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Supplementary Table S1. Preclinical studies of combinations of bortezomib and novel targeted agents being evaluated in clinical trials

Class/agent Cell lines/xenograft models Combination activity and possible mechanism of action Reference

HDAC inhibitors

Vorinostat U266 and MM.1S cells, and

CD138+ patient bone marrow cells

Synergistic apoptosis/cytotoxicity; increased ROS generation resulting in

mitochondrial dysfunction, caspase-3, -8, and -9 activation, NF-κB

inhibition, JNK activation, and p53 induction

Pei et al. (1)

Jeko-1 and Granta-519 cells Markedly increased ROS generation and decreased NF-κB activity Heider et al. (2)

Hodgkin’s lymphoma cell lines HD-

LM2, L-428, and KM-H2

Increased apoptosis; inhibition of Stat6, Akt, and ERK Georgakis et al.

(3)

NSCLC: NCI-H157, NCI-H358, NCI-

H460, and NCI-A549

Induced apoptosis through generation of ROS Denlinger et al.

(4)

Pancreatic cancer cells and

orthotopic pancreatic cancer

xenograft model

Aggresome disruption, resulting in ER stress and synergistic apoptosis Nawrocki et al.

(5)

Hepatoma cells: HepG2 and Huh6 Synergistic apoptosis and increased expression of c-Jun, phosphor-c-

Jun, and FasL, and production of Bcl-Xs

Emanuele et al.

(6)

Murine SCID-hu xenograft

LAGlambda-1 model

Slight inhibition of tumor growth and reduction of paraprotein levels Campbell et al.

(7)

Belinostat Osteoclasts, MM.1S, RPMI-8226,

OPM2 cell lines and xenograft

murine model

Synergistic inhibition of osteoclastogenesis; greater inhibition of MM cell

proliferation, increased apoptosis and cell death – greater caspase

cleavage; increased xenograft tumor inhibition

Feng et al. (8)

HNSCC cell lines and bortezomib-

resistant UMSCC-11A xenografts

NF-κB inhibition; increased antitumor activity Duan et al. (9)

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LBH589

Panobinostat

RPMI8226, MM.1S and OPM1 cells

and CD138-selected patient cells;

KMS-12PE, KMS-18, LP-1, NCI

H929, KMS-11, RPMI8226, OPM-2,

and U266 and 1S-luciferase tumor

mouse model

Formation of abnormal bundles of hyperacetylated α-tubulin, plus

diminished aggresome size; induces apoptosis

Catley et al.

(10);

Growney et al.

(11)

Depsipeptide

romidepsin

Human myeloid leukemia cell lines

HL-60 and K562 Activation of the mitochondrial apoptotic pathway; translocation of the

proapoptotic Bax, cytochrome c release

Sutheesophon

et al. (12)

Kinase inhibitors

Flavopiridol Bcr/Abl- human leukemia cells

Promotes bortezomib-mediated downregulation and apoptosis.

Inhibits cyclin-dependent kinase 1, 2, 4, 6 and 7, downregulates cyclin

D1 and VEGF

Dai et al. (13)

MCL cell lines Z138 and NCEB-1

Activated caspase-dependent apoptotic pathways Kapanen et al.

(14)

PD0332991

CDK 4, 6 inhibitor

5T33 MM cells Synergistic induction of G1 cell cycle arrest, apoptosis and cell death

with combination of bortezomib and PD0332991. Non-significant

improvement in survival in xenograft model

Menu et al. (15)

Sorafenib Multiple tumor cell lines: A549,

786-O, HeLa, MDA-MB-231, K562,

Jurkat, MEC-2, U251, D37

Induction of apoptosis through Akt and c-Jun NH2-terminal kinase

pathways

Yu et al. (16)

Farnesyl transferase inhibitors

Tipifarnib MM.1S, MM.1R, RPMI8226 and

U266 cell lines and primary human

Increased caspase-3, -8, and -9 cleavage and downregulation of p-Akt Kaufman et al.

(17)

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tumor cells

RPMI8226/S and U937 fibronectin-

adhered cells

Activation of ER stress, overcoming CAM-DR Yanamandra et

al. (18)

HNSCC: Tu212, 686LN & Sqcc/Y1 Sequence-dependent synergistic apoptosis; downregulation of p-Akt Klass et al. (19)

HSP90 chaperone inhibitors

Tanespimycin

and IPI-504

Human MM cells: MM.1s

and xenograft models

Increased accumulation of ubiquinated proteins; increased cleavage of

capsase-12; ER-stress-induced apoptosis

Mitsaides et al.

(20) and

Sydor et al. (21)

Tanespimycin MCF-7 human breast tumor cell line Increased accumulation of aggregated ubiquinated proteins; ER-derived

cystolic vacuolization

Mimnaugh et al.

(22)

Tanespimycin Human leukemia K562 & MV4-11 Synergistically induced apoptosis; abrogated aggresome formation and

ER stress response

Rao et al. (23)

Tanespimycin 9 lymphoma cell lines (Hodgkin

lymphoma, anaplastic large cell

lymphoma, mantle cell lymphoma)

NR Georgakis et al.

(24)

Pan-Bcl-2 inhibitor

Obatoclax

MM: LP1 and L363 cells Possible induction of the proapoptotic Noxa Gomez-Bougie

et al. (25) &

Trudel et al. (26)

MCL: UPN-1 and Jeko cell lines

and primary patient cells

Abrogation of bortezomib-induced Mcl-1 upregulation and possible

induction of the proapoptotic Noxa

Pérez-Galán et

al. (27)

DNA MM cell death Increased caspase-8 and -9, and Mcl-1 cleavage, plus Bax, Puma, and Kiziltepe et al.

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methyltransferase

inhibitor 5-

azacytidine

Noxa upregulation (28)

Akt inhibitor

perifosine

Myeloma cell lines β-catenin and survivin inhibition Hideshima et al.

(29)

Hydroxychloroquine

autophagy inducer

MM1.S and RPMI-8226 MM cell

lines

Bortezomib and hydroxychloroquine synergistic toxicity with combination

index <1; increased activated caspase 3

Shen et al.

(30)

CAM-DR, cell-adhesion-mediated drug resistance; CLL, chronic lymphocytic leukemia; ER, endoplasmic reticulum; HNSCC, Head and neck

squamous cell carcinoma cell lines; HDAC, histone deacetylase; HSP, heat shock protein; MCL, mantle cell lymphoma; MM, multiple myeloma;

NR, not reported/discussed; ROS, reactive oxygen species; NSCLC, non-small-cell lung cancer; VEGF, vascular endothelial growth factor.

