Multiple Myeloma beyond Daratumumab

María-Victoria Mateos

University Hospital of Salamanca

University of Salamanca

Spain

Cancer Research CenterUniversity of SalamancaInstitute of Biomedical

Research of Salamanca

Multiple Myeloma beyond Daratumumab

Disclosures

Research Support/P.I.: Research support from Celgene

Employee:

Consultant:

Major Stockholder:

Speakers Bureau:

Honoraria: Janssen, Celgene, Takeda, Amgen, BMS, Pharmamar

Scientific Advisory Board: Janssen, Celgene, Takeda, Amgen, BMS, Pharmamar

• This meeting is organized and supported by Janssen, Pharmaceutical Companies of Johnson & Johnson in Portugal.

• The views expressed in these slides are those of the individual faculty members and do not necessarily reflect the views of

Janssen, Pharmaceutical Companies of Johnson & Johnson in Portugal

• The presentations may include discussions on off-label use of drugs

Milestones in the development of mAbs for

therapy

• 1975 George Kohler and Cesar Milstein provided the most outstanding

proof of the clonal selection theory by fusion of normal and malignant

cells. This resulted in the first monoclonal antibodies, for which they

received the Nobel Prize in 1984.

• 1986 First mAbs, muromonab-CD3 (OKT3) approved by FDA

• 1997 First mAbs to treat cancer (rituximab) approved

The first mAb single agent approved for Multiple Myelomahas been Daratumumab

Newly-diagnosed MM patientsESMO guidelines 2017

Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61

Lenalidomide maintenance

200 mg/m2 melphalan

followed by ASCT

INDUCTION:

3 drug regimensVTD

VCD

PAD

RVD

First option: VMP, Rd, VRD

Second option: VCD, MPT

Other options : BP, CTD, MP

Trx eligible Trx non-eligible

Daratumumab is not present in these guidelines in the upfront setting

Relapse/Refractory MM patientsESMO guidelines 2017

Pomalidomide-Dex

(as a backbone)

+ Cyclo or Ixa or Bort or

Dara or Elo

Daratumumab

(single agent or

combination)

First relapse after Bortezomib-based

induction

Triplets based on Rd

DaraRd or KRd or IxaRd or

EloRd

Rd

Clinical trial

At second or subsequent relapse

First relapse after IMiD-based

induction

Doublets

Kd / Vd

Triplets based on Bortezomib

DaraVD or PanoVD or

EloVD or VCD


Daratumumab is present in these guidelines in the RR setting

Daratumumab is having and will have a key role in the treatment of patients with MM and it

will take part of the upfront setting of most of our NDMM patients

Second ASCT/Allo-RIC

MPV-Dara

LD-Dara

VTD/VRD-Dara

ASCT (melphalan 200)

Dara as consolidation/maintenance

Transplant Candidate Non Transplant Candidate

Subsequent relapses

1st relapseIMiD’s based combinations

Elotuzumab plus RdCarfilzomib plus Rd

Dara plus Rd Ixazomib plus Rd

Kd-Dara

Vd plusPanobinostat

Vd-Daratumumab

Elo-Bd

Selinexor-Bd

Venetoclax-Bd

PI’s based combinations

DaratumumabPom-Dex + Dara

MOR-202/Isatuximab

Check-point inhibitors/Adoptive cell therapyOther new agents for subsequent relapses

Daratumumab in Smoldering

VRD-Dara

Ocio, Leukemia. 2014 Mar;28(3):525-42, Updated

New drugs and mechanisms of action in MM

Raf

MEK

MAPK

PI3K

Akt

Ras

mTORC1 mTORC2

Lymph.

NK cell

Approved

Bortezomib

Carfilzomib

Ixazomib

Oprozomib

Marizomib

Proteasome Inh.

Panobinostat

Vorinostat

Romidepsin

Givinostat

Rocilinostat

DACi

Melphalan

Cyclophosphamide

Bendamustine

Melflufen

TH-302

Alkylators

Thalidomide

Lenalidomide

Pomalidomide

IMIDs

Tanespimycin

AUY922

Hsp-90 Inh.

DNA Damaging Zalypsis

PARP Inhibitor Veliparib

Other DNA damaging

KSP Inh Filanesib

Aurora K Inh MLN8237

CDK 4/6 Inh Seleciclib

Cell cycle Inh.

AKT Perifosine / Afuresertib

mTORC1 Everolimus / Temsirolimus

mTOR C1/C2 MLN0128 / INK128

Farn Transf Tipifarnib

p38/MAPK inh SCIO-469

p38/JNK act Aplidin

MEK Selumetinib

Bcl-2 Venetoclax

Mcl1 MIK665; AMG176/397; AZD5991

XPO Selinexor

PIM PIM447

Signaling Pathways

CDK 1, 2, 5, 9 Dinaciclib / TG02

FGFR3 Dovitinib / AB1010 / MFGR 1877S

cKit /PDGFR Imatinib / Dasatinib

VEGF-R Bevacizumab

IGF-1R AVE1642 / CP-751, 851

EGF-R Cetuximab

PKC Enzastaurin

BTK Ibrutinib

Kinase Inh.

CS-1 Elotuzumab

CD38 Daratumumab / Isatuximab

CD138 nBT062-DM4

CD56 Lorvotuzumab

CD40 Dacetuzumab / Lucatumumab

BAFF Tabalumab

KiR IPH2101

PD1/PDL1 Pembrolizumab / Nivolumab /

Pidilumab

IL-6

Siltuxima

b

MoAb

Is there anything else beyond Daratumumab?

• Other mAbs targeting CD38

• Other mAbs targeting other molecules

• Other drugs with different MoA

• New immunotherapic strategies

Isatuximab (SAR650984, anti-CD38) MoA

Deckert et al. Clin Cancer Res 2014;20(17):4574-83; Martin et al. ASH 2014 (Abstract 83); oral presentation; *Jiang et al. Leukemia 2016;30(2):399-408.

