Myeloma 2020 and Beyond
Dr. Keith Stewart
Insert Photo
Princess Margaret Cancer Centre
Myeloma 2020 and Beyond
Keith Stewart
Director, Princess Margaret Cancer Centre
VP Cancer, University Health Network
Richard H. Clark Chair in Cancer Medicine
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
USA versus Rest of the World
56 days to go
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
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
So whats different?
Molecular work upTriplet Including KR (now quads)Consolidation (more KR)Intensification (Dara/Pom) MRD monitoring NGS
High rate of attrition
Br J Haematol. 2016 Oct;175(2):252-264
61% 38% 15% 1%
So whats slightly ahead?
Advanced MolecularMass Spec Immunofix, possibly MRDVenetoclax t(11;14)
QuadsS/C DaraIsatuximabBCMA ADCCAR-T BCMA (by end of year?)
Some cool new things in MM
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
Prognostic Genetic testing will move to Genome
Correlation of TP53 Mutations and Deletions
Chromosome 17
LOSS
GAIN
Keats et al: Unpublished
Mutation
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Keats et al: Unpublished
Multivariate Association of Markers With PFS/OS
PFS OSLeukemia. 2019; 33(1): 159 170.
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.
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
*
*
*DDB1
CUL4
ROC1*
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
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%
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
Some thoughts on treatment today
26
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
27
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
38
Quads Already Here (USA only)
MASTER trial
Population Best Post induction Best on Study
Regimen/Trial N High-risk
VGPR
MRD
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
Attal M et al. N Engl J Med. 2017;376:1311.
Transplant Required for Now But Will Decline Over Time
P
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
P
MRD as a Destination Will Be More Important Than The Journey
P
What I have been up to recently
-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
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
Landscape of MM patient drug sensitivity
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