New Agents in Multiple Myeloma 2015 and Beyond

MMWG Moffitt Myeloma Working Group
Newly approved agents in multiple myeloma:
2015 and beyond.
Kenneth H. Shain M.D., Ph.D.
Department of Malignant Hematology
Moffitt Cancer Center Tampa. FL
FLASCO 2016

• Evolving diagnostic criteria for active multiple myeloma- MDEs(?)
• Evolving prognostic scoring system for multiple myeloma- R-ISS
• New indications for novel proteasome inhibitors in relapsed multiple
myeloma (Carfilzomib & Ixazomib).
• The dawn of antibody therapy in multiple myeloma (Elotuzumab &
Daratumumab)
• Histone deacetylase inhibitors and multiple myeloma (Panobinostat)
• A glimpse into the next generation of anti-myeloma therapeutics.
Learning Objectives

What is multiple myeloma?
>11.5

Myeloma Continuum
*C: Calcium elevation (> 11 mg/dL or > 1 mg/dL higher than ULN)
R: Renal insufficiency (creatinine clearance < 40 mL/min or serum creatinine > 2 mg/dL)
A: Anemia (Hb < 10 g/dL or 2 g/dL < normal)
B: Bone disease (≥ 1 lytic lesions on skeletal radiography, CT, or PET-CT)
Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.
MGUS
 M protein < 3 g/dL
 Clonal plasma cells in BM
< 10%
 No myeloma defining
events
Smoldering Myeloma
 M protein ≥ 3 g/dL (serum)
or ≥ 500 mg/24 hrs (urine)
 Clonal plasma cells in BM ≥
10% to 60%
 No myeloma defining
events
Multiple Myeloma
 Underlying plasma cell
proliferative disorder
 AND 1 or more myeloma
defining events
 ≥ 1 CRAB* feature
 Clonal plasma cells in BM
≥ 60%
 Serum free light chain ratio
≥ 100
 > 1 MRI focal lesion*

New ways of parsing risk/prognosis for our patients.
Chng et al. Leukemia 2013
High-Risk
-ISS II/III + t(4;14) or del
17p13
-mOS: <2 years
-20% of MM patients
Standard-Risk
-All others (not Low or High)
-mOS: 7 years
-60% MM patients
Low- Risk
-ISS I/II no t(4;14), del17,
+1q21 & age <55
mOS: >10 years
-20% MM patients
R-ISS III
-ISS III; + CA [t(4;14),
t(14;16), &
del17p13]; inc LDH
-5 yr OS: 40%
-5 yr PFS: 24%
-10% MM patients
R-ISS II
-All others (not Low or High)
-5 yr OS: 62%
-5 yr PFS: 36%
-62% MM patients
R-ISS I
-ISS I; no CA [t(4;14),
t(14;16), & del17p13];
normal LDH
-5 yr OS: 82%
-5 yr PFS: 55%
-28% MM patients
Palumbo et al. JCO 2015
Revised ISS
IMWG Risk

New ways of parsing risk/prognosis for our patients- the
expressed genome.
Gene Expression Profiling
– LOW RISK: (MyPRS score<45.2) 77% Probability of being recurrence-free at 5-years*.
– HIGH RISK: (MyPRS score>45.2) 34% Probability of being recurrence-free at 5 years*.
Shaughnessy et al Blood 2007; Zhang et al Blood 2006; Zhou et al Blood 2007.

How can we improve outcomes
for our relapse patients?
Question

Our growing agents in MM

New Proteasome Inhibitor
combinations
Early relapsed MM

ASPIRE: Phase 3 -Carfilzomib, Lenalidomide and
Dex vs. Len/dex in RRMM.
Stewart et al NEJM 2014

ASPIRE: Improved PFS rates –KRD vs. Rd
Months since randomization
Proportionsurviving
withoutprogression
ITT population (792 patients)

ASPIRE: Unprecedented response rates in
RRMM –KRD vs. Rd

ENDEAVOR Study: Carfilzomib & Dex (Kd56) vs
Bortezomib & Dex (Vd)
Relapsed/Refractory
MM (929)
-1-3 prior lines
-CrCl ≥ 30 mL/min;
not refractory to PIs or
lenalidomide
Carfilzomib 20/56mg/m2
IV D1,2,8,9,15, &16
Dex 20 mg D1,2,8,9,15,
&16/q28 days
(464)
Bortezomib 1.3mg/m2
D1,4,8, & 11 (IV/SQ)
Dex 20mg D1,2.4.5.8,9, 11,
&12/21 days
(465)
Primary Endpoint
-PFS
Secondary Endpoints
-ORR
-DOR
-Grade 2 PN
-Safety
Dimopoulos et al Lancet Onc 2016

ENDEAVOR: KD56 vs. Vd
B.A.
months
18.7mo
9.4mo
NE
11.2mo
15.6mo
8.1mo
HR 0.53
HR 0.56
HR 0.48
Total Population Prior Bortezomib
Bortezomib Naive
C.

