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This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902. A phase 3 study is ongoing (#NCT01659658).

Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.

Key Points Twice-weekly oral ixazomib appears tolerable, with no severe neuropathy seen to date, in heavily pretreated multiple myeloma patients. These phase 1 data suggest clinical activity including 76% stable disease or better, with durable responses and sustained disease control.

Background: Isatuximab (ISA) is an anti-CD38 mAb with potent anti-myeloma (MM) activity given alone or in combination with lenalidomide (LEN) and dexamethasone in relapsed and refractory MM (RRMM). Carfilzomib (CFL) is a second generation proteasome inhibitor approved for the treatment of RRMM. This is an initial report of safety and efficacy data from an ongoing Phase Ib dose-escalation trial combining ISA and CFL in RRMM. (clinicaltrials.gov: NCT02332850) Objectives: The primary objective is to determine the maximum tolerated dose (MTD) of ISA with standard dose CFL in RRMM. Secondary objectives include characterization of pharmacokinetics, safety (including immunogenicity) and disease response (overall response rate [ORR]; IMWG criteria). Methods: ISA is given IV every 2 weeks (Q2W), or weekly (QW) for 4 doses then Q2W in combination with standard CFL (20®27 mg/m2: Day 1, 2, 8, 9, 15, 16, every 28 days). Three ISA dosing levels (DL) have been tested: 10 mg/kg Q2W, 10 mg/kg QW x 4 then Q2W and 20 mg/kg QW x 4 then Q2W using a classic 3+3 dose escalation design based on dose-limiting toxicities. Standard premedications (dex 20 mg IV/PO, acetaminophen 650 mg, diphenhydramine 25-50 mg IV/PO and famotidine 20mg IV) were given prior to each ISA infusion. Results: Eleven patients have been treated across the 3 DL (DL1=3, DL2=3, DL3=5). Treatment disposition: 4 patients have progressed, 7 remain on therapy. This was a heavily pretreated population with a median of 4.5 prior lines of therapy (range: 2-8). All subjects had received prior LEN, 10/11 had received prior BORT and 9/11 had received prior CFL. 10/11 were refractory (refr) to their previous regimen (4 quad refr and 7/11 refr to CFL). 10 patients are evaluable for response. The ORR is 80%: 2VGPR, 6 PR, and CBR is 90% (DL1: 2PR, 1SD; DL2: 3PR; DL3:2VGPR, 1PR, 1MR). The median # of cycles given is 6 (range 1-20). No DLT's or severe adverse drug reactions have been observed. No dose reduction for ISA or CFL have been needed. The most frequent occurring non-hematologic (NH) adverse events ( occurring in ≥ 15%) at all DLs are dyspnea (45%), fatigue (45%), nausea (45%), pain (back, chest wall and pelvis; 36%), peripheral neuropathy (36%), HTN (27%), cough (27%), anorexia (27%), GERD (18%), constipation (18%), diarrhea (18%), nasal congestion (18%) and hypokalemia (18%); Conclusion: Combining ISA and CFL appears to be well tolerated; no unexpected adverse drug reactions were noted. MTD has not been reached. Encouraging anti-MM activity is reported in heavily pretreated patients with RRMM. Expanded accrual is ongoing, additional safety, pharmacokinetics and response data will be presented. (Figure 1: spider plot of % change in serum m-protein over time) Figure 1. Figure 1. Disclosures Martin: Sanofi Aventis: Research Funding; Amgen: Research Funding. Chari:Amgen Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Campana:Sanofi Aventis: Employment. Hui:Sanofi Aventis: Employment. Wolf:Pharmacyclics: Honoraria; Telomere Diagnostics: Consultancy; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

Background Renal impairment (RI) is a major complication of MM. The oral PI ixazomib is currently under phase 3 investigation in MM. PK data from pts with mild or moderate RI (creatinine clearance [CrCl] ≥30 mL/min) suggest no ixazomib dose modification is needed in these pts (Gupta et al BJCP 2015). Hence, this study ([NCT01830816][1]) aimed to characterize the PK of ixazomib in pts with severe RI or ESRD requiring hemodialysis to provide posology recommendations in these pt populations. Methods Pts with RRMM or advanced malignant solid tumors were enrolled in the normal (N, CrCl ≥90 mL/min), severe (S, CrCl

Background Ixazomib is the first orally administered PI to be studied in the clinic. The feasibility of combining a PI with cyclophosphamide and dexamethasone has been demonstrated with the PI bortezomib (Reeder et al Leukemia 2009; Mai et al Leukemia 2015). This open-label, multicenter, phase 2 study is evaluating the all-oral triplet combination of ICd, with two different doses of cyclophosphamide, as a 12-month induction therapy in previously untreated, transplant-ineligible pts with NDMM, and is the first study to assess ICd for the frontline treatment of MM. Methods Adult pts with previously untreated, symptomatic NDMM who were ineligible for stem cell transplantation due to age and/or comorbidities, had ECOG PS 0-2, and adequate hematologic, hepatic, and renal function, were included. Pts were randomized 1:1 to receive up to 13 x 28-day cycles of induction therapy with ixazomib 4.0 mg PO on days 1, 8, and 15, plus cyclophosphamide 300 mg/m2 (ICd-300 arm) or 400 mg/m2 (ICd-400 arm) PO on days 1, 8, and 15, plus dexamethasone 40 mg PO (20 mg in pts aged >75 years) on days 1, 8, 15, and 22. A safety lead-in evaluation of dose-limiting toxicities (DLTs) was performed in 6 evaluable pts in each arm after cycle 1. The primary endpoint was the combined rate of complete response plus very good partial response (CR+VGPR). Secondary endpoints included overall response rate (ORR; CR+VGPR+ partial response [PR]) and safety (adverse events [AEs]). Response was investigator-assessed at the end of every cycle per IMWG criteria. Sample size (n=70) was determined to provide 80% power for the primary endpoint of CR+VGPR rate (1-sided alpha=0.10). Here we present a preliminary analysis of data post-induction (data cut-off: July 1, 2015). Results 70 pts were randomized (36 to ICd-300, 34 to ICd-400): median age 72.5 and 75.5 years; 42% and 53% male; 64% and 59% ISS stage II/III (92% and 79% Durie-Salmon stage II/III), respectively. Mean duration of follow-up was 7.0 months in both arms. Response