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Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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Hot Topics in Multiple Myeloma Treatment
Webinar 3; November 1, 2017Precision Medicine
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Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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Multiple Myeloma Research Foundation
Moderator: • Mary DeRome
Multiple Myeloma Research FoundationNorwalk, Connecticut
www.themmrf.org
https://www.facebook.com/theMMRF
https://twitter.com/theMMRF
https://www.youtube.com/user/TheMMRF
Speakers• Jeffrey L. Wolf, MD
University of California, San FranciscoSan Francisco, California
• Amy S. Marsala, RN, MPH, ANP-BC University of California, San FranciscoSan Francisco, California
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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Topics for Discussion• The potential to adapt therapy to particular
subtypes of MM
• The MMRF CoMMpass StudySM results and key precision medicine trials
• What precision medicine mean for patients
Multiple Myeloma Is Not Just One Disease!
How do we customize treatment?
MM is a heterogeneous disease even within cytogenetically defined molecular subtypes
Treatment should not be applied in a one-size-fits-all fashion
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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How do we match the right myeloma medicines to each patient?
Precision Medicine
• Gene expressionprofiling (GEP)
• Whole-genome/ whole-exomesequencing
• Next-generation sequencing
MM cell
Chromosome
DNA
Personalizing medical care with DNA testing of many different genes (genomics) at the same time
Genomictesting
Tailoredtreatment
Bone marrow tissue samplesNewly diagnosed → relapse
Whole-Genome Sequencing at Diagnosis
Courtesy of Nikhil Munshi MD, DFCI
ComplexityAt
Diagnosis
DNA base-pair substitutions, n
5,286
Deletions and insertions, n
51
Rearrangements, n 49
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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Whole-Genome Sequencing at Relapse
ComplexityAt
DiagnosisAt
Relapse
DNA base-pair substitutions, n
5,286 12,581
Deletions and insertions, n
51 606
Rearrangements, n 49 113
Significant increase in complexity
Courtesy of Nikhil Munshi MD, DFCI
The Concept of Clonal Tides
• Five unique clones at diagnosis• Variable chemotherapy response• Minor drug-resistant clone lethal
Diagnosis~2N Relapse 2
~2N
Relapse 1~2N
Remission~2N
Relapse 3~2N
Plasma cell leukemia~3N
clg-high37%
clg-low34% clg-low
63%
Relapse 4~3N
Clone 1.1Clone 1.2Clone 2.1Clone 2.2Misc
72%
31%64%
21%
64%
19%58%
17%
71%
78%95%
96%96%
Keats JJ et al. Blood. 2012;120:1067.
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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MMRF CoMMpassSM Study: Advancing Personalized Medicine Research
• Landmark study focusing on the genomics of myeloma
• Goals – Learn which patients
respond best to which therapies
– Achieve better treatments targeted to each patient’s biological makeup
• 1,000 newly diagnosed patients will be followed for at least 8 years
For more information call the MMRF at 866-603-6628
or visit www.themmmrf.org.
Enrollment complete!
MMRF CoMMpassSM Study:Advancing Personalized Medicine Research
AgeHow old were the
people in CoMMpass?
GenderWhat gender were the people in CoMMpass?
Race/ethnicityWhat ethnicity were thepeople in CoMMpass?
64
Average
27
Youngest
93
Oldest
2/3Male
77%
Caucasian
16%
African American
2%
Asian
5%
Other
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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Should I be on three drugs?
MMRF CoMMpassSM Study: Advancing Personalized Medicine Research
Should I do a transplant?
MMRF CoMMpassSM Study: Advancing Personalized Medicine Research
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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MMRF CoMMpassSM Study: Advancing Personalized Medicine Research
12 Subtypes of Multiple Myeloma
We’ve identified 12 different molecular types of multiple myeloma, each with its own level of risk. They include:
MyD88 CDKN2C
IDH1/2 CCND1
IGF1R BRAF
ALK KRAS
FGFR3 NRAS
PI3K-AKT Others
Molecular Profiling for Precision Therapeutic Strategies in Myeloma
BRAF inhibition (for example, with vemurafenib) has now been clinically validated in multiple myeloma.
