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Saad Z. Usmani, MD FACP Chief, Plasma Cell Disorders Division Director, Clinical Research in Hematologic Malignancies Department of Hematologic Oncology & Blood Disorders LEVINE CANCER INSTITUTE Are We Ready To Personalize Therapy Today? No

Are We Ready To Personalize Therapy Today? Nocme-utilities.com/mailshotcme/Material for Websites/COMy... · 2019. 5. 19. · Challenges To Personalizing Therapy for MM Today. GEP

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Page 1: Are We Ready To Personalize Therapy Today? Nocme-utilities.com/mailshotcme/Material for Websites/COMy... · 2019. 5. 19. · Challenges To Personalizing Therapy for MM Today. GEP

Saad Z. Usmani, MD FACP

Chief, Plasma Cell Disorders Division

Director, Clinical Research in Hematologic Malignancies

Department of Hematologic Oncology & Blood Disorders

LEVINE CANCER INSTITUTE

Are We Ready To Personalize Therapy Today? No

Page 2: Are We Ready To Personalize Therapy Today? Nocme-utilities.com/mailshotcme/Material for Websites/COMy... · 2019. 5. 19. · Challenges To Personalizing Therapy for MM Today. GEP

Disclosures

• Research funding: Amgen, Array Biopharma, BMS, Celgene, Janssen, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, Takeda.

• Consulting Fees: Amgen, BMS, Celgene, Janssen, Sanofi, SkylineDx, Takeda.

• Speaking Fees: Celgene, Janssen, Takeda.

Presented by: Saad Z. Usmani, MD FACP, @szusmani

Page 3: Are We Ready To Personalize Therapy Today? Nocme-utilities.com/mailshotcme/Material for Websites/COMy... · 2019. 5. 19. · Challenges To Personalizing Therapy for MM Today. GEP

•We think we understand myeloma biology but do not do examine it during the disease course:• No uniform definition of biologic risk (low, high)• No uniform way of measuring ‘high risk’ features

• Is it FISH? Yes, then what cutoff to use? • Is it GEP? Is it Sequencing?

•We are just starting to understand interplay of MM cells with the immunome and the BM microenvironment.

•Even if we sorted the above, do we have the MoAs in our armamentarium to personalize therapy? • The answer is no..

Challenges To Personalizing Therapy for MM Today

Page 4: Are We Ready To Personalize Therapy Today? Nocme-utilities.com/mailshotcme/Material for Websites/COMy... · 2019. 5. 19. · Challenges To Personalizing Therapy for MM Today. GEP

GEP in CD138 +ve PC Defines 7 MM Subtypes

Zhan et al., 2006

Ge

ne

Exp

ress

ion

100 up & 100 down per subgroup

Page 5: Are We Ready To Personalize Therapy Today? Nocme-utilities.com/mailshotcme/Material for Websites/COMy... · 2019. 5. 19. · Challenges To Personalizing Therapy for MM Today. GEP

Molecular

subtype

% of Newly

Diagnosed

Cytogenetics/FISH

Characteristic genes elevated

in class

Risk of Relapse

MS 17 t(4;14) FGFR3, MMSET, CCND2, IL6R Moderate

MF 6 t(14;16) or t(14;20) MAF or MAFB, CCND2, IL6R High

CD-1 6 t(11;14) or t(6;14) CCND1 or CCND3 Low

CD-2 12 t(11;14) or t(6;14) CCND1 or CCND3, CD20,

VPREB3

Low

HY 31 Trisomies +3, +5, +7, +9,

+11, +15, 19

GNG11, DKK1, FRZB Moderate

LB 12 typical HY trisomies;

Frequent del13, gain of 1q,

rare gain of 11

CCND2, CST6, ARHE, IL6R Low

PR 10 Made up of all subgroups CCNB1, CCNB2, PCNA, MKI67,

TOP2A, TYMS

High

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FIG 1. Kaplan-Meier survival curves for myeloma-specific survival according to the three categories of the cytogenetic prognostic index. (A)

Training set (n = 647). (B) Internal validation set (n = 234). (C) External validation data set 1 (n = 359). (D) External validation data set 2 (n =

322). Cox proportional hazards regression models were stratified by treatment group. HR, hazard ratio.

