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Supplementary Table S1. Preclinical studies of combinations of 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 U266 and MM.1S cells, and Synergistic apoptosis/cytotoxicity; increased ROS generation resulting in Pei et al. (1) CD138+ patient bone marrow cells mitochondrial dysfunction, caspase-3, -8, and -9 activation, NF-κB inhibition, JNK activation, and p53 induction 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- Increased apoptosis; inhibition of Stat6, Akt, and ERK Georgakis et al. LM2, L-428, and KM-H2 (3) NSCLC: NCI-H157, NCI-H358, NCI- Induced apoptosis through generation of ROS Denlinger et al. H460, and NCI-A549 (4) Pancreatic cancer cells and Aggresome disruption, resulting in ER stress and synergistic apoptosis Nawrocki et al. orthotopic pancreatic cancer (5) xenograft model Hepatoma cells: HepG2 and Huh6 Synergistic apoptosis and increased expression of c-Jun, phosphor-c- Emanuele et al. Jun, and FasL, and production of Bcl-Xs (6) Murine SCID-hu xenograft Slight inhibition of tumor growth and reduction of paraprotein levels Campbell et al. LAGlambda-1 model (7) Osteoclasts, MM.1S, RPMI-8226, Synergistic inhibition of osteoclastogenesis; greater inhibition of MM cell Feng et al. (8) OPM2 cell lines and xenograft proliferation, increased apoptosis and cell death – greater caspase murine model cleavage; increased xenograft tumor inhibition HNSCC cell lines and bortezomib- NF-κB inhibition; increased antitumor activity Duan et al. (9) resistant UMSCC-11A xenografts

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LBH589 RPMI8226, MM.1S and OPM1 cells Formation of abnormal bundles of hyperacetylated α-tubulin, plus Catley et al.

Panobinostat and CD138-selected patient cells; diminished aggresome size; induces apoptosis (10); KMS-12PE, KMS-18, LP-1, NCI Growney et al. H929, KMS-11, RPMI8226, OPM-2, (11)

and U266 and 1S-luciferase tumor mouse model Depsipeptide Human myeloid leukemia cell lines Activation of the mitochondrial apoptotic pathway; translocation of the Sutheesophon HL-60 and K562 proapoptotic Bax, cytochrome c release et al. (12) Kinase inhibitors - Flavopiridol Bcr/Abl human leukemia cells Promotes bortezomib-mediated downregulation and apoptosis. Dai et al. (13) Inhibits cyclin-dependent kinase 1, 2, 4, 6 and 7, downregulates cyclin D1 and VEGF MCL cell lines Z138 and NCEB-1 Activated caspase-dependent apoptotic pathways Kapanen et al. (14) PD0332991 5T33 MM cells Synergistic induction of G1 arrest, apoptosis and cell death Menu et al. (15) CDK 4, 6 inhibitor with combination of bortezomib and PD0332991. Non-significant improvement in survival in xenograft model Sorafenib Multiple tumor cell lines: A549, Induction of apoptosis through Akt and c-Jun NH2-terminal kinase Yu et al. (16) 786-O, HeLa, MDA-MB-231, K562, pathways Jurkat, MEC-2, U251, D37 Farnesyl transferase inhibitors MM.1S, MM.1R, RPMI8226 and Increased caspase-3, -8, and -9 cleavage and downregulation of p-Akt Kaufman et al. U266 cell lines and primary human (17)

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tumor cells RPMI8226/S and U937 fibronectin- Activation of ER stress, overcoming CAM-DR Yanamandra et adhered cells al. (18) HNSCC: Tu212, 686LN & Sqcc/Y1 Sequence-dependent synergistic apoptosis; downregulation of p-Akt Klass et al. (19)

