Myeloma 2020 and Beyond - careeducation.ca · Relapse 1 KPD 2015 6. Relapse 2 Daratumumab 7....
Transcript of Myeloma 2020 and Beyond - careeducation.ca · Relapse 1 KPD 2015 6. Relapse 2 Daratumumab 7....
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Myeloma 2020 and Beyond
Dr. Keith Stewart
Insert Photo
Princess Margaret Cancer Centre
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Myeloma 2020 and Beyond
Keith Stewart
Director, Princess Margaret Cancer Centre
VP Cancer, University Health Network
Richard H. Clark Chair in Cancer Medicine
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Disclosures for A. Keith Stewart, MBChB, MBA
Consultancy or Honoraria: Amgen; Bristol-Meyers Squibb; Celgene; GSK, Janssen; Ono, Oncopeptide; Roche/Genentech, Sanofi Aventis
Membership on a Board or Advisory Committee: Genomics England; Tempus
Discussion of off-label drug use: Venetoclax
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USA versus Rest of the World
56 days to go
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Janet: Age 70
August 2011
Del 17 MM
1. Carfilzomib, Cyclo,
Thalidomide, Dex
2. ASCT
3. Rev-Vel maintenance
4. D/C maintenance 2014
5. Relapse 1 KPD 2015
6. Relapse 2 Daratumumab
7. Relapse 3 KPD again
8. Ixa/Pred maintenance
9. Relapse Oct 2018 CAR-T
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Angela: age 29Humerus and T spine, blurred visionHyperdiploid, IDH2 mutant, High LDHKRd 5 cycles, Rads to left eyeASCTKRd consolidation x 4Marrow, Labs negative, MRD 63/million + concern for residual disease L armStarted Dara-Pom-Dex intensification12 month PET negative, MRD 3/millionDara-Pom-Dex ongoingRepeat MRD in one year (Allo considered)If relapses consider IDH inhibitor / CAR-T
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So whats different?
Molecular work upTriplet Including KR (now quads)Consolidation (more KR)Intensification (Dara/Pom) MRD monitoring NGS
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High rate of attrition
Br J Haematol. 2016 Oct;175(2):252-264
61% 38% 15% 1%
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So whats slightly ahead?
Advanced MolecularMass Spec Immunofix, possibly MRDVenetoclax t(11;14)
QuadsS/C DaraIsatuximabBCMA ADCCAR-T BCMA (by end of year?)
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Some cool new things in MM
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No HR
1 HR
Double hit: 2 HR Triple hit: 3 HR
HR abnormalitiest(4;14) or t(14;16)del17p/ monosomy 171q gain/amplification
Median: 18, 40, 60, 91 mths
Double Hit 1,639 patients 2004-2018
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Prognostic Genetic testing will move to Genome
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Correlation of TP53 Mutations and Deletions
Chromosome 17
LOSS
GAIN
Keats et al: Unpublished
Mutation
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Survival by TP53 Status(DNA assays; N=859)
Only 25% of the the 17p13 deleted patients had poor outcome.Are we giving patients misinformation?
Keats et al: Unpublished
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Multivariate Association of Markers With PFS/OS
PFS OSLeukemia. 2019; 33(1): 159 170.
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Double-Hit MM: A New and Distinct Disease Segment
Biallelic P53
ISS III + amp CKS1B
6.1% NDMM
Median PFS 15.4 m
Median OS 20.7 m
Leukemia. 2019; 33(1): 159 170.
