ALBERT

Beschreibung: Levels of Mcl-1, an anti-apoptotic Bcl-2 family member that plays an important role in MM cell survival, are tightly regulated by the proteasome, and recent data has demonstrated that proteasome inhibition with bortezomib leads to Mcl-1 accumulation, thereby attenuating its activity. Previously, we reported that inhibition of IL-6 signaling with the chimeric antibody, CNTO328, potentiated the anti-myeloma activity of bortezomib in IL-6-dependent cell line models of MM, and that the enhanced activity was associated with inhibition of downstream IL-6 signaling pathways and repression of bortezomib-mediated induction of the anti-apoptotic heat shock response. Based on our promising results with this combination and the role that IL-6 plays in Mcl-1 regulation, we have extended our preclinical studies and investigated whether CNTO328 could inhibit bortezomib-mediated Mcl-1 induction and how the bone marrow microenvironment affects the activity of the combination. Pre-treatment of the IL-6-dependent MM cell lines KAS-6 and ANBL-6 with CNTO328, but not an isotype control antibody, blunted bortezomib-mediated induction of anti-apoptotic Mcl-1L, and enhanced the cytotoxicity and pro-apoptotic activity of bortezomib. In contrast, CNTO328 did not attenuate bortezomib-mediated Mcl-1L accumulation in the IL-6-independent MM cell line RPMI 8226, nor did it enhance the cytotoxicity of bortezomib in these cells. In the presence of patient-derived bone marrow stromal cells, CNTO328 and bortezomib resulted in a greater reduction of cell viability than with either agent alone in both ANBL-6 and KAS-6 cells. Furthermore, although CNTO328 alone did not lead to an increase in apoptosis of ANBL-6 cells in the presence of bone marrow stroma, it significantly potentiated the pro-apoptotic activity of bortezomib in a synergistic manner at clinically achievable concentrations. As opposed to our cell viability data using the co-culture system, CNTO328 was not able to increase levels of apoptosis in KAS-6 cells either as a single agent or in combination with bortezomib, suggesting that CNTO328 may be inducing cell cycle arrest of KAS-6 cells in the presence of bone marrow stroma but is not able to potentiate the apoptotic activity of bortezomib. Finally, given the important role of IL-6 in glucocorticoid resistance and the additive preclinical and clinical activity of bortezomib and dexamethasone in MM, we evaluated the activity of dexamethasone in combination with CNTO328 and bortezomib in ANBL-6 cells. Whereas the combination of bortezomib (2.5 nM) and CNTO328 reduced viability to 58%, the addition of dexamethasone (10 mM) reduced viability further to 26%. Taken together, the above data demonstrate that CNTO328 enhances the activity of bortezomib in part by attenuating bortezomib-mediated Mcl-1 accumulation, and provide the rationale for clinical evaluation of CNTO328 and bortezomib, with or without dexamethasone, in patients with MM.

Beschreibung: Activating mutations in the receptor tyrosine kinase FLT3 are present in approximately 30% of patients (pts) with acute myeloid leukemia (AML), and they have a significantly worse prognosis than pts with wild type (WT) FLT3, suggesting that the activated kinase is a driver of the disease and a potential target for kinase inhibitor therapy. AC220 is a novel 2nd generation class III receptor tyrosine kinase (RTK) inhibitor with potent in vitro and in vivo activity in FLT3-dependent tumors. It is highly selective for WT and mutant FLT3 and several other class III RTKs, including KIT, CSF1R, RET and PDGFR. AC220 is in a first-in-human phase 1 study for relapsed or refractory AML pts, unselected for FLT3 mutations. The study has a standard 3+3 dose escalation design with 50% dose increments. AC220 is administered once daily as an oral solution for 14 days followed by a 14 day rest period (1 cycle) with a starting dose of 12 mg. Concurrently, pts are being dosed on a continuous dosing regimen starting at 200 mg/day for 28 days (1 cycle). Pts with clinical benefit may continue to receive further cycles. Currently, 52 pts have been dosed with AC220 up to 450 mg/day (10 dose cohorts). Median age was 60 yrs (range, 23 to 86 yrs), median number of prior therapies was 3 (range, 0 to 8) and 2 pts had prior allogeneic hematopoietic stem cell transplant (HSCT). Two elderly patients (age ≥ 78 yrs) unfit for induction chemotherapy were previously untreated. Fifteen patients have FLT3 mutations (12 ITD and 3 TKD), 25 are WT, and 12 are undetermined. Pts are also evaluated for PK, pFLT3, pSTAT5, FLT3 genotyping and ex vivo plasma inhibitory activity. AC220 is well tolerated and MTD has not yet been observed with either schedule. One pt had a possibly drug-related DLT in the 18 mg cohort (grade 3 CHF, although pt had a