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This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
The evolving therapeutic landscape in
relapsed/refractory multiple myeloma
Sagar Lonial, MD, FACP
Chief Medical Officer, Winship Cancer Institute
Emory University, Atlanta, GA, USA
Adam Cohen, MD
Director, Myeloma Immunotherapy
Assistant Professor, Hematology/Oncology
Abramson Cancer Center,
University of Pennsylvania, Philadelphia, PA, USA
Shaji Kumar, MD
Consultant, Division of Hematology,
Department of Internal Medicine
Mayo Clinic, Rochester, MN, USA
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
2
Agenda
5 min Welcome and introductions
Sagar Lonial, MD, FACP
20 min Standard of care and need for diverse treatments in triple-class refractory MM
Adam Cohen, MD
30 min Current and emerging novel therapeutic targets for RRMM
Shaji Kumar, MD
Sagar Lonial, MD, FACP
30 min Panel discussion and Q&A
All
5 min Closing remarks
Sagar Lonial, MD, FACP
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
Standard of care and need
for diverse treatments in
triple-class refractory MMAdam Cohen, MD
Director, Myeloma Immunotherapy
Assistant Professor, Hematology/Oncology
Abramson Cancer Center,
University of Pennsylvania, Philadelphia, PA
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
• Relapse is inevitable for the majority of
patients, including those who respond to first-
line therapy1
• With each additional relapse, patients
experience a shorter PFS2
– PFS in first-line patients was 18 months, but by the
fourth line of therapy, PFS was only 4.7 months2
• Cumulative relapses lead to progressively
shorter remission or worse response to
salvage therapy3
• Patients who relapse after at least 3 lines of
therapy (refractory to immunomodulatory
agents, PIs, and anti-CD38 mAbs) have a
poor prognosis4-6
– Event-free survival in patients was 5 months4
4
Despite advances in treatment, patients with RRMM have poor prognosis and a high risk of relapse
MM disease evolution1,2,7,8
CD, cluster of differentiation; mAb, monoclonal antibody; MGUS, monoclonal gammopathy of undetermined significance; misc, miscellaneous; MM, multiple myeloma; PFS, progression-free survival; PI, proteasome inhibitor;
RRMM, relapsed/refractory multiple myeloma.
1. Kurtin SE. J Adv Pract Oncol. 2013;4(6)(suppl 1):5-14. 2. Chim CS et al. Leukemia. 2018;32(2):252-262. 3. Verelst SGR et al. HemaSphere. 2018;2(4):e45. doi:10.1097/HS9.0000000000000045 4. Nijhof IS et al. Drugs. 2018;78:19-37. 5. Gandhi UH et al. Leukemia. 2019;33(9):2266-2275. 6. Lonial S et al. Lancet Oncol. 2020;21(2):207-221. 7. International Myeloma Foundation. Case studies: evolving paradigms in myeloma care. www.myeloma.org/sites/default/files/slides/ONS_2018.pdf Accessed March 26, 2019. 8. Bolli N et al. Nat Commun. 2014;5:2997. doi:10.1038/ncomms3997
10
5
2
Time
Mye
lom
a-p
rote
in (
g/L
)
MGUS or
smoldering
myeloma
Active
myeloma
1st
relapse
2nd
relapse
3rd
relapse
ASYMPTOMATIC SYMPTOMATIC REFRACTORY
Clone 1.1
Clone 1.2
Clone 2.1
Clone 2.2
MiscRemission
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
• 90% (249/275) of patients received ≥1 therapy after T0, the time point at which progression occurred on a CD38 mAb-containing regimen
(Median interval between MM diagnosis and T0 was 50.1 months)
• 47% of these 249 patients had an objective response to ≥1 subsequent therapy
• ORR was highest during the first subsequent therapy (31%) and declined with each subsequent therapy (18% by fifth subsequent therapy)
5
Outcomes of patients refractory to anti-CD38 monoclonal antibodies*mOS: 9.3 months with subsequent therapy and 1.3 months with no subsequent therapy
*MAMMOTH is a retrospective analysis. Treatment groups were not mutually exclusive.CD, cluster of differentiation; CR, complete response; mAb, monoclonal antibody; MM, multiple myeloma; mOS, median overall survival; ORR, overall response rate; PD, progressive disease; PR, partial response;
SD, stable disease; T0, time at which patients met PD criteria after starting index regimen; VGPR, very good PR.
Gandhi UH et al. Leukemia. 2019;33(9):2266-2275.