Canonical and lysosome-dependent cell death*

• ADCC was observed in all the CD38+ lines tested

• CDC activity was dependent on receptor density

• Crosslinking-independent apoptosis

• Inhibition of the CD38 ectoenzyme activity

Synergistic and/or additive effect in combination with Len, Bort, Car and Mel in animal models

Isatuximab monotherapy in RRMM patients• 84 pts with RRMM progressing on/after PI and IMiD’s therapy

• Median PL: 5 (1-13)

• Dose-escation study and the MTD is 20 mg/kg QW cycle 1, then Q2W

Martin et al.Blood Cancer Journal 2019

Median PFS: 3.7 m

• IRRs occurred in 43% of patients, G2/2 in 94%

Isatuximab single agent is similar to Daratumumab in efficacy

Isatuximab monotherapy and in combination with dexamethasone in RRMM: phase II study

PFS

The addition of dexamethasone to isatuximab increased response and median PFS

Isatuximab 20 mg/kg was generally well-tolerated

Steroid prophylaxis with single-agent anti-CD38 monoclonal antibodies may enhance their efficacy

0

10

20

30

40

50

Isatuximab monotherapy (n=109) Isatuximab + dexamethasone (n=55)

CR

VGPR

PR

17.4

7.3

0.9

25.5

16.4

1.8

Censored

patient

1.0

0.8

0.6

0.4

0.2

00 2 4 6 8 10 12 14 16 18 20

Time (months)

PF

S (

pro

ba

bil

ity)

Isatuximab monotherapy (69 events)

Isatuximab + dexamethasone (29 events)

Median PFS = 4.86 months (95% CI 3.78–7.69)

Median PFS = 9.26 months (95% CI 4.86–15.05)

Best response (ITT population)

ORR Isa mono 26% vs 44% Isa-Dex

Dimopoulos et al., ASH 2018; abstract 155

Pati

en

ts (

%)

Isatuximab is being combined with different backbones

Isatuximab plus Pom-dex in RRMM: phase II study

Cohort 3

20 mg/kg (n=6)

Standard dose escalation (3 + 3 design)

Cohort 1

5 mg/kg (n=8)

Cohort 2

10 mg/kg (n=9)

Isatuximab IV QW in Cycle 1, then Q2W per 28-day cycle

Pom 4 mg on Days 1–21 per 28-day cycle

Dex 40 mg (20 mg if aged ≥75 years) on Days 1, 8, 15, and 22 per 28-day cycle

Based on PK/PD modeling and simulations,

isatuximab 10 mg/kg QWx4/Q2W was chosen as

the recommended dose for the expansion

cohort (n=22)

45 pts with R/R MM after at least 2PL, PI and IMiD; refractory to the last line of therapy. Median number of PL: 3

25.0

41.9

16.7

35.6

25.0

19.4

33.3

22.2

12.5 2.23.2 2.2

0

10

20

30

40

50

60

70

5 QW/Q2W(n=8)

10 QW/Q2W(n=31)

20 QW/Q2W(n=6)

All patients(n=45)

OR

R (

%)

Isatuximab dose (mg/kg) and schedule

PR VGPR62.5 62.264.5

Time (months)

5 mg/kg

All: 17.6 months

10 mg/kg

20 mg/kg

4 8 12 16 20 24 280

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Su

rviv

al p

rob

ab

ility 20 mg/kg QW/Q2W (n=6)

10 mg/kg QW/Q2W (n=31)a

All (n=45)

Ph3 ICARIA study: Isa-Pom-dex vs Pom-dex: met its primary end point

Mickael J et al. EHA 2018, abstract S850, oral presentation

MOR202 (CD38) mAb: main modes of action

Raab et al. ASCO 2015 (Abstract 8574), poster presentation.

antibody-dependent cellular

cytotoxicity (ADCC)

phagocytosis (ADCP)

Synergistic effect in combination with Len, Pom and additive with Bortezomib

• Len and Pom showed to increase the CD38 expression, and thus enhance the cytotoxic

effects of MOR202 in cell lines. Both IMiD’s induce activation of immune effector cells.

• Reductions in bone lysis in combination with Len, Bort or Pom in animal models.

MOR202 plus dex or plus IMiD’s

Raab M, ASH 2016 (Abstract 1152), oral presentation

2-hour IV infusion (4816 mg/Kg)

q1w plus low dose Dex, n=17 pts

2-hour IV infusion (4816 mg/Kg) q1w plus

low dose Dex + Len (n=10) or Pom (n=7)

• ORR: 78%

• Median of number of prior lines of therapy: 3/2

• 100% of pts refractory to the last line of therapy for Pom-dex arm (n=9)

and 50% for len-dex arm

• Median PFS: NR

Where are we going to use these other CD38 mAbs?

Pomalidomide-Dex

(as a backbone)

+ Cyclo or Isa or Bort or

Dara or Elo

Daratumumab/Isatuximab

/MOR202

(single agent or

combination)


induction



EloRd

Rd

Clinical trial



induction

Doublets

Kd / Vd


DaraVD or PanoVD or

EloVD or VCD




- Isatuximab is being developed accross the different stages of the disease since Smoldering, NDMM, first

relapse,……

- Is there any possibility for using Isa after Dara or Dara after Isa?




Phase I single agent n=25 26% SD

Elotuzumab (Anti-SLAM F7 MoAb) in MM

1. Hsi ED et al. Clin Cancer Res. 2008;1; 2. Tai YT et al. Blood. 2008; 3. Van Rhee F et al. Mol Cancer Ther. 2009;

4. Collins SM et al. Cancer Imm. Immunother. 2013; 5. Guo H et al. Mol Cell Biol. 2014; 6. Zonder et al Blood 2012

• SLAMF7: Signaling Lymphocyte Activation Molecule-1. Also called CS1

• Elotuzumab is a humanized IgG1 mAb targeting human CS1, a cell surface glycoprotein1,2

• CS1 is highly expressed on >95% of MM cells1-3: also in NK cells

Binding to SLAMF7 directly activates

Natural Killer cells,4 but not myeloma

cells5

When bound to myeloma via SLAMF7,

Elo activates Natural Killer cells via a

CD16 mediated pathway, enabling

selective killing via antibody-dependent

cellular cytotoxicity (ADCC) with

minimal effects on normal tissue

DirectactivationA

B

Myelomacelldeath

EAT-2Downstreamactivatingsignalingcascade Degranulation

Perforin,granzyme Brelease

Taggingforrecognition

Elotuzumab

SLAMF7

Naturalkillercell

Granulesynthesis

Polarization

Elotuzumab

SLAMF7

Myelomacell

Dual mechanism of action

Elotuzumab synergizes with Lenalidomide in MM

ADCC, antibody-dependent cellular cytotoxicity; NK, natural killer; SLAMF7, signaling lymphocytic activation molecule family member 7

Balasa B et al. Cancer Immunol Immunother. 2015;64:61-73.

