multiple myeloma beyond daratumumab
TRANSCRIPT
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
Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61
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
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)
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
Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61
Is there anything else beyond Daratumumab?
• Other mAbs targeting CD38
- 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?
• Other mAbs targeting other molecules
• Other drugs with different MoA
• New immunotherapic strategies
Is there anything else beyond Daratumumab?
• Other mAbs targeting CD38
- 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?
• Other mAbs targeting other molecules
• Other drugs with different MoA
• New immunotherapic strategies
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)
+ Cyclo or Ixa or Bort or
Dara or Elo
Daratumumab/Isatuximab
/MOR202
(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
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
Daratumumab/Isatuximab
(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
Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61
Novel mAbs anti BCMA
Belantamab madofotin
Bispecifics/Bites mAbs
Is there anything else beyond Daratumumab?
• Other mAbs targeting CD38
• Other mAbs targeting other molecules
- 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
• Other drugs with different MoA
• New immunotherapic strategies
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)
+ Cyclo or Ixa or Bort or
Dara or Elo
Daratumumab
(single agent or
combination)
Melflufen + Dara
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
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)
+ 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
Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61
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
Normal bone MM MMmarrow PC Diagnosis Relapse
(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
Normal bone MM MMmarrow PC Diagnosis Relapse
(n= 7) (n= 24) (n= 19)
HMCL RP
Normal bone MM MMmarrow PC Diagnosis Relapse
(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
Where are we going to use these novel agents?
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
Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61
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
Where are we going to use these novel agents?
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
Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61
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
Is there anything else beyond Daratumumab?
• Other mAbs targeting CD38
• Other mAbs targeting other molecules
• 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.
• New immunotherapic strategies
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
Zhao et al., ASH 2018; abstract 955
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
Zhao et al., ASH 2018; abstract 955
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%
142
• 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