Patients who did not achieve at least a VGPR to subsequent therapy had poor survival outcomes
MAMMOTH study
Triple/quad-refractory mOS: 9.2 months
Penta-refractory mOS: 5.6 months
0 100.0
0.2
20 30 40 50
0.4
0.6
0.8
1.0
Months
Pro
po
rtio
n s
urv
ivin
g
Triple- and quad-refractory (n=148)
Penta-refractory (n=70)P=0.002
Patients receiving >1 subsequent treatments
mOS overall: 9.3 months
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
6
Patients resistant to daratumumab demonstrated an mPFSof nearly 4 months with subsequent treatment*mPFS and mOS were longest with daratumumab + immunomodulatory agent and carfilzomib + alkylator
Response to first subsequent treatment regimen by subsequent treatment type
All
regimens
N=249
Any dara
n=57
Dara +
immuno-
modulatory
agent
n=41
Dara +
proteasome
inhibitor
n=13
Elo +
immuno-
modulatory
agent
n=19
Any carf
n=68
Carf +
immuno-
modulatory
agent
n=34
Carf +
alkylator
n=19
Any
alkylator
n=90
PACE-like
n=24
Benda
n=15
ORR, n (%) 78 (31.3) 14 (24.6) 15 (36.6) 0 (0.0) 4 (21.1) 22 (32.3) 11 (32.4) 9 (47.4) 40 (44.4) 11 (45.8) 5 (33.3)
mPFS, months
(95% CI)
3.4
(2.8-4.0)
3.9
(2.7-5.1)
4.5
(2.8-6.3)
1.8
(1.2-2.5)
2.6
(1.1-4.1)
4.2
(2.3-6.2)
4.1
(3.1-5.1)
5.7
(1.6-9.7)
3.2
(2.9-3.5)
3.0
(2.5-3.4)
3.2
(2.3-4.1)
mOS, months
(95% CI)
9.31
(8.1-10.6)
11.4
(8.8-14.0)
12.6
(8.5-16.6)
7.7
(0.0-19.6)
8.3
(1.9-14.6)
10.9
(9.5-12.4)
11.2
(8.9-13.6)
12.7
(5.9-19.5)
7.7
(4.9-10.5)
5.9
(2.6-9.1)
9.3
(5.0-13.6)
The poor outcomes with subsequent treatments for CD38 mAb-refractory patients highlight the unmet need for effective treatments
MAMMOTH study
Treatment groups were not mutually exclusive.benda, bendamustine; carf, carfilzomib; dara, daratumumab; elo, elotuzumab; mAb, monoclonal antibody; mOS, median overall survival; mPFS, median progression-free survival; ORR, overall response rate; PACE, cisplatin, adriamycin, cyclophosphamide, and etoposide.
Gandhi UH et al. Leukemia. 2019;33(9):2266-2275.
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
7
Triple-class refractory multiple myeloma is a hard-to-treat patient population1
ASCT, autologous stem cell transplant; BCL-2; B-cell lymphoma 2; CAR-T, chimeric antigen receptor T-cell; CD, cluster of differentiation; dex, dexamethasone; OS, overall survival; PD-1, programmed death 1.
1. Mikhael J. Clin Lymphoma Myeloma Leuk. 2020;20(1):1-7. doi:10.1016/j.clml.2019.09.621 2. Schjesvold F et al. Future Oncol. 2020;16(11):631-641. 3. Lonial S et al. First clinical (phase 1b/2a) study of the CELMoDiberdomide (CC-220) in combination with dexamethasone (DEX) in patients with relapsed/refractory multiple myeloma (RRMM). Presented at: American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. 4. Clinicaltrials.gov. NCT04246047. https://clinicaltrials.gov/ct2/show/NCT04246047. Accessed May 18, 2020.
Median OS of 5 to 8 months1Poorest outcomes
Recycling of previous treatments yieldslow response rates1
Fewest treatment
options
Cytotoxic chemotherapy
Salvage ASCT
Panobinostat + bortezomib + dex
Selinexor + dex
Melflufen + dex
Iberdomide + dex
Alternative approaches1-3
Antibody-drug conjugate
CAR-T
Bispecific antibody
BCL-2 inhibitor
Anti–PD-1 antibody
Novel immunotherapies1,4
Triple-class refractory disease: refractory to at least a proteasome inhibitor, an
immunomodulatory agent, and an anti-CD38 agent1
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
8
New therapeutic options may resolve certain unmet needs in the triple-class refractory MM treatment landscape
MM, multiple myeloma.
1. Genadieva Stavric S et al. Expert Rev Hematol. 2017;10(6):551-561. 2. Kumar SK et al. Nat Rev Dis Primers. 2017;3:17046. doi:10.1038/nrdp.2017.46 3. Pawlyn C, Morgan GJ. Nat Rev Cancer. 2017;17(9):543-556. 4. Chen Q et al. Blood. 2005;106(2):698-705. 5. Kortum KM et al. Blood. 2016;128(9):1226-1233. 6. Landgren O, Iskander K. J Int Med. 2017;281:365-382.
There is promising potential for combination regimens, including novel targeted
therapies, to achieve durable responses and long-term disease control6
Current therapies result in unfavorable outcomes for several reasons
Genetic mutations
resulting in drug
resistance4,5
Clonal
evolution3
High rates
of relapse1,2
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
9
Emerging immunotherapy and non-immunotherapy options to treat triple-class refractory MM
Non-exhaustive listClass and/or target
XPO-1 inhibitor1
Peptide-drug conjugate2
BCL-2 inhibitor3
CELMoD4
Antibody-drug conjugate: BCMA5
CAR-T: BCMA6
T-cell engager: BCMA7
Bispecific antibody: BCMA8
No
n-i
mm
un
o-
the
rap
yIm
mu
no
the
rap
y
BCL-2, B-cell lymphoma 2; BCMA, B-cell maturation antigen; CAR-T, chimeric antigen receptor T-cell; CELMoD, cereblon E3 ligase modulation drugs; MM, multiple myeloma; XPO-1, exportin-1.
