Download Nieuwste middelen

Nieuwste middelen
NIELS VAN DE DONK
Department of Hematology, VU University Medical Center Amsterdam
DHC2016, Januari 2016
VU University Medical Center
Amsterdam The Netherlands
Waar komen we vandaan ?
VU University Medical Center
Amsterdam The Netherlands
1844
1844: First description of Multiple Myeloma by Solly;
39-year old Sarah Newbury
R/ rhubarb and orange skin
Solly Med Chir Trans Lond 1844
VU University Medical Center
Amsterdam The Netherlands
Melphalan
1958: Blokhin, 3 out of 6 patients respond to melphalan
1962: Daniel Bergsagel starts phase 2 studies in
MD Anderson Houston, TX
Third drug tested was melphalan
Response in 8/24 patients
Blokhin Ann NY Acad Sci 1958; Bergsagel Cancer Chemother Rep 1962
VU University Medical Center
Blokhin Ann NY Acad Sci 1958; Bergsagel Cancer Chemother Rep 1962
Amsterdam The Netherlands
Melphalan en Prednisone
1969: Alexanian starts phase 3 study with melphalan-prednisone (MP
versus melphalan.
Survival benefit of 6 months for MP
Melphalan-prednisone as standard of care for next 40 years
Alexanian JAMA 1969
Alexanian JAMA 1969
VU University Medical Center
Amsterdam The Netherlands
2000+: Anti-myeloma drugs
IMIDs
PIs
Alkylators/
Steroids
Thalidomide
Bortezomib
anthracyclins
Dexamethasone
Melphalan
Prednisone
Lenalidomide
Cyclophosphamide
Doxorubicin
Patient features
Age
Co-morbidities
Performance status
Myeloma features
ISS
Cytogenetics
LDH
Previous therapy
Response
Duration
Adverse events
Transplant?
Waar gaan we naar toe ?
VU University Medical Center
Amsterdam The Netherlands
Nieuwste middelen

Nieuwe medicijnen die toegepast worden in huidige Myeloom
studies in Nederland

Monoclonale antistoffen
 Daratumumab
 Durvalumab
 Elotuzumab

Nieuwe proteasoom remmer
 Ixazomib
 Carfilzomib

Nieuwe IMID
 Pomalidomide

Andere middelen
 Selinexor
VU University Medical Center
Amsterdam The Netherlands
Dara, SAR, ELo
2014
Behring en Ehrlich: magic bullet
DARATUMUMAB
VU University Medical Center
Amsterdam The Netherlands
CD38 as a Therapeutic Target

1.
2.
3.
4.
High expression on myeloma cells combined with its
role in cell signaling suggest CD38 as a potential
therapeutic antibody target for treatment of multiple
myeloma (MM)
Malavasi F, et al. Physiol Rev. 2008;88(3):841-886.
Lin P, et al. Am J Clin Pathol. 2004;121(4):482-488.
Santonocito AM, et al. Leuk Res. 2004;28(5):469-477.
Deaglio S, et al. Leuk Res. 2001;25(1):1-12.
VU University Medical Center
Amsterdam The Netherlands
12
Generation of
daratumumab



