402 (oral presentation)
International Myeloma Foundation
23
Proteasome inhibitor resistance-related genes
PAAF1: proteasomal ATPase-associated factor 1
PSMA6: proteasome subunit, alpha type, 6
PSMB10: proteasome subunit, beta type, 10
POMP: proteasome maturation protein
PSME1: proteasome activator subunit 1
PSMD10: proteasome 26S subunit, non-ATPase, 10
PSMB6: proteasome subunit, beta type, 6
PSME3: proteasome activator subunit 3
PSMA2: proteasome subunit, alpha type, 2
Low
Paiva B, et al. Blood 2013;122(21): abstract 402 (oral presentation)
International Myeloma Foundation
24
PDL1 - PD1 axis is up-regulated after therapy at the MRD stage
Percentage of cells with PD1 surface expression
Amount of PD-L1 MFI-expression / PC
P = .05
CD4 T-cells
CD8 T-cells
P <.05
100
6000
80
4000
60
2000
40
0
20
Normal PCs
Clonal PCs
0
Paiva B, et al. Leukemia. 2015; doi: 10.1038/leu.2015.79.
International Myeloma Foundation
25
Antigen/Receptor Targets
VSV
T
Cell
Measles
PD-1 checkpoint
inhibitor
PD-L1
CD 28
NK
Cell
LDL-R
CD 46
CD 117
KIR
CD 45
CD 16
SLAM F7
CD 56
CD 33
CD 20
CD 19
CAR
T cell
Lorvo/Dace
CD 138 Inda
CD 319 Elo
(SLAM F7)
CD 38
DARA/SAR/MOR202
4%
Monoclonal
Antibodies
100%
CD 19
International Myeloma Foundation
Multiple
Targets
26
Specific Targets
Antigens
36%
Molecular
PD-L1
CD 28
CD 117
18%
CD 45
CD 56
CD 33
CD 138
CD 20
CD 19
4%
KRAS
NRAS
CD 319
(SLAM F7)
CD 38
100%
BRAF
4%
CCND1
DIS3
NFKB
HOX A9
Hundreds of mutations,
SNPs, and pathways
International Myeloma Foundation
27
Transitioning from conventional CR
Complete Response (CR)
• Negative serum and urine immunofixation
• <5% PCs in marrow
MRD negative
• Flow negative MRD
• Sequencing negative MRD
• Imaging negative MRD
Stringent Complete Response (sCR)
• Normal FLC ratio
• No clonal plasma cells in marrow
International Myeloma Foundation
28
New Criteria for MRD
MRD-negative by
Next-generation flow
MRD-negative by
Next-generation
sequencing
Conventional CR PLUS
Absence of phenotypically aberrant clonal plasma cells by nextgeneration flow cytometry on bone marrow aspirates using the
EuroFlow standard operation procedure for MRD detection in MM
(minimum sensitivity of 1 in 105 nucleated cells)
Conventional CR +PLUS
A clonotype was defined AND Less than 2 identical sequencing reads
obtained after DNA sequencing of bone marrow aspirates using the
Lymphosight® platform (minimum sensitivity of 1 in 105 nucleated
cells)
Imaging plus cellular
MRD-negative
MRD negative as defined above (MFC or sequencing) PLUS
Disappearance of every area of increased tracer uptake found at
baseline by PET/CT
International Myeloma Foundation
29
Upcoming Trials
NGF in
Blood
New Trial
Options
MM
MRD NEG
SMM
MGUS
CURE Trials
Low MRD
Status
MGUS
Signature
Resistant
MRD
International Myeloma Foundation
30
CESAR Trial
C urative E strategy S moldering A lto R isk
HR SMM
KRd x 6 cycles
ASCT
KRd x 2 cycles
Rd x 2 years
International Myeloma Foundation
31
ASCENT Trial
Aggressive Smoldering Cure Evaluating Novel Rx Transplant
HR SMM
KRd + DARA x 4 cycles
KRd + DARA x 4 cycles
ASCT
KRd + DARA x 4 cycles
International Myeloma Foundation
K – DARA x 2 years
32
Poor Maturation
Patients with long-term survival have a unique immune signature
TAMs
Plasmacytoid-Dcs
TReg
Myeloid-Dcs
MO
CD8
Numbers
Inhibition
CD8
NK
CD8
N-Pcs
NK
B
NK
N-Pcs
Bone Marrow Stromal Cells
B
B
Bone Marrow Stromal Cells
Bone Marrow Stromal Cells
International Myeloma Foundation
Pessoa de Magalhães RJ, et al. Haematologica. 2013;98(1):79-86
33
Forward Expectations and Plans
2019
• Expanding cure fraction
• Documenting cure
2017
• Validation of clinical correlates
• Expanding achievement of MRD-negative
2016
• Studying MRD-positive; introducing Rx to eradicate
• Understanding MRD-negative
• Introducing new MRD blood test
2015
• Cross correlate with NGS and imaging
Now • Standardized NGF test for bone marrow
2018
International Myeloma Foundation
34
35
International Myeloma Foundation
36