nuevas dianas moleculares en el tratamiento del mieloma ... hematologia_dr_ocio...flow cytometry, wb...

Centro de Investigación del Cáncer


Servicio de Hematología

Hospital Universitario


Hospital UniversitarioUniversidad de Salamanca

Nuevas Dianas Moleculares Nuevas Dianas Moleculares en el Tratamiento del en el Tratamiento del

Mieloma MúltipleMieloma MúltipleEnrique M. Ocio

Hospital Universitario y Centro de Investigación del CáncerUniversidad de Salamanca

Novel therapeutic targets

Classic Chemotherapeutics

Plants alkaloidsVinca alkaloidsTopoisomerase II inhibitorsT

Etoposide (VP16) / Teniposide (VM16)•Vincristine / Vimblastine

Taxanes

MethotrexateAntifolate analogs

P i l 6-Mercaptopurine / 6-Tioguanine

Paclitaxel

Antimetabolites

Purine analogs

Pyrimidine analogs

6 Mercaptopurine / 6 TioguanineFludarabine / Cladribine

5-FluoruracilCytosine Arabinoside (Ara-C)

• y g

Ribonucleotide reductase inhibitor

Cytosine Arabinoside (Ara C)Gemcitabine

Hydroxyurea

Alkylating agents•CyclophosphamideChlorambucil (Leukeran)Melphalan / BusulfanCarmustine (BCNU)

Antibiotics•

Carmustine (BCNU)Platinum analogs (Cisplatin)

Anthracyclines (Daunorubicine / Doxorubicine)Bl iAntibiotics

Miscellaneous•Bleomycin

L-AsparaginaseEsteroids San Miguel & Sánchez-Guijo, Cuestiones en Hematología. Harcourt 2008

Novel therapeutic targets

Classic Chemotherapeutics

Plants alkaloids• Interphere with mitotic apparatus (microtubules)

Antimetabolites• Interphere withSynthesis of Nucleotides

or its

incorporation into DNA

Alkylating agents• Interphere withReplication

TranscriptionInterphere with

h i

Antibiotics•

Transcription

Interphere withDNA synthesis

mechanisms of cell division

Antibiotics

Miscellaneous• San Miguel & Sánchez-Guijo, Cuestiones en Hematología. Harcourt 2008

Interphere withDNA repair

Treatment of MMTreatment of MM

1844 1844 1960 1970 1980 1970 1980 1990 2000 2000 2003 2004 2010

Melphalan(1958 Blokhin)(1958 Blokhin)

Mr. McBean1844 Hi h d h(1958, Blokhin)(1958, Blokhin)

Ann NY Acad Sci

MelphalanMelphalan

1844 High-dose chemoStem cell transplantationStem cell transplantation

BisphosphonatesBisphosphonates

Combination chemoCombination chemo

GlucocorticoidsGlucocorticoids(1969)(1969)

Combination chemoCombination chemoVincristine

Doxorubicin DexamethasoneDexamethasone


Despite the benefit observed in the last years,

1971–761977–820 8

1.0

1994–001989–941983–88

viva

l

0.6

0.8

viva

lSu

rv

0.4

Surv

0 0

0.2

TimeTime0 20 40 60 80 100 120 140

0.0

Kumar, Blood 2008

, … other drugs are still needed for relapsed/refractory patients


1844 1844 1960 1970 1980 1970 1980 1990 2000 2000 2003 2004 2010



Ann NY Acad Sci

MelphalanMelphalan





Bortezomib IMIDsIMIDs


Doxorubicin Dexamethasone

Thalidomide

Dexamethasone


Despite the benefit observed with novel agents in the last years,

1971–761977–820 8

1.0

1994–001989–941983–88

viva

l

0.6

0.8

2001 06viva

lSu

rv

0.4

2001–06

Surv

0 0

0.2

TimeTime0 20 40 60 80 100 120 140

0.0

Kumar, Blood 2008

, … other drugs are still needed for relapsed/refractory patients


1844 1844 1960 1970 1980 1970 1980 1990 2000 2000 2003 2004 2010



Ann NY Acad Sci

MelphalanMelphalan





Bortezomib IMIDsIMIDs


Doxorubicin Dexamethasone

Thalidomide

GleevecDexamethasone Gleevec(CML) 2001

Herceptin(Breast) 1998

¿?Rituximab(NHL) 1997

( )

“The Hallmarks of Cancer”Novel therapeutic targets

(-) Tyrosin-K receptors

(+) death receptors (-) proliferative

thpathways(-) antiapopt.

proteins

Unfolded prot resp

proteins

(-) angiogenesis

prot. resp.