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Supplementary Table S2. Ongoing clinical trials program of bortezomib in combination with novel targeted agents

Class/agent

Study type Institution(s) Study number (clinicaltrials.gov)

Tumor types Regimen Key findings and comments

HDAC inhibitors

Vorinostat Phase l dose

escalation

University of

Wisconsin

NCT00227513

Metastatic or

unresectable solid

tumors

A: Bortezomib iv d 1, 4,

8, 11; vorinostat po d 1–

14, QD q 21 d cycle

B: Bortezomib iv d 1, 4,

8, 11; vorinostat po d 1–

14, BID q 21 d cycle

Stratum A MTD: bortezomib 1.3

mg/m2; vorinostat 400 mg qd.

Stratum A responses, PR in 2

patients: sarcoma and NSCLC.

Bortezomib administered after

vorinostat

Vorinostat Phase l dose

escalation

University of

Maryland

NCT00310024

Relapsed or

refractory multiple

myeloma

Bortezomib iv, d 1, 4, 8,

11; vorinostat po d 4–11,

BID q 21 day cycle

dexamethasone (20 mg)

after cycle 2

MTD: Bortezomib 1.3 mg/m2;

vorinostat 400 mg. Evaluable

patients=21; 2 VGPR, 9 PR, 10 SD.

Responses in prior bortezomib-

treated patients.

Co-administration did not affect

vorinostat pharmacokinetics

Vorinostat Phase l dose

escalation

University of Virginia

Surgically resectable

stage IB–IIIA non-

small cell lung cancer

Bortezomib iv, d 1, 8, 15

q 28 d; vorinostat po d 1,

2, 3, 8, 9, 10, 15, 16, and

Treatment of newly diagnosed

patients prior to tumor resection

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NCT00731952 17 QD q 21 d cycle

Vorinostat Phase I dose

escalation

Multisite,

M.D. Anderson

Cancer Center, lead

NCT00111813

Advanced multiple

myeloma

Bortezomib iv, d 1, 4, 8,

11; vorinostat po d 1–14

BID or QD q 21 d cycle

MTD not reached at 400 mg

vorinostat and 1.3 mg/m2

bortezomib: 33 evaluable pts;

12 PR, 6 MR and 18 SD.

Subset of 17 patients previously

treated with bortezomib received

this regimen – 6 PR, 4 MR and 7 SD

Vorinostat Phase II

North Central Cancer

Treatment Group

NCT00641706

Progressive,

recurrent

glioblastoma

Bortezomib iv, d 1, 4, 8,

11; vorinostat po d 4–11,

QD q 21 d cycle.

Pre-surgery treatment

cohort evaluated

Primary endpoint of 6-month

progression-free survival.

Patient subset undergoing surgery

will receive 2 days’ combination

therapy and resected tissue

evaluated for pAKT, p27, Bax,

histone acetylation, proteasome

inhibition and microarray gene

expression profile

Vorinostat Phase II

Moffit Cancer Center

NCT00703664

Mantle cell lymphoma

and diffuse large B-

cell lymphomas

Bortezomib iv, d 1, 4, 8,

11; vorinostat po d 1–5,

8–12 QD q 21 d cycle

Three cohorts: Mantle cell

lymphoma with or without prior

bortezomib and diffuse large B-cell

lymphomas without prior

bortezomib.

Analyzing nuclear RelA by

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immunohistochemistry as predictor

of response

Vorinostat Phase ll

University of

Wisconsin

NCT00798720

Non-small cell lung

cancer

Bortezomib iv 1.3 mg/m2,

d 1, 4, 8, 11; vorinostat

po 400 mg, d 4–11, QD q

21 d cycle

Third-line therapy trial with 3-month

progression-free survival as primary

endpoint

Vorinostat Phase ll

Multisite

NCT00773838

Relapsed/refractory

multiple myeloma

(2 prior therapies)

Bortezomib iv 1.3 mg/m2,

d 1, 4, 8, 11; vorinostat

po 400 mg, d 4–11, QD q

21 d cycle;

dexamethasone (20 mg)

d 1, 2, 4, 5, 8, 9, 11, and

12

VANTAGE 095 trial; open label

phase II

Vorinostat Phase lll

Multisite

NCT00773747

Relapsed/refractory

multiple myeloma

(1–3 prior therapies)

Bortezomib iv 1.3 mg/m2,

d 1, 4, 8, 11; vorinostat

po 400 mg, d 1–14, QD q

21 d cycle

vs bortezomib + placebo

VANTAGE 088: International, trial ~

33 month treatment duration.

Primary outcome: progression-free

survival

Belinostat Phase l dose

escalation

University of

Colorado

Advanced solid

tumors or lymphomas

Bortezomib iv 1.3 mg/m2,

d 1, 4, 8, 11; belinostat

po d 1–5 q 21 d cycle

None reported

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NCT00348985

Panobinostat

Phase l dose

escalation

Hackensack

University Medical

Center

NCT00532389

Relapsed multiple

myeloma

Bortezomib iv, d 1, 4, 8,

11; oral panobinostat d 1,

3, 5 thrice-weekly;

dexamethasone (20 mg)

after cycle 1

Dexamethasone could be started

after cycle 1 if no response. Accrual

of 14 heavily pretreated patients, 8

with prior bortezomib. MTD pending

after 2 dose escalation cohorts. 1

CR, 1 VGPR and 3 PR (24)

Romidepsin Phase l/ll

Peter MacCallum

Cancer Centre,

Australia

NCT00431990

Relapsed/refractory

multiple myeloma

Bortezomib iv, 1.3 mg/m2

d 1, 4, 8, 11; romidepsin

iv 8, 10, 12, 14 mg/m2, d

1, 8, 15 q 28 d cycle

dexamethasone po, 20

mg d 1, 2, 4, 5, 8, 9, 11,

12

MTD romidepsin 10 mg/m2

18 pts evaluable; ORR 12/18 (67%)

(4 CR/nCR, 4 VGPR, 4 PR) and 5

MR (28%) (25).

Maintenance bortezomib on d 1, 8 q

28 d schedule

Romidepsin Phase II

Multisite US

NCT00765102

Relapsed/refractory

multiple myeloma

with prior bortezomib

therapy

Bortezomib iv, 1.3 mg/m2

d 1,4,8,11; romidepsin, d

1, 8,15 q 28 d cycle

Two strata; bortezomib resistant and

bortezomib sensitive

Bortezomib administered prior to

romidepsin

Kinase inhibitors

Alvocidib Phase l dose

escalation

Virginia

Commonwealth

Recurrent or

refractory indolent B-

cell neoplasms

Bortezomib iv, d 1, 4, 8,

11; alvocidib iv, d 1, 4, 8,

11 (1 h bolus) q 21 d

cycle or hybrid infusion

Bortezomib followed by alvocidib

administration; 38 patients accrued;

2 CR, 7 PR, 3 MR, 15 SD. 2 MR in 3

patients with prior bortezomib.