data are summarized in the Table. Best unconfirmed CR+VGPR rates across all 13 cycles were 27% (ICd-300) and 23% (ICd-400); ORRs were 80% and 73%. Best M-protein reductions are shown in the Figure. Twelve pts (6 ICd-300; 6 ICd-400) were DLT-evaluable; no DLTs were observed in either arm. Pts received a median of 6.0 (1-13) and 6.5 (1-13) cycles in the ICd-300 and ICd-400 arms, respectively. Mean ixazomib relative dose intensity was 90.7% in the ICd-300 arm and 89.8% in the ICd-400 arm. Across all 13 cycles of treatment (ICd-300 and ICd-400, respectively), rates of Gr ≥3 AEs were 53% and 62%, serious AEs 33% and 53%, AEs leading to dose reduction in any study drug 17% and 21%, discontinuation of all study drugs due to AEs 14% and 12%, and on-treatment deaths 2 pts (cardiac arrest; upper gastrointestinal hemorrhage) and 1 pt (pneumonia) which were not deemed as treatment-related. In the ICd-300 and ICd-400 arms, respectively, rates of anti-emetic use were 36% and 44% (8% and 18% for AEs) and G-CSF use 11% and 50% (11% and 35% for AEs); erythropoietin was used in only 1 pt (ICd-300 arm). Thrombocytopenia events occurred in 5 pts (no Gr ≥3) in the ICd-300 arm and 4 pts (3 Gr ≥3) in the ICd-400 arm. Most common AEs (>15% all pts) were anemia (19% and 29%), neutropenia (17% and 32%), nausea (14% and 24%), peripheral neuropathy (PN; 17% and 21%), diarrhea (19% and 15%), vomiting (14% and 21%), constipation (17% and 15%), and fatigue (14% and 18%). Most common Gr ≥3 AEs were neutropenia (14% and 32%), anemia (11% and 15%), and pneumonia (8% and 9%); no Gr ≥3 PN was observed. Conclusion These preliminary data suggest that the all-oral triplet combination of ICd is tolerable in transplant-ineligible pts with NDMM, with a manageable toxicity profile in line with that previously seen with ixazomib and with manageable myelosuppression. Comparably high response rates were reported in both the ICd-300 and ICd-400 arms. Toxicity rates appeared higher with ICd-400, suggesting that ICd-300 may be a more preferable regimen for elderly NDMM pts. Updated data, including long-term outcomes after additional follow-up will be presented at the meeting. Table. Best unconfirmed response by IMWG criteria during cycles 1-13 (response-evaluable pts) Response, n (%) ICd-300(n=30) ICd-400(n=30) CR 3 (10) 3 (10) PR 21 (70) 19 (63) VGPR 5 (17) 4 (13) CR+VGPR 8 (27) 7 (23) ORR (CR+VGPR+PR) 24 (80) 22 (73) SD 6 (20) 8 (27) SD, stable disease Disclosures Dimopoulos: Amgen: Honoraria; Onyx: Honoraria; Celgene: Honoraria; Genesis: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Janssen: Honoraria. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with cyclophosphamide and low-dose dexamethasone for patients with newly diagnosed multiple myeloma who are transplant-ineligible.. Nahi:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Byrne:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

Background Ixazomib is the first orally administered PI studied in the clinic. The feasibility of combining ixazomib weekly and lenalidomide-dexamethasone (Rd) in the first all-oral PI- and immunomodulatory drug-containing triplet regimen was evaluated in a phase 1/2 trial of 65 pts with newly diagnosed MM. Results indicated a 90% ORR (62% ≥VGPR) using ixazomib 4 mg (recommended phase 2/3 dose), with a manageable safety profile, including 14% gr ≥3 skin/subcutaneous tissue disorders and limited (4% gr 3) peripheral neuropathy (PN) (Kumar et al, Lancet Oncol 2014). These data provided the rationale for phase 3 investigation of IRd vs placebo-Rd in pts with RRMM in this randomized, double-blind, placebo-controlled, international, multicenter study. Methods Adults with RRMM after 1-3 prior lines of therapy who were not refractory to prior lenalidomide or PI-based therapy were randomized 1:1 to receive ixazomib 4 mg or matching placebo weekly on d 1, 8, and 15, plus lenalidomide 25 mg PO on d 1-21 (dose reduced for renal impairment per local label/practice) and dexamethasone 40 mg PO on d 1, 8, 15, and 22, in 28-d cycles. Randomization was stratified by number of prior therapies (1 vs 2/3), PI exposure (naïve vs exposed), and ISS disease stage (I/II vs III). Cycles were repeated until disease progression or unacceptable toxicity. Primary endpoint was PFS as assessed by an independent review committee blinded to treatment, per IMWG criteria. Key secondary endpoints were OS and OS in high-risk pts with del(17). Sample size was determined to provide 80% power for the OS endpoint and adequate power to test PFS. Three interim analyses (IAs) and a final analysis were planned to test PFS and OS; here, we report data from the first IA, the final analysis for PFS. Results 722 pts were randomized (360 IRd; 362 Rd). Baseline characteristics were balanced between groups; overall median age was 66 yrs (30-91), 70% were PI-exposed, 88% were ISS stage I/II, 59% had received 1 prior therapy, and 77%/11%/11% were relapsed/refractory/relapsed and refractory, with 6% primary refractory. Based primarily (97%) on central laboratory evaluation, 19% had high-risk cytogenetics by FISH (del(17), t(4;14), or t(14;16)), including 10% del(17). Prior therapies included 69% bortezomib, 45% thalidomide, and 12% lenalidomide. The study met the primary endpoint at the first IA (median follow-up 14.8 vs 14.6 mos with IRd vs Rd), demonstrating a 35% improvement in PFS with IRd vs Rd (HR 0.742; p=0.012; Table). In pts with high-risk cytogenetics, the PFS HR was 0.543 with IRd vs Rd (HR 0.596 in pts with del(17)), with a median PFS similar to the overall IRd group, indicating ixazomib may overcome the negative impact of cytogenetic alterations. OS data were not yet mature. Key response data are shown in the Table. Pts received a median of 13 (1-26) vs 12 (1-25) cycles of IRd vs Rd; 55% and 52% of pts remained on treatment. With IRd vs Rd, 68% vs 61% of pts had gr ≥3 AEs (driven by thrombocytopenia), 40% vs 44% had serious AEs, 13% vs 11% discontinued all study drugs due to AEs, and 3% vs 5% died on treatment. AEs observed with IRd were consistent with reported safety profiles for the individual agents. Common gr ≥3 AEs were neutropenia (19% vs 16%), anemia (9% vs 13%), thrombocytopenia (13% vs 