Cell cycle

Epigenetics

Hanahan & Weinberg, Cell 2000

Cell cycle blockade

ClassificationTreatment of MM

Cell cycle•Cyclin inhibitorsCDK inhibitorsCell cycleAurora Kinases inhibitors

Surface molecules•Activators of Death ReceptorsSurface AntigensTyrosin Kinase inhibitors

Signaling Pathways• PI3K/AKT; MAPK; JAK/STAT; NFKB; WNT

y

“Unfolded protein response”•“Heat Shock Proteins” inhibitorsProteasome inhibitorsUnfolded protein response• Proteasome inhibitorsAgressome formation inhibitors

Epigenetics• Demethylating agentsHistone Deacetilases Inhibitors

Cell Cycle RegulationNovel therapeutic targets

Cyclins & CDKs inhibitorsp16

p15p18

p19p57

p53

Cyclin D Cyclin B

p

p21

p57

p27

G1MCDK 4/6

Cyclin ECDK 1

PP

CDK 2

G1MPPAurora

SG2 E2FRb

Kinases

SG2 E2FCyclin A Cyclin A

CDK 1p27

Schwartz GK. “Targeting the cell cycle: A new approach to cancer therapy”. JCO 2005Schwartz GK. “Targeting the cell cycle: A new approach to cancer therapy”. JCO 2005

CDK 2 CDK 1

p21

p21

Primary IgH translocationsNovel Agents for MM

20%

Cyclin D3Cyclin D3

Cyclin D1Cyclin D115%

p21p21

q13q13FGFR3 /MMSETFGFR3 /MMSET

Oncogenic receptortyrosine kinase

pp

Cyclin D2Cyclin D2Nuclear SET domain

protein

p13p13 p16p16

protein

q32q32B-ZIP transcription

factor

5%CDK

inhibitorsCyclin D1 inhibitors

Aurora K inhibitors

IgHIgH C-MAFC-MAFq23q23P276-00CYC202

PD0332991 VX-680





y



Host-tumor interactionsNovel Agents for MM

IL-6IL-6

Direct contact & soluble molecules

CD138

IL 6

IGF-1

VEGF

IL 6

IGF-1

VEGFCD44

MM cell

CXCR4CXCR4

ICAM-2TNFTNF

CD44

SDF1

β1-integrinsCXCR4CXCR4

VLA-4LFA-1

BMSC

ECM (Fibronectin, laminin)

ECM (Fibronectin, laminin)

VCAM-1ICAM-1

β1-integrins: VLA-4 (CD49d), VLA-5 (CD49e), VLA-6 (CD49f)β1-integrins: VLA-4 (CD49d), VLA-5 (CD49e), VLA-6 (CD49f)

Cell adhesion induces drug resistance:Cell adhesion induces drug resistance: 1) cell cycle arrest (↑ p27); 2) apoptosis inhibition (↑ FLIP-1 –FAS inhibitor-); 3) protection from drug-induced DNA damagePC adhesion to Fn induces overexpresion of 53 genes ( 11 regulated by NFkB)