1. Chari A et al. N Engl J Med. 2019;381(8):727-738. 2. Schjesvold F et al. Future Oncol. 2020;16(11):631-641. 3. Kaufman JL et al. Blood. 2019;134(suppl 1):926. doi:10.1182/blood-2019-125871 4. Lonial S et al. First clinical (phase 1b/2a) study of the CELMoD iberdomide (CC-220) in combination with dexamethasone (DEX) in patients with relapsed/refractory multiple myeloma (RRMM). Presented at: American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. 5. Clinicaltrials.gov. NCT04246047. https://clinicaltrials.gov/ct2/show/NCT04246047. Accessed May 18, 2020. 6. Munshi NC et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results. Presented at: American Society of Clinical Oncology Annual Meeting; May 29-31, 2020; Chicago, IL. 7. Costa LJ et al. Blood. 2019;134(suppl 1):143. doi:10.1182/blood-2019-122895 8. Cooper D et al. Blood. 2019;134(Suppl 1):3176 doi:10.1182/blood-2019-126818
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
10
Selinexor + dex: progression-free and overall survival1,2
*Non-evaluable patients were censored on day 1 for PFS (n=10) per statistical analysis plan.
CI, confidence interval; dara, daratumumab; dex, dexamethasone; DOR, duration of response; mo, month; MR, minimal response; NE, not evaluated; NR, not reported; ORR, overall response rate; PD, progressive disease; PFS, progression-free survival; PI, proteasome inhibitor; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.
1. Chari A et al. Results of the pivotal STORM study (part 2): deep and durable responses with oral selinexor plus low dose dexamethasone in patients with penta-exposed and triple class refractory MM. Presented at: 60th American Society of Hematology Annual Meeting (ASH); December 1-4, 2018; San Diego, CA. 2. Chari A et al. N Engl J Med. 2019;381(8):727-738.
Perc
en
t su
rviv
al
STORM: part 2
Population1 ORR (%) sCR (%) VGPR (%) PR (%) MR (%) DOR (mo)
All patients
(N=122)26.2 1.6 4.9 19.7 13.1 4.4
2 PIs, 2 immunomodulatory
drugs, and dara refractory
(n=83)
25.3 1.2 4.8 19.3 12.0 NR
Pro
ba
bilit
y o
f s
urv
iva
l
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
11
Selinexor + dex: safety profile
STORM: part 2
AE, adverse event; dex, dexamethasone.Chari A et al. N Engl J Med. 2019;381(8):727-738.
• 18% of patients discontinued
treatment due to an AE
• 80% of patients had a dose
modification or interruption
due to an AE
– The most common AEs
leading to dose
reduction/interruption were
thrombocytopenia (43%),
fatigue (16%), and
neutropenia (11%)
35%
19%
38%
51%
62%
15%
48%
3%
21%
7%
5%
44%
10%
59%
25%
0 20 40 60 80 100
Vomiting
Neutropenia
Diarrhea
Decreased appetite
Anemia
Nausea
Thrombocytopenia
Fatigue
Grades 1-2 Grades 3-4
24%
Percentage of patients
AEs by grade (N=123)
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
12
Melflufen + dex: an ongoing phase II study in triple-class refractory MM patients demonstrated clinical activityMelflufen is a novel peptide-drug conjugate that rapidly delivers a highly cytotoxic payload causing
DNA damage
dex, dexamethasone; mDOR, median duration of response; MM, multiple myeloma; mOS, median overall survival; mPFS, median progression-free survival; MR, minimal response; ORR, overall response rate; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.
Mateos M, Oriol A, Larocca A et al. Clinical activity of melflufen in patients with triple-class refractory multiple myeloma and poor-risk features in an updated analysis of HORIZON (OP-106), a phase 2 study in patients with relapsed/refractory multiple myeloma. Poster presented at: 61st Annual Meeting of the American Society of Hematology (ASH); December 7-10, 2019; Orlando, FL.
Horizon study
Population ORR, % sCR, % VGPR, % PR, % MR, % SD, %
Overall (n=125) 29 1 10 18 15 27
Triple-class
refractory (n=93)24 0 9 15 13 29
0 10 20 30
Months
OS
pro
ba
bil
ity
0.00
0.25
0.50
0.75
1.00
Overall
mOS=11.6 months
mPFS=4.2 months
mDOR=4.4 months
Triple-class refractory
mOS=11.3 months
mPFS=4.0 months
mDOR=7.5 months
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
13
Melflufen + dex: serious AEs in patients included infection and hematological abnormalities
*Grade 3 and 4 TEAEs occurring in ≥5% of patients.
AE, adverse event; dex, dexamethasone; TEAE, treatment-emergent adverse event.Mateos M, Oriol A, Larocca A et al. Clinical activity of melflufen in patients with triple-class refractory multiple myeloma and poor-risk features in an updated analysis of HORIZON (OP-106), a phase 2 study in patients with relapsed/refractory multiple myeloma. Poster presented at: 61st Annual Meeting of the American Society of Hematology; December 7-10, 2019; Orlando, FL.
Horizon study
Incidence of grade 3 and 4 TEAEs in the overall
patient population (N=154)
TEAE*
Anemia
Grade 3, n (%) Grade 4, n (%)
Neutropenia
Thrombocytopenia
Serious TEAEs in the overall safety population
(N=154)
Serious TEAE
Infections and infestations
Serious melflufen-related TEAE, n (%)
Febrileneutropenia
Thrombocytopenia
56 (36)
47 (31)
32 (21)
1 (1)
54 (35)
74 (48)
8 (5)
8 (5)
7 (5)
An estimated 14% of patients discontinued therapy due to an AE
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
14
Iberdomide (CC-220) + dex: preliminary data reported favorable activity in RRMM patientsIberdomide (CC-220) is a novel CELMoD compound with enhanced tumoricidal and immune
stimulatory effects in preclinical studies1,2
Evaluable patients include patients who have received ≥1 dose of IBER, had measurable disease at baseline and ≥1 post-baseline response assessment.1
ASCT, autologous stem cell transplant; CBR, clinical benefit rate; CELMoD, cereblon E3 ligase modulator; DARA, daratumumab; DCR, disease control rate; dex, dexamethasone; IBER, iberdomide; MR, minimal response; ORR, overall response rate; PD, progressive disease; pom, pomalidomide; PR, partial response; SD, stable disease; RRMM; relapsed/refractory multiple myeloma; VGPR, very good partial response.
