The evolving therapeutic landscape in relapsed/refractory ......Elo + immuno-modulatory agent n=19 Any carf n=68 Carf + immuno-modulatory agent n=34 Carf + alkylator n=19 Any alkylator

$Page 1: The evolving therapeutic landscape in relapsed/refractory ......Elo + immuno-modulatory agent n=19 Any carf n=68 Carf + immuno-modulatory agent n=34 Carf + alkylator n=19 Any alkylator$
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


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


30 min Panel discussion and Q&A

All

5 min Closing remarks



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


• 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


• 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


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.


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


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


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


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


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)


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


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


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


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.


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.


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


Current and emerging novel therapeutic targets for RRMMShaji Kumar, MD

Consultant, Division of Hematology,

Department of Internal Medicine

Mayo Clinic, Rochester,

Minnesota, USA

18


Chief Medical Officer,

Winship Cancer Institute

Emory University, Atlanta,

Georgia, USA


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


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


21



BCL-2 BCMA

Novel targets

XPO-1


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.


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.


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


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


26



XPO-1 BCL-2 BCMA

Novel targets


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


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.


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


30



XPO-1 BCMABCL-2

Novel targets


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.


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.


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.


34



XPO-1 BCMA

Novel targets

BCL-2


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


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


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


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


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


• 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.


• 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


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.


Panel discussion and Q&ASagar Lonial, MD, FACP


Emory University, Atlanta, Georgia, USA

43


Closing remarksSagar Lonial, MD, FACP


Emory University, Atlanta, Georgia, USA

44

The evolving therapeutic landscape in relapsed/refractory ......Elo + immuno-modulatory agent n=19 Any carf n=68 Carf + immuno-modulatory agent n=34 Carf + alkylator n=19 Any alkylator

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