Published in: Aurore Perrot; Valérie Lauwers-Cances; Elodie Tournay; Cyrille Hulin; Marie-Lorraine Chretien; Bruno Royer; Mamoun Dib;

Olivier Decaux; Arnaud Jaccard; Karim Belhadj; Sabine Brechignac; Jean Fontan; Laurent Voillat; Hélène Demarquette; Philippe Collet;

Philippe Rodon; Claudine Sohn; François Lifermann; Frédérique Orsini-Piocelle; Valentine Richez; Mohamad Mohty; Margaret Macro;

Stéphane Minvielle; Philippe Moreau; Xavier Leleu; Thierry Facon; Michel Attal; Hervé Avet-Loiseau; Jill Corre; Journal of Clinical

Oncology Ahead of Print

DOI: 10.1200/JCO.18.00776

Copyright © 2019 American Society of Clinical Oncology

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How To Personalize Therapy Without Knowing What One’s Treating?

Clone 1.1Clone 1.2Clone 2.1Clone 2.2Misc

Diagnosis~ 2N

Remission ~ 2N

Relapse 1 ~ 2N

Relapse 2 ~ 2N

Relapse 3 ~ 2N

Plasma Cell Leukemia ~ 3N Relapse 4 ~ 3N

clg-high37%

clg-high66%

clg-low34% clg-low

63%

72%11%

10%

31%64%

64%

21%

9%

19%58%

71%

17%

78%95%

96%96%

• Multiple clones may be present at the time of

diagnosis

• The predominant clone may change over

time, especially after sequential treatment

rounds

• Relapse can occur when:

o Existing clone no longer has to compete for space with the formerly dominant clone

o Acquires additional mutation(s) providing a growth and/or survival advantage

• Combination chemotherapy needed for

optimal disease control

Keats JJ, et al. Blood. 2012;120:1067-1076.

01_Kenneth Anderson01_Kenneth Anderson

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Chapman MA et al. Nature. 2011;471:467. Lohr JG et al. Cancer Cell. 2014;25:91.

MM Genomics Initiative (MMGI) FINDING:BRAF V600E (4%); confirmed in CoMMpass

Preclinical validation of BRAFi

CLINICAL VALIDATION:Treatment with vemurafenib,

Morgan G, ASH 2012;

Andrulis M et al. Cancer Discov

2013

My Colleague Will Say “BRAFi have now been validated clinically in MM”

Before treatment Post 1 cycle

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Chapman MA et al. Nature. 2011;471:467. Lohr JG et al. Cancer Cell. 2014;25:91.

MM Genomics Initiative (MMGI) FINDING:BRAF V600E (4%); confirmed in CoMMpass

Preclinical validation of BRAFi

CLINICAL VALIDATION:Treatment with vemurafenib,

Morgan G, ASH 2012;

Andrulis M et al. Cancer Discov

2013

Harry Potter and the Precision Therapeutic Strategies in MM

Before treatment Post 1 cycle

Page 10: Are We Ready To Personalize Therapy Today? Nocme-utilities.com/mailshotcme/Material for Websites/COMy... · 2019. 5. 19. · Challenges To Personalizing Therapy for MM Today. GEP

•Every study that has lead to improved PFS/OS in MM has been done with the ‘one-size-fits-all’ approach.

•We also learn the most about disease biology, immunome and BM microenvironment interplay in uniformly treated patient populations.

Advances in MM Survival

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SWOG S0777: Randomized, phase III study of Rd vs RVd for newly-diagnosed multiple myeloma patients with no intent for early ASCT

• Median PFS: 43 vs 30 months in favor of RVD (P = 0.0037)

• Median OS: 75 vs 64 months in favor of RVD (P = 0.025)

Du

rie

BG

, et

al. L

ance

t: 2

01

7:3

89

:51

9-5

27

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ASCT Vs. Novel Drugs

Palumbo. NEJM. 2014;371:895.