PET CT before and after 2 months of vemurafenib treatment in patient with BRAF V600E mutation showing significant improvement in bone lesions.
Sharman JP et al. Clin Lymphoma Myeloma Leuk. 2014;14:e161.
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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Another Example: Venetoclax Targets BCL-2, an Anti-Apoptotic Protein
That Promotes Myeloma Cell Survival
• t(11;14) is associated with sensitivity to venetoclax (Venclexta), a drug approved in CLL• t(11;14) correlates with higher ratios of BCL2:MCL1 and BCL2:BCL2L1
BCL-2Pro-apoptoticprotein
Cancer Cell Survival
BCL-2 overexpression allows cancer cells to evade apoptosis by
sequestering pro-apoptotic proteins.1-3
BCL-2
Pro-apoptoticprotein
Cancer Cell Death
Venetoclax binds selectively to BCL-2, freeing pro-apoptotic proteins that initiate
programmed cell death (apoptosis).4-6
Venetoclax
Apoptosisinitiation
BIMBAX
BAK
BAX
Cytochrome c
Activationof caspases
From Kumar et al. ASH 2016.1. Leverson JD et al. Sci Transl Med 2015.2. Czabotar PE et al. Nature Reviews. 2014;15:49.3. Plati J et al. Integr Biol (Camb). 2011;3:279.
4. Certo M et al. Cancer Cell. 2006;9:351.5. Souers AJ et al. Nat Med. 2013;19:202.6. Del Gaizo Moore V et al. J Clin Invest. 2007;117:112.
Studies Showing Responses to Venetoclax
Phase 1 study in relapsed/refractory MM2
• 67% patients responded• Highest responses seen in patients who
were not refractory to proteasome inhibitors or immunomodulatory drugs
• Acceptable safety profile• A phase 3 trial is ongoing
Venetoclax + Velcade + dex
66 patients
1. Kumar S et al. Haematologica. 2017;102: Abstract P675.2. Moreau P et al. Haematologica. 2017;102: Abstract S460.
t(11;14) t(4;14) del(17p) del(13q)
Cytogenetic abnormality present
+ – + – + – + –
Overall response rate (%) 78 65 60 67 47 73 63 69
Phase 1 study in relapsed/refractory MM1
• Acceptable safety profile• Promising single-agent activity in
patients with t(11;14)
Venetoclax alone
66 patients
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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Beyond Single Hypothesis Testing: Master Protocols
Functional high-risk patientsFunctional high-risk patients
Backbone regimen
No detectable actionable alterations
Backbone regimen + immune
checkpoint inhibitor
RAF/RAS mutations
MAPKi
MAPKi +backbone regimen
IDH activating mutations
IDHi
IDHi +backbone regimen
CCND1 activating alteration
CDKi
CDKi + backbone regimen
PI3K/AKT activating alterations
AKTi
AKTi +backbone regimen
t(11;14)
BCLi + backbone regimen
BCLi
FGFR3 activating alterations
FGFRi
FGFRi +backbone
regime
Profiling for alterations (NCT02884102)Profiling for alterations (NCT02884102)
Additional Precision Medicine Trials
TrialPatient
PopulationGene Mutations
Targeted Primary Site
JNJ-42756493* + dexamethasone RRMM FGFR3 University Health Network,
Toronto, Canada
Dabrafenib† + Trametinib† RRMM BRAF, NRAS, or KRAF
Massachusetts General Hospital Cancer Center/Dana-Farber
Idasanutlin* + Ninlaro + dexamethasone RRMM 17p deletion Mayo Clinic
NCI-MATCH Advanced MM Various National Cancer Institute
GSK-2816126* Advanced MM Enhancer of Zeste 2 (EZH2) Northwestern University
Targeted Agent and Profiling Utilization Registry Study (TAPUR)
MM Various Multiple
*Experimental therapy not yet FDA approved; †FDA approved for a non-MM indicationBold = treatments studied in MMRC trialsTrials found at www.clinicaltrials.gov
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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What new genomic tests are available for patients?