Human Ig transgenic mice were immunized with
recombinant CD38 protein and CD38-transfected NIH
3T3 cells
Generation of hybridomas (fusion of mice
spleen/lymph node cells with SP2/0 MM cells)
Testing of 42 anti-CD38 mAbs in CDC assays
 only one mAb was capable to induce CDC
 this antibody was selected for further
testing=daratumumab
VU University Medical Center
Amsterdam The Netherlands
How do monoclonal antibodies work?
Monoclonal antibodies
Natural killer
cell the
bind to
surface of the myeloma cell
Macrophage
As a results……
Adapted from:
VU
University
Medical
Center
Golay & Introna M. Arch Biochem Biophys 2012 ;526(2):146-53
Amsterdam
The Res
Netherlands
Tai & Anderson
Bone Marrow
2011;2011:924058
Monoclonal antibodies bind to malignant cells
and act through different modes of action
Activation of natural
Natural killer
killer cells
cell
Antibody-dependent
cellular cytotoxicity
(ADCC)
Macrophage
Adapted from:
VU
University
Medical
Center
Golay & Introna M. Arch Biochem Biophys 2012 ;526(2):146-53
Amsterdam
The Res
Netherlands
Tai & Anderson
Bone Marrow
2011;2011:924058
Monoclonal antibodies bind to malignant cells
and act through different modes of action
Activation of natural
Natural killer
killer cells
cell
Antibody-dependent
cellular cytotoxicity
(ADCC)
Activation of macrophages
Induction of phagocytosis
(Antibodydependent cellmediated
phagocytosis =
ADCP)
Macrophage
Adapted from:
VU
University
Medical
Center
Golay & Introna M. Arch Biochem Biophys 2012 ;526(2):146-53
Amsterdam
The Res
Netherlands
Tai & Anderson
Bone Marrow
2011;2011:924058
Monoclonal antibodies bind to malignant cells
and act through different modes of action
Activation of natural
Natural killer
killer cells
cell
Antibody-dependent
cellular cytotoxicity
(ADCC)
Activation of macrophages
Activation of the
complement system
Complement-dependent
cytotoxicity (CDC)
Induction of phagocytosis
(Antibodydependent cellmediated
phagocytosis =
ADCP)
Macrophage
Adapted from:
VU
University
Medical
Center
Golay & Introna M. Arch Biochem Biophys 2012 ;526(2):146-53
Amsterdam
The Res
Netherlands
Tai & Anderson
Bone Marrow
2011;2011:924058
Monoclonal antibodies bind to malignant cells and
act through different modes of action
Activation of natural
Natural killer
killer cells
cell
Antibody-dependent
cellular cytotoxicity
(ADCC)
Activation of macrophages
Activation of the
complement system
Complement-dependent
cytotoxicity (CDC)
Induction of phagocytosis
(Antibodydependent cellmediated
phagocytosis =
ADCP)
Macrophage
Direct induction of apoptosis
Apoptosis / growth arrest via
targeting of signaling pathways
Adapted from:
VU
University
Medical
Center
Golay & Introna M. Arch Biochem Biophys 2012 ;526(2):146-53
Amsterdam
The Res
Netherlands
Tai & Anderson
Bone Marrow
2011;2011:924058
Induction of ADCP
Daratumumab 3:1
Isotype control
- Effector cell: mouse mø (green)
- Target cell: Daudi (red)
- In vitro 30 minutes
VU University Medical Center
Amsterdam The Netherlands
Macrophage-mediated Phagocytosis of CD38+
Tumor Cells in the Presence of Daratumumab
0 sec
300 sec
400 sec
500 sec
600 sec
700 sec
800 sec
• Time-lapse imaging microscopy, bright field images of
mouse macrophages (arrow) that sequentially engulfed
5 individual Daudi cells (numbers) over a period of
800 seconds
Overdijk MB, et al. MAbs. 2015;7(2):311-321.
VU University Medical Center
Amsterdam The Netherlands
20
Daratumumab: waterfall plot
16 mg/kg: ORR 35%
VU University
Medical
Center
Lokhorst
NEJM
2015
Amsterdam The Netherlands
Van De Donk Cancer Manag Res 2012
LENALIDOMIDE
VU University Medical Center
Amsterdam The Netherlands
Nijhof Clinical Cancer Res 2015
DARA and Len: synergistic killing of MM cells
from a LEN/Bort-double refractory MM patient
VU University Medical Center
Amsterdam The Netherlands
VU University Medical Center
Amsterdam The Netherlands
MMY3006 (cassiopeia)
Screening
(-28 days)
Stratify by: Cytogenetics, ISS, region
Randomize #1
Arm A
Arm B
VTD
4 cycles
Stage 1
VTD + Dara
4 cycles
Induction Phase
Stem cell mobilization, conditioning, and transplant
VTD + Dara
2 cycles
VTD
2 cycles
Consolidation Phase
Subjects with PR or better
Stage 2
Randomize #2
Dara Q8Wk
until PD
Stratify by: dara treatment, response, MRD status
Observation
until PD
(maximum of 2 years)
Followed by
observation until PD
Maintenance Phase
Follow-up
VU University Medical Center
Amsterdam The Netherlands
Other monoclonal antibodies


