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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
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
•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
GEP in CD138 +ve PC Defines 7 MM Subtypes
Zhan et al., 2006
Ge
ne
Exp
ress
ion
100 up & 100 down per subgroup
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
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
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
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
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
•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
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
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)
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
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
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
ASPIRE : OS
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
• 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
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