HSP90 chaperone inhibitors Tanespimycin Human MM cells: MM.1s Increased accumulation of ubiquinated proteins; increased cleavage of Mitsaides et al. and IPI-504 and xenograft models capsase-12; ER-stress-induced apoptosis (20) and Sydor et al. (21) Tanespimycin MCF-7 human breast tumor cell line Increased accumulation of aggregated ubiquinated proteins; ER-derived Mimnaugh et al. cystolic vacuolization (22) Tanespimycin Human leukemia K562 & MV4-11 Synergistically induced apoptosis; abrogated aggresome formation and Rao et al. (23) ER stress response Tanespimycin 9 lymphoma cell lines (Hodgkin NR Georgakis et al. lymphoma, anaplastic large cell (24) lymphoma, mantle cell lymphoma) 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 Abrogation of bortezomib-induced Mcl-1 upregulation and possible Pérez-Galán et and primary patient cells induction of the proapoptotic Noxa 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 Noxa upregulation (28) inhibitor 5- azacytidine Akt inhibitor Myeloma cell lines β-catenin and survivin inhibition Hideshima et al. perifosine (29) Hydroxychloroquine MM1.S and RPMI-8226 MM cell Bortezomib and hydroxychloroquine synergistic toxicity with combination Shen et al. autophagy inducer lines index <1; increased activated caspase 3 (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, ; HSP, heat shock protein; MCL, mantle cell lymphoma; MM, ; NR, not reported/discussed; ROS, reactive oxygen species; NSCLC, non-small-cell ; 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 Tumor types Regimen Key findings and comments Institution(s) Study number (clinicaltrials.gov) HDAC inhibitors Vorinostat Phase l dose Metastatic or A: Bortezomib iv d 1, 4, Stratum A MTD: bortezomib 1.3 escalation unresectable solid 8, 11; vorinostat po d 1– mg/m2; vorinostat 400 mg qd. University of tumors 14, QD q 21 d cycle Stratum A responses, PR in 2 Wisconsin B: Bortezomib iv d 1, 4, patients: sarcoma and NSCLC. NCT00227513 8, 11; vorinostat po d 1– Bortezomib administered after 14, BID q 21 d cycle vorinostat

Vorinostat Phase l dose Relapsed or Bortezomib iv, d 1, 4, 8, MTD: Bortezomib 1.3 mg/m2; escalation refractory multiple 11; vorinostat po d 4–11, vorinostat 400 mg. Evaluable University of myeloma BID q 21 day cycle patients=21; 2 VGPR, 9 PR, 10 SD. Maryland dexamethasone (20 mg) Responses in prior bortezomib- NCT00310024 after cycle 2 treated patients. Co-administration did not affect vorinostat Vorinostat Phase l dose Surgically resectable Bortezomib iv, d 1, 8, 15 Treatment of newly diagnosed escalation stage IB–IIIA non- q 28 d; vorinostat po d 1, patients prior to tumor resection University of Virginia small cell lung cancer 2, 3, 8, 9, 10, 15, 16, and