pre-existing heart condition) leading to cohort expansion, but no other cases of drug-related CHF or other DLT have been seen. Other possibly drug-related AEs (most frequently gastrointestinal events) were mild (grade ≤ 2). Response data based on investigator’s assessment are available on the first 45 pts. Responses were observed in 11 (24%) pts. Four pts achieved a complete response (CR) – 2 with incomplete platelet recovery (CRp) and 2 with incomplete platelet and neutrophil recovery (CRi), one of these pts also had complete resolution of leukemia cutis. In addition, 7 pts had partial responses (PR, defined as a decrease of ≥ 50% blasts to levels of 5%–25% in the bone marrow). Most responses (8/11, 73%) occurred after cycle 1 and one was observed after cycle 3. Median duration of response is 18 weeks (range, 4 to 26+ weeks). Three responders are FLT3 mutants (2 ITD and 1TKD), 5 are WT, 3 are undetermined. Six of the 9 non-responding pts with ITD mutations had initial rapid clearing of peripheral blasts with intermittent AC220 dosing, but subsequently progressed or had disease-related mortality. All these pts had aggressive disease and received a median of 6 prior treatment regimens (range, 3 to 8). AC220 plasma exposure is sustained between dose intervals and continues to increase in a dose-proportional manner from 12 mg to 300 mg. FLT3 phosphorylation is strongly suppressed when plasma obtained from study pts is tested ex vivo in FLT3-ITD and WT cell lines at 12 mg and 60 mg doses, respectively. Assessments of pFLT3 and pSTAT5 from treated pts’ peripheral blood are ongoing and will be presented. Encouraging preliminary efficacy results and an acceptable safety profile warrants continued evaluation of AC220 as a single agent and in combination with other therapeutics for the treatment of AML.

Beschreibung: Abstract 2576 FLT3-ITD mutations in Acute Myeloid Leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. AC220 is a potent, selective, oral FLT3 tyrosine kinase inhibitor that showed promising activity in FLT3-ITD+ patients (pts) in a Phase I study. This Phase II monotherapy trial was conducted to examine the safety and efficacy of AC220 monotherapy in pts with relapsed/refractory FLT3-ITD+ AML. Patients were enrolled into two cohorts: Cohort 1 enrolled pts ≥60 yrs and relapsed/refractory to 1st-line chemotherapy and Cohort 2 pts ≥18 yrs and relapsed/refractory to 2nd-line chemotherapy or hematopoietic stem cell transplantation (HSCT). A planned analysis was performed in February 2011 on the first 62 pts which comprised the exploratory group with the subsequent ∼240 pts being the confirmatory group for which the data will remain sequestered until study completion. The exploratory group was enrolled between 19 November 2009 and 25 August 2010. 53/62 (85%) pts were evaluable for efficacy (FLT3-ITD+ by central laboratory, received at least 1 dose of AC220, 1 post-tx response assessment and no major efficacy-related protocol deviations). The composite CR (CRc=CR+CRp+CRi) rate was 45% (24/53: 2 CRp, 22 CRi) and PR rate was 24% (13/53). Importantly, of the pts refractory to any prior therapy, 62% (16/26) had CRc and 19% (5/26) had PR in response to AC220. Median duration of CRc has not yet been reached in Cohort 1 and was 10.6 wks in Cohort 2. Overall, 8% (2/25) of pts in Cohort 1 and 30% (11/37) of pts in Cohort 2 underwent HSCT and were censored for duration of CRc. Median overall survival was 24.7 weeks for efficacy evaluable pts, 24.1 wks for Cohort 1 and not yet reached in Cohort 2 (pts were not censored at HSCT). At the time of the analysis 51/62 patients were off study (most commonly due to disease progression (19), HSCT (13) or adverse event (7). 55% of pts were still alive. The most common (〉19%) drug-related AEs were nausea, QTc prolongation, vomiting, fatigue, dysgeusia, anorexia, febrile neutropenia, diarrhea, and dyspepsia. QTc prolongation occurred in 21 (34%) pts (Grade 3 in 11 pts, 18%). The incidence of QTc prolongation was decreased by reducing AC220 starting dose from 200 (35%) to 135 mg/day (8.3%) (males) and 90 mg/day (5.9%) (females). 15 pts (24%) experienced fatal treatment-emergent AEs; none were considered drug-related. An additional analysis will be conducted when all pts have 〉 1 yr follow up which will be available at the time of the meeting. These preliminary data suggest that AC220 achieves clinically meaningful reductions in marrow blasts in a substantial proportion of pts with both refractory and relapsed FLT3-ITD+ AML, and many of these pts were successfully bridged to HSCT. These encouraging efficacy results and an acceptable safety profile in this high risk population support continued clinical evaluation in mono- and combination therapy. Disclosures: Cortes: Ambit: Research Funding; Novartis: Research Funding.