1. Lonial S, van de Donk NWCJ, Popat R et al. First clinical (phase 1b/2a) study of the CELMoD iberdomide (CC-220) in combination with dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL. 2. Bjorklund CC et al. Blood. 2016;128(22):1592.
Patient characteristics (N=66)1
• Median age (years):
– 65 (33-79)
• Median prior lines of therapy:
– 5 (2-12)
• Prior ASCT:
− 78.8%
• Prior proteasome inhibitors:
− 100%
• Prior lenalidomide:
− 100%
• Prior pomalidomide:
− 68.2%
• Prior CD38 monoclonal antibody:
− 74.2%
9 (15.3) 7 (13.7) 5 (18.5)
21 (35.6)17 (33.3)
10 (37.0)
10 (16.9)9 (17.7)
4 (14.8)
17 (28.8) 17 (33.3) 7 (25.9)
2 (3.4) 1 (2.0) 1 (3.7)
0
20
40
60
80
100
All evaluable(n=59)
Immunomodulatory agent–refractory(n=51 evaluable)
Dara + pom–refractory(n=27 evaluable)
Res
po
nse
, n
(%
)1
VGPR
PR
MR
SD
PD
ORR, 32.2% ORR, 35.3% ORR, 29.6%
CBR
49.2%
DCR
84.7%
CC-220-MM-001 study
Data cutoff date: April 15, 2019.1
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
15
Iberdomide (CC-220) + dex: infection and anemia were the most common AEs seen in patients
*Common (>20%, all grade) treatment-emergent adverse events and events of interest for all cycles.
AE, adverse event; dex, dexamethasone.
Lonial S, van de Donk NWCJ, Popat R et al. First clinical (phase 1b/2a) study of the CELMoD iberdomide (CC-220) in combination with dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL.
31 (47.0)
AEs* (N=66)
24 (36.4)
22 (33.3)
20 (30.3)
15 (22.7)
15 (22.7)
10 (15.2)
0
2 (3.0)
1 (1.5)
9 (13.6)
0
Grade 3, n (%)All Grade, n (%) Grade 4, n (%)
Anemia
Infection
Neutropenia
Fatigue
CC-220-MM-001 study
Data cutoff date: April 15, 2019.
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
16
Several antigenic targets for immunotherapy are being investigated in RRMM
Malignant plasma cell
CD19
CD46
CD38
CD56
CD74
FcRH5
SLAMF7
BCMA
NKG2D
GPRC5D
TACI
CD229
CD138
NY-ESO-1
BCMA, B-cell maturation antigen; CD, cluster of differentiation; FcRH5, Fc receptor-like protein 5; GPRC5D, G-protein coupled receptor family C group 5 member D; NKG2D, natural killer group 2D; NY-ESO-1, New York esophageal squamous cell carcinoma 1; RRMM, relapsed/refractory multiple myeloma; SLAMF7, signaling lymphocytic activation molecule family member 7; TACI, transmembrane activator and CAML interactor.
For more information on antigen targets currently in clinical trials, please go to www.clinicaltrials.gov.
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
17
More diverse treatments are needed in the triple-class refractory multiple myeloma setting
BCMA, B-cell maturation antigen; GI, gastrointestinal; mDOR, median duration of response; mPFS, median progression-free survival; ORR, overall response rate.
1. Nijhof IS et al. Drugs. 2018;78:19-37. 2. Gandhi UH et al. Leukemia. 2019;33(9):2266-2275. 3. Lonial S et al. Lancet Oncol. 2020;21(2):207-221. 4. Mikhael J. Clin Lymphoma Myeloma Leuk. 2020;20(1):1-7. doi:10.1016/j.clml.2019.09.621 5. Chim CS et al. Leukemia. 2018;32(2):252-262. 6. Chari A et al. N Engl J Med. 2019;381(8):727-738.
Triple-class refractory multiple myeloma has a poor prognosis and
presents unique treatment challenges1-4
Current therapies are associated with short PFS and DOR4,5
The STORM study reported an ORR of 26% with mPFS of 3.7 months and
mDOR of 4.4 months. Major GI and hematological toxicities were observed6
Both immune-targeted and non-immune-targeted therapies are emerging1
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
Current and emerging novel therapeutic targets for RRMMShaji Kumar, MD
Consultant, Division of Hematology,
Department of Internal Medicine
Mayo Clinic, Rochester,
Minnesota, USA
18
Sagar Lonial, MD, FACP
Chief Medical Officer,
Winship Cancer Institute
Emory University, Atlanta,
Georgia, USA
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
19
Several immunomodulatory targets are being investigated in RRMM
BCMA, B-cell maturation antigen; CD, cluster of differentiation; FcRH5, Fc receptor-like protein 5; GPRC5D, G-protein coupled receptor family C group 5 member D; NKG2D, natural killer group 2D; NY-ESO-1, New York esophageal squamous cell carcinoma 1; RRMM, relapsed refractory multiple myeloma; SCD1, syndecan-1; SLAMF-7, signaling lymphocytic activation molecule family member 7; XPO-1, exportin-1.