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NCT00731952 17 QD q 21 d cycle Vorinostat Phase I dose Advanced multiple Bortezomib iv, d 1, 4, 8, MTD not reached at 400 mg escalation myeloma 11; vorinostat po d 1–14 vorinostat and 1.3 mg/m2 Multisite, BID or QD q 21 d cycle bortezomib: 33 evaluable pts; M.D. Anderson 12 PR, 6 MR and 18 SD. Cancer Center, lead Subset of 17 patients previously NCT00111813 treated with bortezomib received this regimen – 6 PR, 4 MR and 7 SD Vorinostat Phase II Progressive, Bortezomib iv, d 1, 4, 8, Primary endpoint of 6-month North Central Cancer recurrent 11; vorinostat po d 4–11, progression-free survival. Treatment Group glioblastoma QD q 21 d cycle. Patient subset undergoing surgery NCT00641706 Pre-surgery treatment will receive 2 days’ combination cohort evaluated therapy and resected tissue evaluated for pAKT, p27, Bax, histone acetylation, proteasome inhibition and microarray gene expression profile Vorinostat Phase II Mantle cell lymphoma Bortezomib iv, d 1, 4, 8, Three cohorts: Mantle cell Moffit Cancer Center and diffuse large B- 11; vorinostat po d 1–5, lymphoma with or without prior NCT00703664 cell lymphomas 8–12 QD q 21 d cycle 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 Non-small cell lung Bortezomib iv 1.3 mg/m2, Third-line therapy trial with 3-month University of cancer d 1, 4, 8, 11; vorinostat progression-free survival as primary Wisconsin po 400 mg, d 4–11, QD q endpoint NCT00798720 21 d cycle Vorinostat Phase ll Relapsed/refractory Bortezomib iv 1.3 mg/m2, VANTAGE 095 trial; open label Multisite multiple myeloma d 1, 4, 8, 11; vorinostat phase II NCT00773838 po 400 mg, d 4–11, QD q (2 prior therapies) 21 d cycle; dexamethasone (20 mg) d 1, 2, 4, 5, 8, 9, 11, and 12 Vorinostat Phase lll Relapsed/refractory Bortezomib iv 1.3 mg/m2, VANTAGE 088: International, trial ~ Multisite multiple myeloma d 1, 4, 8, 11; vorinostat 33 month treatment duration. NCT00773747 po 400 mg, d 1–14, QD q (1–3 prior therapies) 21 d cycle Primary outcome: progression-free vs bortezomib + placebo survival

Belinostat Phase l dose Advanced solid Bortezomib iv 1.3 mg/m2, None reported escalation tumors or lymphomas d 1, 4, 8, 11; belinostat University of po d 1–5 q 21 d cycle Colorado

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NCT00348985 Phase l dose Relapsed multiple Bortezomib iv, d 1, 4, 8, Dexamethasone could be started escalation myeloma 11; oral panobinostat d 1, after cycle 1 if no response. Accrual Hackensack 3, 5 thrice-weekly; of 14 heavily pretreated patients, 8 University Medical dexamethasone (20 mg) with prior bortezomib. MTD pending Center after cycle 1 after 2 dose escalation cohorts. 1 NCT00532389 CR, 1 VGPR and 3 PR (24) Romidepsin Phase l/ll Relapsed/refractory Bortezomib iv, 1.3 mg/m2 MTD romidepsin 10 mg/m2 Peter MacCallum multiple myeloma d 1, 4, 8, 11; romidepsin 18 pts evaluable; ORR 12/18 (67%) Cancer Centre, iv 8, 10, 12, 14 mg/m2, d (4 CR/nCR, 4 VGPR, 4 PR) and 5 Australia 1, 8, 15 q 28 d cycle MR (28%) (25). NCT00431990 dexamethasone po, 20 Maintenance bortezomib on d 1, 8 q mg d 1, 2, 4, 5, 8, 9, 11, 28 d schedule 12 Romidepsin Phase II Relapsed/refractory Bortezomib iv, 1.3 mg/m2 Two strata; bortezomib resistant and Multisite US multiple myeloma d 1,4,8,11; romidepsin, d bortezomib sensitive NCT00765102 with prior bortezomib 1, 8,15 q 28 d cycle Bortezomib administered prior to therapy romidepsin Kinase inhibitors Phase l dose Recurrent or Bortezomib iv, d 1, 4, 8, Bortezomib followed by alvocidib escalation refractory indolent B- 11; alvocidib iv, d 1, 4, 8, administration; 38 patients accrued; Virginia cell neoplasms 11 (1 h bolus) q 21 d 2 CR, 7 PR, 3 MR, 15 SD. 2 MR in 3 Commonwealth cycle or hybrid infusion patients with prior bortezomib.