Elotuzumab
Immuun checkpoint remmers
VU University Medical Center
Amsterdam The Netherlands
VU University Medical Center
Amsterdam The Netherlands
VU University Medical Center
Amsterdam The Netherlands
Myeloom: rem op de T cel
T cel
MM cel
VU University Medical Center
Amsterdam The Netherlands
PD-L1 downregulates cytotocix T-cell
activity to maintain immune
homeostasis
MM cell
PD-L1 downregulates cytotocix T-cell
activity to maintain immune
homeostasis
MM cell
PD-L1 downregulates cytotocix T-cell
activity to maintain immune
homeostasis
MM cell
Targeting the PD-1/PD-L1 Pathway
PD-1 immunologic checkpoint
Postow, MA, et al. J Clin Oncol. 2015 Jan 20. [Epub ahead of print]
Targeting the PD-1/PD-L1 Pathway
PD-1 immunologic checkpoint
Postow, MA, et al. J Clin Oncol. 2015 Jan 20. [Epub ahead of print]
MM001
– Durvalumab
– Durvalumab + pomalidomide
– Durvalumab + pomalidomide + dexamethasone
Other “new” novel agents
VU University Medical Center
Amsterdam The Netherlands
MLN9708 (ixazomib citrate)

MLN9708 is an orally availbale proteasome inhibitor
VU University Medical Center
Amsterdam The Netherlands
HOVON-126: Ixazomib-thalidomidedexamethason
Randomized phase 2 study in NDMM
Ixazomib until progression
9Td
Ixazomib 1x/week oral
Thalidomide 100 mg/day
Dexamethasone 40 mg/week
9 cycles every 4 weeks
Placebo until progression
VU University Medical Center
Amsterdam The Netherlands
Carfilzomib
VU University Medical Center
Amsterdam The Netherlands
Background Carfilzomib
• Carfilzomib is a selective irreversible proteasome
inhibitor1,2
– Sustained target suppression
– Effective in bortezomib-refractory disease
– Low frequency of polyneuropathy
Tetrapeptide
H
N
N
O
1.
2.
O
O
N
H
Adapted from Kuhn DJ, et al. Blood. 2007;110:3281-3290.
Arastu-Kapur S, et al. Clin Cancer Res. 2011;17:2734-2743.
H
N
O
Epoxyketone
O
O
N
H
O
Carfilzomib versus bortezomib
VU University Medical Center
Amsterdam The Netherlands
HOVON 129

Primary plasma cell leukemia
 Meest agressieve myeloom variant
 Tumorcellen stromen vanuit beenmerg uit naar het
bloed
 Slechte prognose
VU University Medical Center
Amsterdam The Netherlands
Survival improvement in pPCL vs MM
Multiple myeloma (Mayo)
Primary PCL (SEER analysis)
Early mortality due to aggressive
presentation with severe complications
Gonsalves Blood 2014; Kumar Leukemia 2014
KRd
• Carfilzomib + lenalidomide +
dexamethason
EMN12: Elderly patients: ≥65 years
Induction
Maintenance
8 x carfilzomiblenalidomidedexamethasone
Lenalidomide 10 mg daily on days 1-21
Carfilzomib once daily on days 1,2,15,16 until
progression
EMN12: Younger patients
Induction
Auto-SCT
Consolidation
4 x carfilzomiblenalidomidedexamethasone
High-dose melphalan
(200 mg/m2)
2 x carfilzomiblenalidomidedexamethasone
Stem cell harvest
RIC Allo-SCT
-allo-SCT in patients with a sibling or MUD
donor
-Conditioning: busulfan+fludarabine
Maintenance
carfilzomib: starting 2 months post-alloSCT for 6 months; followed by
lenalidomide plus carfilzomib until
progression
Carthadex