Pro

bab

ility

of

PFS

(%

)

Pro

bab

ility

of

4-Y

r O

S (%

)

High-dose melphalan MPR

Mos

100

75

50

25

022.4 43.0

600 6 12 18 24 30 36 42 48 54

HR for progression or death with high-dose melphalan: 0.44 (95% CI: 0.32-0.61; P < .001)

Mos

100

75

50

25

0600 6 12 18 24 30 36 42 48 54

HR for death with high-dose melphalan: 0.55 (95% CI: 0.32-0.93; P = .02)

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ASCT Vs. Novel Drugs

Attal. NEJM. 2017;376:1311.

PFS OS

Pat

ien

ts (

%)

Mos of Follow-up

100

75

50

25

00 12 24 36 48

P < .001

Transplantation

RVD alone

P = .87

Transplantation

RVD alone

Pat

ien

ts (

%)

Mos of Follow-up

100

75

50

25

00 12 24 36 48

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Lenalidomide Maintenance

McCarthy. JCO. 2017;35:3279.

Pro

bab

ility

of

OS

Mos

0

0.2

0.4

0.6

0.8

1.0

0 20 40 60 10010 30 50 70 80 11090 120

No. of Events/No. of Patients

Median OS, Mos

(95% CI)

HR (95% CI)

215/605NR

(NR to NR) 0.75(0.63-0.90)

275/60386.0

(79.8-96.0)

Len maintenancePlacebo/observation

Favors LenMaintenance

Favors Placebo/Observation

HR

≤ 59

≥ 60

Male

Female

I/II

III

CR

CR/VGPR

PR/SD

Len Placebo

372

233

322

283

411

113

65

314

227

375

228

349

254

439

90

80

334

215

Age, yrs

Sex

ISS stage

Response afterASCT (prior tomaintenance)

40.25 20.5 1

P = .001

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ALCYONE: PFS

Dimopoulos. ASH 2018. Abstr 156.

Daratumumab monotherapy phase

PFS

(%

)

0

20

40

60

80

0 3 6 9 12 15 18 27Mos

356350

304322

277312

262298

245292

206265

169243

00

102203

Patients at Risk, nVMPD-VMP

21 24

127220

HR: 0.43 (95% CI: 0.35-0.54; P < .0001)

VMP Median: 19.1 mos

D-VMP Median: not reached

60%63%

28%36%

100

30 33 36 39

24 mos 30 mos

59138

2773

531

09

57% reduction in risk of progression or death in

Dara-VMP arm

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ASPIRE : OS

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MM Treatment Paradigm

Induction

Induction followed by continuous therapy

Consolidation MaintenanceSCT

Elig

ible

SCT

Ine

ligib

le

Dia

gno

sis

and

ri

sk

stra

tifi

cati

on

GOALDisease control and reversal of

symptoms and signs

Maximize disease control to provide most durable disease control, with eye on

limiting long-term adverse events

Tumor burden

Page 18: Are We Ready To Personalize Therapy Today? Nocme-utilities.com/mailshotcme/Material for Websites/COMy... · 2019. 5. 19. · Challenges To Personalizing Therapy for MM Today. GEP

• Let’s Treat Patients Based on Data, Not ‘Gut Feeling’.

• There Are No Prospective Randomized Data To Support ‘Personalized’ Medicine in Myeloma.

• We Have No Data To Support ‘Personalizing’ Therapy for Myeloma Today.

Conclusions

Page 19: Are We Ready To Personalize Therapy Today? Nocme-utilities.com/mailshotcme/Material for Websites/COMy... · 2019. 5. 19. · Challenges To Personalizing Therapy for MM Today. GEP

Saad UsmaniManisha BhutaniPeter VoorheesShebli AtrashMauricio Pineda-RomanReed FriendJordan RobinsonChelsea SprouseAmi NdiayeIssam Hamdeh

❑ Clinical Team

❑ Lab Team

Qing Zhang*Myra RobinsonJames Symanowski

❑ Biostatistics Team

David FoureauFei GuoKatherine RigbyRina LeonidasNury SteuerwaldLarry DruhanElise TjadenAndee Foxx

Acknowledgements

FUNDING:

BRITTON FAMILY FOUNDATION

GENE WOODS SR MYELOMA FUND

FREEDLAND FOUNDATION