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University (30 min bolus, 4 h CD138+ cells assessed for NFκB NCT00082784 infusion) d 1, 8 q 21 d nuclear localization, pJNK, Mcl-1 cycle and XIAP PD 0332991 Phase I/II Relapsed/refractory Bortezomib iv d 8, 11, Dexamethasone, 20 mg also taken CDK4/6 Inhibitor Multi-site US multiple myeloma 15, 18 q 28 d (Schedule on d 8, 11, 15 and 18. NCT00555906 A) or q 21 d (Schedule B) Rb phosphorylation status to be PD 0332991 po d 1–21 assessed (Schedule A) or 1–12 (Schedule B) Sorafenib Phase l dose Advanced cancer: Bortezomib iv, d 1, 4, 8, MTD: 200 mg BID sorafenib, 1.0 escalation Group 1: Solid tumors 11; sorafenib po, d 1–21 mg/m2 bortezomib Mayo Clinic Group 2: Multiple BID q 21 d cycle NCT00303797 myeloma or chronic lymphocytic leukemia Sorafenib Phase l/ll Relapsed/refractory Bortezomib iv, d 1, 8, 15, Assessing weekly bortezomib Sarah Cannon multiple myeloma 22; sorafenib po 200 mg schedule Research Institute BID q 35 d cycle NCT00536575 Sunitinib Phase I dose Chemorefractory Bortezomib iv, d 1, 8, 15, Two stages, dose escalation of escalation advanced solid 22; sunitinib po, d 1–28 sunitinib with fixed dose bortezomib Emory University tumors qd q 42 d cycle and then vice-versa NCT00720148

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Temsirolimus Phase l/ll Relapsed/refractory Bortezomib iv, d 1, 8, 15, None reported Dana-Farber Cancer multiple myeloma 22; temsirolimus iv d 1, Institute 8, 15, 22, 29 q 35 d cycle NCT00483262 Everolimus Phase I dose Relapsed/refractory Bortezomib iv, d 1, 4, 8, Baseline tumor expression of mTOR escalation mantle cell 11; everolimus po d 1–21 and NFκB-related proteins (i.e. Case Comprehensive lymphoma, other qd or qod q 21 d cycle pS6K, pAKT, and cREL) and Cancer Center indolent non- FOXP3 by immunohistochemistry NCT0067112 Hodgkin’s lymphoma

Erlotinib Phase ll Relapsed/refractory Bortezomib+erlotinib vs Randomized study terminated due University of metastatic non-small erlotinib to insufficient activity at a planned Tennessee cell lung cancer interim analysis NCT00283634 (one prior cytotoxic therapy) Cetuximab Phase l dose Advanced solid Bortezomib iv, d 1, 8; EGFR-expressing tumor necessary escalation tumors cetuximab iv d 1, 8,15 q for eligibility. University of 21 d cycle MTD not reached Minnesota NCT00622674 Dasatinib Phase I Relapsed/refractory Bortezomib iv 1.0 or 1.3 Three cohorts: Multisite, multiple myeloma mg/m2 d 1, 4, 8, 11; B: 1.0, D: 50 international dasatinib po, 50, 100, B: 1.3, D: 100

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M.D. Anderson 140 mg d 1–21 qd q 21 d B: 1.3, D: 140. Cancer Center, lead cycle Dexamethasone: 20 mg qd with NCT00560352 cohorts 2 and 3 Perifosine Phase l/ll Relapsed/refractory Bortezomib iv, 1.3 mg/m2 Dexamethasone allowed for patients Dana-Farber Cancer multiple myeloma d 1, 4, 8, 11; perifosine with PD after cycle 1. Institute (patients with prior po, d 1–21 qhs q 21 d MTD: 50 mg perifosine and 1.3 NCT00401011 progression on cycle mg/m2 bortezomib. bortezomib Subset of 35 patients refractory to treatment) bortezomib – ORR 37% and CR 3% (51) Farnesyl transferase inhibitors Tipifarnib Phase l dose Advanced acute Bortezomib iv, d 1, 4, 8, MTD: tipifarnib 600 mg BID, escalation leukemias or chronic 11; tipifarnib po, d 1–14, bortezomib 1.3 mg/m2. H. Lee Moffitt Cancer myelogenous BID q 21 d cycle FTase inhibition and proteasome Center leukemia in blast inhibition assessed in PBMC. NCT00383474 phase NF-κB binding, p-AKT, Bax or Bim measured in leukemic blasts pre- and post-treatment Tipifarnib Phase I/II Newly diagnosed Bortezomib iv, d 1, 8, 15; MTD: tipifarnib 600 mg BID, University of Bologna acute myeloid tipifarnib po, 600 mg, d bortezomib 1.0 mg/m2. 22 evaluable NCT00510939 lymphoma ineligible 1–21, BID q 28 d cycle pts: 5 CR, 1 PR, 19 SD, 12 PD.

