NIELS VAN DE DONK - Welcome na congres · Nieuwste middelen NIELS VAN DE DONK Department of...

Nieuwste middelen

NIELS VAN DE DONK

Department of Hematology, VU University Medical Center Amsterdam

DHC2016, Januari 2016

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&docid=6Fwd-rSLizDLHM&tbnid=-l8-zBxpTQmU8M:&ved=0CAUQjRw&url=http%3A%2F%2Fwww.vumc.com%2Fbranch%2Fcca%2F&ei=0p0QVMWWNcrmPKLRgJgG&bvm=bv.74894050,d.bGQ&psig=AFQjCNF1xmiM3xeyW4MhTUXDV39FQPSvag&ust=1410461505666510

VU University Medical Center

Amsterdam The Netherlands



Waar komen we vandaan ?



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

http://bloodjournal.hematologylibrary.org/content/vol111/issue6/images/large/zh80040815080002.jpeg



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

Melphalan

Blokhin Ann NY Acad Sci 1958; Bergsagel Cancer Chemother Rep 1962

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http%3A%2F%2Fthepmcf.ca%2FOur-Impact%2FClinical-Research%3Fpage%3D4&ei=LNlbVOfcH83GPeXIgJgE&bvm=bv.78677474,d.ZWU&psig=AFQjCNGaHfKzbMmHuTQ35C5HavcXaTaJBQ&ust=1415391859631403



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

Melphalan en Prednisone

Alexanian JAMA 1969

http://upload.wikimedia.org/wikipedia/commons/b/b5/Prednison.png

2000+: Anti-myeloma drugs IMIDs

Thalidomide

Lenalidomide

PIs

Bortezomib

Alkylators/

anthracyclins

Melphalan

Cyclophosphamide

Doxorubicin

Steroids

Dexamethasone

Prednisone

Patient features

Age

Co-morbidities

Performance status

Myeloma features

ISS

Cytogenetics

LDH

Previous therapy

Response

Duration

Adverse events

Transplant?



Waar gaan we naar toe ?



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

Dara, SAR, ELo

2014

Behring en Ehrlich: magic bullet

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&docid=8MbSA6OTr3cvIM&tbnid=LN4i17_Ea1zbkM:&ved=0CAcQjRw&url=http%3A%2F%2Fchemothermia.com%2Fcancer-coaching%2Ftargets&ei=TaktVPfuG8nWPbn1gMgM&psig=AFQjCNGhiVTRIocRXknw4TH6cNQ1gbLXwg&ust=1412364914406706



DARATUMUMAB



CD38 as a Therapeutic Target

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)

1. Malavasi F, et al. Physiol Rev. 2008;88(3):841-886. 2. Lin P, et al. Am J Clin Pathol. 2004;121(4):482-488. 3. Santonocito AM, et al. Leuk Res. 2004;28(5):469-477. 4. Deaglio S, et al. Leuk Res. 2001;25(1):1-12.

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

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http%3A%2F%2Finvestinutrecht.com%2Futrecht_science_park&ei=ShZJVYupH9DvaPjwgagD&bvm=bv.92291466,d.d2s&psig=AFQjCNHITl11RS6fGEQV8JKNbufZHBRQlQ&ust=1430939585724859



Adapted from:

Golay & Introna M. Arch Biochem Biophys 2012 ;526(2):146-53

Tai & Anderson Bone Marrow Res 2011;2011:924058

Natural killer

cell

Macrophage

Monoclonal antibodies bind to the surface of the myeloma cell

As a results……

How do monoclonal antibodies work?



Monoclonal antibodies bind to malignant cells

and act through different modes of action

Adapted from:



Natural killer

cell

Macrophage

Activation of natural

killer cells Antibody-dependent

cellular cytotoxicity

(ADCC)





Adapted from:



Natural killer

cell

Macrophage




(ADCC)

Activation of macrophages Induction of phagocytosis

(Antibody-

dependent cell-

mediated

phagocytosis =

ADCP)





Adapted from:



Activation of the

complement system Complement-dependent

cytotoxicity (CDC)

Natural killer

cell

Macrophage




(ADCC)


(Antibody-

dependent cell-

mediated

phagocytosis =

ADCP)



Monoclonal antibodies bind to malignant cells and

act through different modes of action

Adapted from:



