1. No category

PRECISION MEDICINE and
COMPUTER AVATARS IN
MULTIPLE MYELOMA RESEARCH
of the FUTURE
MMRF Model Evolution
The MMRF continues to transform cancer research by building innovative
collaborative models that drive science and successful drug development.
Immunotherapy
Program
Tissue Banking
Clinical Trials
Accelerate Novel Drugs
Immune Biology
Novel Antibodies
Modified T-Cells
Cellular/Vaccines
MMGI
MMPM
(Multiple Myeloma
Genomics Initiative)
(Multiple Myeloma
Precision Medicine)
Patient Community
Accelerate Discovery
Drive Collaboration
Myeloma Genome Sequenced
Public Researcher Portal
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CoMMpass℠ Study
GNS Collaboration
Public Bioinformatics Platforms
MMRF Precision Medicine
Initiatives
MMPM Initiatives: MMGI
The start of MMPM: The MMGI comprehensive set of analyses on a total of
400+ patients.
Clinical Data
FISH
250 GRS*
aCGH and GEP
250 GRS*
DNA and RNA Sequencing
203 DNA analyzed/ 75 RNA
Epigenetics
4
~200 GRS*
68 MM Cell Lines: WES/RNA Seq
•Original Genomic Reference Set
(GRS)
MMPM Initiatives: MMGI
Lessons Learned from MMGI: genomic heterogeneity of multiple myeloma
• MM patients had not just one but a number of different
mutations
• MM patient tumors consisted of a number of subclones, each
of which had their own mutation profile
• Over time, subclonal populations waxed and waned
• mutational status of a given subclone could change, ie
mutations found at diagnosis would not necessarily be
present at progression, new mutations could appear at
progression that were not present at diagnosis, etc.
A compelling case was made for developing precision medicine approaches
5
MMPM Initiatives: MMGI and
CoMMpass
The next step in MMPM: CoMMpass study builds on the MMGI which the
MMRF launched in 2007.
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Cohort
Target Enrollment
400 patient samples (50% newly
diagnosed and 50% relapsed)
1,000 newly diagnosed patients
with longitudinal sampling
Clinical Data
Clinical Data
Partial and survival
Complete, collected quarterly
Molecular Profiling
Molecular Profiling
GEP and aCGH on 252;
WES/WGS on 213; RNAseq 75
WES/WGS/RNAseq; CLIA-grade
flow and BRAF, CMMC
Evaluation
Evaluation
MMRC TB samples since 2004
8 years enrollment and follow up
Sites
Sites
16 MMRC sites
108 sites in US, Canada, EU
Investment
Investment
$12 Million
$40 Million
MMGI
2007
CoMMpass/MMPM
2011
MMPM Initiatives: Data in the public
domain
Data from the MMGI and CoMMpass are put into the public domain.
MMGI
http://www.broadinstitute.org/mmgp/home
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CoMMpass
https://research.themmrf.org
MMPM Initiatives: Identify “Actionable”
Genomic Alterations
The various genomic efforts have identified molecular alterations for which
there are drugs in the clinic in approximately 50% of MM patients.
MyD88
(3%)
IDH1/2
(5%)
IGF1R and ALK
(5%)
FGFR3
(5%)
Others
(11%)
KRAS and NRAS
(40%)
PI3K-AKT
(5%)
CDKN2C and CCND1
(18%)
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BRAF
(8%)
MMPM Initiatives: MM Master Protocol
MMRF brought together on Oct 22, the NCI, FNIH, and FDA with academic
and industry partners to initiate the development of a MM master protocol.
• Trial Development
.
• MM-Mutation
panel
INDUSTRY
• Multiple new
Oct. 22,
2014
Kick-Off
Meeting
.
targets, drugs
• Ph. II/III accelerated
design
• Incorporation of
MRD
.
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MMPM Initiatives: Myeloma Umbrella
Protocol
A protocol testing targeted single agents in molecularly-selected patients.
Relapsed/refractory patients
Genomic profiling for alterations
No Alteration (50%)
Alteration identified (50%)
Randomize
M+
SOC
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Immune
M-
BRAFi
M+
M-
1p/1q (CDKi)
M+
M-
Del17(Mdm2i)
M+
M-
FGFR3i
M+
M-
PI3K/AKTi
M+
M-
IGF1R/ALKi
M+
M-
IDH1/2i
MMPM Initiatives: CoMMpass℠
CoMMpass℠ patients - access to personalized medicine
Molecular Tests
Multiplex MM panel Flow cytometry & BRAF
mutations*
RNA sequencing expression analysis
Whole exome DNA sequencing
Whole genome chromosome analysis
Cytospin slides for FISH
Veridex Circulating MM Cell Assay
Future tests under active consideration:
CLIA grade sequencing for relapsed pts. w/return
of results to physicians to inform treatment
* Performed by Spectrum Health – Physician provided with results from these
assays
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What is an avatar and how will it
transform disease treatment?
Clinical information
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Computer Avatars in Medicine
The making of a patient avatar:
1. Collect the aggregate data
–
CoMMpass trial
2. Analyze the data; build the models
–
–
MMRF Researcher Gateway
Gene Network Sciences
3. Create the individualized avatar
–
–
–
Patient tumor sequencing
Patient clinical data
MMRF Community Gateway
4. Apply models to avatar to inform disease
progression and treatment
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GNS REFS™ Mathematics Platform –
Patented, supercomputer-driven
• Leverages three major advances in technology and science:
1 Exponential increase in quantity of digital information
2 Rise in use of computers to solve problems without human intervention
3 Turing Award recognized mathematic advances that establish probabilistic cause-andeffect, which is more powerful than correlation of events
Mechanistic
Massive,
multimodal
patient data
Predictive
Reverse
Engineering
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Forward
Simulation
Data-driven,
personalized
predictions
Network Models
•
•
•
•
Harnesses unique multi-modal data at industrial-scale
Combines best-in-class machine learning and 1st-in-class causal inference
Creates highly-individualized predictions
Developed and deployed platform for 10+ years with two US patents
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Leveraging Big Data to Deliver Key Insights
Effectiveness
Treatment Landscape for Multiple Myeloma
This axis subsumes
genetics, labs, genomics,
demographics, drugs, procedures, and
their ordering, etc. – measures that
characterize a patient
Along with lifestyle choices
MMRF CoMMunity Gateway:
Overview
• www.TheMMRFCoMMunityGateway.org
• The MMRF CoMMunity Gateway allows patients and caregivers to:
• Track treatment overtime
• Ability to connect and share information with other patient/caregivers
• Join groups based on common molecular profiles, myeloma status and
symptoms that are moderated by myeloma experts and nurses
• Find clinical trials
• Learn about the latest in
news and information about treatments
• Find myeloma centers
MMRF CoMMunity Gateway:
Clinical Trials Tool
• In Spring of 2015 – estimated launch time May – the MMRF CoMMunity
Gateway will have a clinical trials tool that will return priority ranking of trial
relevance to a user based on their shared data (Avatar) in the MMRF
CoMMunity Gateway
• Patient Data Facets Will Include:
• Geography (distance from zip code of trial center)
• Disease status
• Therapeutic Line
• Prior Treatment History
• Genomic Mutation
• The Tool Will Also Include:
• Keyword Text Search
• Saved Search
• Save Trials
• Compare Trials