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for cytotoxic Evaluating 2 gene expression (>18 algorithms (RASGRP1/APTX) for years) or in first tipifarnib sensitivity (59) relapse (>60 years) Tipifarnib Phase l dose Relapsed/refractory Bortezomib iv, 1.0mg/m2 16 evaluable patients, 2 MR, 5 SD. escalation multiple myeloma d 1, 4, 8, 11; tipifarnib po MTD pending. Effects on HDAC6 Emory University d 2–15, BID q 21 d cycle and aggresome formation to be assessed (61) HSP90 chaperone inhibitors Tanespimycin Phase l dose Advanced solid Bortezomib iv, d 1, 4, 8, None reported escalation tumors or lymphoma 11; tanespimycin iv d 1, Mayo Clinic 4, 8, 11 q 21 d cycle NCT000960005 Tanespimycin Phase l dose Relapsed/refractory Bortezomib iv, d 1, 4, 8, None reported escalation hematologic 11; tanespimycin iv d 1, Ohio State University malignancies 4, 8, 11 q 21 d cycle NCT00103272 Tanespimycin Phase lll Multiple myeloma Bortezomib iv, 1.3 mg/m2 Progression-free survival endpoint Multicenter after first relapse d 1, 4, 8, 11; powered to show a 2.75 months NCT00546780 tanespimycin iv 340 benefit with addition of tanespimycin TIME-1 trial mg/m2 d 1, 4, 8, 11 q 21 to bortezomib

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d cycle Tanespimycin Phase ll/lll Relapsed/refractory Bortezomib iv, 1.3 mg/m2 Three arm trial comparing standard Multisite US multiple myeloma (at d 1, 4, 8, 11; bortezomib dose and three different NCT00514371 least 3 prior tanespimycin iv doses of tanespimycin TIME-2 trial therapies) q 21 d cycle AUY-922 Phase I/II Relapsed/refractory Bortezomib iv; Combination with and without Multisite, multiple myeloma (1 AUY-922 iv; dexamethasone will be assessed US/international prior therapy) dexamethasone and also the PK and NCT00708292 pharmacodynamics of combination Other Targets Pan-Bcl-2 family Phase l/ll Mantle cell Bortezomib iv, 1.0–1.3 None reported inhibitor obatoclax Multisite US lymphoma mg/m2; obatoclax iv 30– NCT00407303 60 mg (24 h infusion) q 21 d cycle Obatoclax Phase l/ll Relapsed/refractory Bortezomib iv, d 1, 4, 8, None reported Mayo Clinic multiple myeloma 11; obatoclax iv (3 h NCT00719901 infusion) d 1, 8, 15 q 21 d cycle Obatoclax Phase I dose Aggressive Bortezomib iv, d 1, 8, 15, Bortezomib follows obatoclax escalation relapsed/recurrent 22 cycle; obatoclax iv, (3 administration. California Cancer non-Hodgkin’s h infusion) d 1, 8, 15, 22 Immunohistochemistry analysis of Consortium lymphoma q 35 d cycle Bcl-2, p53, Noxa, and Puma NCT00538187 proteins DNA Phase I dose Relapsed/refractory Bortezomib iv, d 2, 5, 9, Evaluation of target gene