Direct induction of apoptosis Apoptosis / growth arrest via

targeting of signaling pathways

Activation of the

complement system Complement-dependent

cytotoxicity (CDC)

Natural killer

cell

Macrophage




(ADCC)


(Antibody-

dependent cell-

mediated

phagocytosis =

ADCP)



- Effector cell: mouse mø (green) - Target cell: Daudi (red) - In vitro 30 minutes

Daratumumab 3:1

Isotype control

Induction of ADCP



Macrophage-mediated Phagocytosis of CD38+

Tumor Cells in the Presence of Daratumumab

• 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

0 sec 300 sec 400 sec 500 sec 600 sec 700 sec 800 sec

Overdijk MB, et al. MAbs. 2015;7(2):311-321.

20



Daratumumab: waterfall plot

16 mg/kg: ORR 35%

Lokhorst NEJM 2015



LENALIDOMIDE

Van De Donk Cancer Manag Res 2012



DARA and Len: synergistic killing of MM cells

from a LEN/Bort-double refractory MM patient

Nijhof Clinical Cancer Res 2015



Stem cell mobilization, conditioning, and transplant

Screening (-28 days)

VTD + Dara 4 cycles

VTD 4 cycles

VTD + Dara 2 cycles

VTD 2 cycles

Dara Q8Wk until PD

(maximum of 2 years) Followed by

observation until PD

Observation until PD

Randomize #2

Randomize #1

Arm A Arm B

Induction Phase

Consolidation Phase

Maintenance Phase

Stag

e 1

St

age

2

Subjects with PR or better

Follow-up

Stratify by: Cytogenetics, ISS, region

Stratify by: dara treatment, response, MRD status

MMY3006 (cassiopeia)



Other monoclonal antibodies

Elotuzumab

Immuun checkpoint remmers



http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjIvZLe5bbKAhXGlA8KHRfhABgQjRwIBw&url=http%3A%2F%2Fimmuno-oncologynews.com%2F2015%2F12%2F11%2F4-new-blood-cancer-trials-readying-test-immunotherapy-drug%2F&psig=AFQjCNHM12dK7t5pkyc62PxpS76FCwTnpQ&ust=1453324408781329



http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiChoj95bbKAhWDew8KHTY-CH8QjRwIBw&url=http%3A%2F%2Fimmuno-oncologynews.com%2F2015%2F12%2F21%2Fdurvalumab-atlantic-trial-supports-clinical-activity-and-astrazenecas-overall-immuno-oncology-strategy%2F&psig=AFQjCNHaPe0J-DehzmZGGdNpLhFSMdukaA&ust=1453324537093224



Myeloom: rem op de T cel

MM cel T cel

https://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiQwvuo6LbKAhVGmw4KHax_CL4QjRwIBw&url=https%3A%2F%2Fwww.youtube.com%2Fwatch%3Fv%3Dv9NBUeU3PG0&psig=AFQjCNGCfiCcMXivNCSt0X2XwKagKkdepQ&ust=1453325102253004

PD-L1 downregulates cytotocix T-cell activity to maintain immune

homeostasis

MM cell


homeostasis

MM cell

https://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjjwbm0t7rKAhWHvRoKHaH_BFsQjRwIBw&url=https%3A%2F%2Fwww.geocaching.com%2Fgeocache%2FGC5QFDG_stop-on-rt-130&psig=AFQjCNGwAOUcsHTAuIxTmbVygiNG38w-zA&ust=1453449415617565



homeostasis

MM cell



http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiitOK6vbrKAhXInRoKHVY3DLcQjRwIBw&url=http%3A%2F%2Fwww.clipartpanda.com%2Fcategories%2Fantibody-20clipart&psig=AFQjCNGYN-nz2QCdb6KszBkWug-TnWMyRQ&ust=1453451098431866

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiitOK6vbrKAhXInRoKHVY3DLcQjRwIBw&url=http%3A%2F%2Fwww.clipartpanda.com%2Fcategories%2Fantibody-20clipart&psig=AFQjCNGYN-nz2QCdb6KszBkWug-TnWMyRQ&ust=1453451098431866

Postow, MA, et al. J Clin Oncol. 2015 Jan 20. [Epub ahead of print]