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University

NCT00082784

(30 min bolus, 4 h

infusion) d 1, 8 q 21 d

cycle

CD138+ cells assessed for NFκB

nuclear localization, pJNK, Mcl-1

and XIAP

PD 0332991

CDK4/6 Inhibitor

Phase I/II

Multi-site US

NCT00555906

Relapsed/refractory

multiple myeloma

Bortezomib iv d 8, 11,

15, 18 q 28 d (Schedule

A) or q 21 d (Schedule B)

PD 0332991 po d 1–21

(Schedule A) or 1–12

(Schedule B)

Dexamethasone, 20 mg also taken

on d 8, 11, 15 and 18.

Rb phosphorylation status to be

assessed

Sorafenib Phase l dose

escalation

Mayo Clinic

NCT00303797

Advanced cancer:

Group 1: Solid tumors

Group 2: Multiple

myeloma or chronic

lymphocytic leukemia

Bortezomib iv, d 1, 4, 8,

11; sorafenib po, d 1–21

BID q 21 d cycle

MTD: 200 mg BID sorafenib, 1.0

mg/m2 bortezomib

Sorafenib Phase l/ll

Sarah Cannon

Research Institute

NCT00536575

Relapsed/refractory

multiple myeloma

Bortezomib iv, d 1, 8, 15,

22; sorafenib po 200 mg

BID q 35 d cycle

Assessing weekly bortezomib

schedule

Sunitinib Phase I dose

escalation

Emory University

NCT00720148

Chemorefractory

advanced solid

tumors

Bortezomib iv, d 1, 8, 15,

22; sunitinib po, d 1–28

qd q 42 d cycle

Two stages, dose escalation of

sunitinib with fixed dose bortezomib

and then vice-versa

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Temsirolimus Phase l/ll

Dana-Farber Cancer

Institute

NCT00483262

Relapsed/refractory

multiple myeloma

Bortezomib iv, d 1, 8, 15,

22; temsirolimus iv d 1,

8, 15, 22, 29 q 35 d cycle

None reported

Everolimus Phase I dose

escalation

Case Comprehensive

Cancer Center

NCT0067112

Relapsed/refractory

mantle cell

lymphoma, other

indolent non-

Hodgkin’s lymphoma

Bortezomib iv, d 1, 4, 8,

11; everolimus po d 1–21

qd or qod q 21 d cycle

Baseline tumor expression of mTOR

and NFκB-related proteins (i.e.

pS6K, pAKT, and cREL) and

FOXP3 by immunohistochemistry

Erlotinib Phase ll

University of

Tennessee

NCT00283634

Relapsed/refractory

metastatic non-small

cell lung cancer

(one prior cytotoxic

therapy)

Bortezomib+erlotinib vs

erlotinib

Randomized study terminated due

to insufficient activity at a planned

interim analysis

Cetuximab Phase l dose

escalation

University of

Minnesota

NCT00622674

Advanced solid

tumors

Bortezomib iv, d 1, 8;

cetuximab iv d 1, 8,15 q

21 d cycle

EGFR-expressing tumor necessary

for eligibility.

MTD not reached

Dasatinib Phase I

Multisite,

international

Relapsed/refractory

multiple myeloma

Bortezomib iv 1.0 or 1.3

mg/m2 d 1, 4, 8, 11;

dasatinib po, 50, 100,

Three cohorts:

B: 1.0, D: 50

B: 1.3, D: 100

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M.D. Anderson

Cancer Center, lead

NCT00560352

140 mg d 1–21 qd q 21 d

cycle

B: 1.3, D: 140.

Dexamethasone: 20 mg qd with

cohorts 2 and 3

Perifosine

Phase l/ll

Dana-Farber Cancer

Institute

NCT00401011

Relapsed/refractory

multiple myeloma

(patients with prior

progression on

bortezomib

treatment)

Bortezomib iv, 1.3 mg/m2

d 1, 4, 8, 11; perifosine

po, d 1–21 qhs q 21 d

cycle

Dexamethasone allowed for patients

with PD after cycle 1.

MTD: 50 mg perifosine and 1.3

mg/m2 bortezomib.

Subset of 35 patients refractory to

bortezomib – ORR 37% and CR 3%

(51)

Farnesyl transferase inhibitors

Tipifarnib Phase l dose

escalation

H. Lee Moffitt Cancer

Center

NCT00383474

Advanced acute

leukemias or chronic

myelogenous

leukemia in blast

phase

Bortezomib iv, d 1, 4, 8,

11; tipifarnib po, d 1–14,

BID q 21 d cycle

MTD: tipifarnib 600 mg BID,

bortezomib 1.3 mg/m2.

FTase inhibition and proteasome

inhibition assessed in PBMC.

NF-κB binding, p-AKT, Bax or Bim

measured in leukemic blasts pre-

and post-treatment

Tipifarnib Phase I/II

University of Bologna

NCT00510939

Newly diagnosed

acute myeloid

lymphoma ineligible

Bortezomib iv, d 1, 8, 15;

tipifarnib po, 600 mg, d

1–21, BID q 28 d cycle

MTD: tipifarnib 600 mg BID,

bortezomib 1.0 mg/m2. 22 evaluable

pts: 5 CR, 1 PR, 19 SD, 12 PD.

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for cytotoxic

chemotherapy (>18

years) or in first

relapse (>60 years)

Evaluating 2 gene expression

algorithms (RASGRP1/APTX) for

tipifarnib sensitivity (59)

Tipifarnib Phase l dose

escalation

Emory University

Relapsed/refractory

multiple myeloma

Bortezomib iv, 1.0mg/m2

d 1, 4, 8, 11; tipifarnib po

d 2–15, BID q 21 d cycle

16 evaluable patients, 2 MR, 5 SD.