5%), and pneumonia (6% vs 8%). Gastrointestinal events included 42% vs 36% diarrhea (6% vs 2% gr 3), 26% vs 21% nausea (2% vs 0% gr 3), and 22% vs 11% vomiting (1% vs Conclusion At this first prespecified IA, addition of ixazomib to Rd in pts with RRMM increased median PFS to 20.6 from 14.7 mos without a substantial increase in overall toxicity, including cardiac and PN toxicity. Benefit with IRd was also noted in pts with high-risk cytogenetics, including those with del(17), in whom median PFS was similar to all IRd-treated pts indicating that ixazomib may have a favorable impact on the adverse prognosis associated with genetic mutations. If approved, this all-oral combination of IRd may become a new standard of care in this setting. Table. Key efficacy data IRd Rd HR / OR Median PFS, mos 20.6 14.7 HR 0.742; 95% CI: 0.587-0.939; p=0.012 Confirmed ORR, % 78.3 71.5 OR 1.44; p=0.035 CR 11.7 6.6 OR 1.87; p=0.019 ≥VGPR 48.1 39.0 OR 1.45; p=0.014 Median time to first response (ITT analysis), mos 1.1 1.9 Median duration of response (≥PR), mos 20.5 15.0 Disclosures Moreau: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sandhu:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Ganly:Novartis: Honoraria; Roche: Honoraria; Medipics: Equity Ownership. Baker:Janssen-Cilag New Zealand: Membership on an entity's Board of Directors or advisory committees. Stoppa:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Simpson:Celgene: Honoraria; Janssen-Cilag: Honoraria; Onyx Pharmaceuticals: Research Funding; Roche: Honoraria. Gimsing:Amgen: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Garderet:Bristol-Myers Squibb: Consultancy. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Kumar:AbbVie: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding. Touzeau:AbbVie: Research Funding. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Lin:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. DiBacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background Systemic AL amyloidosis is a life-threatening disease with limited treatment options. Response criteria have been recently updated and retrospectively validated (Palladini et al, J Clin Oncol 2012). Hematologic response (suppression of FLCs) has been shown to predict for both organ response and survival (ibid). Preliminary results from the present phase 1 study ([NCT01318902][1]) regarding the safety, tolerability, and maximum tolerated dose (MTD) of ixazomib (the first oral PI to be investigated in the clinic) in RRAL were reported previously (Merlini et al, ASH 2012). At that time, 11 pts had received the MTD/RP3D of ixazomib - 4.0 mg. Here we update the safety data (primary objective) and report hematologic and organ responses, progression-free survival (PFS), and overall survival (OS) (secondary objectives) for the extended population of 22 pts receiving the RP3D. Methods Pts with RRAL after ≥1 prior therapy and with measureable heart/kidney involvement and cardiac biomarker stage I/II disease were eligible. Two expansion cohorts (PI-naive and PI-exposed) were enrolled at the RP3D. Pts received oral ixazomib on days 1, 8, and 15 for up to 12 x 28-day cycles; continuation until disease progression was allowed. Pts with less than partial response (PR) after 3 cycles received added dexamethasone (Dex) 40 mg, days 1–4 from cycle 4 onwards. Adverse events (AEs) were graded by NCI-CTCAE v4.03. Responses were assessed per standard criteria (Palladini et al, J Clin Oncol 2012). Results At data cut-off (Dec 6, 2013), 27 pts had been enrolled, 22 at the RP3D of ixazomib 4.0 mg; the other 5 pts were enrolled at 5.5 mg and are not included in these analyses. In pts who received ixazomib 4.0 mg, median age was 64.5 yrs (range 54–78); 13 were male. Mayo cardiac biomarker risk stage was I/II/III in 11/10/1 pts, respectively. Median baseline FLC differential (dFLC) and NT-proBNP were 146 mg/L (range 40–734) and 849 pg/mL (range 51–5691). Major organ involvement included heart, kidney, or both in 9, 8, and 5 pts, with a median of 2 (range 1–6) organ systems involved. Pts had received a median of 3 prior therapies, including transplantation in 16 pts; 16 pts had received prior bortezomib (PI exposed) and 6 were PI naive. Other prior therapies included melphalan (n=21), Dex (n=16), IMiDs (n=11), and cyclophosphamide (n=10). Best hematologic response to prior therapy was complete response (CR) in 3 pts, very good PR (VGPR) in 4, PR in 14, and stable disease (SD) in 1 pt; organ response was achieved by 5 pts, with 12 pts having no response. Exposure and outcome data by prior PI exposure are shown in the table. Pts discontinued due to disease progression (n=6), pt withdrawal, symptomatic deterioration (each n=3), or unsatisfactory response (n=2); 5 pts completed 12 cycles; 3 pts are ongoing. Overall hematologic response rate (ORR) was 52%. After a median follow-up of 16.9 mos, the 9 pts who achieved ≥VGPR, had a median PFS of 17.0 mos compared with 10.7 mos in pts who achieved a lesser response (p=0.03). Cardiac/renal response was observed in 50%/18% of pts (all ≥VGPR). The most common drug-related AEs included diarrhea, nausea (each n=7), fatigue, thrombocytopenia (each n=6), peripheral neuropathy, and pyrexia (each n=4). Drug-related grade 3 AEs (>1 pt) were thrombocytopenia (n=3), diarrhea, and maculo-papular rash (each n=2). | | PI naive n=6 | PI exposed n=16 | Total N=22 | | ----------------------------------------- | ------------------- | ----------------------- | ----------------- | | Cycles received, median (range) | 12 (1–22) | 3.5 (1–16) | 5.5 (1–22) | | Dex added, n | 3 | 5 | 8 | | Hematologic response-evaluable pts | n=5 | n=16 | N=21 | | Response, n (%) | | | | | ORR | 5 (100) | 6 (38) | 11 (52) | | CR | 2 (40) | | 2 (10) | | VGPR | 3 (60) | 4 (25) | 7 (33) | | PR | | 2 (13) | 2 (10) | | SD | | 9 (56) | 9 (43) | | Cardiac response/heart evaluable, n/N (%) | 3/4 (75) | 3/8 (38) | 6/12 (50) | | Renal response/kidney evaluable, n/N (%) | 1/3 (33) | 1/8 (13) | 2/11 (18) | | 1 yr hematologic PFS rate, % | 83 | 41 | 60 | | 2 yr OS rate, % | 83 | 51 | 57 | Table. Conclusions This is one of the first studies prospectively assessing hematologic and organ response according to