PFS benefit with KD56 seen in all prespecified subgroups, including
cytogenetic high risk (del17p), PI-exposed and naïve.
Characteristic
Kd56
(n = 464)
Vd
(n = 465)
Median PFS, mos 18.7 9.4
>ORR, %
>VGPR
 CR
 VGPR
 PR
77
54
13
42
22
62
29
6
22
34
*HR: 0.53 p<0.0001
ENDEAVOR: KD56 vs. VD

Tourmaline-MM1 Study: Ixazomib Rd vs
Rd
Relapsed/Refractory
MM (722)
-1-3 prior lines
-CrCl ≥ 30 mL/min;
not refractory to PIs or
lenalidomide
Ixazomib 4 mg PO D1,8,15
Lenalidomide 25 mg D1-21
Dex 40 mg D1,8,15,22
(360)
Placebo 4 mg PO D1,8,15
Lenalidomide 25 mg D1-21
Dex 40 mg D1,8,15,22
(362)
Primary Endpoint
-PFS
Secondary Endpoints
-ORR
-OS
-OS in del17p
Moreau et al ASH 2015 abst 727
Stratified by prior therapy (1 vs
2-3), ISS stage (I-II vs III), and
prior PI exposure (yes vs no) 28-day cycles until PD or unacceptable toxicity

Tourmaline-MM1 Study: Ixazomib Rd vs
Rd
1.0
0.8
0.6
0.4
0.2
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Probabilityofprogression-freesurvival
Time from randomization (months)
Log-rank test p=0.012
Hazard ratio (95% CI): 0.742 (0.587, 0.939)
Number of events: IRd 129; placebo-Rd 157
IRd: 20.6 months
Placebo-Rd: 14.7 months

Tourmaline-MM1 Study: IRd vs Rd
PFS benefit with ixazomib seen in all prespecified subgroups,
including cytogenetic high risk (del17p), PI and IMiD exposed
Characteristic
Ixazomib + Rd
(n = 360)
Placebo + Rd
(n = 362)
P Value
Median PFS, mos 20.6 14.7 .012*
ORR, %
 CR
 VGPR
 PR
78.3
11.7
36.4
66.7
71.5
6.6
32.3
64.9
.035
.019
Median time to response, mos 1.1 1.9
Median DoR, mos 20.5 15.0
Median TTP, mos 21.4 15.7 .007†
*HR: 0.742. †HR: 0.712.

New Immuno-modulatory
combinations
Early relapsed MM

ELOQUENT-2: A Phase 3-Elotuzumab in combination with
Lenalidomide/Dexamethasone in relapsed/refractory MM.
Slide from Paul Richardson et al ASH 2015

ELOQUENT-2: A Phase 3-Elotuzumab in combination with
Rd in relapsed MM.
From N Engl J Med, Lonial S et al, Elotuzumab therapy for relapsed or refractory multiple myeloma,
373, 621–31.

Slide from Saad Usmani et al ASH 2015
Relapsed and Refractory
MM (Late)
– Median OS of 9 months in patients refractory to bortezomib and at least 1 IMiD1
– Median OS of 8 months in patients with relapsed or refractory MM who were
double refractory or had relapsed after ≥3 prior lines of therapy, including
pomalidomide and carfilzomib2

1. Lin P, et al. Am J Clin Pathol. 2004;121(4):482-488.
2. Santonocito AM, et al. Leuk Res. 2004;28(5):469-477.
3. de Weers M, et al. J Immunol. 2011;186(3):1840-1848.
4. Overdijk MB, et al. MAbs. 2015;7(2):311-321.
5. Krejcik J, et al. Presented at: 57th American Society of
Hematology (ASH) Annual Meeting & Exposition; December 5-
8, 2015; Orlando, FL. Abstract 3037.
DARA: Mechanisms of Action
Immunomodulation
MM cell
CD38
DARA
NK cellMacrophageComplement
Immune-mediated
activity
ADCP ADCCCDC
DARA
Tumor cell
death
Adenosine
CD8+
T cell
CD38
CD38
MDSC
B reg
CD38+
T reg
DARA
CD38
Decreased
immunosuppression
cADPR
ADPR
NAADP
Ca2+
NAD
MM cell
Adenosine
AMP
Ca2+
Ca2+
Ca2+
CD38enzymatic
inhibition
Direct
anti-tumor effect
Apoptosisvia
cross-linking

