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Rafael Fonseca MD
Chair, Department of Medicine Mayo Clinic in AZ
Myeloma 2017
New Options
Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Disclosures
• Consulting: AMGEN, BMS, Celgene, Takeda, Bayer, Jansen, Novartis, Pharmacyclics, Sanofi
• Speakers Bureaus: None
• SAB: Adaptive Biotechnologies
• Patent for FISH in MM - ~$2000/year
• Registered independent – Libertarian
• Believe in stem cell transplant
• Dislike wasting your time with this slide
• My only true conflict is that I do not know fi I like Nutella: sometimes I do sometimes I don’t!
Improving Survival in MM
*Year ranges represent the year of diagnosis.
Note: By linking to the SSA Master Death File, survival was measured as time from diagnosis date to the
date of death obtained from the SSA, time from diagnosis date to the date of inpatient death, or time
from diagnosis date to September 30, 2015; Survival estimates were presented for multiple myeloma
patients diagnosed and treated during 2006-2012 (n=9,521).
What is the strategy for myeloma?
5
ASPIRE—Len/Dex ± Carfilzomib in R/R MM
Response & Safety
Carfilzomib Group
(n=396)
Control group
(n=396)
Median Time To Response – mo 1.6±1.4 2.3±2.4
Mean Time To Response – mo 1.0 1.0
Duration of Response - mo 28.6 (24.9-31.3) 21.2 (16.7-25.8)
0
20
40
60
80
100
Carfilzomib Group Control Group
ORR 87.1%
ORR 66.7%
69.940.4
Stew art, et al. N Engl J Med. 2015; 372:142-115.
Resp
on
se R
ate
CR: 31.8
VGPR: 38.1
PR: 17.2
CR: 9.3
VGPR: 31.1
PR: 26.3
• Rates of grade ≥ 3 dyspnea, cardiac failure,
ischemic heart disease, & hypertension were slightly higher in
carfilzomib group
TOURMALINE-MM1—Len/Dex ±Ixazomib Response & Safety
6
IRd Rd HR/OR
Confirmed ORR, % 78.3 71.5 OR 1.44; P=.035
CR 11.7 6.6 OR 1.87; P=.019
≥VGPR 48.1 39.0 OR 1.45; P=.014
Median time to 1st response mos 1.1 1.9
Median duration response, mos 20.5 15.0
0
20
40
60
80
100
Ixazomib-Rd Placebo-Rd
ORR 78.3% ORR 71.5%
48.1% 39%
Moreau, P. et al. ASH 2015 Abstract 727
CR: 11.7
VGPR: 36.4
PR: 30.3
CR: 6.6
VGPR: 32.3
PR: 32.6
Common grade ≥3 AEs • Neutropenia (19% vs 16%)
• Anemia (9% vs 13%)• Thrombocytopenia (13% vs
5%)
• Pneumonia (6% vs 8%)
Antibody-dependentcellular cytotoxicity (ADCC)
ADCC
Effector
cells:
MM
FcR
Complement-dependent
cytotoxicity (CDC)
CDC
MM
C1q
C1q
Apoptosis/growth
arrest via targeting
signaling pathways
MM
Elotuzumab (SLAMF7)
Daratumumab (CD38)
SAR650984 (CD38)
Daratumumab (CD38)
SAR650984 (CD38)
Tai YT, et al. Bone Marrow Res. 2011;2011:924058.
MAb-Based Targeting of Myeloma
Daratumumab (CD38)
SAR650984 (CD38)
7
0
20
40
60
80
100
Elo-Rd Rd
Res
po
ns
e R
ate
, %
ELOQUENT-2—Len/Dex ± Elotuzumab in R/R MMResponse & Safety
8Dimopoulos, et al. ASH Annual Meeting and Exposition 2015. Abstract 28. Lonial, S. et al. N Engl J Med. 2015; 373:621-663.