MTD pending. Effects on HDAC6

and aggresome formation to be

assessed (61)

HSP90 chaperone inhibitors

Tanespimycin Phase l dose

escalation

Mayo Clinic

NCT000960005

Advanced solid

tumors or lymphoma

Bortezomib iv, d 1, 4, 8,

11; tanespimycin iv d 1,

4, 8, 11 q 21 d cycle

None reported

Tanespimycin Phase l dose

escalation

Ohio State University

NCT00103272

Relapsed/refractory

hematologic

malignancies

Bortezomib iv, d 1, 4, 8,

11; tanespimycin iv d 1,

4, 8, 11 q 21 d cycle

None reported

Tanespimycin Phase lll

Multicenter

NCT00546780

TIME-1 trial

Multiple myeloma

after first relapse

Bortezomib iv, 1.3 mg/m2

d 1, 4, 8, 11;

tanespimycin iv 340

mg/m2 d 1, 4, 8, 11 q 21

Progression-free survival endpoint

powered to show a 2.75 months

benefit with addition of tanespimycin

to bortezomib

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d cycle

Tanespimycin Phase ll/lll

Multisite US

NCT00514371

TIME-2 trial

Relapsed/refractory

multiple myeloma (at

least 3 prior

therapies)

Bortezomib iv, 1.3 mg/m2

d 1, 4, 8, 11;

tanespimycin iv

q 21 d cycle

Three arm trial comparing standard

bortezomib dose and three different

doses of tanespimycin

AUY-922 Phase I/II

Multisite,

US/international

NCT00708292

Relapsed/refractory

multiple myeloma (1

prior therapy)

Bortezomib iv;

AUY-922 iv;

dexamethasone

Combination with and without

dexamethasone will be assessed

and also the PK and

pharmacodynamics of combination

Other Targets Pan-Bcl-2 family

inhibitor obatoclax

Phase l/ll

Multisite US

NCT00407303

Mantle cell

lymphoma

Bortezomib iv, 1.0–1.3

mg/m2; obatoclax iv 30–

60 mg (24 h infusion) q

21 d cycle

None reported

Obatoclax Phase l/ll

Mayo Clinic

NCT00719901

Relapsed/refractory

multiple myeloma

Bortezomib iv, d 1, 4, 8,

11; obatoclax iv (3 h

infusion) d 1, 8, 15 q 21 d

cycle

None reported

Obatoclax Phase I dose

escalation

California Cancer

Consortium

NCT00538187

Aggressive

relapsed/recurrent

non-Hodgkin’s

lymphoma

Bortezomib iv, d 1, 8, 15,

22 cycle; obatoclax iv, (3

h infusion) d 1, 8, 15, 22

q 35 d cycle

Bortezomib follows obatoclax

administration.

Immunohistochemistry analysis of

Bcl-2, p53, Noxa, and Puma

proteins

DNA Phase I dose Relapsed/refractory Bortezomib iv, d 2, 5, 9, Evaluation of target gene

46021_1_supp_1_l0z6ns.doc 14

methyltransferase

inhibitor

azacytidine

escalation

Ohio State University

NCT00624936

acute myeloid

leukemia and

myelodysplastic

syndromes

12; azacytidine iv, 75

mg/m2 d 1–7 q 21 d cycle

methylation and expression, DNA

methyltransferase 1 (DNMT1)

protein expression and global

methylation

Monoclonal Antibodies

Elotuzumab

(anti-CS1)

Phase I/II

Multisite US

NCT00726869

Relapsed/refractory

multiple myeloma

(1–3 prior therapies)

Bortezomib iv, d 1, 4, 8,

11; elotuzumab iv, 2.5,

5.0, 10, 20 mg/kg d 1, 11

q 21 d cycle

Elotuzumab infusion follows

bortezomib administration

Mapatumumab

(anti-TRAIL-R1)

Phase II

Multisite

US/international

NCT00315757

Relapsed/refractory

multiple myeloma

(<2 prior therapies)

Bortezomib iv, 1.3 mg/m2

d 1, 4, 8, 11;

mapatumumab iv, 10

mg/kg, 20 mg/kg d 1, q

21 d cycle

Three arm randomized study of

bortezomib monotherapy

comparator arm and combination

with two doses of mapatumumab

CNTO-328

(anti-IL6)

Phase II

Multisite

US/international

NCT00401843

Relapsed/refractory

multiple myeloma

Bortezomib iv, 1.3 mg/m2

d 1, 4, 8, 11 q 21 d;

CNTO 328 iv, 6 mg/kg, d

1, 15, 29 q 42 d cycle;

dexamethasone, 20 mg

at disease progression

Randomized, double blind, placebo

controlled trial; CNTO-328 +

bortezomib vs placebo + bortezomib

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Bevacizumab

(anti-VEGF)

Phase I dose

escalation

M.D. Anderson

Cancer Center

NCT00428545

Solid tumors,

lymphoma,

myeloma

Bortezomib iv,

0.7 mg/m2 d 1, 8;

bevacizumab iv,

2.5 mg/kg iv d 1 q 21 d

cycle

Both agents will be dose escalated

from the listed starting doses

Bevacizumab Phase II

Duke University

NCT00611325

Recurrent glioma or

gliosarcoma

Bortezomib iv 1.7 mg/m2

d 1, 4, 8, 11, 22, 25, 29,

32; bevacizumab iv 15

mg/kg d 1, 21 q 42 d

cycle

Primary endpoint: 6-month

progression-free survival.

Two cohorts: patients using enzyme

inducing and non-enzyme inducing

anti-epileptic drugs

Bevacizumab Phase I/II

UCLA Cancer Center

NCT00184015

Advanced or

recurrent renal cell

cancer

A: Bortezomib iv, 1 or 1.3

mg/m2 d 1, 4, 8, 11;

bevacizumab 15 mg/kg,

d 1 q 21 d cycle

B: Bortezomib iv, 1.6 or

1.8 mg/m2 d 1, 8;

bevacizumab 15 mg/kg d

1, q 21 d cycle

Two arms assessing twice weekly or

weekly bortezomib schedules.

Phase II primary endpoint: response

rate

Bevacizumab Phase II

Multisite US

NCT00473590

Relapsed/refractory

multiple myeloma

Bortezomib +

bevacizumab vs

bortezomib + placebo

AMBER study: randomized, placebo

controlled study.

Primary endpoint: progression-free

survival

Rituximab Phase II Waldenstrom’s Bortezomib iv 1.6 mg/m2 Primary treatment of symptomatic

46021_1_supp_1_l0z6ns.doc 16

(anti-CD20) M.D. Anderson

Cancer Center

NCT00492050

macroglobulinemia –

newly diagnosed

d 1, 8, 15, 22; rituximab

iv 375 mg/m2 d 8, 22 q

35 d cycle

Waldenstrom’s macroglobulinemia,

no prior therapy allowed; two cycles

of investigational regimen given.