Circulating tumor DNA
Circulating tumor cells
Sample receipt
CD138Enrichment/library prep
Exome capture
processing
Sequencing HiSeq rapid
modeSequence analysis
Report generationand review
Day 0 Days 1–3 Day 4 Days 5–6 Days 6–8 Day 9
ONCOSEQ 1700
Molecular Profiling Initiative: 500 Relapsed and Refractory Multiple Myeloma Patients
Myeloma patients provide their bone marrow and peripheral blood samples at many cancer centers across the US
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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Tumor Sequencing• Identifies mutations in genes and the expression
levels of these genes in tumor cells
Tumor sequencing
Actionable mutations
Immunogenic mutations
Targetedagents
Immunologictherapy
Getting the Brakes Checked
X X X
Courtesy of Jonathan Keats, PhD
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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Today CoMMpass Tells Us
Having no brakes is a bad thing but having half the brakes is okay.
Progression-Free Survival
Courtesy of Jonathan Keats, PhD
An Example of the Importance of Personalized Medicine
CoMMpassMMRF2172 CoMMpassMMRF2250
Age 72 71
Ethnicity Caucasian Caucasian
ISS stage II II
Baseline treatment VRD VRD
Cytogenetics t(4;14), del13, del17p t(4;14), del13, del17p
Time of progression 1 month >18 months
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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An Example of the Importance of Personalized Medicine
CoMMpassMMRF2172 CoMMpassMMRF2250
Age 72 71
Ethnicity Caucasian Caucasian
ISS stage II II
Baseline treatment VRD VRD
Cytogenetics t(4;14), del13, del17p t(4;14), del13, del17p
Time of progression 1 month >18 months
p53 status Mutated Wild-type
Applying Precision to Practice: How can patients help tailor their therapy?
• Become informed about screening tools and tests that can identify specific features of clonal disease
• Discuss precision medicine practices with primary oncologists (such as availability and timing of testing)
• Be willing to undergo additional biopsies and screening tests to better identify these mutations
• Participate in clinical trials to expand the network of samples to help researchers better understand how to engineer new therapies
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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Precision Medicine: Lab to Real Life
• Identifying mutations and higher-risk features earlier in disease will hopefully result in superior responses
• Faster disease control will allow recovery of damaged organs and improve overall functional status
• Longer and deeper periods of remission can predict increased progression-free survival and can translate into improved quality of life
• Targeted therapies tend to have few side effects and be better tolerated
• Screening for depths of response can result in possibly shorter time on maintenance therapy or the option of drug holidays
Precision Medicine SummaryA one-size-fits-all treatment approach for MM is inappropriate due to its heterogeneity
Efforts are under way to better understand the nature of the disease and to provide patients with a more personalized approach to treatment
Genomic sequencing and data from MM patients are key to identifying subtype
Participation in clinical trials to provide bone marrow and peripheral blood paramount
Precision medicine provides the right treatment at the right time for each myeloma patient
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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Questions & Answers
Closing
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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Resources for You!
Accelerator Magazine
Have questions about the trials or information you heard today?
Call our MMRF Nurse Patient Navigators.
MMRF Patient Support Center
Our MMRF Nurse Patient Navigators can guide you through
your multiple myeloma journey every step of the way.
Call Mon–Fri, 9:00 am–7:00 pm ET
Call now1-866-603-MMCT(6628)
Stay connected!www.theMMRF.org
@theMMRF on TwitterMMRF on Facebook
MMRF Website/Social Media
Hot Topics in Multiple Myeloma Treatment Webinar 3: Precision Medicine
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MMRF Multiple Myeloma SummitsFall 2017
Friday, November 3, 2017New York City, New YorkAjai Chari, MD—ChairMount Sinai Health System
Saturday, November 18, 2017Los Angeles, CaliforniaJames Berenson, MD—Co-Chair Institute for Myeloma and Bone
Cancer Research
Amrita Y. Krishnan, MD—Co-ChairJudy and Bernard Briskin Center for
Multiple Myeloma ResearchCity of Hope Medical Center
To register, please visit:theMMRF.org/Patient