Beschreibung: Abstract 636 Activating mutations in the FLT3 RTK are present in ∼30% of AML patients (pts), who have a significantly worse prognosis than pts with wild type (WT) FLT3. AC220 is a novel 2nd generation RTK inhibitor with potent in vitro and in vivo activity in FLT3- and KIT-dependent tumor cell lines. It is highly selective for both WT and mutant FLT3 with significant activity against KIT. A first-in-human Phase 1 study investigating AC220 in predominantly relapsed or refractory AML pts, unselected for FLT3 mutations, was recently completed, using a standard 3+3 dose escalation with 50% dose increments. AC220 was administered once daily as an oral solution initially with an intermittent dosing (ID) regimen: 14 days on and 14 days off (1 cycle). Starting dose was escalated from 12 to 450 mg/day ID. Additional cohorts were investigated on a continuous dosing (CD) regimen: 200 and 300 mg/day for 28 days (1 cycle). A total of 76 pts (46 male, 30 female) were dosed with AC220. Median age was 60 yrs (23-86), median number of prior therapies was 4 (0-9), 12 pts had prior allogeneic transplant and 3 elderly pts (≥72 yrs) unfit for induction chemotherapy were previously untreated. Eighteen pts (24%) had FLT3 ITD mutations, 47 (62%) were WT, and 11 (14%) were undetermined. Pts were also evaluated for PK, phosphorylated (p) FLT3, pKIT, pSTAT5, and ex vivo plasma inhibitory activity. AC220 plasma exposure was sustained between dose intervals and continued to increase in a dose-proportional manner from 12 to 450 mg with a half-life of ∼1.5 days. An active metabolite, AC886, was detected that has similar potency and activity to AC220. Patient plasma at '12 mg potently inhibited pFLT3 in ex vivo FLT3-ITD cell lines and complete inhibition of pFLT3 in WT cell lines was observed at higher doses. Target inhibition was also observed, with suppression of pFLT3, pSTAT5 and pKIT in peripheral blasts. The most commonly reported possibly drug-related AEs were GI events, peripheral edema, and dysguesia, which were Grade ≤2. DLT was observed at 300 mg CD and 200 mg CD was declared as the MTD. Two pts at 300 mg CD had possibly study drug-related DLTs with grade 3 QTc prolongation, but had confounding factors including concomitant medications known to prolong QTc. Responses (IWG criteria) were observed in 23 (30%) pts. PR and CR were observed as low as the 18 and 40 mg cohorts, respectively. Most responses occurred within cycle 1. Overall, 9 (12%) pts had a complete response (CR) with 2 CR, 5 CRi, and 2 CRp. One of these pts also had complete resolution of leukemia cutis. In addition, 14 (18%) pts achieved PR. Overall median duration of response (MDOR) was 14 (4-62+) weeks and overall median survival (MS) was 14 (1-68+) weeks. In FLT3-ITD pts the MDOR was 12 (4-27+) weeks and the MS was 18 (3-42) weeks. In FLT3-WT pts the MDOR was 32 (8-62+) weeks and the MS was 11 (1-68+) weeks. 10 (56%) of 18 FLT3-ITD pts were responders (1 CR, 3 CRi, 6 PR), 9 (19%) of 47 FLT3-WT pts (1 CRi, 2 CRp, 6 PR), and 4 (36%) of 11 undetermined pts (1 CR, 1 CRi, 2 PR). At 200 mg CD (MTD expansion), 4 of 6 FLT3-ITD pts responded (1 CR, 1 CRp, 1 CRi, 1 PR). Of the 4 responders, 2 failed prior treatment with sorafenib and 2 previously refractory pts went onto transplant. The 2 FLT3-ITD non-responders had 6 and 8 prior lines of therapy, respectively. These encouraging efficacy results and an acceptable safety profile warrant continued evaluation of AC220 as monotherapy