San Miguel, Hematol J. 2003

Signaling pathways in MM PCNovel Agents for MM

IGF-1IGF-1IL6IL6

SDF1αSDF1αTNFαTNFα

IL-21IL-21SDF1αSDF1α

VEGFVEGF

JAK/STATRAS

PI3K/AKTRAF/MEK/MAPK

P lif tiProliferation Prevents apoptosis

Surface receptors in MM PCNovel Agents for MM

CD56

CD40 CS1

CD56

VEGFRIL-6R

IGF-1RCD74

FGFR3DR4 5

EGFR

TACI

BCMA

FGFR3DR4-5

Fas

TRAIL

APO010 APRILc-kitc-kit

Surface receptors in MM PCTreatment of MM

CD56

CD40 CS1IMGN901

Dacetuzumab Elotuzumab

CD56

VEGFRIL-6RCNTO-328

IGF-1RCD74Milatuzumab

FGFR3DR4 5

EGFR Cetuximab

TACI

BCMA

FGFR3DR4-5

Fas

TRAIL

APO010 APRILc-kit

Dasatinib Imatinib

c-kit


CD56

CD40 CS1IMGN901

ElotuzumabDacetuzumab

CD56

IL-6RCNTO-328VEGFR

CD74MilatuzumabIGF-1R

FGFR3

EGFR Cetuximab

DR4 5TACI

BCMA

FGFR3

APRILc-kit

DR4-5

Fas

TRAIL

APO010

Dasatinib Imatinib

c-kit

Anti-CS1 in MMTreatment of MM

• Cell surface glycoprotein• Universal gene expression in MM 80

HuLuc63: MoAb that induces ADCCg p

• Confirmed CS1 protein expression by flow cytometry, WB and IHC

c ki

lling

4050607080

• Normal tissue staining shows expression only in tissue PC

% s

peci

fic

10203040

0

0

0.00

01

0.00

1

0.01 0.1 1 10

HuLuc63 μg/ml

PC in normal gut Plasmacytoma MM1RMM1S

U266CD19+B cells

HuLuc63, μg/ml

g y MM1S CD19+B cells

CS1

Tai, Blood 2007. Bensinger ASH 2007. Abstract 1180

Elotuzumab (Anti-CS1 MoAb) in MMTreatment of MM

• Phase I in monotherapy n=23 26% SD Zonder, ASH 2008. Abstract 2773

• Phase I/II Elotuzumab + Len + dex Lonial, ASH 2009. Abstract 432

Elotuzumab days 1, 8, 15 22

Lenal “prepares” PBMCs & then Elotuzumab induces ADCC

n=13 relapsed MM ORR 92% (15% VGPR, 77% PR, 8% SD)

Toxicity: 25% infusion reaction. Haematological.

• Phase I Elotuzumab + Bort Jakubobiak, ASH 2009. Abstract 3876

Elotuzumab days 1, 11

n=16 relapsed MM ORR 44% (6% CR, 19% nCR, 19% PR, 31% MR, 19% SD)

Toxicity: GI, Haematological


CD40 CS1

Elotuzumab

CD56

DaclizumabDacetuzumab

IMGN901

VEGFR

CD56

IL-6RCNTO-328

IGF-1RCD74Milatuzumab

FGFR3

EGFR Cetuximab

DR4 5TACI

BCMA

FGFR3

APRILc-kit

DR4-5

Fas

TRAIL

APO010

Dasatinib Imatinib

c-kit

Drugs targeting TK receptorsNovel Agents for MM

FGFR Kit

MetFLT3

PDGFR

Tie2

FLT3

Zap-70IGF 1R

AblIGF-1R

Jak

Her

SrcEGFR

Primary IgH translocationsNovel Agents for MM

20%

FGFR3 i hibit

PD173074CHIR258

Cyclin D3Cyclin D3

Cyclin D1Cyclin D115%

inhibitors CHIR258AB1010

p21p21

q13q13FGFR3 /MMSETFGFR3 /MMSET

Oncogenic receptortyrosine kinase

pp

Cyclin D2Cyclin D2Nuclear SET domain

protein

p13p13 p16p16

protein

q32q32B-ZIP transcription

factor

5%

IgHIgH C-MAFC-MAFq23q23





y




IGF-1IGF-1IL6IL6

SDF1αSDF1αTNFαTNFα

IL-21IL-21SDF1αSDF1α

VEGFVEGF

JAK/STATRAS


P lif tiProliferation Prevents apoptosis


IGF-1IGF-1IL6IL6

SDF1αSDF1αTNFαTNFαFT inhibition STAT3 inhibition

(Atiprimod)IL-21IL-21

SDF1αSDF1αVEGFVEGF(Tipifarnib) (Atiprimod)

JAK/STATRAS PI3K inhibition (BEZ235)

RAF inhibition (RAF265)


(BEZ235)(RAF265)

AKT inhibition

P lif ti

MEK inhibition (AZD6244)

AKT inhibition (Perifosine)

Proliferation Prevents apoptosis mTOR inhibition (RAD001)(Rapamycin)(CCI 779)

P38/MAPK inhibition (SCIOS 469) (CCI-779)(SCIOS-469)

AKT inhibitorsNovel Agents for MM

PerifosinePerifosinePerifosine

• Phase I/II + Bort ± Dex*

Perifosine

• Phase I/II + Bort ± Dex* *Richardson, IMW 2009. Abstract 349

n=86 all previous Bort.n=86 all previous Bort.