For more information on antigen targets currently in clinical trials, please go to www.clinicaltrials.gov.
XPO-1
Phase IIPhase I Phase III
BCL-2
CD19
CD38
CD74
CD138
SLAMF-7
SLAMF-7/CD38
CD38
CD56
CD138/SDC1
NY-ESO-1
FcRH5
GPRC5D
NKG2D
CD46
SLAMF-7
BCMA
BCMA/SLAMF-7
BCMA
BCMA/CD19
BCMA
BCMA/CD38
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
20
Current novel therapeutic targets being studied in RRMM
BCL-2, B-cell lymphoma 2; BCMA, B-cell maturation antigen; RRMM, relapsed/refractory multiple myeloma; SLAMF7, signaling lymphocytic activation molecule F7; XPO-1, exportin 1.
BCL-2 BCMA
Novel targets
XPO-1
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
21
Current novel therapeutic targets being studied in RRMM
BCL-2, B-cell lymphoma 2; BCMA, B-cell maturation antigen; RRMM, relapsed/refractory multiple myeloma; SLAMF7, signaling lymphocytic activation molecule F7; XPO-1, exportin 1.
BCL-2 BCMA
Novel targets
XPO-1
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
XPO-1 is present in all eukaryotic cells1
• Transports more than 200 proteins, including regulatory
proteins, from the nucleus to the cytoplasm1
• Important regulator of cell division through binding and
export of mitotic proteins1
Upregulation of XPO-1 has cancer-promoting
consequences1
• Increases transport of growth regulatory proteins to the
cytoplasm, such as c-Myc or BCR-ABL1
– Activates downstream signaling and leads to
sustained cell proliferation1
• Tumor suppressor proteins, such as Rb, p53, p21, and
p27, are inactivated upon export, leading to
inappropriate cell growth1,2
22
XPO-1 transfers tumor suppressor proteins and oncoproteins to the cytoplasm1,2
ABL, Abelson murine leukemia virus transforming element; BCR, breakpoint cluster region protein; BCR-ABL, Philadelphia chromosome; c-Myc, avian myelocytomatosis virus oncogene cellular homolog; p21, cyclin-dependent kinase inhibitor 1; p27, cyclin-dependent kinase inhibitor 1B; p53, tumor protein p53; Rb, retinoblastoma protein; XPO-1, exportin-1.
1. Wang AY, Liu H. Stem Cell Investig. 2019;6:1-9. doi:10.21037/sci.2019.02.03 2. Gao W. Transl Cancer Res. 2017;6(suppl 1):S83-S86.
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
Inhibition of XPO-1 results in MM cell apoptosis
through various mechanisms1
• Activation of p53 and caspases
• Nuclear localization of tumor suppressor proteins
(p53, p21, p27, Rb)
• Downregulation of c-Myc and cell cycle regulatory genes
and promotion of G1/S cell cycle arrest
XPO-1 overexpression is associated with poor
prognosis and drug resistance in
hematologic malignancies1
• Expression in MM cells increases with disease progression
and is associated with increased lytic bone lesions and
shorter survival2
23
XPO-1 is overexpressed in MM cells and its inhibition leads to MM cell apoptosis1-3
c-Myc, avian myelocytomatosis virus oncogene cellular homolog; G1, first gap; MM, multiple myeloma; p21, cyclin-dependent kinase inhibitor 1; p27, cyclin-dependent kinase inhibitor 1B; p53, tumor protein p53; Rb, retinoblastoma protein; S, synthesis; XPO-1, exportin-1.
1. Wang AY, Liu H. Stem Cell Investig. 2019;6:1-9. 2. Nachmias B, Schimmer AD. Leukemia. 2020. doi:10.1038/s41375-020-0958-y 3. Gao W. Transl Cancer Res. 2017;6(suppl 1):S83-S86.
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
24
Advantages and disadvantages of targeting XPO-1
Advantages
MM cells have higher XPO-1
expression compared to normal
plasma cells1
Combination therapies have
synergistic effects across
multiple malignancies2
XPO-1 inhibition may also affect the
tumor microenvironment with
antitumor effects1
Disadvantages
Irreversible inhibition of XPO-1 on
normal cells cripples nuclear export,
likely resulting in marked toxicity1
XPO-1 is present in all eukaryotic cells
and not limited to plasma cells2
MM, multiple myeloma; XPO-1, exportin-1.
1. Nachmias B, Schimmer AD. Leukemia. 2020. doi:10.1038/s41375-020-0958-y 2. Wang AY, Liu H. Stem Cell Investig. 2019;6:1-9. doi:10.21037/sci.2019.02.03
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
25
XPO-1 combination targets under investigation
CD, cluster of differentiation; dex, dexamethasone; NDMM, newly diagnosed multiple myeloma; PI, proteasome inhibitor; RRMM, relapsed/refractory multiple myeloma; XPO-1, exportin-1.
1. Clinicaltrials.gov. NCT02343042. https://clinicaltrials.gov/ct2/show/NCT02343042. Accessed July 06, 2020. 2. Clinicaltrials.gov. NCT03110562. https://clinicaltrials.gov/ct2/show/NCT03110562. Accessed July 09, 2020. 3. Clinicaltrials.gov. NCT03589222. https://clinicaltrials.gov/ct2/show/NCT03589222. Accessed July 06, 2020.