and in combination therapy for the treatment of AML. Phase 2 studies in FLT3-ITD positive and WT pts are in progress. Disclosures: Cortes: Ambit Biosciences: Research Funding. Foran:Ambit Biosciences: Research Funding. Ghirdaladze:Ambit Biosciences: Research Funding. DeVetten:Ambit Biosciences: Research Funding. Zodelava:Ambit Biosciences: Research Funding. Holman:Ambit Biosciences: Research Funding. Levis:Ambit Biosciences: Consultancy, Research Funding. James:Ambit Biosciences: Employment. Zarringkar:Ambit Biosciences: Employment. Gunawardane:Ambit Biosciences: Employment. Armstrong:Ambit Biosciences: Employment. Padre:Ambit Biosciences: Employment. Wierenga:Ambit Biosciences: Employment. Corringham:Ambit Biosciences: Employment. Trikha:Ambit Biosciences: Employment.

Beschreibung: Background: Bortezomib represents a significant advance in the treatment of relapsed/refractory myeloma, but its efficacy is limited by a number of resistance mechanisms including activation of the anti-apoptotic heat shock protein (HSP) and stress response pathways. CNTO 328 is an anti-IL-6 chimeric monoclonal antibody shown to have anti - myeloma activities in vitro. Because IL-6 signaling augments the HSP response, downregulation of IL-6 signaling may enhance bortezomib’s clinical anti-myeloma activity. Pre-clinical studies demonstrated that this combination had an additive to synergistic effect in inducing apoptosis in IL-6-dependent and independent multiple myeloma cell lines (Voorhees et al., 2007, in press). Methods: In this safety lead-in cohort of a pivotal trial (clinicaltrials.gov), CNTO 328, 6 mg/kg, was administered by IV every 2 weeks in combination with bortezomib, 1.3 mg/m2, given by IV on days 1, 4, 8, and 11 every 3 weeks. Pateints received a maximum of four, 6-week treatment cycles, after which the bortezomib schedule was reduced to four, once weekly doses in a 5-week maintenance cycle. When disease progression was documented, oral dexamethasone was added at 20 mg and given on the day of, and day after each bortezomib infusion, for a maximum of two cycles. All later cycles included 20 mg dexamethasone given only on the day of bortezomib administration. Results: Preliminary results from the first 6 patients are available. Pateint characteristics included median age of 68 years; B2M 〉 3.0 mg/L, (n = 4 pateints); CRP 〉 3.0 mg/L (3); a median of 2 prior regimens (range 1 – 3), and prior bone marrow or peripheral blood stem cell transplantation in three patients. Using the EBMT response criteria, three patients achieved confirmed partial responses (PRs). Additionally, two patients had unconfirmed PRs. One patient discontinued prior to confirmation, while a follow up assessment for the other patient is pending. The median number of cycles administered was 3. Two of the patients ended treatment prematurely, 1 due to disease progression and 1 due to adverse events. The remaining 4 patients continue on study. Grade 3/4 adverse events (AEs) considered possibly related to CNTO 328 and bortezomib include neutropenia (2 patients), leukopenia (1), lymphopenia (1), and bloody diarrhea (1). Conclusion: Treatment with anti-IL-6 CNTO 328 in combination with bortezomib has been evaluated for safety and efficacy in the first 6 patients of an ongoing pivotal trial for the treatment of relapsed or refractory multiple myeloma. Initial activity observed with this combination is encouraging, and enrollment is continuing to explore its full potential.