≥MR 38% (3% CR, 19% PR, 16% MR)

In 45 Bort refrac. ≥MR 33%

≥MR 38% (3% CR, 19% PR, 16% MR)

In 45 Bort refrac. ≥MR 33%In 45 Bort refrac. ≥MR 33%In 45 Bort refrac. ≥MR 33%

• Phase I + Len + Dex**

30 l/ f ≥MR 70% (7% CR 10% VGPR 33% PR 20% MR)

• Phase I + Len + Dex**

30 l/ f ≥MR 70% (7% CR 10% VGPR 33% PR 20% MR)

**Jakubowiak, IMW 2009. Abstract 347

n=30 rel/ref ≥MR 70% (7% nCR, 10% VGPR, 33% PR, 20% MR)n=30 rel/ref ≥MR 70% (7% nCR, 10% VGPR, 33% PR, 20% MR)

mTOR inhibitors in MMNovel Agents for MM

Temsirolimus - (CCI-779)

• Phase II + Bortezomib

Temsirolimus - (CCI-779)

• Phase II + Bortezomib Ghobrial, ASH 2009. Abstract 748

n=19 rel/refr. MM ≥MR 73% (5% CR, 16% VGPR, 26% PR, 26% MR, 10% SD)n=19 rel/refr. MM ≥MR 73% (5% CR, 16% VGPR, 26% PR, 26% MR, 10% SD)

• Phase I + Lenalidomide

n= 21 1 CR, 1 PR, 3 MR

• Phase I + Lenalidomide

n= 21 1 CR, 1 PR, 3 MR

Hofmeister, ASH 2009. Abstract 2884

Everolimus - (RAD001)Everolimus - (RAD001)

Guenther, ASH 2009. Abstract 3850• Phase I/II Monotherapy

n=7 14% PR, 57% SD

• Phase I/II Monotherapy

n=7 14% PR, 57% SD

Raje, ASH 2009. Abstract 3856• Phase I + Lenalidomide• Phase I + Lenalidomide

MTD: Len 15 mg & Ever. 5 mg x21 days of 28 days cycle (Hemat. Tox.)

n=15 ≥MR 46% (13% PR, 33% MR, 7% SD)

MTD: Len 15 mg & Ever. 5 mg x21 days of 28 days cycle (Hemat. Tox.)

n=15 ≥MR 46% (13% PR, 33% MR, 7% SD)

Ig production and DNA regulation in MM PCNovel Agents for MM

Inhibitors of

Agents acting on

epigenetics

–AcAc–

Inhibitors of the unfolded

protein responseAc

–AcAc

p

Ac–





y



Unfolded Protein ResponseTreatment of MM

TanespimycinAl i i

Ub

Hsp90

Alvespimycin

inhibitors Novel proteasome

inhibitors

Hsp-90Chaperone

NPI-0052Carfilzomib

AB1010

HDAC6HDAC6 inhibitors

Kindly provided by Dr. James Bradner and adapted

TubacinVorinostat

Panobinostat

Effects of Proteasome Inhibition in MMTreatment of MM

↓ Adhesion ↓ Cytokines ↓ Angiogenesis

MM cells TNFa↓↓ Extracellular level

BMSCBMSC VEGF

IGF-I

IL-6 BM Vessels

X↓↓

↓

26S P

NFkBNFkB

Intracellular levelIL-6, VEGF

Block activationBlock activation

26S Proteasome

X NFkBNFkB

↓ Apoptosis Inhibitors↓ Apoptosis Inhibitors

Block activation NFkB

Block activation NFkB ↑ pIkB↑ pIkBX

(IAP, FLICE)(IAP, FLICE)

Caspases 8,3Caspases 8,3

↑ FAS

MAPKMAPKPI3KPI3K

InhibitionDNA-repair effectors

InhibitionDNA-repair effectors

Decreased P lif tiDecreased

P lif tiIncreased A t iIncreased A t i

Disruption of Disruption of Disruption of Disruption of ProliferationProliferationApoptosisApoptosis unfolded protein unfolded protein

responseresponseunfolded protein unfolded protein

responseresponseSan Miguel J. Hematol J. 2003;4(suppl 3):201-207.