SIRIUS & GEN501 combined baseline
characteristics.
16 mg/kg
GEN501, Part 2
n = 42
SIRIUS
n = 106
Combined
N = 148
Median (range) age, y
≥65 years of age, n (%)
64.0 (44-76)
20 (48)
63.5 (31-84)
48 (45)
64 (31-84)
68 (46)
Female/male sex, % 36/64 51/49 53/47
ECOG score, n (%)
0
1
2
12 (29)
28 (67)
2 (5)
29 (27)
69 (65)
8 (8)
41 (28)
97 (66)
10 (7)
Median (range) time since diagnosis, y 5.8 (0.8-23.7) 4.8 (1.1-23.8) 5.1 (0.8-23.8)
Median (range) number of prior lines
>3 prior lines, n (%)
4 (2-12)
26 (62)
5 (2-14)
87 (82)
5 (2-14)
113 (76)
Prior ASCT, n (%) 31 (74) 85 (80) 116 (78)
Prior PI, n (%)
Bortezomib
Carfilzomib
42 (100)
42 (100)
8 (19)
106 (100)
105 (99)
53 (50)
148 (100)
147 (99)
61 (41)
Prior IMiD, n (%)
Lenalidomide
Pomalidomide
Thalidomide
40 (95)
40 (95)
15 (36)
19 (45)
106 (100)
105 (99)
67 (63)
47 (44)
146 (99)
145 (98)
82 (55)
66 (45)

• 40 of 46 responders are still alive at a median follow-up of 14.8
months
SIRIUS & GEN501 combined change in
paraprotein from baseline
A. B.

New HDACi combinations
RRMM

PANORAMA1 Subset analysis and approval.
Panobinostat in combination with
bortezomib and dexamethasone, is
indicated for the treatment of patients
with multiple myeloma who have
received at least 2 prior regimens,
including bortezomib and an
immunomodulatory agent. This
indication is approved under
accelerated approval based on
progression free survival.
PFS- subset analysis
12.5 mo
4.7 mo

Cereblon
Lenalidomide
Pomalidomide
Thalidomide
Immune
Effector
cell
HDACs
Vorinostat
Panobinostat/Farydak
ACY1215/Ricolinostat
ACY241
Proteasome
Bortezomib
Carfilzomib
Ixazomib
Oprozomib
Mirazomib
Cell Cycle
ARRY-520
MLN8237
Seleciclib
Dinacicib
DNA Damaging Agents
Alkylators
-Melaphalan
-Cyclosphosphmoide
-Bendamustine
-TH302 (hypoxia)
-Zalypsis
TopoII inhibitors
-Doxil/Adraimycin
Others
-Velaparib
Nuclear Transport
KPT330/Selinexor
KCY880
RTK
BCR
PI3K
AKT
mTORC1/2
Integrin
RAS
RAF
MEK
MAPK
JAK
STAT
Intracellular Signaling
Perifosine
Everolimus
MLN0128
INK128
Plitidepsin/Aplidin
Selumetinib
VSFI-113/Dafactinib
Monoclonal Antibodies
Elotuzumab
Daratumumab
SAR650984
nBT062-DM4
Lorvotuzumab
G protein
Extracellular Signaling
AMD3100/Plerixafor
MTI101
Ibrutinib
Dovitinib
CP-751,851
Apoptosis
LCL161
ABT-199
PYK2
Topo II, p53
GR, IkB
Bcl-2 Family
BMSC VECs
Our growing agents in MM
Checkpoint Inhibititors
Pembrolizumab
Nivolumab
Durvalumab

KEYNOTE-023: Efficacy of Pembrolizumab +
Len/Dex in RRMM
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)
• PD-L1 overexpression associated with invasiveness and tumor-mediated immune
suppression in MM
• High PD-L1 in relapsed and MRD+ MM
• Pembrolizumab: highly selective anti–PD-1 mAb approved in advanced NSCLC and
melanoma
• May synergize with IMiDs

Phase Ib MMY1001: Daratumumab Plus Pom/Dex
for Patients With RRMM
Outcome Evaluable Pts (n = 75)
ORR, %
• Stringent CR
• CR
• VGPR
• PR
71
5
4
33
28
MR 3
SD 23
ORR in double-refractory pts, % 67
Median time to first response, mo 1.2
M-protein reduction ≥ 50% from baseline, % 77
6-mo PFS, % 66
Chari A, et al. ASH 2015. Abstract 508.
Median of 4 prior therapies, 67% double refractory