Beschreibung: Given the critical role that IL-6 plays in MM cell proliferation, survival, and resistance to GCs, we evaluated the ability of CNTO328, a chimeric monoclonal IL-6 neutralizing antibody, to overcome GC resistance in cell line models of human MM. In the presence of IL-6, the MM cell lines ANBL-6 and KAS-6 were resistant to the cytotoxic activity of dexamethasone (Dex) as assessed by cell viability assays both in suspension culture and in the context of patient-derived stromal cells. Resistance to dexamethasone was readily reversed by CNTO328, but not an isotype control antibody, in suspension culture. For example, in the case of the ANBL-6 model, viability was reduced by 12% with CNTO328 alone, 8% with Dex, but 74% with the combination, consistent with a synergistic interaction Given the ability of other growth factors in the bone marrow microenvironment to confer GC resistance in preclinical models of MM, we evaluated the activity of the CNTO328 and Dex combination in ANBL-6 and KAS-6 cells using a physiologically-relevant MM cell/patient-derived bone marrow stromal cell co-culture system. Importantly, bone marrow stromal cells rendered ANBL-6 and KAS-6 cells resistant to Dex in cell viability assays, and CNTO328 was able to reestablish Dex sensitivity, thus confirming a central role of IL-6 in bone marrow stroma-mediated GC resistance. Furthermore, treatment of ANBL-6 and KAS-6 cells with Dex alone did not induce apoptosis in this co-culture system, whereas the combination of CNTO328 and Dex led to a synergistic induction of apoptosis. In KAS-6 cells, IL-6-mediated Dex resistance was not overcome using pharmacologic inhibitors to p38, PI-3 kinase, mTor or MEK, suggesting that other IL-6 signaling pathways are likely involved. In contrast, the mTor inhibitor rapamycin was capable of sensitizing ANBL-6 cells to Dex in the presence of IL-6, suggesting that this pathway may be relevant to IL-6-mediated GC resistance in these cells. Induction of the pro-apoptotic Bcl-2 family member, Bim, has been shown to play an important role in GC-mediated cell death in lymphocytes as well as preclinical lymphoma and acute lymphoblastic leukemia models. Interestingly, although treatment of ANBL-6 cells in the presence of IL-6 with either CNTO328 or dexamethasone did not lead to induction of Bim, the combination led to a 3.3-fold increase in its expression. Taken together, the above data demonstrate that inhibition of IL-6 signaling with CNTO328 can effectively overcome IL-6-mediated GC resistance even in the presence of bone marrow stroma, and provide a compelling rationale for translation of this combination into clinical trials for patients suffering from MM. Furthermore, we show that the ability of CNTO328 to overcome GC resistance may be mediated in part by its ability to reverse IL-6-mediated repression of GC-induced Bim expression. Studies evaluating the relevance of Bim modulation in IL-6-mediated GC resistance and the molecular pathways that mediate this effect are on-going.

Beschreibung: We developed a serum-free process in a closed system using culture cassettes and bags for large-scale and clinical-grade DC vaccination, accepted by the “Afssaps-French drug Agency” (Tarte K. et al. Leukemia2000; 14:2152 & patent). Intermediate mature DCs are generated from mononucleated cells obtained by mobilized leukapheresis, followed by Mo selection using adherence in specific cassettes (CLINIcell, Mabiol). Non-adherent cells are removed and Mo are cultured for 5 days (D) in X-VIVO15 medium (Cambrex) with 2% of human albumin, 100ng/ml of GM-CSF (Leukine, Berlex) and 25 ng/ml of IL-4 (CellGenix-Cellgen). At D5, immature DCs are harvested, pulsed with autologous tumor lysate (or peptides) for 4 h in X-VIVO15 medium + GM-CSF (100ng/ml) and maturation factors (TNF-α: 20ng/ml, CellGenix-CellGen, and PGE2: 100ng/ml; Prostine, Pharmacia). Maturation of DCs was allowed to proceed for 20 h with TNF-α and PGE2. Mo-conditioned media, or IL-6 as well as IL-1 are used for enhancing ex vivo DC maturation by different groups in spite of the fact that IL-6 has been described as a blocker of DC differentiation from CD34+ cells particularly in MM. We demonstrated that in our process, IL-6 is produced by activated Mo during their selection (mean= 378pg/mL, range 37–1219). The amount of the IL-6 released in the medium correlated with the % of CD14+ cells