Carfilzomib (PR-171) monotherapyTreatment of MM

Irreversible & specific inh. of the chymotrypsin-like activity of the proteasomeDosing schedule: 20 mg/m2 iv d 1-2, 8-9, 15-16 of 28 days cycles (up to 12 cycles)

• 2 Phase I trials ≥ MR 38% - 51% Orlowsky, ASH 2007. Abstract 409 Alsina, ASH 2007. Abstract 411

Dosing schedule: 20 mg/m iv d 1 2, 8 9, 15 16 of 28 days cycles (up to 12 cycles)

• 2 Phase II trials in monotherapy

PX-171-004

PX-171-003 Brtz naive (54 ev) ORR 46%

In pts prev. Btz & IMID pts (n=39)

2% CR, 44 % PR, 15% MR & 22% SD TTP 7.6 m

Brtz treated (33 ev) ORR 18%13% PR, 13% MR & 41% SD

Bz refr (n=26) 4% PR, 15% MR

Brtz treated (33 ev) ORR 18%

3% CR, 15% PR, 12% MR & 39% SD TTP 5.3 m

Brtz refr/intol (15) 6% PR 6% MR 53% SDJagannath, IMW 2009. Abstract 377

Wang, ASH 2009. Abstract 302

Brtz refr/intol (15) 6% PR, 6% MR, 53% SD

Siegel, ASH 2009. Abstract 303





y



Agents acting on EpigeneticsNovel Agents for MM

Hypomethylating agents (5-Azacytidine)Hypomethylating agents (5-Azacytidine) Kiziltepe, Mol Cancer Ther 2007

• DNA methyltransferase inhibitors

• Anti-MM effect through induction of DSBs

• DNA methyltransferase inhibitors

• Anti-MM effect through induction of DSBsg

• Synergy with Doxorubicine and Bortezomib

• Clinical trial ongoing

g

• Synergy with Doxorubicine and Bortezomib

• Clinical trial ongoing• Clinical trial ongoing

Histone deacetylase inhibitors

• Clinical trial ongoing

Histone deacetylase inhibitorsHistone deacetylase inhibitors• Panobinostat (LBH589)

• V i t t (SAHA)

Histone deacetylase inhibitors• Panobinostat (LBH589)

• V i t t (SAHA)• Vorinostat (SAHA)

• ITF-2357

• Vorinostat (SAHA)

• ITF-2357

• Depsipeptide• Depsipeptide

Effect of HDAC on transcriptionTreatment of MM

Balanced HAT and HDAC Activity Results in Regulated Gene Expression

Hi t t l ti llHistone deacetylation prevents gene expression

Histone acetylation allows gene expression HAT

TFAc Ac

HDAC

Ac Ac Ac

Deacetylation Acetylation

Normal Cell

• DNA is packaged by wrapping around histone octamers

Effect of HDAC on transcriptionTreatment of MM

In tumor cells unbalance: deacetilation and inhibition of transcription

IncreasedIncreasedHDAC ActivityHDAC Activity

Decreased Decreased HAT ActivityHAT Activity

TFAc

HDAC

HAT

Ac

Ac Ac

Ac

AcHDAC

HDAC

Uncontrolled CellUncontrolled CellGrowth and SurvivalGrowth and Survival

DACInhibitor

Decreased TumorDecreased Tumor

TumorCell

Decreased Tumor Decreased Tumor Suppressor Gene Suppressor Gene Activity (p21, p27)Activity (p21, p27)

Effect of DAC on Non Histone proteinsTreatment of MM

DACInhibitor

DACDAC DAC DAC

DAC

Proteins modulatedby DACs

Histone p53 α-tubulin HSP90HIF-1α

Loss of tumor Microtubule depolymerization VEGF OncoproteinsDownstream

Tumorsuppressor

functiondepolymerization aggresome form.

VEGF Oncoproteins Downstream effects

suppressorgene activity

Tumor ff t

Cell proliferation

Cell motility and Invasion

Cell proliferation and survivaleffects proliferation

Apoptosis Angiogenesis

Activity of HDACi in monotherapy in MMHDACi in MM

ORR Rn ORR Responses

Vorinostat 10 10% 1 PR 9 SDVorinostat 10 10% 1 PR, 9 SD

Panobinostat 38 3% 1PR 1 MR 1 SDPanobinostat 38 3% 1PR, 1 MR, 1 SD

ITF2357 15 7% 1 PR 1 SDITF2357 15 7% 1 PR, 1 SD

Romidepsin 12 0% 11 SDRomidepsin 12 0% 11 SD

Richardson PG, Leuk Lymphoma 2008

Wolf, ASH 2008. Abstract 2774

Galli, ASH 2007. Abstract 1175

Niesvizky, ASH 2005. Abstract 2574

Triple combinations of Panobinostat in MMPanobinostat in MM

Panobinostat + Bortezomib + Dexamethasone

trol

)

100

120

1.0

upta

ke (%

con

t

40

60

80

0.20.40.60.8

Effe

ct

0 0.2 0.4 0.6 0.8 1.00

0.20.40.6

mb.

inde

x.