Non-exhaustive list
+ CD38 + PI + CD38 + PI
XPO-1
• Phase I/II
• RRMM and NDMM
• Agents:
– selinexor + dex
– pomalidomide
STOMP arm 11
• Phase III
• RRMM
• Agents:
– selinexor + dex
– bortezomib
BOSTON2
• Phase II
• RRMM
• Agents:
– selinexor + dex
– bortezomib
– daratumumab
SELIBORDARA3
• Phase I/II
• RRMM and NDMM
• Agents:
– selinexor + dex
– daratumumab
STOMP arm 51
+ immunomodulatory agent
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
26
Current novel therapeutic targets being studied in RRMM
BCL-2, B-cell lymphoma 2; BCMA, B-cell maturation antigen; RRMM, relapsed/refractory multiple myeloma; SLAMF7, signaling lymphocytic activation molecule F7; XPO-1, exportin 1.
XPO-1 BCL-2 BCMA
Novel targets
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
SLAMF7 is a member of the immunoglobulin
receptor superfamily1
• Can uniquely act as a self ligand with the same receptor
present on another cell1
• Whether it binds to SLAM-associated proteins dictates
whether SLAMF7 receptors stimulate or inhibit immune
cell functions1
SLAMF7 is expressed on MM cells, NK cells,
monocytes, and macrophages3
• Mediates activating signals in NK cells by coupling
with its adaptor protein, EAT-21
27
SLAMF7 is an activating receptor for NK cell–mediated immunosurveillance1,2
CD, cluster of differentiation; EAT-2, Ewing's sarcoma-associated transcript 2; MM, multiple myeloma; NK, natural killer; SLAMF7, signaling lymphocytic activation molecule F7.
1. Veillette A, Guo H. Crit Rev Oncol Hematol. 2013;88:168-177. 2. Campbell KS et al. Front Immunol. 2018;9:2551.doi:10.3389/fimmu.2018.025513. Pazina T et al. Cancer Immunol Res. 2019;7:1-14. doi:10.1158/2326-6066.CIR-18-0579
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
SLAMF7 is highly expressed on abnormal
plasma cells2
• Induces proliferative activity of tumor cells in patients
with MM
• High soluble SLAMF7 levels in the serum have been
associated with shorter PFS
Targeting SLAMF7 results in antitumor effects
from immune cell activation mechanisms such as1
• NK cell–mediated ADCC
• FcγR-dependent macrophage-mediated ADCP
• CD16-independent costimulation of NK cells via
interaction with SLAMF7
28
SLAMF7 is highly expressed in greater than 95% of MM cells1,3
ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; CD, cluster of differentiation; FcγR, Fc gamma receptor; mAB, monoclonal antibody; MM, multiple myeloma;NK, natural killer; PFS, progression-free survival; SLAMF7, signaling lymphocytic activation molecule F7.
1. Pazina T et al. Cancer Immunol Res. 2019;7:1-14. doi:10.1158/2326-6066.CIR-18-0579 2. Ishibashi M et al. Oncotarget. 2018;9(78):34784-34793. 3. Veillette A, Guo H. Crit Rev Oncol Hematol. 2013;88:168-177.
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
29
Advantages and disadvantages of targeting SLAMF7
Advantages
High levels of SLAMF7 are almost
universal and persistent in MM1
SLAMF7-SLAMF7 interactions
between NK and MM cells can
uniquely enhance cytotoxicity2
Not expressed in nonhematopoietic
cells, therefore permitting highly
targeted effects1
Disadvantages
Normal plasma cells express SLAMF7;
which may compromise humoral
immunity if targeted1
Studies suggest SLAMF7-SLAMF7
cytotoxicity may only occur on a
subset of MM cells2
MM, multiple myeloma; NK, natural killer; SLAMF7, signaling lymphocytic activation molecule F7.
1. Veillette A, Guo H. Crit Rev Oncol Hematol. 2013;88:168-177. 2. Pazina T et al. Cancer Immunol Res. 2019;7:1-14. doi:10.1158/2326-6066.CIR-18-0579
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
30
Current novel therapeutic targets being studied in RRMM
BCL-2, B-cell lymphoma 2; BCMA, B-cell maturation antigen; RRMM, relapsed/refractory multiple myeloma; SLAMF7, signaling lymphocytic activation molecule F7; XPO-1, exportin 1.
XPO-1 BCMABCL-2
Novel targets
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
BCL-2 encodes an outer mitochondrial membrane
protein that suppresses cell apoptosis1
• Regulates cell death by controlling permeability of the
mitochondrial membrane
• Functions in a feedback loop system with caspases
• Inhibits caspase activity by preventing the release of
cytochrome c from the mitochondria or by binding
to APAF-1
BCL-2 may result in anti-inflammatory activity1
• Inhibits NLRP-1-inflammasome activation, which may attenuate
cell inflammation
31
BCL-2 inhibits cell apoptosis and may mitigate inflammation1,2
APAF-1, apoptotic peptidase activating factor 1; BAX, BCL-2–associated X protein; BCL-2, B-cell lymphoma 2; BIM, BCL-2–like protein 11; NLRP-1, nucleotide-binding oligomerization leucine rich repeat and pyrin domain.