obtained at D5 (CD1422.6%: mean IL-6=682.9 pg/mL), indicating that the intrinsic production of IL-6 is one major parameter of variability of the cellular product. By adding IL-6 from D1 to D5, the percentage of CD14+ cells at D5 was enhanced by a mean of 23-fold in samples from patients with MM (n=7) and 17-fold in ML (n=7). The modifications of other DCs markers including CD1a, CD 84 and CCR7 were modest. By using CNTO 328, an anti-IL-6 MAb (Centocor Inc) at 1–10μg/mL, we totally blocked the activity of added IL-6 and samples with high IL-6 intrinsic production, with a reduction of CD14+ cells at D5. In contrast, neither IL-6 nor CNTO 328 had any activity on terminal DC maturation after D5. IL-6 and CNTO328 are tested on DC functions. This means that in B-cell malignancies and other solid tumors with high levels of circulating IL-6: 1) anti-IL-6 treatment such as CNTO 328 may be associated with active immune therapy, including vaccinations; 2) mature and intermediate mature DCs are the only cells to be administered in vaccination programs because of a de-differentiation effect of immature DCs due to IL-6; 3) anti-IL-6 MAbs, particularly CNTO 328 could be added for ex vivo DC differentiation, instead of IL-6. mean % (range) of CD14+ cells at Day5 samples MM ML Control 2.9 (0.1–7.1) 12.2 (0–44.8) IL-6 (100ng/mL) 20 (6–35) 34.2 (0–71.4) IL-6+CNTO328 1μg/mL 2.8 (0.5–7.5) 15.7 (0–45.6) IL-6+CNTO328 10μg/mL 0.4 (0–0.8) 6.8 (0–20.3) CNTO328 1μg/mL 0.4 (0.1–0.7) 6.5 (0–19.5) CNTO328 10μg/mL 0.2 (0–0.4) 5.3 (0–15.3)

Beschreibung: The proteasome inhibitor bortezomib represents a significant advance in the treatment of multiple myeloma, but its efficacy is limited by a number of resistance mechanisms. One of the most important is the heat shock protein (HSP) and stress response pathways which, through members such as HSP-70 and mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1, oppose the pro-apoptotic activities of bortezomib. Because interleukin (IL)-6 signaling augments the heat shock response through signal transducer and activator of transcription (STAT)-1 and heat shock transcription factor (HSF)-1, we hypothesized that downregulation of IL-6 signaling would attenuate HSP induction by bortezomib, thereby enhancing its anti-myeloma activity. Treatment of the IL-6-dependent multiple myeloma cell lines KAS-6 and ANBL-6 with the combination of bortezomib and CNTO328, a chimeric monoclonal IL-6 neutralizing antibody, resulted in greater reduction of cell viability than with either drug alone in a time- and concentration-dependent manner. This was associated with an enhanced induction of apoptosis which, under some conditions, was greater than the sum of the two individual agents alone, suggesting a synergistic interaction. Similar findings were not seen when using isotype control antibodies, and in studies of the IL-6-independent RPMI 8226 myeloma cell line. Increased activity was seen when cells were pre-treated with CNTO328 followed by bortezomib, or when they were treated with both agents concurrently, compared to treatment with bortezomib followed by CNTO328. Treatment with CNTO328 potently inhibited IL-6-mediated downstream signaling pathways, as demonstrated by marked blockade of STAT-3 and p44/42 MAPK phosphorylation. Enhanced activity of the combination regimen correlated with attenuated induction by bortezomib of the heat shock and stress response proteins HSP-70 and MKP-1 by up to 45% and 90%, respectively. Notably, CNTO328 markedly reduced levels of transcriptionally active phospho-STAT-1 and hyperphosphorylated HSF-1. Other strategies to suppress the heat shock response, including the use of the pharmacologic inhibitor KNK437, also yielded evidence for a synergistic anti-myeloma effect in combination with bortezomib. The synergistic activity of KNK437 and bortezomib was reproduced in normal mouse embryo fibroblasts (MEFs), but blunted in HSF-1 knockout MEFs. Taken together, the above data demonstrate that inhibition of IL-6 signaling enhances the anti-myeloma activity of bortezomib. They also support the hypothesis that this occurs, at least in part, by attenuating proteasome inhibitor-mediated induction of the heat shock response through downregulation of transcriptionally active STAT-1 and HSF-1. These findings provide a strong rationale for future translation of the CNTO328/bortezomib combination into the clinic.