Panobinostat

MTT

u

0

20

40

- + - + - +- +

0 1 2 3 40

DosePanob+BortPanob + Dex

Bort + DexPanob + Bort + Dex

0 0.2 0.4 0.6 0.8 1.0

-0.6-0.4-0.2

Fractional Effect

Com

)

120

Dex Bort+DexBort

Panobinostat + Lenalidomide + Dexamethasone

ake

(% c

ontr

ol)

60

80

100

0 40.60.81.0

ffect

0.20.40.6

ndex

MTT

upt

a

0

20

40

0 200 400 600 800 1.0000

0.20.4

Dose

Ef

0 0.2 0.4 0.6 0.8 1.0

-0.6-0.4-0.20

0.2

F ti l Eff t

Com

b. in

Ocio EM, Haematologica in press

Panobinostat

Len Dex Len+Dex

- + - + - +- + Panob + Lenal

Panob + DexLenal + DexPanob + Len + Dex

Fractional Effect

Panobinostat in MM

In vivo combinations of PanobinostatEfficacy in a xenograft of human sc plasmocytoma in mice

120 CB17-SCID mice were sc injected with 3x106 MM1S cells

When tumors became palpable randomization to:p p

• Vehicle

P bi t t 10 /K 21 d d 5 /K ft d• Panobinostat 10 mg/Kg x 21 days and 5 mg/Kg afterwards

• Dexamethasone 1 mg/Kg

• Bortezomib 0 1 mg/Kg• Bortezomib 0.1 mg/Kg

• Lenalidomide 15 mg/Kg

• Doubles: PD PB PL BD LD• Doubles: PD, PB, PL, BD, LD

• Triples: PBD, PLD

M it i ti f t l & t i it i 3 ti / kMonitorization of tumor volume & toxicity signs: 3 times / week

Mice were sacrificed when the tumor diameter > 2 cm

Triple combinations of Panobinostat in MMPanobinostat in MM

* p<0.05 related to singles

In vivo anti-MM activity of Panobinostat + Dex + either Len or Bort

Panobinostat + Bort + Dex ** p<0.05 related to doublesPanobinostat + Bort + Dex

Panobinostat + Lenal + DexPanobinostat Lenal Dex


Unique genes deregulated by triple comb.Panobinostat in MM

GEP of MM1S cells treated with single agents and the triple combinationsApoptosis 15 25%Apoptosis 15-25%

895 genes exclusive of PBD

Panobinostat + Bort + Dex

gApoptosis

APAF1 3.01

C 1 3 54

Cell Cycle regulation

CDK 4 -2.95

C li E1 2 58Casp-1 3.54

Casp-4 4.76

TP53 -2.87

Cyclin E1 -2.58

Cyclin D2 -4.29

E2F2 -4.49

1323 genes exclusive of PLDApoptosis Cell Cycle regulation

Panobinostat + Lenal + Dex

APAF1 3.16GADD45 7.88Casp-8 2.73

Cyclin E1 -2.34

Cyclin A2 -2.76

Cyclin D2 -2.63


Casp-10 2.62 E2F2 -3.03

Deacetylase inhibitors in MMTreatment of MM

Panobinostat (LBH589)

• Single agent (n=38 prev Bort & IMIDs) ORR 6%

Panobinostat (LBH589)

• Single agent (n=38 prev Bort & IMIDs) ORR 6% Wolf, ASH 2008. Abstract 2774Single agent (n 38 prev Bort & IMIDs) ORR 6%

• Bort ± Dex (n=29) ORR 64% (4 CR IF-)

In 10 pts prev ref to Bz 6 responses (4 PR 2 MR)

Single agent (n 38 prev Bort & IMIDs) ORR 6%

• Bort ± Dex (n=29) ORR 64% (4 CR IF-)

In 10 pts prev ref to Bz 6 responses (4 PR 2 MR)

San Miguel JF. ASH 2009 Abstract 3852

In 10 pts prev ref to Bz 6 responses (4 PR, 2 MR)

• Len + Dex (n=13. No prev Len) ≥MR 69% (2CR, 4 VGPR, 2 PR, 1MR)

In 10 pts prev ref to Bz 6 responses (4 PR, 2 MR)

• Len + Dex (n=13. No prev Len) ≥MR 69% (2CR, 4 VGPR, 2 PR, 1MR) Spencer, IMW 2009. Abstract 329