PD-1 immunologic checkpoint

Targeting the PD-1/PD-L1 Pathway

MM001 – Durvalumab

– Durvalumab + pomalidomide

– Durvalumab + pomalidomide + dexamethasone

https://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiByKW2x7rKAhVJOhQKHSOtB2AQjRwIBw&url=https%3A%2F%2Fwww.astrazeneca.com%2Four-focus-areas%2Foncology.html&psig=AFQjCNG2M5a5mlaaxCkL8zOYm9diNAtpPg&ust=1453453755746067



Other “new” novel agents



MLN9708 (ixazomib citrate)

MLN9708 is an orally availbale proteasome inhibitor



HOVON-126: Ixazomib-thalidomide-

dexamethason

Randomized phase 2 study in NDMM

9Td

Ixazomib 1x/week oral

Thalidomide 100 mg/day

Dexamethasone 40 mg/week

9 cycles every 4 weeks

Ixazomib until progression

Placebo until progression



Carfilzomib

• Carfilzomib is a selective irreversible proteasome

inhibitor1,2

– Sustained target suppression

– Effective in bortezomib-refractory disease

– Low frequency of polyneuropathy

1. Adapted from Kuhn DJ, et al. Blood. 2007;110:3281-3290. 2. Arastu-Kapur S, et al. Clin Cancer Res. 2011;17:2734-2743.

HN

NH

OHN

O

O

NH

O

N

O O

O

Epoxyketone Tetrapeptide

Background Carfilzomib



Carfilzomib versus bortezomib



HOVON 129

Primary plasma cell leukemia

Meest agressieve myeloom variant

Tumorcellen stromen vanuit beenmerg uit naar het

bloed

Slechte prognose

Gonsalves Blood 2014; Kumar Leukemia 2014

Primary PCL (SEER analysis) Multiple myeloma (Mayo)

Survival improvement in pPCL vs MM

Early mortality due to aggressive

presentation with severe complications

KRd

• Carfilzomib + lenalidomide +

dexamethason

EMN12: Elderly patients: ≥65 years

8 x carfilzomib-

lenalidomide-

dexamethasone

Lenalidomide 10 mg daily on days 1-21

Carfilzomib once daily on days 1,2,15,16 until

progression

Induction Maintenance

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCPbm6vrGhcgCFQSzFAodiAsHTA&url=http%3A%2F%2Fmyeloma-europe.org.linux9.curanetserver.dk%2Findex.php%3Femn-trialist-group-1&psig=AFQjCNH6dFYr25yLdYF6fKqmKcQIFW9mZw&ust=1442836466216329

EMN12: Younger patients

4 x carfilzomib-

lenalidomide-

dexamethasone

High-dose melphalan

(200 mg/m2)

-allo-SCT in patients with a sibling or MUD

donor

-Conditioning: busulfan+fludarabine

Stem cell harvest

carfilzomib: starting 2 months post-allo-

SCT for 6 months; followed by

lenalidomide plus carfilzomib until

progression

2 x carfilzomib-

lenalidomide-

dexamethasone

Induction Auto-SCT Consolidation

RIC Allo-SCT

Maintenance

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCPbm6vrGhcgCFQSzFAodiAsHTA&url=http%3A%2F%2Fmyeloma-europe.org.linux9.curanetserver.dk%2Findex.php%3Femn-trialist-group-1&psig=AFQjCNH6dFYr25yLdYF6fKqmKcQIFW9mZw&ust=1442836466216329



Carthadex

Newly diagnosed MM

Induction and consolidation with carfilzomib-

thalidomide-dexamethasone (CTd)

Last cohort almost full !

Anti-myeloma drugs: 2016 IMIDs

Thalidomide

Lenalidomide

Pomalidomide

PIs

Bortezomib

Carfilzomib

Ixazomib

Oprozomib

Alkylators/

anthracyclins

Melphalan

Cyclophosphamide

Doxorubicin

MoAbs

Anti-CD38 (daratumumab, SAR, MOR)

Anti-CS1 (elotuzumumab)

Anti-PD1/anti-PD-L1

(nivolumab/durvalumab/..)

Steroids

Dexamethasone

Prednisone

Patient features

Age

Co-morbidities

Performance status

Myeloma features

ISS

Cytogenetics

LDH

Previous therapy

Response

Duration

Adverse events

Transplant?



Myeloma: prognosis

Antibodies: DARA /SAR/ ELO



Questions ?