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Detecting Drug Resistance: Cereblonpathway in 22 % of Relapsed patients
CRBN 1
CUL4B 1 1
IKZF3 1 1 1
IRF4 1 1 1 1 1
* = gene found mutated in cohort
IRF4MYC
MM cytotoxicity
IMiDs
IKZF1/3
*
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*DDB1
CUL4
ROC1*
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Mate Pair WGS Identifies Structural Change in CRBN pathway
FISH found: Gain 1q, +3, +11
WGS also found:MYC/IGKTP53 del
CRBN green
7 Mb deletion 3p26.3 to 3p26.1
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FISH found: Gain 1q, -13, MYC rearrangements, IGH/MAFB
WGS also found:MYC to 2q
CRBN green
Deletion of 2 different regions of 3p
Mate Pair Sequencing Identifies CRBN pathway Change in 19%
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Mutations in theCereblon - IKZF1/3 -IRF4 pathway in 41% of relapsed patients An Incomplete Story
Rare in NDMMInduced by IMiDexposureSignificantly underestimated by WES (depth)Not fully studied yet in documented refractory patientsStructural variation examination just beginningRole of regulators eg. EP300 understudied
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Some thoughts on treatment today
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Daratumumab will be front line therapy
Key eligibility
criteria:
Transplant-
ineligible NDMM
ECOG 0-2
Creatinine
mL/min
1:1
Ra
nd
om
iza
tion
Primary endpoint:
PFS
Key secondary
endpointsc:
MRD-negative rate (NGS;
10 5)
ORR
OS
Safety
Stratification factors
ISS (I vs II vs III)
Region (NA vs other)
Cycle: 28 days
Rd (n = 369)
R: 25 mg PO daily on Days 1-21 until PD
d: 40 mgb PO or IV weekly until PD
D-Rd (n = 368)
Daratumumab (16 mg/kg IV)a
Cycles 1-2: QW
Cycles 3-6: Q2W
Cycles 7+: Q4W until PD
R: 25 mg PO daily on Days 1-21 until PD
d: 40 mgb PO or IV weekly until PD
aOn days when daratumumab was administered, dexamethasone was administered to patients in the D-Rd arm and served as the treatment dose of steroid for that day, as well as the required pre-infusion medication.bFor patients older than 75 years of age or with BMI
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Median (range) follow-up: 16.8 (15.9-18.7) months
Responses continued to deepen over time
56%
6%
100%
63%94%
100%
ORR = 94% ORR = 100% ORR = 100%
Treatment will be for longer: VRD-Dara
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Quads Already Here (USA only)
MASTER trial
Population Best Post induction Best on Study
Regimen/Trial N High-risk
VGPR
MRD
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The Price of Progression-Free Survival
Cycles 1 - 2 Cycles 3 6 Cycle 7+
Rd 15,130 / cycle 15,130 / cycl 15,130 / cycl
DR
d
35,290 / cycle 25,210 / cycl 20,170 / cycl
4 Cycles (12 16 Weeks)
VTd 50,400
Dara-VTd 134,310
RVd 59,600
Dara-RVd* 143,600
KRd 127,400
Dara-KRd 211,310
Non-Transplant Setting
Wholesale Acquisition Costs (WAC)
Calculations made using a weight of 70 kg and
BSA of 1.7 / m2
catalog or list price for a drug product to
wholesalers and may not represent actual
transaction prices.
*Does not take into account the higher likelihood of
plerixafor use with D-RVd
WAC data is based on National average (compliments of Dr Voorhees)
1 year of RVd: $239,614; DRVd: $354,000
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Attal M et al. N Engl J Med. 2017;376:1311.
Transplant Required for Now But Will Decline Over Time
P
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0102030
405060708090
100
Patients
(%
)
0 12 24 36 48Months of Follow-Up
RVD Arm Transplant Arm
Attal M et al. Blood. 2015;126: Abstract 391.Avet-Loiseau H et al. Blood. 2015;126: Abstract 191.
Obtaining MRD Will Become a Standard of Care
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MRD as a Destination Will Be More Important Than The Journey
P
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What I have been up to recently
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-to-
High Throughput ScreeningEstablishment of a panel of ~80 FDA approved, late stage clinical trial,
or drugs of interest in standardized screening platform
1 Venetoclax 16 Ruxolitinib
2 Idelalisib 17 Vismodegib
3 Panobinostat 18 Ixazomib
4 Pomalidomide 19 Alisertib
5 Vemurafenib 20 Sorafenib
6 Everolimus 21 Lenalidomide
7 Carfilzomib 22 Romidepsin
8 Ibrutinib 23 Belinostat
9 apy0201 24 Dinaciclib
10 Selinexor 25 Bendamustine hydrochloride
11 Afuresertib 26 Enasidenib (Agios ag-221)
12 Trametinib 27 Sunitinib
13 Ponatinib 28 Dasatinib
14 palbociclib 29 jq1
15 Vorinostat 30 quizartinib
First 30 drugs in MM drug
panel
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Ex vivo Drug Sensitivities in MM13 drugs active in < 10%, including decitabine, ibrutinib, and ruxolitinib
12 drugs active in > 70% samples at nanomolar concentrations, including bortezomib, carfilzomib, ixazomib, panobinostat, selinexor, venetoclax, dinaciclib, romidepsin, belinostat,
Most potent drugs with EC50 < 10nM:
DinaciclibCarfilzomibPanobinostatRomidepsin
Ex vivo drug sensitivity profiles recapitulate cell line findings
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Landscape of MM patient drug sensitivity