Vorinostat (SAHA)

• Single agent (n=10) 10% MR

Vorinostat (SAHA)

• Single agent (n=10) 10% MR Richardson, ASH 2007. Abstract 1179 Badros, Clin Cancer Res 2009

• Bort ± Dex (n=23, 34 & 21) ≥MR 42%, 47% & 42%

Prev Btz: n=22 ≥MR 41% (36% PR, 5% MR) + 50% SD

• Bort ± Dex (n=23, 34 & 21) ≥MR 42%, 47% & 42%

Prev Btz: n=22 ≥MR 41% (36% PR, 5% MR) + 50% SD

Marunder, IMW 2009. Abstract 306Weber, IMW 2009. Abstract 242 & 248

• Len + Dex (n=28) ≥MR 64% (2 CR, 11 PR, 5 MR, 6 SD)

Romidepsin (D i tid )

• Len + Dex (n=28) ≥MR 64% (2 CR, 11 PR, 5 MR, 6 SD)

Romidepsin (D i tid )

Siegel D. ASH 2009 Abstract 305

Romidepsin (Depsipeptide)• Bort + Dex (n=25) ORR 67% (22% CR, 22% VGPR, 22% PR)

Romidepsin (Depsipeptide)• Bort + Dex (n=25) ORR 67% (22% CR, 22% VGPR, 22% PR)

Harrison, ASH 2008. Abstract 3698

Immunomodulatory DrugsTreatment of MM

antiproliferativeMM Plasma Cells

IL-6

Bone Marrow

TNF-αIL-1βAdhesion

Molecules Lenalidomide Lenalidomide

Stromal cells

Lenalidomide

IL-2

interferon-γ

Bone Marrow vessels

VEGF (FGFb) Lymphocytes

γ

T ll CD8

(FGFb)

Lenalidomide

immunomodulatoryLenalidomide

ti i i T cells CD8NK cells

immunomodulatoryantiangiogenic

Immunomodulatory Drugs - LenalidomideNovel Agents for MM

O

NHO

NH

O O

N O

O

N O

O

ThalidomideNH2

Lenalidomide

• More “potent” immunomodulator • Different side-effect profile

– more potent inhibitor of TNF-α– increased stimulation of T-cell proliferation– augmented production of IL-2 and IFN-γ

– no significant constipation, neuropathy, or sedation

– greater myelosuppression augmented production of IL 2 and IFN γ– Augmented NK-cell activity • Not teratogenic in animal models

(including New Zealand white rabbit)

– embryotoxic at 100 × human dose

Bartlett JB, et al. Nat Rev Cancer. 2004;4:314-22. Marriott JB, et al. Curr Drug Targets Immune Endocr Metabol Disord. 2003;3: 181-6. Rajkumar S, Kumar SV. Eur J Cancer. 2006;42:1612-22. Richardson P, Anderson K. J Clin Oncol. 2004;22:3212-4.

– embryotoxic at 100 × human dose

Immunomodulatory DrugsTreatment of MM

NHO O

HO ON

NO

NNH

OO

Thalidomide

O O

ONH2

Thalidomide

Actimid™ (pomalidomide) (CC-4047)

NNHO O

O

NH2

Revlimid ™ (lenalidomide)(CC-5013)

Pomalidomide (CC-4047) monotherapy Treatment of MM

• Phase I/II Richardson, ASH 2009. Abstract 301

Pomalidomide escal. (2, 3, 4, 5 mg) days 1-21 (28 days) + Dex (40 mg /wk) if PD

n=21 relapsed/refr. patients

15% ORR (5% CR, 10% PR + 24% MR + 43% SD) TTP 8.3 weeks

Dex added in 13 pts 38% ORR (15% CR, 23% PR + 46% SD) TTP 20 weeks

• Phase I

Pomalidomide every day or alternate days (+ Dex added if no response)

Streetly, ASH 2009. Abstract 3878

Pomalidomide every day or alternate days (+ Dex added if no response)

n=44 rel/ref pts

52% ORR (14% CR 39% PR 9% MR 30% SD)52% ORR (14% CR, 39% PR, 9% MR, 30% SD) PFS 13.7 m

Dex added in 10 pts 50 % ≥MR

Pomalidomide (CC-4047) + Dex Treatment of MM

• Phase II Pomalidomide + Dex Lacy, JCO 2009 Lacy, ASH 2009. Abstract 429

n=60 relapsed MM pts to 1-3 previous lines (62% previous IMID)

2 mg/24h vo continuous + Dex 40 mg vo days 1, 8, 15, 22

63% ORR (5% CR, 28% VGPR, 30% PR + 25% SD)

34 Len refr. Pts 32% ORR (3% VGPR, 29% PR, 18% MR, 32% SD)

Toxicity: Myelosupression (Neutropenia).