• Incorporation of new diagnostic criteria for active multiple myeloma-
MDEs(?)
• Adoption of a new prognostic scoring system for multiple myeloma- R-
ISS
• 4 new FDA approvals for treatment of early relapsed MM (1-3 prior
lines of therapy)- KRD, ERD, IRD, KD56
• 2 new FDA approvals for relapsed and refractory MM- Daratumumab,
and Velcade, Panobinostat, & Dex.
• A glimpse into the next generation of anti-myeloma therapeutics
demonstrates the potential of further targeted therapy and immune
regulation.
Summary of MM 2015 + a little 2016

• There is no easy algorithm for managing relapsed/refractory
myeloma, especially once facing IMID and PI refractory
disease.
• Patient-specific issues and prior therapy should be used to
determine choice of agents.
• In the right patient population(s) effective new targeted
agents will improve patient outcomes.
• New exciting targets and agents are being explored in
numerous phase 1, 2, and 3 clinical trials that will continue to
change the landscape of MM.
Conclusions

MM Clinical Trials at Moffitt
• Newly Diagnosed MM
– Phase 2: Carfilzomib/Revlimid/Dex (weekly Carfilzomib at 70mg/m2)- in all comers
– Phase 3: DFCI/IFM: VRD with early vs delayed HDM-ASCT and maintenance Rev (<65 years old).
– Phase 2: Pembrolizomab/Revlimid/Dex for transplant ineligible myeloma.
– Phase 1-2: Oprozomib/Revlimid/Dex or Oprozomib/Cytoxan/Dex in transplant ineligible.-closed to accrual.
– Phase 1-2: CaRPaDiem- Carfilzomib/Revlimid/Panobinostat/Dex in transplant eligible. Coming soon.
• HDM-ASCT and maintenance
– CTN study allogeneic transplant for HR patients
– Phase 2: HDM-ASCT with Marrow infiltrating lymphocytes (MILs)- HR risk transplant eligible in collaboration
with John’s Hopkins
– Phase 1-2: Panobinostat maintenance. Coming soon.
• Relapsed and/or Refractory MM:
– Phase 2: Carfilzomib/Rev/Dex (weekly Car at 70mg/m2)
– Phase 2: KPT330/Dex (novel nuclear export inhibitor targeting XPO1/Crm1)
– Phase 1: KPT330/Doxil/Dex
– Phase 1: KCP880 (novel SINE)
– Phase 1-2: Pomalidomie/ACY-241/Dex (ACY241- novel HDAC6 selective inhibitor)
– Phase 1: Oprozomib/Dex (2 dose schedules & 1-5 prior lines of therapy)- closed to accrual
– Phase 1: SAR650984/Rev/Dex in Revlimid RRMM patients- closed to accrual
– Phase 3: Pembrolizomiab/Pom/Dex vs Pom/Dex. Coming soon.
– Phase 2: Personalized therapy for MM with early relapsed disease. Coming soon.

Acknowledgements
Our Patients, their families, and care-givers
MMWG:
Melissa Alsina M.D.
Rachid Baz M.D.
Jason Brayer M.D., Ph.D
William S Dalton Ph.D, M.D.
Lori Hazlehurst Ph.D.
Dan Sullivan M.D.
Lia Perez M.D.
Taiga Nishihori M.D.
Claudio Anasetti M.D.
J-Lionel Ochoa-Bayona M.D.
Ling Zhang M.D.
Chris Cubitt Ph.D.
John Koomen Ph.D.
Said Sebti Ph.D.
Ariosto Silva PH.D
Bob Gatenby M.D.
Dung-Tsa Chen Ph.D.
Beth Finley-Oliver
Christine Simonelli
Sheri Lemanski
Aunskha Collins

Questions.
What important ultra- high risk feature(s) of smoldering MM are
now including in the diagnostic criteria for active MM?
a. Bone marrow plasmacytosis >60%
b. Serum free light chain ratio >100 (involved/uninvolved)
c. >1 lesions on MRI (whole body) or alternatively PET/CT.
d. All of the above.

Questions.
What novel SLAMF7/CS-1 specific antibody has been approved
for use in combination with Rd for the treatment of patients
with multiple myeloma who have received one to three prior
therapies?
a. Daratumumab
b. Isatuximab
c. Pembrolizumab
d. Elotuzumab.

Questions.
What novel CD38 specific antibody has been approved for
relapsed MM patients who have received at least three prior
lines of therapy including a proteasome inhibitor (PI) and
an immunomodulatory agent or who are double-refractory to a
PI and an immunomodulatory agent?
a. Daratumumab
b. Isotuximab
c. Pembrolizumab
d. Elotuzumab.

Questions.
What novel oral proteasome inhibitor has been approved for
relapsed MM patients in combination with lenalidomide and
dexamethasone for the treatment of patients with multiple
myeloma who have received at least one prior therapy?
a. Carfilzomib/Kyprolis
b. Oprozomib
c. Ixazomib/Ninlaro
d. Mirazomib.

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