Effect on stem cells analyzed

Rituximab Phase ll

Gruppo Italiano

Multiregional

NCT00509379

Relapsed/refractory

indolent and mantle

cell lymphoma

Bortezomib iv,1.6 mg/m2

d 1, 8, 15, 22; rituximab

iv 375 mg/m2 d 8, 22 q

35 d cycle

Rituximab naive or sensitive

patients

Rituximab Phase II

Ohio State University

NCT 00201877

Relapsed/refractory

mantle cell and

follicular non-

Hodgkin’s lymphoma

Bortezomib iv, 1.3 mg/m2

d 1, 4, 8, 11; rituximab iv,

375 mg/m2 d 1, 8 q 21 d

cycle

Induction and maintenance phases

evaluated

Trastuzumab

(anti-HER2)

Phase I dose

escalation

Jules Bordet Institute

NCT00199212

HER2 expressing

breast cancer

Bortezomib iv, d 1,4,8,

11; trastuzumab iv

weekly or q 3 week

Any prior HER2 therapy not allowed

Abbreviations: AMBER , A randomized, blinded, placebo-controlled, Multicenter, phase ll study of Bevacizumab in combination with bortEzomib

in patients with Relapsed or refractory multiple myeloma; CR, complete response; EGFR, epidermal growth factor receptor; FTase,

farnesyltransferase; HDAC6, histone deacetylase 6; HER2, human epidermal growth factor receptor 2 ; HSP, heat-shock protein; JNK, c-Jun

N-terminal kinase; Mcl-1, myeloid cell leukemia 1 protein; MR, minimal response; MTD, maximum tolerated dose; mTOR, mammalian target of

rapamycin; nCR, near-complete response; NF-κB, nuclear factor kappa B; NSCLC, non-small cell lung cancer; ORR, objective response rate;

PBMC, peripheral blood mononuclear cells; PD, progressive disease; pJNK, phosphorylated JNK; PK, pharmacokinetics; PR, partial response;

pS6K, p70 S6 kinase; Rb, Retinoblastoma protein; SD, stable disease; TIME, Tanespimycin in Myeloma Evaluation; TRAIL, tumor necrosis

46021_1_supp_1_l0z6ns.doc 17

factor-related apoptosis inducing ligand; VEGF, vascular endothelial growth factor; VGPR, very good partial response; XIAP, X-linked inhibitor

of apoptosis protein.

46021_1_supp_1_l0z6ns.doc 18

Supplementary Table S3. Other novel agents investigated in combination with bortezomib in preclinical studies

Agent Cell lines/xenograft models Possible mechanism of action Reference

HDAC inhibitors

PCI-24781 NHL (Ramos, HF1, SUDHL4) and

HL (L428) cell lines

Combination caused synergistic apoptosis in NHL cell

lines (combination index <0.2)

Bhalla et al. (31)

Tubacin

MM.1S cells and patient bone

marrow cells

Synergistically augments bortezomib-induced

cytotoxicity by c-Jun NH2-terminal kinase/caspase

activation, plus combined proteasome and aggresome

inhibition

Hideshima et al.

(32)

UCL67022

RPMI8226/S and U266 cell lines

and primary patient cells

HDAC6 and aggresome inhibition Maharaj et al. (33)

Valproic acid U266 cells Increased G1 cell cycle arrest and caspase-3

activation;, p21 and p27 up-regulated; reduced IL-6

secretion and expression of cyclin A, cyclin D1, cyclin E,

CDK2, CDK4, and CDK6

Kim et al. (34)

KD7150 CD138+ primary MM cells Induction of apoptosis due to DNA damage and

mitochondrial signaling; increase of acetylation of

histones and activation of caspase-3, -8 and -9; induced

oxidative stress and oxidative DNA by upregulation of

heme oxygenase-1 and H2A.X phosphorylation,

respectively

Feng et al. (35)

JNJ-26481585 MEC1 cell line and patient-derived

CLL cells

Induces apoptosis; induces potent histone acetylation

and HSP70 upregulation and bcl-2 downregulation

Bommert et al. (36)

46021_1_supp_1_l0z6ns.doc 19

Farnesyl transferase inhibitors

Lonafarnib MM.1S, MM.1R, RPMI8226, and

U266 cell lines and primary human

tumor cells

p-Akt downregulation plus increased caspase-3, -8, and

-9 cleavage

David et al. (37)

Kinase inhibitors

Pazopanib

VEGFR, PDGFR,

c-Kit inhibitor

MM.1S Synergistic cytotoxicity (combination index <1) in MM-

endothelial cell co-culture assay

Podar et al. (38)

P276-00

CDK inhibitor

MM.1S Combination was synergistic (combination index <1) ,

pRB, Cdk4, cyclinD1 downregulated

Raje et al. (39)

SCIO-469

p38 MAPK inhibitor

MM cells and mouse xenograft

plasmacytoma model of MM

p53 induction, Hsp27 downregulation, Bcl-XL and Mcl-1

downregulation

Navas et al. (40)

BIRB 796

p38 MAPK inhibitor

MM.1S Hsp27 downregulation; increased caspase-8, and -9 and

PARP cleavage

Yasui et al. (41)

BIBF 1000

PDGF,bFGF,VEGF

inhibitor

Non-Ras-mutated t(4;14)- and

t(14;16)-positive cell lines

with/without dexamethasone

Increased activation of the extrinsic apoptotic pathway –

MAPK p44/42 and PI3K/Akt inhibition, caspase-3 and -8

(but not -9) and PARP activation

Bisping et al. (42)

LSN2322600

p38 MAPK inhibitor

Myeloma cells Hsp27 downregulation Ishitsuka et al. (43)

Enzastaurin

PKCβ, PI3K

inhibitor

WM cell lines BCWM.1 & WM-WSU Inhibition of Akt signaling, together with increased

caspase-3, -8, and -9 cleavage

Moreau et al.

(44,45)

SF1126 MM.1R, OPM1, MM.1S myeloma Combination with cell killing >50% vs cell killing rate of David et al.

46021_1_supp_1_l0z6ns.doc 20

PI3K inhibitor cell lines individual agents of <20% (additive effect) (46)

CAL-101

PI3K δ inhibitor

Eleven MM cell lines (INA-6 & LB).

Primary myeloma cells from 24

patients

Synergistic cytotoxicity with bortezomib against MM cells

(combination index = 0.64)

Ikeda et al.

(47)

TAE226

FAK, IGF-1R

inhibitor

NCI H929 MM cell line Combination with synergistic killing at sub-lethal

concentration of bortezomib (synergism quotient = 1.5)

Sharkey et al.

(48)

Pan-Bcl-2 inhibitor

HA14-1 Epstein-Barr virus-immortalized

lymphoblastoid cell lines (Sweigh

cells)

Increased caspase-3, -8, and -9 cleavage Srimatkandada et

al. (49)

ABT-737 MM.1S cells Mcl-1 downregulation Chauhan et al.