Lenalidomide

Induces myeloma cell injury and lowers threshold for

NK cell–mediated killing of myeloma cells by elotuzumab

Direct NK cell activation

NK cell

Elotuzumab

SLAMF7

ADCC

CD16a +

Lenalidomide

Enhances adaptive and innate immune system,

including production of IL-2, to increase NK cell activity

Myeloma Cell

Elotuzumab plus Lenalidomide-dexamethasone is approved for the treatment of MM patients who

have received at least 1L of therapy

Progression-Free Survival – All Randomized Patients

ELOQUENT-2: Phase 3 randomized study comparing Rd vs Elotuzumab-Rd in RRMM patients

after 1-3 PL

ELdn=321

Ldn=325

HR=0.71 (95% CI: 0.59–0.86); p=0.0004

Median PFS(95% CI)

19.4 mo(16.6–22.3)

14.9 mo(12.1–17.3)

A 29% reduction in the risk of progression or death and a relative improvement of 50% in the PFS rate

(21% vs 14%) were observed with ELd vs Ld

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ilit

y o

f P

FS

Patients at risk

ELd

Ld

Ld

1-year PFS 2-year PFS 3-year PFS 4-year PFS

69%

41%

27%21%

57%

28%

19%

14%

ELd

Time (months)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62

321 304 280 260 233 216 196 180 160 147 132 125 111 103 94 91 79 70 63 60 55 52 49 46 36 31 24 17 13 6 2 0

325 295 249 216 192 173 158 141 124 108 91 76 68 64 61 54 47 41 39 37 33 31 30 27 22 13 9 6 3 1 1 0

Dimopoulos M, EHA 2017

Eloquent-2: Overall survival

Dimopoulos MA, et al. Presented at EHA 2017 (Abstract S456), oral presentation.

Time to Next TreatmentELOQUENT-2

Dimopoulos M, ASH 2015 Abst 28

460 2 4 6 14 16 20 22 26 28 32 34 36 40 448 10 12

E-Ld

Ld

0.0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

No. of patients at risk:

E-Ld

Ld

321

325

315

305

282

251

259

232

208

174

198

166

174

135

165

120

153

105

138

89

126

85

94

46

65

30

46

20

Time to next treatment (months)

Pro

ba

bil

ity o

f p

ati

en

ts w

ith

ou

t

ne

xt

tre

atm

en

t

14

5

225

193

3

1

18 24 30 38 4842

294

276

239

206

182

148

144

96

118

76

32

13

6

3

0

0

0.1

E-Ld Ld

HR 0.62 (95% CI 0.50, 0.77)

Median TTNT

(95% CI)

33 mos

(26.15, 40.21)

21 mos

(18.07,

23.20)

E-Ld-treated patients had a median delay of 1 year in the time to next treatment

vs Ld-treated patients

Phase 2: Pomalidomide + low-dose dexplus/minus elotuzumab

Benefit sustained across the different subgroups of patients,

including high-risk CA, or double refractoriness

Analysis of 117 pts, 70% of them double refractory to PI and

lenalidomide after a median number of 3 lines

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22Time (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Pd

EPd

Pro

babi

lity

of P

FS

• 46% reduction in the risk of progression or death with EPd

• Median PFS was more than twice as long with EPd vs Pd

EPd

n=60

Pd

n=57

HR=0.54 (95% CI 0.34, 0.86); p=0.0078

Median

PFS

95% CI

10.3 mo

5.6, NE

4.7 mo

2.8, 7.2

Dimopoulos MA, et al., N Engl J Med 2018;379(19):1811-1822

PFS median follow-up 15.4 months

Where are we going to use these other mAbs?

Pomalidomide-Dex

(as a backbone)


Dara or Elo


/MOR202

(single agent or

combination)


induction



EloRd

Rd

Clinical trial



induction

Doublets

Kd / Vd


DaraVD or PanoVD or

EloVD or VCD

BCMA as another target in MM

Belantamab madofotin (GSK2857916): BCMA-ADC in MM

Cohen et al. Blood;128(22):1148.

Humanized IgG1 anti-BCMA Ab conjugated to Monomethyl auristatine-F

BCMA is restricted to B cells at later stages of differentiation, broadly expressed on malignant PC

Phase 1 study with GSK 916

N=35 patients

• 57% 5 prior lines of therapy

-97% PI refractory

-91% IMiD refractory

-30% Dara refractory

Ph 1 DREAMM-1 study: BCMA-ADC in MM Part 2 (dose expansión): 3.4 mg/kg iv once every 3 weeks

35 RRMM patients after ASCT, PIs, IMiD’s and mAbs

Trudel et al. Blood Cancer Journal (2019)9:37

Median PFS: 12 months

Median DOR: 14.3 m

ORR: 60%, CR+sCR: 15%Dara-refractory patients, ORR of 43%

PFS for respondersPFS

Toxicity profile includes: Thrombocytopenia in 63% (G3 in 26%) and corneal events in 69% (G3 in 14%), reversible after a median duration of 35 days

BCMA bispecific antibodies in myeloma

• Potential to overcome the limitations of immunosuppressive tumor microenvironment by redirecting T cells to kill tumor target cells

• BCMA (B-cell maturation antigen, CD269)

• IgG-like bispecific antibody (long serum half-life, retain Fc function):1–3

– Anti-BCMAxCD3 (Pfizer)4

– Ab-957 (GenmabDuoBody/Janssen)1

– CC-93269 (EngMab/Celgene)2,3

– Bi-Fab5

• Non-IgG like BiTE® (better tissue penetrance, accessto epitopes):

– BI 836909 (Boehringer Ingelheim; AMG420, Amgen)6

BCMA, B cell maturation antigen; CTL, cytotoxic T cell; Ig, immunoglobulin; TCB, T-cell bispecific.