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methyltransferase escalation acute myeloid 12; azacytidine iv, 75 methylation and expression, DNA inhibitor Ohio State University leukemia and mg/m2 d 1–7 q 21 d cycle methyltransferase 1 (DNMT1) azacytidine NCT00624936 myelodysplastic protein expression and global syndromes methylation Monoclonal Antibodies Elotuzumab Phase I/II Relapsed/refractory Bortezomib iv, d 1, 4, 8, Elotuzumab infusion follows (anti-CS1) Multisite US multiple myeloma 11; elotuzumab iv, 2.5, bortezomib administration NCT00726869 (1–3 prior therapies) 5.0, 10, 20 mg/kg d 1, 11 q 21 d cycle Mapatumumab Phase II Relapsed/refractory Bortezomib iv, 1.3 mg/m2 Three arm randomized study of (anti-TRAIL-R1) Multisite multiple myeloma d 1, 4, 8, 11; bortezomib monotherapy US/international mapatumumab iv, 10 comparator arm and combination NCT00315757 (<2 prior therapies) mg/kg, 20 mg/kg d 1, q with two doses of mapatumumab 21 d cycle CNTO-328 Phase II Relapsed/refractory Bortezomib iv, 1.3 mg/m2 Randomized, double blind, placebo (anti-IL6) Multisite multiple myeloma d 1, 4, 8, 11 q 21 d; controlled trial; CNTO-328 + US/international CNTO 328 iv, 6 mg/kg, d bortezomib vs placebo + bortezomib NCT00401843 1, 15, 29 q 42 d cycle; dexamethasone, 20 mg at disease progression

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Bevacizumab Phase I dose Solid tumors, Bortezomib iv, Both agents will be dose escalated (anti-VEGF) escalation lymphoma, 0.7 mg/m2 d 1, 8; from the listed starting doses M.D. Anderson myeloma bevacizumab iv, Cancer Center 2.5 mg/kg iv d 1 q 21 d NCT00428545 cycle

Bevacizumab Phase II Recurrent glioma or Bortezomib iv 1.7 mg/m2 Primary endpoint: 6-month Duke University gliosarcoma d 1, 4, 8, 11, 22, 25, 29, progression-free survival. NCT00611325 32; bevacizumab iv 15 Two cohorts: patients using enzyme mg/kg d 1, 21 q 42 d inducing and non-enzyme inducing cycle anti-epileptic drugs Bevacizumab Phase I/II Advanced or A: Bortezomib iv, 1 or 1.3 Two arms assessing twice weekly or UCLA Cancer Center recurrent renal cell mg/m2 d 1, 4, 8, 11; weekly bortezomib schedules. NCT00184015 cancer bevacizumab 15 mg/kg, Phase II primary endpoint: response d 1 q 21 d cycle rate B: Bortezomib iv, 1.6 or 1.8 mg/m2 d 1, 8; bevacizumab 15 mg/kg d 1, q 21 d cycle Bevacizumab Phase II Relapsed/refractory Bortezomib + AMBER study: randomized, placebo Multisite US multiple myeloma bevacizumab vs controlled study. NCT00473590 bortezomib + placebo Primary endpoint: progression-free survival Rituximab Phase II Waldenstrom’s Bortezomib iv 1.6 mg/m2 Primary treatment of symptomatic