the updated consensus criteria. These data suggest weekly oral ixazomib 4.0 mg is feasible and generally well tolerated in RRAL pts with vital organ dysfunction. High quality hematologic responses (≥VGPR) were observed in 43% of pts; these responses were sustained at 1 yr in 60% of this heavily-pretreated population. Achieving ≥VGPR was associated with cardiac response and extended PFS. These results warrant a phase 3 study of ixazomib plus Dex vs physician's choice of treatment, which is ongoing ([NCT01659658][2]). Disclosures Merlini: Pfizer: Honoraria; Millennium: the Takeda Oncology Company: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Use of the investigational agent ixazomib, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Sanchorawala: Celgene: Research Funding; Millennium: the Takeda Oncology Company: Research Funding; Onyx: Research Funding. Jeffrey: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Kukreti: Celgene: Consultancy, Honoraria. Schoenland: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau. Jaccard: Celgene: Honoraria, Research Funding; Janssen: Honoraria. Dispenzieri: Millennium: the Takeda Oncology Company: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Janssen: Research Funding. Cohen: Onyx Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Advisory Board, Advisory Board Other, Research Funding; Janssen: Advisory Board, Advisory Board Other; Celgene: Member, Independent Response Adjudication Committee Other. Berg: Takeda Pharmaceutical International Co.: Employment. Yuan: Takeda Pharmaceutical International Co.: Employment. Hui: Takeda Pharmaceutical International Co.: Employment. Comenzo: Millennium:the Takeda Oncology Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01318902&atom=%2Fbloodjournal%2F124%2F21%2F3450.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01659658&atom=%2Fbloodjournal%2F124%2F21%2F3450.atom

Background: Triplet regimens combining a proteasome inhibitor, an immunomodulatory drug, and a steroid have been shown to be active and well tolerated in previously untreated MM pts. Extended treatment represents an alternative paradigm to induction followed by ASCT in this setting; however, agents for continuous therapy need to be convenient and well tolerated. The investigational agent ixazomib is the first oral proteasome inhibitor to be studied clinically. Phase 1 studies have indicated single-agent activity in relapsed/refractory MM and shown ixazomib to be well tolerated with a manageable safety profile, including limited peripheral neuropathy (PN) (Richardson PG et al, Blood 2014; Kumar SK, et al, Blood 2014). Weekly ixazomib plus lenalidomide-dexamethasone has been investigated in a phase 1/2 study in previously untreated MM pts (NCT01217957); treatment comprised triplet induction therapy followed by single-agent ixazomib maintenance therapy. Results of induction therapy have been previously reported (Kumar SK, et al, ASH 2012). Here we report phase 2 efficacy and safety data in pts receiving ixazomib maintenance. Methods: In phase 2, pts aged ≥18 yrs with measurable disease and no grade ≥2 PN received oral ixazomib 4.0 mg on d 1, 8, 15, lenalidomide 25 mg on d 1–21, and dexamethasone 40 mg on d 1, 8, 15, 22, for up to twelve 28-d induction cycles, followed by maintenance ixazomib on d 1, 8, 15 every 28 d until progression at the dose last tolerated during induction. Transplant-eligible pts could discontinue from study for ASCT after 6 cycles. The primary objective was CR+VGPR rate. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded by NCI-CTCAE v4.02. Results: Fifty pts were enrolled in phase 2; 29 discontinued during induction (cycles 1–12), primarily to undergo ASCT (n=14) or due to AEs (n=6) or pt withdrawal (n=4). Twenty-one pts received ixazomib maintenance therapy (cycle ≥13); 13 (62%) were male, and median age was 68 (range 34–77) years. At data cut-off (June 11, 2014), pts had received a median of 27 treatment cycles (range 15–32), including both induction and maintenance, with a median treatment duration of 26.6 mos (range 13.4–29.6). Mean ixazomib relative dose intensity was 95% and 89% in the induction and maintenance phases, respectively. The mean ixazomib dose administered during maintenance was 3.6 mg weekly. At data cut-off, 11 (52%) pts remained on ixazomib maintenance. Among 49 evaluable phase 2 pts, 44 (90%) achieved ≥PR, including 29 (59%) ≥VGPR. All 21 pts who received ixazomib maintenance had responded to induction therapy. Overall best confirmed/unconfirmed responses in the 21 pts included ≥CR in 11 (52%, of which 4 [19%] were stringent CRs [sCR]), ≥near-CR in 13 (62%), and ≥VGPR in 15 (71%), plus 6 (29%) PR. Responses were rapid and improved during treatment. Median time to first response (≥PR) was 0.99 mos (range 0.92–5.78) and to best response was 7.46 mos (range 1.02–24.74); 33% of pts improved their response during maintenance, including 2 VGPR to near-CR, 3 VGPR to CR, 1 VGPR to sCR, and 1 CR to sCR. At data cut-off, median duration of response was 26.5 mos (range 5.6–26.6+). Among 15 pts achieving ≥VGPR, 5 (33%) had progressed; median duration of ≥VGPR was 23.0 mos (range 3.7–26.1+). All pts were alive after follow-up of 24.6–30.3 mos, including a median follow-up from start of maintenance of 16.9 mos (range 12.9–18.9). Ixazomib maintenance was well tolerated; 15 (71%) pts had drug-related AEs, with only 2 (10%) pts with grade 3 drug-related AEs (hypokalemia, thrombocytopenia) and no grade 4 AEs. The most common (>1 pt) grade 1–2 drug-related AEs were diarrhea (n=8, 38%), nausea, pain in extremity (each n=3, 14%), anemia, and headache (each n=2, 10%). No PN was reported. Serious AEs were reported in 3 (14%) pts during maintenance, including grade 3 acute myocardial infarction, grade 3 pneumonia, and grade 3 orthostatic hypotension; all were considered not related to treatment. Only 1 pt required an ixazomib dose reduction due to an AE (neuralgia). Conclusions: These data indicate that single-agent ixazomib maintenance for up to 1.5 yrs was feasible and generally well tolerated, improved responses following ixazomib-lenalidomide-dexamethasone induction, and contributed to durable responses (median >2 yrs) in previously untreated MM pts not undergoing ASCT. The results support the ongoing phase 3 trial of ixazomib in the maintenance setting (NCT02181413). Disclosures Kumar: Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone and as maintenance therapy for patients with previously untreated multiple myeloma.. Niesvizky:Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Research Funding, Speakers Bureau. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding. Laubach:Novartis: Research Funding; Onyx Pharmaceuticals: Research Funding. Hamadani:Millennium: The Takeda Oncology Company: Research Funding. Stewart:Takeda Pharmaceuticals International Co.: Research Funding; Sanofi: Consultancy; Array BioPharma: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Novartis: Consultancy. Hari:Celgene: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Millennium: The Takeda Oncology Co.: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding. Vescio:Celgene: Speakers Bureau; Millennium: The Takeda Oncology Co.: Speakers Bureau; Onyx Pharmaceuticals: Speakers Bureau. Kaufman:Millennium: The Takeda Oncology Co.: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Berg:Takeda Pharmaceuticals International Co.: Employment. Liao:Takeda Pharmaceuticals International Co.: Employment. Hui:Takeda Pharmaceuticals International Co.: Employment. Richardson:Millennium: The Takeda Oncology Co.: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Introduction Amyloidosis is a very rare blood disease characterized by the production of abnormal misfolded extracellular proteins that are deposited in body tissues or organs, leading to organ dysfunction. The most common form is systemic light chain (AL) amyloidosis. With no cure, treatment is directed at suppressing development of the abnormal protein, correcting or stabilizing organ function, and managing symptoms. Very little research has been done to assess patients’ symptoms in this disease and how they may be mitigated by available therapies. The first objective of this study was to understand the symptoms and impact of the disease and treatment from the patients’ perspective. This insight was used to develop a comprehensive conceptual model of AL amyloidosis. A second objective was to confirm the content of a draft amyloidosis symptom diary and provide recommendations to refine the measure. Methods Three data sources were included in this study: 1) A literature review using OvidSP (includes MEDLINE and Embase)using disease-specific and quality of life search terms; 2) An internet search to identify blogs (online diaries) written by patients about their disease/treatment experience; and 3) One-on-one telephone interviews with adult AL amyloidosis patients. Patients were recruited through physician referral and by the Amyloidosis Foundation. Eligible and interested patients were mailed an informed consent form and study questionnaires. Using a standardized guide, a trained interviewer conducted a concept elicitation interview to explore experiences of living with AL amyloidosis, after which the patient completed the symptom diary and underwent a cognitive debriefing interview. The cognitive debriefing was designed to explore patient understanding of each instruction, item, and response option. Interview transcripts were coded to identify key concepts and themes emerging from the data using qualitative data analysis software, MaxQDA. Results Of 270 English language abstracts identified and reviewed, 10 articles appeared to include a patient-reported outcome (PRO) measure and were selected for full review. Nine patient blogs were identified and reviewed. Symptoms identified from the literature and from patient blogs informed the development of a draft symptom measure. Ten patients participated in the concept elicitation / cognitive debriefing interviews (mean age, 61 years, SD=8; 70% male). Eight reported experience with chemotherapy, 6 reported having received a stem cell transplant, and one had received a heart transplant. Patients identified symptoms as being related to both the disease and/or treatments. Symptoms reported by at least 30% of the sample included fatigue (100%), weakness (100%), shortness of breath (90%), neuropathy (90%), edema (100%), dizziness/lightheadedness (80%), decreased/lack of appetite (60%), diarrhea (50%), constipation (40%), and difficulty sleeping (30%). Ninety-four percent of codes had been applied by the 7th interview, and only one new code (“heartburn”) was applied in the last interview, suggesting that key symptom concepts were identified with this sample. A conceptual model illustrating the various impacts of disease and treatment was developed. Findings from cognitive debriefing interviews revealed that overall, patients found the diary to be straightforward and easy to complete. Most patients reported that the symptoms included in the measure adequately captured their experiences with AL amyloidosis. However, feedback suggested that certain symptoms such as swelling in the upper body, needed clarification. Conclusions A comprehensive conceptual model of symptoms and impacts of disease and treatment was developed and could be used to identify important outcomes from the patients’ perspective that should be assessed in clinical trials to capture treatment benefit. AL amyloidosis is associated with a wide range of symptoms related to location of amyloid deposits, as well as side effects related to the treatment administered. Despite this variability, a core set of symptoms emerged and a draft diary capturing symptoms likely to be applicable to most patients was developed. Based on the feedback from the cognitive debriefing interviews, patients found the diary to be straightforward and easy to complete. Additional research and use in trials can provide further evidence for the validity and reliability of the diary. Disclosures: Seldin: Celgene: Research Funding; Prothena: Research Funding; Amyloidosis Foundation: Membership on an entity’s Board of Directors or advisory committees. Hui:Millennium: The Takeda Oncology Company: Employment. Berg:Millennium: The Takeda Oncology Company: Employment. Lin:Millennium: The Takeda Oncology Company: Employment.