1.Pillarisetti K, et al. Abstract 2116; Presented at ASH 2016; San Diego, California; 2. Seckinger A, et al.

Cancer Cell 2017;31:396–410; 3. Cho S-F, et al. Front Immunol 2018;9:1821; 4 Panowski SH, et al. Abstract

383; Presented at ASH 2016; San Diego, California; 5. Ramadoss NS, et al. J Am Chem Soc 2015;137:5288–

91; 6. Hipp S, et al. Leukemia 2017;31:1743–51. 29

Mechanism of action of CC-93269 BCMA-TCB

-BCMA: bivalent high affinity binding

-CD3 chain: monovalent low affinity binding

IgG-like bi-specific T cell engagers mAbs

BCMAxCD3 bispecific antibody (JNJ-957) for the treatment of MM: preclinical activity

JNJ-957, effectively lysed primary MM cells both in samples derived from heavily pre-treated

DARA-refractory patients and those with low BCMA surface expression

in vivo pretreatment with DARA improves the response to JNJ-957

Supports rationale for ongoing phase 1 study with JNJ-957

Frerichs K, et al., EHA 2018; S1579 (oral presentation)

AMG 420, an Anti-BCMA BiTE in RRMM patients: results of a dose escalation FIH phase 1 study

42 pts, progression after ≥ 2 PL, which included both PI and IMiD

Median of PL was 4 but few of them, 26% were exposed to either dara or elo

31% of pts included double refractory to both PI and IMiD

MTD was 400 µg/d with CRS and PN as DLT observed with 800 µg/d

- 13 pts out of 42 included responded (30%)

- Pts who responded had deepen responses with 7 of them in CR/MRD-ve, 3 VGPR and 3 PR

- Toxicity profile: CRS observed in 16 (38%), grade 3 in 1 pt; Infections in 12 pts (29%),

grade 3-5 in 9 pts; PN in 4 pts (10%), grade 3 in all of themTopp et al ASH 2018, abstract 1010

Where are we going to use these novel agents?

Pomalidomide-Dex

(as a backbone)

+ Cyclo or Isa or Bort or

Dara or Elo


(single agent or

combination)


induction



EloRd

Rd

Clinical trial



induction

Doublets

Kd / Vd


DaraVD or PanoVD or

EloVD or VCD


Novel mAbs anti BCMA

Belantamab madofotin

Bispecifics/Bites mAbs




- Although SLAMF7 is other target for MM today used with elotuzumib, BCMA seems to be quite exploited

for new mAbs

- After the use of a mAB targeting BCMA, is it possible to use another-one with different MoA?

- Other targets are coming like GPRC5D through a bispecific mAB



Are there alternative alkylators or

should we forget them for the future?

Melflufen

4. Hydrophilic

alkylating

moieties trapped inside

the cell

2. Lipophilic

melflufen

rapidly

traverses cell

membranes

1. Amino-

peptidases highly

over expressed in

multiple myeloma

(MM) cells

3. Amino-peptidase

potentiated release of

hydrophilic alkylating

moieties

5. Melflufen and

hydrophilic

alkylating

moieties binds

directly to DNA

Melflufen

Amino-peptidase

Alkylating moiety

• Approx. 50-fold higher intra-

cellular exposure in MM cells1,5

• Approx. 50-fold higher anti-MM

potency1,2,5

• Alkylation of DNA with limited

or no induction of DNA repair3,5

• Strong anti-angiogenic

properties 1,4,5

• Therapeutic index of 20 - 40 (MM

cells compared with peripheral

blood mononuclear cells)1,5

Peptidase potentiated activity in

MM cells results in:

1. Chauhan et al. (2013) Clin Cancer Res;19(11):3019-303.

2. Wickstrom et al. (2008) Invest New Drugs;26(3):195-204.

3. Ray et al. (2016) Br J Haematol;174:397-409

4. Strese et al. (2013) Biochem Pharmacol;86:888–895.

5. Wickström et al. (2017) Oncotarget;8(39):66641-66655.

Melflufen is a peptidase enhanced therapy with an alkylating payload

Melflufen + Dex: Horizon trial (OP-106)

Melflufen 40 mg iv every 28 days +Dex 40 mg weekly

Richardson PG. ASH 2018. Abs. 600

n= 83 RRMM pts ≥ 2 prior lines including IMiD & PI and refr to Pom and/or Dara

5 (2-13) prior lines; 55% Alkylator refr.

ORR 33% 1 sCR; 9 VGPR & 17 PR

≥ SD 84%

G3/4 rel. TEAEs: Thromboc. (59%), Neutropenia (61%), Anemia: 25%

PFS: 4 m …… 6.4 m for ≥ PR

Anchor trial (OP-104): Melflufen in combination with

- Dara + Dex. n=3 …. 100% ORR - Bortezomib + Dex. n=9 …. 86% ORR

Ocio EM. ASH 2018, abstract 1967, poster presentation

EDO-S101-> Tinostamustine: bendamustine derivative

DNA Alkylation Moiety

Purine-like

Benzimidazole ring

HDAC Moiety

Butyric acid group

Purine-like

Benzimidazole ring

DNA Alkylation Moiety

Bendamustine

EDO-S101

Ac

Ac

Ac

Ac

Ac

HDAC

HDAC

HDAC DAC

Inhibitor Alkylator

EDO-S101 a molecule including

bendamustine + an DACi radical

The rationale is that the DACi would

open the chromatin so bendamustine

can better exert the alkylating activity

López-Iglesias et al, J Hematol Oncol 2017;10(1):127

In vivo activity of EDO-S101

Small tumors

0

1000

2000

3000

4000

5000

6000

0 10 20 30 40 50 60 70 80 90

Tu

mo

r vo

lum

e(m

m3)

Time in days

Control EDO-S101

Treatment period

Time in days

100806040200

1,0

0,8

0,6

0,4

0,2

0,0

Cu

mu

lati

ve

su

rviv

al

0

50

100

150

200

250

300

350

1 8 19 31 43

Control EDO-S101

Tu

mo

rvo

lum

e(%

)

Time in days

Treatment period

Big tumors

Vk12653 model

EDO-S101 was the only drug

with single agent activity in the

Vk12653 model, where it was

also able to prolong survival

Clinical trials are planned as single agent and in combination with Carfilzomib and Daratumumab

López-Iglesias et al, J Hematol Oncol 2017;10(1):127

Where are we going to use these alkylators?

Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61;

Mateos MV, personal communication

Pomalidomide-Dex

(as a backbone)


Dara or Elo

Daratumumab

(single agent or

combination)

Melflufen + Dara

First relapse after Bortezomib-

based induction



EloRd

Rd

Clinical trial



induction

Doublets

Kd / Vd


DaraVD or PanoVD or

EloVD or VCD

Novel drugs

Melflufen, EDO

Next-generation IMIDs, CELMoDs™ (Cereblon E3 Ligase Modulation Drugs) in Multiple Mieloma

Blood 2015

CC-220: Iberdomide

CC-92480

Nowakowski GS. Blood 2015 126:698-700

Where are we going to use these alkylators?

Pomalidomide-Dex

(as a backbone)


Dara or Elo

Daratumumab

(single agent or

combination)


induction



EloRd

Rd

Clinical trial



induction

Doublets

Kd / Vd


DaraVD or PanoVD or

EloVD or VCD


Novel drugs

Melflufen, EDO

New IMiD’s

Venetoclax (Bcl-2 inhibitor)

• Venetoclax (ABT-199 / GDC-0199) is a potent, selective, orally bioavailable, small-molecule,

BCL-2 inhibitor1

• Anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival2

Touzeau C, et al. Leukemia 2018;32(9):1899-1907

Venetoclax monotherapy

Kumar, et al. Blood 2017;130(22):2401-2409

88% in t(11;14) with a high BCL2:BCL2L1 ratio

n= 66 pts. 5 prior lines (1-15). 79% refr. to last line; 61% double refractory to Btz & Len. t(11;14): 46%

100%

30-1200 mg po (MTD: 1200 mg)

Main toxicities are mild GI symptoms; thrombocytopenia (32% G3-4) and neutropenia (27% G3-4)

t(11;14) 6.6 (3.9-

10.2)

Non t(11;14) 1.9 (1.2-

2.3)

Time to Progression

Venetoclax + Dex: 65% in 20 pts with t(11;14) & 3 prior lines of therapy Kauffman, et al. ASH 2017, abstract 3131, poster presentation

Venetoclax plus bortezomib and dexamethasone

Moreau P, et al. Blood 2017;130(22):2392-2400

The phase 3 Bellini study comparing Vd +/- Venetoclax met its primary end point but an excess of deaths

were observed in the Ven arm so FDA put on hold all VEN studies in MM

n= 66 patients after ≥1 prior lines of therapy (median 3). 39% refractory to Btz

BCL2 quantitation using ddPCR performed on CD138-selected bone

marrow mononuclear cells collected at baseline.

BATTing was used to estimate a threshold of BCL2 to provide

optimum selection of patients likely to have a response.

ORR: 67% (mainly in Btz non-Rfr. & 1-3 prior lines) ORR: 94% in Bcl2 high pts

Similar responses irrespective of t(11;14) status

TTP 9.5 m (95% CI, 5.7, 10.4) & DOR 9.7 m (95% CI, 7.4, 15.8)

BAD

NOXA

BMF

HRK

BIK

Intracellular stress

MCL-1

BCL-2

BCL-XL

BCL-w

BFL-1/A1

BCL-B

BIM

PUMA

tBID

ANTI-APOPTOTIC

PRO-APOPTOTIC

ACTIVATORS

PRO-APOPTOTIC

SENSITIZERS

Mitochondrial

permeabilization

BAX

BAK

BOK

PRO-APOPTOTIC

EFFECTORS BIMBIM

APOPTOSIS

BIM

MCL-1

BCL-2

Algarín et al. EHA 2018

Bcl-2 Family

Sensitivity of MM cell to the BH3 mimetics

Mcl-1 expression correlates with disease severity andclinical outcome

In this group of 25 newly diagnosed patients, two deaths were

observed due to progressive disease, with a median follow-up

for living patients of 12 months (range: 4–40). The OS was

90.7% at 40 months (þ 6%). The median EFSwas 26 months for

the whole group of patients (range: 4–40). The single factor

influencing EFS was the level of Mcl-1 expression (median

MFIR: 13, range: 5.8–22). The median duration of EFS was 12

months (range: 4–18) in the group of 11 patients with an

abnormal expression of Mcl-1 (two deaths and three relapses

were observed), as compared with an EFS of 66.7% at 40

months (median not reached) in the group of 14 patients with a

normal expression of Mcl-1 (1 relapse observed) (P¼0.002)

(Figure 2). These two groups of patients (normal and abnormal

expression of Mcl-1) were identical regarding initial character-

istics and regarding treatment regimen: the percentage of

patients treated with either conventional treatment, or single

autologous stem cells transplantation, or tandem transplant was

similar in both groupsof patients. In thissmall cohort of patients,

chromosome 13 deletion, beta-2-microglobulin level or other

presenting features did not statistically influence survival as

single parameters.