34% 29%
PR: 45%
VGPR: 29%
CR: 5%
PR: 37%
VGPR: 20%
CR: 9%
ORR 79%*
ORR 66%
*P<.001
• Common grade 3 or 4 AEs were lymphocytopenia,
neutropenia, fatigue, and pneumonia
• Infusion reactions occurred
in 33 patients (10%) in the elotuzumab group
Elotuzumab Group
(n=321)
Control group
(n=325)
Median Time To Response (IR) – mo 2.8 2.8
Median Duration of Response (≥ PR) - mo 20.73 16.25
26.3
19.4 20.617.6
14.9 14.7
0
5
10
15
20
25
30
PF
S,
mo
nth
sASPIRE, TOURMALINE, ELOQUENT-
2—Summary of PFS
9
Trial Design PFS Invest. arm PFS Rd arm HR
ASPIRE Rd vs KRd 26.3mo 17.6mo 0.69
ELOUQUENT-2 Rd vs IRd 19.4mo 14.9mo 0.70
TOURMALINE Rd vs EloRd 20.6mo 14.7mo 0.74
KRdERd IRd
Moreau, P. et al. ASH 2015 Abstract 727 Lonial, S. et al. N Engl J Med. 2015; 373:621-663. Stew art, et al. N Engl J Med. 2015;372:142-150.
Rd Rd Rd
ASPIRE ELOQUENT-2 TOURMALINE
ASPIRE, TOURMALINE, ELOQUENT-2—Comparison of Response Rates
10
0
10
20
30
40
50
60
70
80
90
100
Carfilzomib-Rd(ASPIRE)
Ixazomib-Rd(TOURMALINE)
Elo-Rd(ELOQUENT-2)
Res
po
ns
e R
ate
, %
Moreau, P. et al. ASH 2015 Abstract 727 Lonial, S. et al. N Engl J Med. 2015; 373:621-663. Stew art, et al. N Engl J Med. 2015;372:142-150.
PR: 17.2%
VGPR: 38.1%
CR: 31.8%
PR: 30.3%
VGPR: 36.4%
CR: 11.7%
PR: 45%
VGPR: 29%
CR: 5%
Relapsed/Refractory MM—Summary of Combination Therapy: ORR
11
[1] Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. [2] Stew art AK, et al. N Engl J Med. 2015;372:142-152.. [3] Richardson PG, et al. Blood. 2014;123:1461-1469. [4] Lacy MQ, et al. ASH
2014. Abstract 304. [5] San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206. [6] Mikhael JR, et al. Br J Haematol. 2009;144:169-175. [7] Monge J, et al. ASCO 2014. Abstract 8586. [8] Morgan JG,
et al. Br J Haematol. 2007;137:268-269. [9] Baz R, et al. ASH 2014. Abstract 303. [10] San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066. [11] Lendvai N, et al. Blood.
2014;124:899-906. [12] Shah JJ, et al. ASH 2013. Abstract 690.
*Data from phase III trials, all others from phase I or II trials
Median Lines of Tx:
2
RD
*[1]
CR
D[8
]
Pd*[1
0]
CP
d[9
]
Kd
[11]
KR
d*[2
]
KP
d[1
2]
Vd*[6
]
RV
D*[3
]
PV
d[4
]
CyB
orD
[7]
OR
R (
%)
100
80
60
40
20
0
6065
31
65
55
87
706764
85
71
4 53
61
PanV
d[5
]
-2 -1 0 1 2 3 4 5
VGPR Rates/PFS with Triplet vs Doublet Regimens
12
Odds of Achieving ≥VGPR in Early Relapse
Trial Odds Ratio Lower Limit Upper Limit P Value
PANORAMA-1 2.044 1.435 2.914 .000
MM VAR/IFM 2005-004 2.330 1.391 3.903 .001
ELOQUENT 1.250 0.893 1.749 .193
ASPIRE 3.433 2.559 4.606 .000
POOLED ODDS RATIO 2.185 1.832 2.606 .000
Pooled Hazards Ratio: PFS
Trial Hazard Ratio Lower Limit Upper Limit z-Value P Value
PANORAMA-1 0.630 0.521 0.762 -4.773 .000
MM VAR/IFM 2005-004 0.990 0.438 0.796 -3.460 .001
ELOQUENT 0.700 0.573 0.855 -3.499 .000
ASPIRE 0.660 0.572 0.833 -3.87 .000
POOLED ODDS RATIO 0.661 0.596 0.734 -7.788 .000
Odds Ratio and 95% CI for Achieving ≥VGPR
Hazard Ratio and 95% CI for PFS
0 0.5 1 1.5 2
Nooka, et al. Blood. 2015;126:5344.