(50,51)

Other agents & combinations

IPI-504

HSP90 inhibitor

RPMI-8226 xenograft

Eleven human MCL cell lines

Bortezomib-IPI-504 combination resulted in complete

and durable regression of RPMI-8226.

Bortezomib-IPI-504 had synergistic cytotoxicity against

MCL with combination indexes between 0.53 and 1.094

Sydor et al.

(21)

Roue et al.

(52)

CDDO-Im

Triterpenoid

MM.1S and MM.1R cells Reduced mitochondrial membrane potential, superoxide

generation, cytochrome c/Smac release, and caspase-3,

-8, and -9 cleavage

Chauhan et al. (53)

Rapamycin

mTOR inhibitor

RPMI and U266 cell lines, primary

CD138+ patient cells, stromal cells

NF-κB and PI3K/Akt inhibition O’Sullivan et al.

(54)

46021_1_supp_1_l0z6ns.doc 21

TRAIL MM.1S cells NF-κB inhibition Mitsaides et al. (55)

TRAIL MCL B cells NF-κB Inhibition; synergy impaired by intracellular

accumulation of c-FLIP

Roue et al. (56)

Fas ligand APO010 MM1S, MM1R, U266, RPMI-LR5,

RPMI-Dox40, MM144, RPMI8226

and OPM-1 cell lines

Increased caspase-3, -7, -8, and -9, Mcl-1, and BIM

cleavage; decreased BID cleavage

Ocio et al. (57)

WP-1130

Jak2 inhibitor

‘Classic’ and blastoid-variant MCL

cell lines

Bcl-2 down-regulation, Bax upregulation, and NF-κB

inhibition

Pam et al. (58)

Arsenic trioxide K562, NB4, NB4-LR1, Raji, SU-DHL-4 cell lines, primary CML cells Synergistic induction of apoptosis with combination of

bortezomib and arsenic at reduced doses

Yan et al.

(59)

Ritonavir

HIV-protease

inhibitor

Myeloma cell lines U266, RPMI 8226, ARH-77

Synergistic decrease in cell proliferation after treatment

with combination

Shibata et al.

(60)

CRx-501

Adenosine A2A

receptor agonist

Ten MM cell lines including MM.1S,

EJM, ANBL-6, MM.1R, KSM-12PE,

MOLP-8

Combination of the two agents resulted in 2-fold shift in

IC50 compared to single agent

Rickles et al.

(61)

Salmeterol

Β2 Adrenergic

receptor agonist

MM RPMI-8226 xenograft in SCID

CB17 mice

Combination with bortezomib showed 70% tumor

volume reduction in contrast to 34% for salmeterol or

vehicle alone

Rickles et al.

(62)

Nutlin 3

Mdm2 –p53

inhibitor

MDA-MB-231 (breast), DU145

(prostate), ARO/HT-29 (colon),

SW579, FRO, TT (thyroid)

Sub-lethal concentrations of bortezomib and nutlin-3 had

synergistic apoptotic response in solid tumors; increased

expression of p53, p21, Mdm2, Bax, Noxa, PUMA

Ooi et al.

(63)

G6.31 Primary MM cells obtained from Combination caused significant inhibition of tumor Campbell et al.

46021_1_supp_1_l0z6ns.doc 22

VEGF antibody patient when bortezomib sensitive

or resistant

growth and reduction in paraprotein (64)

AVE1642

IGF-1R antibody

CD45(neg) LP-1 MM cell line Selectively inhibits the growth of CD45(neg) myeloma

cells; increases bortezomib-induced apoptosis, which

correlates with an increase of Noxa expression

Descamps et al.

(65)

AML, acute myeloid leukemia; CAM-DR, cell-adhesion-mediated drug resistance; CLL, chronic lymphocytic leukaemia; ER, endoplasmic

reticulum; HDAC, histone deacetylase; HIF1-α, hypoxia-inducible factor alpha; HSP, heat shock protein; IGF, insulin-like growth factor; MCL,

mantle cell lymphoma; mTOR, mammalian target of rapamycin; MM, multiple myeloma; NR, not reported/discussed; ROS, reactive oxygen

species; SCID, severe combined immunodeficiency; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; UPR, unfolded protein

response; VEGF, vascular endothelial growth factor; WM, Waldenström’s macroglobulinemia.

46021_1_supp_1_l0z6ns.doc 23

References Reference List 1. Pei XY, Dai Y, Grant S. Synergistic induction of oxidative injury and apoptosis in human multiple myeloma cells by the proteasome

inhibitor bortezomib and histone deacetylase inhibitors. Clin Cancer Res 2004;10:3839-52. 2. Heider U, Kaiser M, Zavrski L et al. Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor

bortezomib in mantle cell lymphoma [abstract]. Blood 2006;108:710a-1a. 3. Georgakis GV, Yazbeck VY, Li Y, Younes A. The histone deacetylase inhibitor vorinostat (SAHA) induces apoptosis and cell cycle

arrest in Hodgkin lymphoma (HL) cell lines by altering several survival signaling pathways and synergizes with doxorubicin, gemcitabine and bortezomib [abstract]. Blood 2006;108:639a.

4. Denlinger CE, Rundall BK, Jones DR. Proteasome inhibition sensitizes non-small cell lung cancer to histone deacetylase inhibitor-induced apoptosis through the generation of reactive oxygen species. J Thorac Cardiovasc Surg 2004;128:740-8.

5. Nawrocki ST, Carew JS, Pino MS et al. Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res 2006;66:3773-81.

6. Emanuele S, Lauricella M, Carlisi D et al. SAHA induces apoptosis in hepatoma cells and synergistically interacts with the proteasome inhibitor Bortezomib. Apoptosis 2007;12:1327-38.

7. Campbell R, Sanchez E, Steinberg Jet al. In vivo effects of vorinostat in combination with bortezomib [abstract]. Haematologica 2007;92:151.

8. Feng R, Oton AB, Patrene K et al. Combination of the proteasome inhibitor bortezomib and a histone deacetylase inhibitor PXD101 results in synergistic inhibition of osteoclastogenesis and significantly stronger inhibition of multiple myeloma growth in vitro and in vivo [abstract]. Blood 2006;108:153a-4a.

9. Duan J, Friedman J, Nottingham L, Chen Z, Ara G, Van WC. Nuclear factor-kappaB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101. Mol Cancer Ther 2007;6:37-50.