1. National Institutes of Health. Genetics Home Reference. Published July 7, 2020. Accessed July 8, 2020. https://ghr.nlm.nih.gov/gene/BCL2#normalfunction. 2. Konopleva M et al. Cancer Discov. 2016;6(10):1106-1117.
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
The intrinsic apoptosis pathway is regulated by a
balance between2
• Antiapoptotic proteins (eg, BCL-2 and MCL-1) and
proapoptotic proteins (eg, BAX, BAK and BIM)
Proapoptotic proteins are sequestered by BCL-2 or
MCL-1, which prevents cell death2
• Antagonizing BCL-2 allows proapoptotic proteins to
translocate to the mitochondrial membrane, leading to
cellular apoptosis
Other therapies can modulate the profile of BCL-2 and
work synergistically with BCL-2 inhibitors2
• PIs can upregulate NOXA, leading to neutralization of MCL-1
in myeloma cell lines
32
BCL-2 members play a key role in MM cell survival1-3
BAK, BCL-2 homologous antagonist killer; BAX, BCL-2–associated X protein; BCL-2, B-cell lymphoma 2; BIM, BCL-2–like protein 11; MCL-1, myeloid cell lymphoma 1; MM, multiple myeloma; NOXA, phorbol-12-myristate-13–acetate-induced protein 1; PI, proteasome inhibitor.
1. Touzeau C et al. Leukemia. 2018;32(9):1899-1907. 2. Kumar S et al. Blood. 2017;130(22):2401-2409. 3. Konopleva M et al. Cancer Discov. 2016;6(10):1106-1117.
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
33
Advantages and disadvantages of targeting BCL-2
Advantages
MM cells are highly dependent on
BCL-2 family proteins for survival1
MCL-1 identified as one of the most
important and selective genes for MM1
Potential synergistic effects when
BCL-2 inhibitors are combined with
proteasome inhibitors1
Disadvantages
MM is a heterogeneous disease; not
entirely dependent upon BCL-2
members alone2
High expression of MCL-1 may confer
resistance to BCL-2 inhibitors1
BCL-2, B-cell lymphoma 2; MCL-1, myeloid cell leukemia 1; MM, multiple myeloma.
1. Slomp A, Peperzak V. Front Oncol. 2018;8:533. doi:10.3389/fonc.2018.00533 2. Touzeau C et al. Leukemia. 2018;32(9):1899-1907.
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
34
Current novel therapeutic targets being studied in RRMM
BCL-2, B-cell lymphoma 2; BCMA, B-cell maturation antigen; RRMM, relapsed/refractory multiple myeloma; SLAMF7, signaling lymphocytic activation molecule F7; XPO-1, exportin 1.
XPO-1 BCMA
Novel targets
BCL-2
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
BCMA is a cell surface protein1-3
• Expressed predominantly on late-stage B cells and
plasma cells
– Virtually absent on naïve and memory B cells
• Induced during plasma cell differentiation
– BCMA binds to ligands APRIL and BAFF
– Enhances humoral immunity by stimulating the survival of
normal plasma cells
BCMA is required for optimal survival of long-lived
plasma cells in the bone marrow1,2
• Promotes B-cell survival at distinct stages of development
• BCMA is not crucial for overall B-cell homeostasis
35
B-cell maturation antigen (BCMA) aids in humoral immunity and development of normal plasma cells1,2
APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BCMA, B-cell maturation antigen.
1. Tai YT, Anderson KC. Immunotherapy. 2015;7(11):1187-1199. 2. Ryan MC et al. Mol Cancer Ther. 2007;6(11):3009-3018. 3. Cho SF et al. Front Immunol. 2018;9:1821. doi:10.3389/fimmu.2018.01821
Plasma
cell
BCMABCMA
APRIL
BAFF
Activation of signaling cascade
Growth and survival of long-lived plasma cells
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
BCMA is highly expressed on malignant plasma
cells in all patients with MM2-4
• BCMA ligands BAFF and APRIL are detected in increased
levels in the circulation of MM patients2,4
– Stimulate MM cell growth and survival of malignant plasma cells2
• Cleavage by γ-secretase results in release of a soluble form
(sBCMA) into the circulation5
36
BCMA regulates pro-survival pathways for MM cells1
APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BCMA, B-cell maturation antigen; MM, multiple myeloma.
1. Ryan MC et al. Mol Cancer Ther. 2007;6(11):3009-3018. 2. Cho SF et al. Front Immunol. 2018;9:1821. doi:10.3389/fimmu.2018.01821 3. Novak AJ et al. Blood. 2004;103(2):689-694. 4. Tai YT et al. Blood. 2014;123(20):3128-3138. 5. Laurent SA et al. Nat Commun. 2015;6:7333. doi:10.1038/ncomms8333
Malignant plasma
cell
γ-secretase
sBCMA
BCMA
APRIL
BAFF
Activation of signaling cascade
Growth and survival of MM cells
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
37
BCMA is an ideal target being investigated inmultiple myeloma1
BCMA, B-cell maturation antigen; MM, multiple myeloma; sBCMA, soluble BCMA.
1. Tai YT, Anderson KC. Immunotherapy. 2015;7(11):1187-1199. 2. Cho SF et al. Front Immunol. 2018;9:1821. doi:10.3389/fimmu.2018.01821 3. Sanchez E et al. Targ Oncol. 2017;13:39-47. 4. Shah N et al. Leukemia. 2020;35:985-1005.