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(anti-CD20) M.D. Anderson macroglobulinemia – d 1, 8, 15, 22; rituximab Waldenstrom’s macroglobulinemia, Cancer Center newly diagnosed iv 375 mg/m2 d 8, 22 q no prior therapy allowed; two cycles NCT00492050 35 d cycle of investigational regimen given. Effect on stem cells analyzed Rituximab Phase ll Relapsed/refractory Bortezomib iv,1.6 mg/m2 Rituximab naive or sensitive Gruppo Italiano indolent and mantle d 1, 8, 15, 22; rituximab patients Multiregional cell lymphoma iv 375 mg/m2 d 8, 22 q NCT00509379 35 d cycle Rituximab Phase II Relapsed/refractory Bortezomib iv, 1.3 mg/m2 Induction and maintenance phases Ohio State University mantle cell and d 1, 4, 8, 11; rituximab iv, evaluated NCT 00201877 follicular non- 375 mg/m2 d 1, 8 q 21 d Hodgkin’s lymphoma cycle Trastuzumab Phase I dose HER2 expressing Bortezomib iv, d 1,4,8, Any prior HER2 therapy not allowed (anti-HER2) escalation breast cancer 11; trastuzumab iv Jules Bordet Institute weekly or q 3 week NCT00199212 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

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

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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 Combination caused synergistic apoptosis in NHL cell Bhalla et al. (31) HL (L428) cell lines lines (combination index <0.2) Tubacin MM.1S cells and patient bone Synergistically augments bortezomib-induced Hideshima et al.

marrow cells cytotoxicity by c-Jun NH2-terminal kinase/caspase (32) activation, plus combined proteasome and aggresome inhibition UCL67022 RPMI8226/S and U266 cell lines HDAC6 and aggresome inhibition Maharaj et al. (33) and primary patient cells Valproic acid U266 cells Increased G1 cell cycle arrest and caspase-3 Kim et al. (34) activation;, p21 and p27 up-regulated; reduced IL-6 secretion and expression of cyclin A, cyclin D1, cyclin E, CDK2, CDK4, and CDK6 KD7150 CD138+ primary MM cells Induction of apoptosis due to DNA damage and Feng et al. (35) 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 JNJ-26481585 MEC1 cell line and patient-derived Induces apoptosis; induces potent histone acetylation Bommert et al. (36) CLL cells and HSP70 upregulation and bcl-2 downregulation

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Farnesyl transferase inhibitors Lonafarnib MM.1S, MM.1R, RPMI8226, and p-Akt downregulation plus increased caspase-3, -8, and David et al. (37) U266 cell lines and primary human -9 cleavage tumor cells Kinase inhibitors Pazopanib MM.1S Synergistic cytotoxicity (combination index <1) in MM- Podar et al. (38) VEGFR, PDGFR, endothelial cell co-culture assay c-Kit inhibitor P276-00 MM.1S Combination was synergistic (combination index <1) , Raje et al. (39) CDK inhibitor pRB, Cdk4, cyclinD1 downregulated

SCIO-469 MM cells and mouse xenograft p53 induction, Hsp27 downregulation, Bcl-XL and Mcl-1 Navas et al. (40) p38 MAPK inhibitor plasmacytoma model of MM downregulation BIRB 796 MM.1S Hsp27 downregulation; increased caspase-8, and -9 and Yasui et al. (41) p38 MAPK inhibitor PARP cleavage BIBF 1000 Non-Ras-mutated t(4;14)- and Increased activation of the extrinsic apoptotic pathway – Bisping et al. (42) PDGF,bFGF,VEGF t(14;16)-positive cell lines MAPK p44/42 and PI3K/Akt inhibition, caspase-3 and -8 inhibitor with/without dexamethasone (but not -9) and PARP activation LSN2322600 Myeloma cells Hsp27 downregulation Ishitsuka et al. (43) p38 MAPK inhibitor Enzastaurin WM cell lines BCWM.1 & WM-WSU Inhibition of Akt signaling, together with increased Moreau et al. PKCβ, PI3K caspase-3, -8, and -9 cleavage (44,45) inhibitor SF1126 MM.1R, OPM1, MM.1S myeloma Combination with cell killing >50% vs cell killing rate of David et al.