10. Catley L, Weisberg E, Kiziltepe T et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 2006;108:3441-9.

11. Growney JD, Atadja P, Shao W et al. Efficacy of panobinostat (LBH589) in multiple myeloma cell lines and in vivo mouse model: tumor-specific cytotoxicity and protection of bone integrity in multiple myeloma [abstract]. Blood 2007;110:Abstract 1510.

12. Sutheesophon K, Kobayashi Y, Takatoku MA et al. Histone deacetylase inhibitor depsipeptide (FK228) induces apoptosis in leukemic cells by facilitating mitochondrial translocation of Bax, which is enhanced by the proteasome inhibitor bortezomib. Acta Haematol 2006;115:78-90.

46021_1_supp_1_l0z6ns.doc 24

13. Dai Y, Rahmani M, Pei XY, Dent P, Grant S. Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Blood 2004;104:509-18.

14. Kapanen A, Tucker C, Chikh G, Bally M, Klasa R. Cell based assays completed with the mantle cell lymphoma cell lines Z138 and NCEB-1 indicate that combinations of bortezomid and flavopiridol interact to achieve synergistic activity [abstract]. Blood 2005;106:678a.

15. Menu E, Garcia J, Huang X et al. A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model. Cancer Res 2008;68:5519-23.

16. Yu C, Friday BB, Lai JP et al. Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol Cancer Ther 2006;5:2378-87.

17. Kaufman JL, David E, Torre C, Sinha R, Lonial S. Enhanced levels of apoptosis by combination of farnesyl transferase inhibition (tipifarnib) and proteasome inhibition (bortezomib) in myeloma cell lines and primary myeloma cells and its mechanistic effects on Akt and caspase pathways [abstract]. Blood 2005;106:451a.

18. Yanamandra N, Colaco NM, Parquet NA et al. Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated drug resistance in multiple myeloma and acute myeloid leukemia. Clin Cancer Res 2006;12:591-9.

19. Klass CM, Chen G, Zhang X, Lonial S, Khuri FR, Shin DM. Antitumor effects of combined bortezomib and tipifarnib in head and neck squamous cell carcinoma (HNSCC) cells [abstract]. J Clin Oncol 2006;24:300s.

20. Mitsiades CS, Mitsiades NS, McMullan CJ et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood 2006;107:1092-100. 21. Sydor JR, Normant E, Pien CS et al. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-

504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci U S A 2006;103:17408-13. 22. Mimnaugh EG, Xu W, Vos M et al. Simultaneous inhibition of hsp 90 and the proteasome promotes protein ubiquitination, causes

endoplasmic reticulum-derived cytosolic vacuolization, and enhances antitumor activity. Mol Cancer Ther 2004;3:551-66. 23. Rao R, Fiskus W, Herger B, Atadja P, Bhalla K. Inhibition of histone deacetylase (HDAC) 6 and/or heat shock protein (HSP) 90: A

strategy to abrogate multi-level protective responses to misfolded proteins induced by proteasome inhibitors in human leukemia cells [abstract]. Blood 2006;108:80a.

24. Georgakis GV, Li Y, Younes A. Preclinical evaluation of the HSP-90 inhibitor 17AAG in Hodgkin and non-Hodgkin lymphomas: Induction of apoptosis and potentiation of chemotherapy cytotoxicity [abstract]. J Clin Oncol 2005;23:577s.

25. Gomez-Bougie P, Maiga S, Pellat-Deceunynck C, Jouan S, Bataille R, Amiot M. The pan-Bcl-2 inhibitor GX15-O70 induces apoptosis in human myeloma cells by Noxa induction and strongly enhances melphalan, bortezomib or TRAIL-R1 antibody apoptotic effect [abstract]. Blood 2006;108:991a.

26. Trudel S, Li ZH, Rauw J, Tiedemann RE, Wen XY, Stewart AK. Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. Blood 2007;109:5430-8.

27. Perez-Galan P, Roue G, Villamor N, Campo E, Colomer D. The BH3-mimetic GX15-070 synergizes with Bortezomib in Mantle Cell Lymphoma by enhancing Noxa-mediated activation of Bak. Blood 2007;109:4441-9.

46021_1_supp_1_l0z6ns.doc 25

28. Kiziltepe T, Hideshima T, Catley L et al. 5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells. Mol Cancer Ther 2007;6:1718-27.

29. Hideshima T, Yasui H, Catley L et al. Akt inhibitor perifosine-induced cytotoxicity is associated with significant downregulation of survivin in human multiple myeloma (MM) cells [abstract]. Blood 2006;108:974a.

30. Shen JP, Divakarau S, Pnduru S, Vogl D, Amaravadi R, Bradner J. The rationale for combined proteasome and autophagy inhibition in multiple myeloma established using novel translational platforms [abstract]. Blood 2008;112:Abstract 2755.

31. Bhalla S, David K, Mauro L et al. Histone deacetylase inhibitor (HDACi) PCI-24781 and bortezomib result in synergistic apoptosis in Hodgkin lymphoma (HL) and non-Hodgkin's lymphoma (NHL) cell lines: investigation of cell death and NFKB-mediated pathways [abstract]. Blood 2007;110:Abstract 3589.

32. Hideshima T, Bradner JE, Wong J et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A 2005;102:8567-72.

33. Maharaj L, Popat R, Chahwan A et al. The novel HDAC inhibitor UCL67022 is highly potent in multiple myeloma and non-Hodgkins lymphoma and is enhanced by bortezomib [abstract]. Blood 2006;108:735a.

34. Kim B, Ahn K, Kim I, Park S, Kim B, Yoon S. Effect of combined treatment of bortezomib and valproic acid on multiple myeloma cells [abstract]. J Clin Oncol 2007;25:705s.

35. Feng R, Ma H, Hassig A, Payne JE, Smith ND, Mapara MY. KD7150, a novel mercaptoketone-based HDAC inhibitor, exerts potent anti-multiple myeloma effects invitro and in vivo by induction of DNA damage and mitochondrial signaling. Blood 2007;110:Abstract 2519.

36. Bommert K, Knop S, Arts J, King P, Page M, Leo E. Novel, 2nd generation HDAC inhibitor JNJ-26481585 exhibits potent antitumor activity against chronic lymphocytic leukemia cells in-vitro and ex-vivo. Blood 2007;110:Abstract 4679.

37. David E, Sun SY, Waller EK, Chen J, Khuri FR, Lonial S. The combination of the Farnesyl transferase inhibitor (Lonafarnib) and the proteasome inhibitor (Bortezomib) induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT. Blood 2005;106:4322-9.

38. Podar K, Tonon G, Sattler M et al. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. Proc Natl Acad Sci U S A 2006;103:19478-83.