Advantages
BCMA is predominantly expressed on
late-stage B cells and plasma cells2,3
BCMA is expressed on malignant
plasma cells in all patients with
multiple myeloma2
Disadvantages
It is unclear whether changes in
membrane-bound or sBCMA levels
during therapy could alter long-term
efficacy of anti-BCMA therapies4
The interaction between T cells and
MM cells may be blocked by sBCMA
released or shed from tumors into the
surrounding tissue1
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
38
Current investigational approaches targeting BCMA
BCMA, B-cell maturation antigen; CAR-T, chimeric antigen receptor T cell.
Cho SF et al. Front Immunol. 2018;9:1821. doi:10.3389/fimmu.2018.01821
Antibody-drug conjugate
BCMA-targeting
modalities
CAR-T Bispecific antibody
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
ADCs are off-the-shelf drugs that deliver potent
microtubule inhibitors to antigen-positive
malignant cells, resulting in antitumor activity1,2
• Comprised of a microtubule inhibitor linked to a tumor
antigen–targeted antibody
• Internalized and degraded following tumor cell binding,
releasing the microtubule inhibitor within the cell
39
ADCs deliver microtubule inhibitors to antigen-positive malignant cells1,2
ADC, antibody-drug conjugate.
1. Dan N et al. Pharmaceuticals (Basel). 2018;11(2):32. doi:10.3390/ph11020032 2. Herrera AF, Molina A. Clin Lymphoma Myeloma Leuk. 2018;18(7):452-468.3. Parslow AC et al. Biomedicines. 2016;4:14. doi:10.3390/biomedicines4030014
Intracellular
Microtubule
Inhibitor
Release
Antigen
Binding
Internalization
Endosomal
Processing
Lysosomal
Processing
Degradation
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
• T cells are obtained from the blood, activated in
vitro to facilitate gene insertion, and modified to
express CAR1
• Genetically modified CAR-T cells are then reinfused
into the body after patient lymphodepletion1
– CAR-T cells travel to sites of tumor, identify and kill
tumor cells, which can trigger extensive proliferation
of CAR-T cells and release of tumor antigens2
– This activates the immune system to recruit non-CAR-T
cells in a process called cross-priming to elicit further
anti-tumor responses2
40
Patient’s immune cells are genetically engineered to produce chimeric antigen receptor T cells (CAR Ts)1
CAR, chimeric antigen receptor.
1. Strivastava S, Stanley RR. J Immunol 2018;200:459-468. 2. June CH, Sadelain M. N Engl J Med. 2018;379:64-73.
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
• Formation of the cytolytic synapse is independent of
standard antigen recognition and costimulation
mediated by MHC-I
• CD3 is expressed by all CD8+ and CD4+ T cells
and enables polyclonal T-cell activation, expansion,
and tumor cell lysis
41
Bispecific antibody constructs facilitate cell-to-cell interactions via dual-antigen specificity1,2
BCMA, B-cell maturation antigen; CD, cluster of differentiation; MHC-I, major histocompatibility complex class I; TCR, T-cell receptor.
1. Ross SL et al. PLoS One. 2017;12(8):e0183390. doi:10.1371/journal.pone.0183390 2. Labrijn AF et al. Nat Rev Drug Discov. 2019;18(8):585-608.
T cell
BCMA
Malignant
plasma cell
Cellular lysis
CD3
Cellular lysis
TCR
CD3
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
42
New and emerging therapeutic targets may help to address unmet needs in triple-class refractory MM1
SLAMF7 is highly expressed on MM cells and absent on nonhematopoietic cells.
SLAMF7-SLAMF7 interactions may enhance cytotoxicity on a subset of MM cells4,5
BCL-2 plays an important role in the survival of MM cells. Inhibition of BCL-2 in
combination with proteasome inhibition has potential synergistic effects6
XPO-1 overexpression has been associated with drug resistance and poor prognosis.
By inhibiting XPO-1, antitumor effects may be induced in the tumor microenvironment2,3
BCMA is expressed exclusively in B-cell lineage cells and is required for the survival of
plasma cells. Inhibition of BCMA through multiple modalities may enhance cytotoxicity7
BCL-2, B-cell lymphoma 2; BCMA, B-cell maturation antigen; MM, multiple myeloma; SLAMF7, signaling lymphocytic activation molecule F7; XPO-1, exportin-1.
1. Shah N et al. Leukemia. 2020;34(4):985-1005. 2. Wang AY, Liu H. Stem Cell Investig. 2019;6:6. doi:10.21037/sci.2019.02.03 3. Nachmias B, Schimmer AD. Leukemia. Published online July 5, 2020. doi:10.1038/s41375-020-0958-y 4. Veillette A, Guo H. Crit Rev Oncol Hematol. 2013;88(1):168-177. 5. Pazina T et al. Cancer Immunol Res. 2019;7(10):1-14. doi:10.1158/2326-6066.CIR-18-0579 6. Slomp A, Peperzak V. Front Oncol. 2018;8:533. doi:10.3389/fonc.2018.00533 7. Tai YT, Anderson KC. Immunotherapy. 2015;7(11):1187-1199.
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
Panel discussion and Q&ASagar Lonial, MD, FACP
Chief Medical Officer, Winship Cancer Institute
Emory University, Atlanta, Georgia, USA
43
This information is intended for healthcare providers only. Compounds may be investigational. Inclusion in this presentation does not imply regulatory approval for these compounds or indications.
Closing remarksSagar Lonial, MD, FACP
Chief Medical Officer, Winship Cancer Institute
Emory University, Atlanta, Georgia, USA
44