Background MLN9708 (ixazomib citrate) is an oral proteasome inhibitor that is being investigated in phase 3 trials. MLN9708 rapidly hydrolyzes to the biologically active form, MLN2238 (ixazomib). Preliminary findings from studies using weekly and twice-weekly schedules in relapsed/refractory MM have suggested evidence of single-agent activity (Kumar et al, ASCO 2013; Lonial et al, ASCO 2012), and a phase 1/2 study has suggested the feasibility and activity of weekly oral MLN9708 plus len-dex in newly diagnosed MM (Kumar et al, ASH 2012). Here we report the results of a phase 1/2 study, conducted in collaboration with the Multiple Myeloma Research Consortium, of twice-weekly oral MLN9708 plus len-dex (NCT01383928). Methods Phase 1 primary objectives were to determine safety, tolerability, the MTD, and the recommended phase 2 dose (RP2D); secondary objectives included characterizing MLN2238 pharmacokinetics (PK). Phase 2 primary objectives were to determine the combined CR+VGPR rate and further evaluate safety and tolerability; secondary objectives included overall response rate (≥PR), time to response, and duration of response (DOR). Pts aged ≥18 yrs who had no grade ≥2 peripheral neuropathy (PN) and no prior/concurrent DVT/pulmonary embolism received MLN9708 3.0 or 3.7 mg (d 1, 4, 8, 11), len 25 mg (d 1–14), and dex 20/10 mg (cycles 1–8/9–16; d 1, 2, 4, 5, 8, 9, 11, 12) for up to 16 21-day cycles, followed by MLN9708 maintenance (same schedule) until progression or unacceptable toxicity. Transplant-eligible pts could undergo stem cell collection after ≥4 cycles and discontinue for ASCT after ≥8 cycles. Responses were assessed per IMWG uniform response criteria. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points during cycles 1 and 2. Results 64 pts were enrolled; median age was 64 yrs (range 34–82), 63% were male, and 31%/16% had ISS stage II/III MM. In phase 1, 14 pts received MLN9708 3.0 mg (n=7) and 3.7 mg (n=7). No DLTs were seen in cycle 1; based on overall tolerability and incidence of rash at 3.7 mg, the RP2D was chosen as 3.0 mg. 50 pts were enrolled at this dose in phase 2. At data cut-off (July 1, 2013), the median follow-up was 6.9 months and median number of cycles received was 8 (range 1–26); 73% had received ≥8 cycles and 9% had received ≥16 cycles. At data cut-off, 22% of pts had discontinued to undergo ASCT (median CD34+ stem cell yield 14.9 x 106/kg [range 7–52 x 106]), a further 14%, 5%, and 19% had discontinued due to AEs, progressive disease, and other reasons, respectively, and the other 41% remained on treatment. In 58 response-evaluable pts, ≥PR rate to date was 93%, including 67% ≥VGPR (24% CR, including 14% sCR). 54% of pts had 100% decreases in M-protein or serum free light chain from baseline. Analysis of minimal residual disease is ongoing; data will be presented. Depth of response increased over the course of treatment; median time to first response (≥PR) was 0.69 mos and to best response to date was 2.07 mos. Median DOR to date was 5.9+ mos, ranging up to 18+ mos. Most common AEs were rash (61%; pooled high-level terms), fatigue, peripheral edema (each 50%), diarrhea (41%), and neuropathy peripheral (36%). Drug-related (to any drug in the regimen) grade 3 AEs were seen in 56% of pts, including rash (16%), hyperglycemia (8%), pneumonia (6%), and PN (5%; high-level term). No drug-related grade 4 AEs were seen; 58% of pts required dose reductions of at least one drug due to AEs including rash (16%), anxiety (11%), and PN (8%). AEs resulting in discontinuation were seen in 11%, with the majority reported as not related to therapy. There was 1 on-study death due to cardio-respiratory arrest, likely a pulmonary embolism, considered by the investigator to be unrelated to MLN9708 or dex, but probably len. Based on phase 1 preliminary PK data, MLN2238 was absorbed quickly with a Tmaxof 0.5–4 hours. Terminal half-life was 2–8 days. PK data were similar to single-agent twice-weekly dosing studies, suggesting no MLN2238 PK interaction with len or dex. Conclusions These data suggest that twice-weekly oral MLN9708 plus len-dex is feasible and active in pts with newly diagnosed MM. However, rates of rash, PN, and dose reductions appear higher than in the parallel study using weekly MLN9708, with similar response rates and better convenience, supporting use of weekly dosing in ongoing phase 3 trials. Disclosures: Richardson: Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Investigational agent MLN9708 in combination with lenalidomide and dexamethasone for the first-line treatment of patients with multiple myeloma. Hofmeister:Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Rosenbaum:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Speakers Bureau. Vesole:Millennium: The Takeda Oncology Company: Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Liedtke:Celgene: Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Chari:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Lebovic:Celgene: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Berg:Millennium: The Takeda Oncology Company: Employment. Liao:Millennium: The Takeda Oncology Company: Employment. Gupta:Millennium: The Takeda Oncology Company: Employment. Di Bacco:Millennium: The Takeda Oncology Company: Employment. Estevam:Millennium: The Takeda Oncology Company: Employment. Hui:Millennium: The Takeda Oncology Company: Employment. Baz:Celgene: Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding.