39. Raje N, Hideshima T, Mukherjee S et al. Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma. Leukemia 2009;23:961-70.

40. Navas TA, Nguyen AN, Hideshima T et al. Inhibition of p38alpha MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo. Leukemia 2006;20:1017-27.

41. Yasui H, Hideshima T, Ikeda H et al. BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (Hsp) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/Hsp27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth. Br J Haematol 2007;136:414-23.

46021_1_supp_1_l0z6ns.doc 26

42. Bisping G, Wenning D, Kropff MH et al. Enhanced anti-myeloma activity by combination of receptor tyrosine kinase (RTK) inhibition, proteasome inhibition, and dexamethasone: Therapeutic implications for t(4;14) and t(14;16) multiple myeloma (MM) subgroups [abstract]. Blood 2005;106:37a.

43. Ishitsuka K, Hideshima T, Neri P et al. p38MAPK inhibitor LSN2322600 modulates the bone marrow microenvironment and inhibits osteoclastogenesis in multiple myeloma [abstract]. Blood 2006;108:5042.

44. Moreau AS, Jia X, Ngo HT et al. Protein kinase C inhibitor enzastaurin induces in vitro and in vivo antitumor activity in Waldenstrom macroglobulinemia. Blood 2007;109:4964-72.

45. Moreau A-S, Jia X, O'Sullivan G et al. The selective protein kinase C inhibitor, enzastaurin, induces in vitro and in vivo antitumor activity in Waldenstroms macroglobulinemia [abstract]. Blood 2006;108:707a.

46. David E, Peng X, Barwick B, Kaufman J, Garlich J, Lonial S. SF1126, a novel PI3K inhibitor results in downstream inhibition of the PI3K axis and displays sequence specific synergy when combined with bortezomib in multiple myeloma cells [abstract]. Blood 2008;112:Abstract 5167.

47. Ikeda H, Hideshima T, Okawa Y, Vallet S, Pozzi S, Santo L. CAL-101, a specific inhibitor of the p110 isoform of phosphatidylinositide 3-kinase induces cytotoxicity in multiple myeloma (MM) [abstract]. Blood 2008;112:Abstract 2753.

48. Sharkey J, Yeh SL, Spencer A. The focal adhesion kinase (FAK) inhibitor TAE226 exhibits in vitro and in vivo activity against multiple myeloma [abstract]. Blood 2006;108:Abstract 844.

49. Srimatkandada P, Loomis R, Lacy J. Bortezomib (VelcadeTM) and the Bcl-2 inhibitor HA14-1 synergistically stimulate apoptosis in EBV-transformed lymphocytes: A potential approach to treatment of EBV-associated lymphoproliferative disorders [abstract]. Blood 2005;106:677a.

50. Chauhan D, Velankar M, Brahmandam M et al. A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma. Oncogene 2007;26:2374-80.

51. Chauhan D, Brahmandam M, Hideshima T et al. Bcl-2, Mcl-1 and p53 expression confer sensitivity to Bcl-2 inhibitor ABT-737 in multiple myeloma [abstract]. Blood 2006;108:991a.

52. Roue G, Perez-Galan P, Lopez-Guerra M, Villamor N, Campo E, Colomer D. The novel HSP90 inhibitor IPI-504 synergizes with bortezomib in mantle cell lymphoma cells by targeting both NF-kappaB signaling and unfolded protein response and leading to increased mitochondrial apoptosis [abstract]. Blood 2007;110:Abstract 1601.

53. Chauhan D, Li G, Podar K et al. The bortezomib/proteasome inhibitor PS-341 and triterpenoid CDDO-Im induce synergistic anti-multiple myeloma (MM) activity and overcome bortezomib resistance. Blood 2004;103:3158-66.

54. O'Sullivan G, Leleu X, Jia X et al. The combination of the mTOR inhibitor rapamycin and proteasome inhibitor bortezomib is synergistic in vitro in multiple myeloma [abstract]. Blood 2006;108:996a-7a.

55. Mitsiades CS, Treon SP, Mitsiades N et al. TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 2001;98:795-804.

56. Roue G, Perez-Galan P, Lopez-Guerra M, Villamor N, Campo E, Colomer D. Selective inhibition of IkappaB kinase sensitizes mantle cell lymphoma B cells to TRAIL by decreasing cellular FLIP level. J Immunol 2007;178:1923-30.

46021_1_supp_1_l0z6ns.doc 27

57. Ocio EM, Maiso P, Garayoa M, Dupuis M, Pandiella A, San Miguel JF. Effiacacy of APO010, a Fas-activating molecule, in multiple myeloma [abstract]. Haematologica 2007;92:0316.

58. Pham LV, Tamayo AT, Yoshimura LC et al. Bortezomib synergizes with a novel Jak2 inhibitor, WP-1130, to inhibit cell growth and induce apoptosis in classic and blastoid-variant mantle cell lymphoma [abstract]. Blood 2006;108:711a.

59. Yan H, Wang YC, Li D et al. Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cdelta. Leukemia 2007;21:1488-95.

60. Shibata R, Basserman F, Chandra P et al. Ritonavir sensitizes multiple myeloma cells to bortezomib-induced apoptosis [abstract]. Blood 2008;112:Abstract 5194.

61. Rickles RJ, Pierce L, Giordano T, Avery W, Farwell M, Crowe D. Preclinical evaluation of CRx-501, a potent selective A2A agonist as a novel drug candidate for the treatment of multiple myeloma [abstract]. Blood 2009;112:Abstract 252.

62. Rickles RJ, Pierce L, Giordano T, Tam WF, Avery W, Farwell M. Adenosine A2A and beta-2 adrenergic receptor agonism: novel selective and synergistic multiple myeloma targets discovered through systematic combination screening [abstract]. Blood 2008;112:Abstract 252.

63. Ooi M, Hayden P, McMillan DC, Negri J, Delmore J. Interactions of the Mdm2/p53 and proteasome pathways: implications for combination strategies to enhance the anti-myeloma activity of bortezomib [abstract]. Blood 2008;112:Abstract 2651.

64. Campbell R, Sanchez E, Steinberg J, Share M, Wang J, Li M. An anti-VEGF antibody, in combination with bortezomib, markedly inhibits tumor growth in SCID-hu models of human multiple myeloma [abstract]. Blood 2007;110:Abstract 4802.

65. Descamps G, Gomez-Bougie P, Venot C, Moreau P, Bataille R, Amiot M. A humanised anti-IGF-1R monoclonal antibody (AVE1642) enhances Bortezomib-induced apoptosis in myeloma cells lacking CD45. Br J Cancer 2009;100:366-9.