Triplet Better Doublet
Better
Doublet Better Triplet Better
Targeting CD38
13
• CD38 expressed in all myeloma cases
• Cyclic ADP ribose hydrolase is a glycoprotein
• Expressed in many immune response cells and other cells
• Marker of cell activation
• Loss leads to immune loss, metabolic abnormalities and cognitive changes
DaratumumabA human CD38 mAb with broad-spectrum killing activity
14
Lokhorst HM et al. N Engl J Med 2015;373:1207-1219.
Phase III Trial Daratumumab plus Rd
Dimopulous et al NEJM 2016
KEYNOTE-023—Efficacy of Pembrolizumab + Len/Dex in R/R MM
San Miguel J, et al. ASH 2015. Abstract 505.
Outcome
All Response-
Evaluable Pts
(n = 17)
Lenalidomide-Refractory
Pts
(n = 9)
ORR, n (%)
▪VGPR
▪PR
13 (76)
4 (24)
9 (53)
5 (56)
2 (22)
3 (33)
Disease control rate, n (%) 15 (88) 7 (78)
Median time to first response, mos (range) 1.2 (1.0-6.5)
M-protein reduction ≥ 50% from baseline, % 76.5
Median DoR, mos 9.7
Dose
Determination
3 + 3
(n = 9)
R/R MM pts
with ≥ 2 prior
treatments
including a
PI and IMiD
Dose
Confirmation
TPI Algorithm
(n = 8)
Dose
Expansion
(n = 33)
Final MTD:
Pembrolizumab 200 mg* IV Q2W
Lenalidomide 25 mg
Dexamethasone 40 mg
• Primary endpoints:
Safety, Tolerability (on
all pts)
• Secondary endpoints:
ORR, DoR, PFS, OS (on pts
in first 2 stages only)
17
Maximum Change from Baseline in M Protein or Free Light Chains (Efficacy Population)
Data cutoff: April 11, 2016
Pe
rce
nt
chang
e f
rom
base
line
35/40 (88%) of patients with a decrease
-100
-80
-60
-40
-20
0
20
40
60
80
100
Treatment Exposure and Response Duration
• Median follow-up: 9 months (range, 1-25)
• Median DOR: 11.3 months
• Median time to achieve first objective response: 1.5 months
• 4 patients who responded (20%) upgraded the quality of response
Efficacy population is shown (n = 40). Data cutoff: April 11, 2016
Months
PD
PR
VGPR
CR
sCR
Treatment ongoing
0 5 10 15 20 25
Selinexor, Restores Tumor Suppressors
Chen C et al. Presented at: EHA Annual Meeting; June 2014; Milan, Italy. Abstract P953.
CYTOPLASM
Venetoclax + bortezomib: Mechanism
Moreau et al, ASH 2015
Venetoclax in t(11;14) MM
Therapy started
50
40
30
20mg
/dL
0
10
Generalized normal high
Generalized normal low
200
150
100
mg
/dL
0
50
Generalized normal high
Generalized normal low
Kappa FLC Kappa FLC
A.K. Stewart, unpublished
Conclusions
• Plethora of options
• Sequencing and specific agents are key
• Individualized approach to patients
• Likely combinatorial strategies
• Myeloma is still an “unmet need”
• Future is bright!