1 (2%) tromboembolic events (AAS 325 mg/24h)

PN gr. 1/2 in 37%

F ti 1/2 i 57% d 3 i 1Fatigue gr 1/2 in 57%; grade 3 in 1

Zalypsis (PM00104) in MMNovel Agents for MM

• Zalypsis (PM00104) is a new synthetic alkaloid related to Me

Me

Me

OMe

OAc

N

HO

H

Jorumycin, Renieramycins, Safracins and Saframycins.Me

CF3

N

N

OH

O

O

NH

O

• Jorumycin was originally isolated fromJo u yc as o g a y so ated oJorunna funebris, a marine mollusk gastropod.

• Zalypsis has shown preclinical activity in bladder, gastric, breast, pancreatic and liver cancerpancreatic and liver cancer.

• Phase I clinical trial ongoing withpreliminary evidence of activity

• Phase I clinical trial ongoing with favorable safety profile

Potent anti-MM activity of ZalypsisDevelopment of novel drugs

48 hours)

MM cell lines

)

2400 Control Zalypsis 1 /K

Model of subcutaneous plasmacytoma

48 hours120

80

100

ion

(% c

ontr

ol)

1200

1600

2000

olum

e (m

m3 )

Zalypsis 0.8 mg/Kg

1 mg/Kg

Tumor volume

20

40

60

TT m

etab

oliz

at

0 0

400

800

Tum

or v

o

*

*

volume

5 100 0.1 0.5 1 500.2 2 20[Zalypsis], nM (Log)

MT 0

Pl ll

00 10 20 30 40

Days of treatment50

80

100

inin

g (%

)

Plasma cells

ndpo

int

1.0

0.8

0.6Zalypsis 1 mg/Kg

p<0.001*

Survival

0

20

40

60

Ann

exin

V s

tai

Tim

e to

en

0.4

0.2Control Zalypsis

0.8 mg/Kg

g g

* *

Survival

Ocio et al, Blood 2009

01 2 3 4 5 6

Patients 00.0

Days of treatment80604020 100

p53 dependent DNA Damage ResponseDevelopment of novel drugs

48 hours120100

% c

ontr

ol)DNA Damage Response genes deregulated

C &

20

40

60

80

tabo

lizat

ion

(%• ATM repair pathway TLK2, ATR, CHEK2, RAD5 & BRIP1

• DNA repair genes RAD23B, XPC, XRCC1, XRCC5 & GADD45A

5 100 0.1 0.5 1 500.2 2 20[Zalypsis], nM (Log)

20

MTT

me

0

p53 upregulationDSB induction

0 3 6 12

Time with Zalypsis, hours

p53 upregulation

Time with Zalypsis, hours

DSB induction

53

MM1S

MM1R

0 3 6 12

p53

MM1S

0 3 6 12

pH2AX

pCHK2p53

GAPDHMM144

p

GAPDH

The anti-MM activity of Zalypsis is, dependent of p53

WT p53 mutant p53

Ocio et al, Blood 2009

ConclusionsTreatment of MM

• Treatment of MM has improved over the years with several milestones:

Melphalan Polichem. ASCT Novel drugs (Thal / Btz / Len)

• Novel proteasome inhibitors (Carfilzomib) and IMIDs (Pomalidomide)display similar efficacy as their precedent drugs and seem to overcome theresistance to these compounds.

• Other promising drugs (in combination with Btz or Len/Dex) are HDAC(Panobinostat or Vorinostat), AKT pathway inhibitors (Perifosine & mTORinhibitors), Anti-CS1 MoAb and other MoAbs.inhibitors), Anti CS1 MoAb and other MoAbs.

• Urgent need for novel combinations based on preclinical studies and, overall, on good clinical trials. INCLUDE PATIENTS IN CLINICAL TRIALS.




Hospital Universitario


Hospital UniversitarioUniversidad de Salamanca

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Mieloma MúltipleMieloma MúltipleEnrique M. Ocio

Hospital Universitario y Centro de Investigación del CáncerUniversidad de Salamanca

nuevas dianas moleculares en el tratamiento del mieloma ... hematologia_dr_ocio...flow cytometry, wb...

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