Newly diagnosed MM
 Induction and consolidation with carfilzomibthalidomide-dexamethasone (CTd)

Last cohort almost full !
VU University Medical Center
Amsterdam The Netherlands
Anti-myeloma drugs: 2016
IMIDs
PIs
Alkylators/
Steroids
Thalidomide
Bortezomib
anthracyclins
Dexamethasone
Lenalidomide
Carfilzomib
Melphalan
Prednisone
Pomalidomide
Ixazomib
Cyclophosphamide
Oprozomib
Doxorubicin
Patient features
Age
Co-morbidities
Performance status
Myeloma features
ISS
Cytogenetics
LDH
Previous therapy
Response
Duration
Adverse events
Transplant?
MoAbs
Anti-CD38 (daratumumab, SAR, MOR)
Anti-CS1 (elotuzumumab)
Anti-PD1/anti-PD-L1
(nivolumab/durvalumab/..)
Myeloma: prognosis
Antibodies: DARA /SAR/ ELO
VU University Medical Center
Amsterdam The Netherlands
Questions ?
VU University Medical Center
Amsterdam The Netherlands
VUmc, MM team




MM group, clinical
Henk Lokhorst
Sonja Zweegman
Niels van de Donk





MM group, laboratory
Tuna Mutis
Anton Martens
Richard Groen
PhD students/technicians
VU University Medical Center
Amsterdam The Netherlands
Problems with antibodies in MM
VU University Medical Center
Amsterdam The Netherlands
Landsteiner
In 1930 he received the
Nobel Prize in Physiology
or Medicine
VU University Medical Center
Amsterdam The Netherlands
Blood group system
VU University Medical Center
Amsterdam The Netherlands
Other blood groups
Other blood groups: Kell / Kidd / duffy / ….
VU University Medical Center
Amsterdam The Netherlands
Tranfusion with lamb=letal
VU University Medical Center
Amsterdam The Netherlands
VU University Medical Center
Amsterdam The Netherlands
Blood transfusion
VU University Medical Center
Amsterdam The Netherlands
Antibodies against RBCs


Naturally occurring antibodies (anti-A, anti-B)
Acquired antibodies (anti-D (Rhesus))
 Pregnancy
 Previous transfusion
 Transplant
VU University Medical Center
Amsterdam The Netherlands
VU University Medical Center
Amsterdam The Netherlands
VU University Medical Center
Amsterdam The Netherlands
Treatment Interference With The Indirect Coombs Assay
Y
Donor RBCs
Treated Serum
Containing Drug A Abs
Y
Y
Y
Y
Y
Y
Y
YY
Y
Y
Y
YY
Y
Y
Coombs
Reagent
Coombs
Reagent
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Coombs
Reagent
Y
Y
Y
Y
YY
Donor RBCs
Y
Recipient Serum
Containing Abs
Y
Donor RBCs
Treatment Interference
False Positive
Y
Recipient Serum
No Abs
Positive Result Agglutination
Y
Negative Result Agglutination
Y
68
Y
Phase 2 study : KRd upfront
Induction
Auto-SCT
Consolidation
4x KRd
High-dose melphalan
(200 mg/m2)
4x KRd
After 4x
KRd
PostAfter 8x
transplant KRd
After 18x
KRd
≥PR
98
100
100
100
≥VGPR
78
97
100
100
≥nCR
14
44
91
100
sCR
10
25
70
86
Maintenance
KRd with K on
days 1,2,15,16
Cycle 9-18
Maintenance
Lenalidomide
Cycle 19+
PFS 1 year:
PFS 2 yr:
OS 1 yr:
OS 2 yr:
98%
98%
100%
100%
Zimmermann ASCO 2015 abstract 2850; Jakubowiak IMW 2015