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

Normal bone MM MMmarrow PC Diagnosis Relapse

(n= 7) (n= 24) (n= 19)

HMCL RP


(n= 7) (n= 25) (n= 26)

HMCL RP

(n=21) (n=3)

(n=20) (n=8)

Bcl-2

d

Bcl-2

c

Mcl-1Mcl-1

MF

IRM

FIR

Figure 1 Comparison of Mcl-1 and Bcl-2 expression in normal and malignant PC. Comparison of Mcl-1 (a) or Bcl-2 (c) expression in normalbone marrow PC, malignant PC from MM patients either at diagnosis or relapse. Comparison of Mcl-1 (b) or Bcl-2 (d) expression in HMCL and RP.Horizontal lines: mean of fluorescence intensity ratio in each group of patients. MFIR: mean fluorescence intensity ratio.

Mcl-1 expression in normal and malignant human plasma cellsS Wuilleme-Toumi et al

1250

Leukemia

Mcl-1 expression correlates with disease severity andclinical outcome

In this group of 25 newly diagnosed patients, two deaths were

observed due to progressive disease, with a median follow-up

for living patients of 12 months (range: 4–40). The OS was

90.7% at 40 months (þ 6%). The median EFSwas 26 months for

the whole group of patients (range: 4–40). The single factor

influencing EFS was the level of Mcl-1 expression (median

MFIR: 13, range: 5.8–22). The median duration of EFS was 12

months (range: 4–18) in the group of 11 patients with an

abnormal expression of Mcl-1 (two deaths and three relapses

were observed), as compared with an EFS of 66.7% at 40

months (median not reached) in the group of 14 patients with a

normal expression of Mcl-1 (1 relapse observed) (P¼0.002)

(Figure 2). These two groups of patients (normal and abnormal

expression of Mcl-1) were identical regarding initial character-

istics and regarding treatment regimen: the percentage of

patients treated with either conventional treatment, or single

autologous stem cells transplantation, or tandem transplant was

similar in both groupsof patients. In thissmall cohort of patients,

chromosome 13 deletion, beta-2-microglobulin level or other

presenting features did not statistically influence survival as

single parameters.

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35

0

5

10

15

20

25

30

35


(n= 7) (n= 24) (n= 19)

HMCL RP


(n= 7) (n= 25) (n= 26)

HMCL RP

(n=21) (n=3)

(n=20) (n=8)

Bcl-2

d

Bcl-2

c

Mcl-1Mcl-1M

FI R

MF

IR

Figure 1 Comparison of Mcl-1 and Bcl-2 expression in normal and malignant PC. Comparison of Mcl-1 (a) or Bcl-2 (c) expression in normalbone marrow PC, malignant PC from MM patients either at diagnosis or relapse. Comparison of Mcl-1 (b) or Bcl-2 (d) expression in HMCL and RP.Horizontal lines: mean of fluorescence intensity ratio in each group of patients. MFIR: mean fluorescence intensity ratio.

Mcl-1 expression in normal and malignant human plasma cellsS Wuilleme-Toumi et al

1250

Leukemia

MM cells over-express Mcl-1

Wuillème-Toumi et al. Leukemia 2005;19(7):1248-52

Gong et al. Blood 2016; 128(14):1834-1844

Mcl-1

Bcl-2

Several Mcl-inhibitors are currently in Phase I:

MIK665 (S64315): MM, NHL, AML, MDS

AMG-176 (MM, AML) & AMG-397 (MM, NHL, AML)

AZD5991: Hem. Malignancies

Alvocidib (CDK9 inh): AML

Mcl-1 dependence in MM


Pomalidomide-Dex

(as a backbone)


Dara or Elo

Daratumumab

(single agent or

combination)


induction



EloRd

Rd

Clinical trial



induction

Doublets

Kd / Vd


DaraVD or PanoVD or

EloVD or VCD


Novel drugs

Melflufen, EDO

New IMiD’s, Venetoclax

XPO1-Inhibitors: Selinexor

Tai et al. Leukemia 2014;28(1):155-65

Selinexor is a first-in-class XPO1

inhibitor that induces nuclear

retention and activation of TSPs

and the GR in the presence of

steroids and suppresses

oncoprotein expression

Exportin 1 (XPO1) is the nuclear

exporter for the majority of tumor

suppressor proteins (TSPs), the

glucocorticoid receptor (GR), and

eIF4E-bound oncoprotein mRNAs

Selinexor plus dex (STORM study) in

Penta-refractory MM

Chari, et al. ASH 2018, abstract 598

Main AEs: Thromboc. (67%, 53% G3-4), anemia (46%, 28% G3-4), fatigue (68%; 21% G3-4),

nausea (67% 10% G3/4), anorexia 50%; 2% G3/4), weight loss (46%; 0% G3/4)

n=122 pts 7 (3-18) prior lines Penta refractory (bor,carf, len, pom & CD38 mAbs)

100%

ORR (≥ PR): 26% (6.5% VGPR (2 sCR));

≥ MR 39%; ≥SD 79%

Median DOR: 4.4 months PFS: 3.7

Eltanexor (2nd gen. XPO1 inh) n=36 pts. 7 prior lines +/- DexCornell, et al. ASH 2017, abstract 3134

OS: 8 months

Selinexor Combinations

PI IMiDs

Bort-Dex* Cfz-Dex Len-Dex Pom-Dex

n 42 21 18 34

Prior lines 3 (1-11) 4 (2-10) 1 (1-7) 4 (2-9)

ORR83%

in non PI refr. pts63% 73% 44%

In pts Refractory

to the backbone42% 67% 1uPR / 4 38%

PFSnon PI refr.: 18 m

PI refr.: 9 m3.7 m 6.6 m 10.3 m

Bahlis NJ et al. Blood

2018;132(24):2546-2554

Jakubowiak. ASH 2016,

abstract 973

White. ASH 2017,

abstract 1861

Chen. ASH 2018,

abstract 1993

Gasparetto, et al. ASH 2018, abstract 599Daratumumab + Dex (n=25): 74% ORR in Dara naïve pts

* Phase III Boston trial (SVd vs Vd) ongoing


Pomalidomide-Dex

(as a backbone)


Dara or Elo

Daratumumab

(single agent or

combination)


induction



EloRd

Rd

Clinical trial



induction

Doublets

Kd / Vd


DaraVD or PanoVD or

EloVD or VCD


Novel drugs

Melflufen, EDO

New IMiD’s, Venetoclax,

Selinexor+Dex

Selinexor+Bor-Dex

Targeting MM microenvironment

MP0250 + Bort-Dex

VEGF + HGF inhibitor

n=8. ORR 62%, including 3/4 PI refr pts

as last line

Xu et al. Leukemia 2018, 32, 1500–1514

Knop S, et al. ASH 2018. Abst. 1980

Vactosertib (TEW-7197) + Pom

TGF-β Receptor inhibitor

N=5.