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



Problems with antibodies in MM



Landsteiner

In 1930 he received the

Nobel Prize in Physiology

or Medicine

http://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicine

http://en.wikipedia.org/wiki/Nobel_Prize_in_Physiology_or_Medicine



Blood group system

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http%3A%2F%2Fen.wikipedia.org%2Fwiki%2FABO_blood_group_system&ei=8M5LVfyZIYT6ywObyIHgAw&bvm=bv.92885102,d.bGQ&psig=AFQjCNHiPv9NVcmUyI4h4565S22wV3wl0g&ust=1431117717784730



Other blood groups

Other blood groups: Kell / Kidd / duffy / ….

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http%3A%2F%2Fwaynesword.palomar.edu%2Faniblood.htm&ei=sSZNVemXO8ahsAHhu4GIBQ&bvm=bv.92885102,d.bGg&psig=AFQjCNExd0WnaMAEfJBxPBAF_G5PBOFlEw&ust=1431205738157043



Tranfusion with lamb=letal

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http%3A%2F%2Fblog.inceptsaves.com%2Fblog%2F2011%2F06%2F03%2Fblood-transfusions-a-modern-marvel%2F&ei=_yZNVcuWHMaMsAG2-IHYAg&bvm=bv.92885102,d.bGg&psig=AFQjCNHSwRAUVq6nAPydJT_0neKO5tcUnQ&ust=1431206003471679



http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http%3A%2F%2Fwww.alamy.com%2Fstock-photo-animal-to-man-blood-transfusion-in-both-england-and-france-this-procedure-57299954.html&ei=MidNVZGrA4ipsAHv4YD4DQ&bvm=bv.92885102,d.bGg&psig=AFQjCNHSwRAUVq6nAPydJT_0neKO5tcUnQ&ust=1431206003471679



Blood transfusion



Antibodies against RBCs

Naturally occurring antibodies (anti-A, anti-B)

Acquired antibodies (anti-D (Rhesus))

Pregnancy

Previous transfusion

Transplant



https://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=https%3A%2F%2Fak47boyz90.wordpress.com%2F2009%2F09%2F02%2Fl3-blood-transfusion%2F&ei=XM5LVeTRKajhywPp-oGQDA&bvm=bv.92885102,d.bGQ&psig=AFQjCNHiPv9NVcmUyI4h4565S22wV3wl0g&ust=1431117717784730



http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http%3A%2F%2Fcommons.wikimedia.org%2Fwiki%2FFile%3AMain_symptoms_of_acute_hemolytic_reaction.png&ei=Hs5LVebuJIfVywOy3ICADg&bvm=bv.92885102,d.bGQ&psig=AFQjCNHiPv9NVcmUyI4h4565S22wV3wl0g&ust=1431117717784730

Treatment Interference With The Indirect Coombs Assay

Positive Result Agglutination

Donor RBCs Recipient Serum Containing Abs

Coombs Reagent

Y

Y Y

Y

Y Y Y

Y

Y

Y Y

Negative Result Agglutination

Donor RBCs Recipient Serum

No Abs

Coombs Reagent

Y

Y Y

Y

Y

Y

Treatment Interference False Positive

Donor RBCs Treated Serum

Containing Drug A Abs

Coombs Reagent

Y

Y Y

Y

Y Y Y

Y

Y

Y Y Y

Y

Y

Y

Y Y

Y

Y Y Y

Y

Y

68

Phase 2 study : KRd upfront

4x KRd

KRd with K on

days 1,2,15,16

Cycle 9-18

Induction

Maintenance

4x KRd

Consolidation

High-dose melphalan

(200 mg/m2)

Auto-SCT

Zimmermann ASCO 2015 abstract 2850; Jakubowiak IMW 2015

After 4x

KRd

Post-

transplant

After 8x

KRd

After 18x

KRd

≥PR 98 100 100 100

≥VGPR 78 97 100 100

≥nCR 14 44 91 100

sCR 10 25 70 86

PFS 1 year: 98%

PFS 2 yr: 98%

OS 1 yr: 100%

OS 2 yr: 100%

Lenalidomide

Cycle 19+

Maintenance

NIELS VAN DE DONK - Welcome na congres · Nieuwste middelen NIELS VAN DE DONK Department of...

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