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Keats et al: Unpublished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Keats et al: Unpublished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