Malek E, et al. ASH 2018. Abst. 1962

Ulocuplumab (BMS-936564) + Len-Dex or

Bort-Dex

Anti-CXCR4 MoAb

N=46. ORR: 44%; 55% with Len-Dex

Ghobrial I, et al. ASH 2018, abstract 3263




• Other drugs with different MoA- Melflufen, selinexor, venetoclax,….. Are promising drugs to be used

- The landscape of treatment for MM is challenging and we are being very exigent with these new drugs

asking them to be effective in patients exposed and refractory to everything.


CAR-T technology

CAR, chimeric antigen receptor.Maus and Levine The Oncologist 2016; Li and Zhao Protein Cell 2017;

Chang and Chen Trends Mol Med 2017; Brudno JN & Kochenderfer N. Nat Rev Clin Onc 2018;15:31–46.

• CAR structure:– Extracellular domain: antibody domain (scFv) against a tumor antigen– Transmembrane domain– Intracellular domain: First generation CARs: CD3ζ (T cell coreceptor necessary for T cell activation) Second generation CARs: CD3ζ + either CD28 or 4-1BB (costimulatory domain) to increase proliferation and survival Third generation CARs to come: CD3ζ + two costimulatory domains (CD28, 4-1BB, OX40, ICOS, CD27)

BCMA CART for MM: where we are coming from?

1. Ali A, et al. ASH 2015, abstract LBA-1; 2. Raje NS, et al. J Clin Oncol 2018;36:(suppl; abstr

8007); 3. Cohen AD, et al. Blood 2017;130:505; 4. Zhang W, et al. EHA 2017, abstract S103.

Anti-BCMA CAR1

NCT02215967

Bb21212

NCT02658929

CART-BCMA3

NCT02546167

LCAR-B38M4

NCT03090659

Group/company NIH Bluebird/CelgeneUniversity of Pennsylvania/

Novartis

Nanjing Legend

Biotech

Patients16 patients at 9x106/kg

dose level22 (>150 x 106 cells)

21 (3 cohorts):

9 (10-500 x 106, No Cyt)

5 (10–50 x 106 , Cyt)

7 (5 (100–500 x 106 , Cyt)

35

BCMA expression

required?Yes Yes; ≥ 50% BCMA expression No Yes

Median prior lines

of therapy7 7 7 (3–11) 3

Reported efficacy

ORR 14/16 (81%)

11/14 (79%) MRD-

Median EFS: 7,2 m

86.4% ≥VGPR

(50% sCR/CR)

Median PFS: 11.8 m

In MRDneg: mPFS 17.7 m

#1: 67% (1 sCR, 1VGPR)

#2: (40%) 1 PR, 1 MR both PD

#3: (83%) 1 CR, 3 PR, 1 MR

ORR: 100%

15CRs (42%)

13 VGPR (37%)

7 PRs

Safety dataCRS all grades:100%,

37%G3-4

CRS all grades: 63%

2 events of CRS grade ≥3

resolved within 24 hours

CRS: 17 pts (grade 3: 32%)

Neurotoxicity: 3 (2 grade 4)

1 death – PD candidaemia

Transient CRS (5,7% G3)

No neurotoxicity

CRB-401 PHASE 1 STUDY DESIGN IN RRMM PATIENTS

≥50% BCMA expression

<50% BCMA expression (n=10)

≥50% BCMA expression (n=12)

Dose range: 150–450 × 106 CAR+ cells

Dose Escalation (N=21) Dose Expansion (N=22)

Flu 30 m/m2

Cy 300 mg/m2

Manufacturing success rate of 100%

150 × 106 450 × 106 800 × 10650 × 106

Raje N et al. NEJM 2019

Escalation (N=21) Expansion (N=22)

Exposed Refractory Exposed Refractory

Prior therapies, n (%)

Bortezomib 21 (100) 14 (67) 22 (100) 16 (73)

Carfilzomib 19 (91) 12 (57) 21 (96) 14 (64)

Lenalidomide 21 (100) 19 (91) 22 (100) 18 (82)

Pomalidomide 19 (91) 15 (71) 22 (100) 21 (96)

Daratumumab 15 (71) 10 (48) 22 (100) 19 (86)

Exposed/Refractory, n (%)

Bort/Len 21 (100) 14 (67) 22 (100) 14 (64)

Bort/Len/Car/Pom/Dara 15 (71) 6 (29) 21 (96) 7 (32)

Escalation

(N=21)

Expansion

(N=22)

Median (min, max) prior regimens 7 (3, 14) 8 (3, 23)

Prior autologous SCT, n (%) 21 (100) 19 (86)

0 0 3 (14)

1 15 (71) 14 (64)

>1 6 (29) 5 (23)

TREATMENT HISTORY

Data cutoff: March 29, 2018. SCT, stem cell transplant. Raje N et al. NEJM 2019

12.5 9.1

50.0

27.3

37.5

54.5

0

10

20

30

40

50

60

70

80

90

100

450 x 106 low 450 x 106 high

Ob

jec

tive

Re

sp

on

se

Ra

te, %

sCR/CR

VGPR

PR

33.3

7.1 9.17.1

36.4

42.9

50.0

0

10

20

30

40

50

60

70

80

90

100

50 x 106 150 x 106 >150 x 106

Ob

jec

tive

Res

po

nse

Rate

, %

sCR/CR

VGPR

PR

TUMOR RESPONSE: DOSE-RELATED; INDEPENDENT OF TUMOR BCMA EXPRESSION

Data cutoff: March 29, 2018. CR, complete response; mDOR, median duration of response; ORR, objective response rate; PD, progressive disease; PR, partial response; sCR, stringent

CR; VGPR, very good partial response. aPatients with ≥2 months of response data or PD/death within <2 months. ORR is defined as attaining sCR, CR, VGPR, or PR, including confirmed

and unconfirmed responses. Low BCMA is <50% bone marrow plasma cells expression of BCMA; high BCMA is defined as ≥50%.