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PI3K inhibitor cell lines individual agents of <20% (additive effect) (46) CAL-101 Eleven MM cell lines (INA-6 & LB). Synergistic cytotoxicity with bortezomib against MM cells Ikeda et al. PI3K δ inhibitor Primary myeloma cells from 24 (combination index = 0.64) (47) patients TAE226 NCI H929 MM cell line Combination with synergistic killing at sub-lethal Sharkey et al. FAK, IGF-1R concentration of bortezomib (synergism quotient = 1.5) (48) inhibitor Pan-Bcl-2 inhibitor HA14-1 Epstein-Barr virus-immortalized Increased caspase-3, -8, and -9 cleavage Srimatkandada et lymphoblastoid cell lines (Sweigh al. (49) cells) ABT-737 MM.1S cells Mcl-1 downregulation Chauhan et al. (50,51) Other agents & combinations IPI-504 RPMI-8226 xenograft Bortezomib-IPI-504 combination resulted in complete Sydor et al. HSP90 inhibitor and durable regression of RPMI-8226. (21) Eleven human MCL cell lines Bortezomib-IPI-504 had synergistic cytotoxicity against Roue et al. MCL with combination indexes between 0.53 and 1.094 (52) CDDO-Im MM.1S and MM.1R cells Reduced mitochondrial membrane potential, superoxide Chauhan et al. (53) Triterpenoid generation, cytochrome c/Smac release, and caspase-3, -8, and -9 cleavage Rapamycin RPMI and U266 cell lines, primary NF-κB and PI3K/Akt inhibition O’Sullivan et al. mTOR inhibitor CD138+ patient cells, stromal cells (54)

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TRAIL MM.1S cells NF-κB inhibition Mitsaides et al. (55) TRAIL MCL B cells NF-κB Inhibition; synergy impaired by intracellular Roue et al. (56) accumulation of c-FLIP Fas ligand APO010 MM1S, MM1R, U266, RPMI-LR5, Increased caspase-3, -7, -8, and -9, Mcl-1, and BIM Ocio et al. (57) RPMI-Dox40, MM144, RPMI8226 cleavage; decreased BID cleavage and OPM-1 cell lines WP-1130 ‘Classic’ and blastoid-variant MCL Bcl-2 down-regulation, Bax upregulation, and NF-κB Pam et al. (58) Jak2 inhibitor cell lines inhibition K562, NB4, NB4-LR1, Raji, SU- Synergistic induction of apoptosis with combination of Yan et al. DHL-4 cell lines, primary CML cells bortezomib and arsenic at reduced doses (59) Ritonavir Myeloma cell lines U266, RPMI Synergistic decrease in cell proliferation after treatment Shibata et al. 8226, ARH-77 HIV-protease with combination (60) inhibitor CRx-501 Ten MM cell lines including MM.1S, Combination of the two agents resulted in 2-fold shift in Rickles et al.

Adenosine A2A EJM, ANBL-6, MM.1R, KSM-12PE, IC50 compared to single agent (61) receptor agonist MOLP-8 Salmeterol MM RPMI-8226 xenograft in SCID Combination with bortezomib showed 70% tumor Rickles et al. Β2 Adrenergic CB17 mice volume reduction in contrast to 34% for salmeterol or (62) receptor agonist vehicle alone Nutlin 3 MDA-MB-231 (breast), DU145 Sub-lethal concentrations of bortezomib and nutlin-3 had Ooi et al. Mdm2 –p53 (prostate), ARO/HT-29 (colon), synergistic apoptotic response in solid tumors; increased (63) inhibitor SW579, FRO, TT (thyroid) expression of p53, p21, Mdm2, Bax, Noxa, PUMA G6.31 Primary MM cells obtained from Combination caused significant inhibition of tumor Campbell et al.

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VEGF antibody patient when bortezomib sensitive growth and reduction in paraprotein (64) or resistant AVE1642 CD45(neg) LP-1 MM cell line Selectively inhibits the growth of CD45(neg) myeloma Descamps et al. IGF-1R antibody cells; increases bortezomib-induced apoptosis, which (65) correlates with an increase of Noxa expression 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.

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