Tumor Response By Dosea Tumor Response By BCMA Expressiona

ORR=33.3%

mDOR=1.9 mo

ORR=57.1%

mDOR=NE

150 × 106

(n=14)

>150 × 106

(n=22)

50 × 106

(n=3)

ORR=95.5%

mDOR=10.8 mo

450 × 106

High BCMA

(n=11)Median follow-up

(min, max), d87

(36, 638) 84

(59, 94) 194

(46, 556) Median follow-up

(min, max), d

450 × 106

Low BCMA

(n=8) 311(46, 556)

ORR=100%

ORR=91%

168(121, 184)

Raje N et al. NEJM 2019

PROGRESSION-FREE SURVIVAL

PFS at Inactive (50 × 106) and Active (150–800 × 106) Dose Levelsa PFS in MRD-Negative Patients

Data cutoff: March 29, 2018. Median and 95% CI from Kaplan-Meier estimate. NE, not estimable. aPFS in dose escalation cohort.

50 × 106

(n=3)

150–800 × 106

(n=18)

Events 3 10

mPFS (95% CI), mo2.7

(1.0–2.9)

11.8

(8.8–NE)

150–800 × 106

(n=16)

mPFS (95% CI), mo17.7

(5.8–NE)

• mPFS of 11.8 months at active doses (≥150 × 106 CAR+ T cells) in 18 subjects in dose escalation phase

• mPFS of 17.7 months in 16 responding subjects who are MRD-negative

mPFS = 11.8 mo

mPFS = 2.7 mo

mPFS = 17.7 mo

Updated Analysis of a Phase 1, Open-Label Study of LCAR-B38M, a Chimeric Antigen Receptor T Cell Therapy Directed Against B-Cell

Maturation Antigen, in Patients with Relapsed/Refractory Multiple Myeloma

Zhao et al., ASH 2018; abstract 955

VH

VL

Typical CAR LCAR-B38M CAR

VHVH

Binding domains

• LCAR-B38M is a chimeric antigen receptor

(CAR) T cell therapy with 2 BCMA targeting

domains

– Confers high avidity binding and

distinguishes LCAR-B38M from other

BCMA-targeted CAR T cell therapies

• 57 patient experience at Xi’an site as of

25 June 2018 are presented here, with a

12-month (0.7–25.1) follow-up

• n=57. Median nº prior lines: 3 (1-9)

• Prior Bort 68%. Prior Len 44%. Prior PI + IMID

60%. Prior SCT: 18%

Updated Analysis of a Phase 1, Open-Label Study of LCAR-B38M, a Chimeric Antigen Receptor T Cell Therapy Directed Against B-Cell

Maturation Antigen, in Patients with Relapsed/Refractory Multiple Myeloma


a8-color flow cytometry with cell count up to 500,000 cells; bBCMA expression data available for 53 patients

Best Overall Response by Dose

• mDOR = 16 mo (95% CI, 12–NR)

• mDOR for MRD-neg CR = 22 mo (95% CI, 14–NR)

• Median time to initial response = 1 mo (0.4–3.6)

Best Overall Response (N=57)

39 (68%)MRD-neg

0%

20%

40%

60%

80%

100%

1 2 3

NE

PD

SD

PR

VGPR

CR

N=57 n=25 n=32

AllDoses

<0.5x106

cells/kg≥0.5x106

cells/kg

ORR = 88%

42 (74%)

2 (3%)6 (11%)

4 (7%)1 (2%) 2 (3%)

CR VGPR PR SD PD NE

39 (68%)MRD-nega

BCMA <40% (n=26/53)b = 92% ORRBCMA ≥40% (n=27/53)b = 82% ORR

Responses were maintained regardless the dose of T cells infused as well as the BCMA expression

Progression Free Survival and Overall Survival


0 3 6 9 12 15 18 21 24 27

Pro

gre

ssio

n-F

ree

Su

rviv

al (

%)

Months

Patients Achieving MRD-neg CRa

mPFS: 24 mo(95% CI, 15–NR)12-mo PFS: 87%

Patients Not AchievingMRD-neg CRmPFS: 6 mo

(95% CI, 3–8)12-mo PFS: 6%

All PatientsmPFS: 15 mo

(95% CI, 11–NR)12-mo PFS: 61%

100

80

60

40

20

0

0 3 6 9 12 15 18 21 24 27

Ove

rall

Surv

ival

(%

)

All PatientsmOS: not reached

12-mo survival: 75%

Patients Achieving MRD-neg CR

mOS: not reached12-mo survival: 94%

Patients Not Achieving MRD-neg CR

mOS: 8 mo (95% CI, 4–14)12-mo survival: 29%

100

80

60

40

20

0

0 3 6 9 12 15 18 21 24 27

PFS OS

a30/39 patients still in remissionToxicity profile

• 35% G2 CRS. 7% G3. No G4.

• Tocilizumab use: 46%

141

0 3 6 9 12 15 18 21 24 27

Pro

gres

sio

n-F

ree

Surv

ival

(%

)

All PatientsmPFS: 15 mo

(95% CI, 11–NR)12-mo PFS: 61%

• There are many options of treatment beyond Daratumumab

• Daratumumab will be mainly used in the upfront setting

• Novel drugs, like Selinexor, venetoclax, melflufen,….. Are coming

• Novel mABs with other targets like BCMA

• CAR-T targeting BCMA is promising:

• Future perspectives:

To define the target population that will benefit the most from each drug/combination of

drugs

New biomarkers to predict sensitivity

Evaluation of the immune profiling at baseline to identify ideal candidates

Novel immune-related response criteria and new end-points

Mechanism of resistance and how to overcome them

Optimal combinations

Conclusions

Multiple Myeloma beyond Daratumumab

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