Abstract 731 Background: Treatment with bortezomib achieves high hematologic response rates and rapid and durable responses in AL patients (pts), providing the rationale for proteasome inhibition in this population. MLN9708 is an investigational, oral, potent, reversible, and specific 20S proteasome inhibitor (PI). In preclinical studies, MLN9708 has shown improved antitumor activity compared to bortezomib in a range of xenograft models. This phase 1 study (NCT01318902) assessed weekly doses of oral MLN9708 in pts with relapsed or refractory AL. Methods: Pts aged ≥18 years with relapsed or refractory AL after ≥1 prior therapy, cardiac biomarker stage I/II disease, and measurable major organ (heart/kidney) involvement, received increasing doses of oral MLN9708 (standard 3+3 dose escalation fixed doses of 4.0 and 5.5 mg), on days 1, 8, and 15 of 28-day cycles for up to 12 cycles. Pts with no major hematologic response ( Results: At data cut-off (June 29, 2012) 16 pts had been enrolled and received ≥1 MLN9708 dose (safety population). The median age was 66.5 years (range 54–78) and 7 were male. Median number of prior therapies was 3 (range 1–7); 10 received prior transplant, 7 received prior bortezomib. Major organ involvement, defined by standard criteria, included heart, kidney, or both in 7/5/4 pts, respectively, with a median of 2 (range 1–5) involved organ systems, and Mayo cardiac biomarker risk stage was I, II, III in 6, 9, 1 pts. Five pts were treated in the 5.5 mg cohort and 11 pts were treated in the 4.0 mg (n=6 dose escalation; n=5 dose expansion) cohorts. Of the 11 pts treated at 4.0 mg, 4 were PI-naïve, 7 were PI-exposed. Pts received a median of 3 cycles (range 1–12); 5 pts received ≥5 cycles, and 8 pts remain on treatment. Dex was added in 4 pts (2 in each MLN9708 dose level). There were no on-study deaths. Pts discontinued due to disease progression (n=5), AE, withdrawal by pt, or unsatisfactory response (each n=1); 2 pts completed planned 1 year of therapy. One pt in the 4.0 mg cohort experienced a DLT of grade 3 thrombocytopenia. Two pts in the 5.5 mg dose cohort experienced DLTs: grade 3 diarrhea in 1 pt, and renal failure, respiratory failure (both grade 2), and cardiac arrest (grade 4) in another pt. The MTD was determined as 4.0 mg. AEs were reported in 14 pts. The most common drug-related AEs included nausea (n=5), diarrhea and thrombocytopenia (each n=4), abdominal pain and fatigue (each n=3). Grade ≥3 AEs (any cause) reported in >1 pt were thrombocytopenia (n=4), dyspnea (n=3), maculo-papular rash, dehydration, and abdominal pain (each n=2); all were grade 3. Preliminary response data are shown in the table. At data cut-off, one responder had progressed, and the median duration of hematologic response was 7.4 months (range 1.3–11.5+); 2 pts had cardiac organ response. Preliminary PK data showed that MLN9708 was rapidly absorbed, with a median Tmax of 1 hr (range 0.5–6). MLN9708 day 15 plasma Cmax was 73.6 ± 40.2 ng/mL (mean ± SD) and AUC0–168was 1250 ±530 ng*hr/mL (n=8 at 4.0 mg dose cohort). MLN9708 PK parameter values in this study appear similar to other MLN9708 studies in myeloma pts. Conclusions: These data suggest weekly oral administration of MLN9708 is feasible in pts with relapsed or refractory AL. The MLN9708 MTD was determined as 4.0 mg. Assessment is ongoing, with preliminary evidence of hematologic responses noted. A phase 3 study of MLN9708 plus dex versus physician's choice of treatment is planned (NCT01659658). Disclosures: Merlini: Millennium Pharmaceuticals, Inc.: Consultancy. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Sanchorawala:Celgene: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Onyx: Research Funding. Zonder:Celgene: Research Funding; Millennium Pharmaceuticals, Inc: Consultancy, Research Funding. Kukreti:Roche: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria. Schonland:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Dispenzieri:Janssen Research & Development: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Celgene: Research Funding. Cohen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Comenzo:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 332 Background: The high response rates seen with the bortezomib, lenalidomide, and dexamethasone (VRD/RVD) regimen (Kumar S, et al. Blood 2012; Richardson PG, et al. Blood 2010) highlight the feasibility of combining a proteasome inhibitor with an immunomodulatory agent and a steroid in patients with previously untreated multiple myeloma (MM). MLN9708 is an investigational, oral, reversible proteasome inhibitor with promising anti-MM effects and favorable toxicity profile with low rates of peripheral neuropathy (PN). Here we report phase (Ph) 1 and preliminary Ph 2 results of the first study of MLN9708 in combination with lenalidomide and dexamethasone in patients with previously untreated MM (NCT01217957). Methods: Patients aged ≥18 yrs with measurable disease, ECOG performance status 0–2, and no grade ≥2 PN, received oral MLN9708 (days 1, 8, and 15) plus lenalidomide 25 mg (days 1–21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to twelve 28-day cycles, then maintenance therapy with MLN9708 (same schedule) every 28 days until progression. Patients could undergo stem cell collection after 3 cycles and discontinue for autologous stem cell transplant (ASCT) after 6 cycles. In Ph 1, dose escalation (1.68–3.95 mg/m2) proceeded using a standard 3+3 design, based on cycle 1 dose-limiting toxicities (DLTs). Ph 1 primary objectives were determination of safety, maximum tolerated dose (MTD), and recommended Ph 2 dose (RP2D); the Ph 2 primary objective was CR+VGPR rate. Secondary and exploratory objectives included characterization of MLN9708 pharmacokinetics (PK) and measurement of minimal residual disease using multiparameter flow cytometry. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded by NCI-CTCAE v4.02. Results: From 22 November 2010 (Ph 1) and 14 October 2011 (Ph 2) to data cut-off (June 27, 2012), 65 patients (36 male) have been enrolled, 15 in Ph 1 and 50 in Ph 2. Median age was 66 yrs (range 34–86); 43% and 13% had ISS stage II and III. Patients have received a median of 5 cycles (range 1–15) – 6 cycles (range 1–15) in Ph 1 and 5 cycles (range 1–8) in Ph 2. 42 (65%) patients remain on treatment, 4 (27%) in Ph 1 and 38 (76%) in Ph 2. At 10 August 2012, 22 patients have discontinued: 16 to receive ASCT, 4 due to AEs (3 drug-related, 1 not drug-related GI bleed), 2 for other reasons (1 disease progression, 1 due to investigator decision). Of those who have undergone stem cell mobilization, a median yield of 9.1 × 106 CD34+ cells/L was reported. MLN9708 MTD was established as 2.97 mg/m2 and RP2D was selected as 2.23 mg/m2; RP2D converts to a 4.0 mg fixed dose based on population PK results. At 27 June, all-grade AEs related to any regimen drug and seen in ≥25% of patients were fatigue (32%), nausea (31%), and vomiting (25%). Grade 3 any-drug-related AEs were reported in 26 (40%) patients, including erythematous rash, nausea and vomiting (5% each). Grade 4 any-drug-related AEs were end-stage renal disease (related to progressing MM) and deep vein thrombosis in 1 patient each. One patient experienced grade 3 PN at the RP2D. At 10 August, 3 patients discontinued due to drug-related AEs – 1 in Ph 2 who stopped due to grade 1 resting tremor, grade 2 occasional memory loss (neurologic work-up was negative), and grade 2 peripheral sensory neuropathy, 1 patient in Ph 2 due to drug-related RSV pneumonia who subsequently died on study due to this AE, and 1 patient in Ph 1 with syncope (a DLT). Among all 65 patients (at 10 August), median patient follow-up was 3.88 months (Ph 1: 9.03 months, Ph 2: 3.68 months). The overall response rate (ORR; ≥PR, confirmed/unconfirmed) was 88% (100% in Ph 1 and 84% in Ph 2); this includes 40% ≥VGPR (53% in Ph 1 and 36% in Ph 2) and 18% CR (33% in Ph 1 and 14% in Ph 2). Median cycle number is limited, but 50 patients have received ≥4 cycles: ORR was 96%, with 44% ≥VGPR and 26% CR. Analyses by cytogenetic status will be presented at the meeting. At data cut-off, 50 of 52 responders remained in response, with responses durable for up to 13.2+ months. Median time to first response was 0.92 months (range 0.89–6.44). Conclusions: The combination of weekly oral MLN9708 plus lenalidomide and dexamethasone appears generally well tolerated, with one grade 3 PN at the RP2D. Preliminary data show antitumor activity at the RP2D in patients with previously untreated MM, and at data cut-off, 96% of patients had achieved ≥PR, including a ≥VGPR rate of 44% and a CR rate of 26%, with responses consistent with those reported with VRD/RVD. Disclosures: Kumar: Millennium Pharmaceuticals, Inc.: Research Funding; Novartis: Research Funding; Genzyme: Research Funding; Cephalon: Research Funding; Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Off Label Use: A study of the investigational agent MLN9708 in combination with lenalidomide and dexamethasone for the treatment of patients with previously untreated multiple myeloma. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Lonial:Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Hari:Celgene: Consultancy. Vescio:Millennium Pharmaceuticals, Inc.: Speakers Bureau. Berg:Millennium Pharmaceuticals, Inc.: Employment. Lin:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Richardson:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals and Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract 3646 Background: The validity of proteasome inhibition as an effective therapeutic approach in lymphoma has been demonstrated by the first-in-class proteasome inhibitor bortezomib. MLN9708 is a reversible, orally bioavailable, specific investigational 20S proteasome inhibitor that immediately hydrolyzes in vivo to MLN2238, the biologically active form. In mouse models of lymphoma, MLN2238 was associated with greater tumor proteasome inhibition and enhanced antitumor activity versus bortezomib (Lee et al., Clin Cancer Res 2011). The primary objectives of this study of intravenous (IV) MLN9708 in patients with relapsed/refractory lymphoma (NCT00893464) were to determine the safety and maximum tolerated dose (MTD) of once-weekly MLN9708; secondary objectives included characterization of pharmacokinetics (PK) and pharmacodynamics, and assessment of preliminary antitumor activity. Methods: Patients aged ≥18 years with measurable relapsed/refractory lymphoma who had failed ≥2 prior lines of therapies received IV MLN9708 on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Dose doubling proceeded from a starting dose of 0.125 mg/m2 with 1 patient per dose up to 1.0 mg/m2. Dose escalation then occurred in 26–40% increments using a standard 3+3 scheme based on occurrence of dose-limiting toxicities (DLTs) in cycle 1. Adverse events (AEs) were graded using NCI CTCAE v3.0. Blood samples were collected at multiple time points on days 1 and 15 of cycle 1, and day 1 of cycle 2 for PK analyses. Response was assessed using IWG criteria. Results: At data cut-off (June 29, 2012), 26 patients (16 male) had been enrolled: 1 each at 0.125, 0.25, 0.5 and 1 mg/m2, 4 at 1.4 mg/m2, 7 at 1.76 mg/m2, 6 at 2.34 mg/m2, and 5 at 3.11 mg/m2. Median age was 56.5 years (range 23–78). Median number of prior therapies was 5 (range 1–12); 31% had prior radiation therapy, 23% had a prior stem cell transplant. Eight patients had Ann Arbor stage IV, 3 had stage III, 6 had stage II, and 2 had stage I; staging was unknown in 4 patients and not applicable in 3. Histologies included follicular lymphoma (FL; n=8), diffuse large B-cell lymphoma (n=6), peripheral T-cell lymphoma (PTCL; n=4), mycosis fungoides (n=2), Hodgkin lymphoma (n=3), and others (n=3). Patients have received a median of 2 cycles of MLN9708 (range 1–29). Four DLTs were reported: 1 grade 4 neutropenia at 1.76 mg/m2, 1 grade 3 neutropenia at 2.34 mg/m2, and 2 grade 3 acute pre-renal failure due to GI toxicities and dehydration at 3.11 mg/m2. The MTD has been determined as 2.34 mg/m2. All patients experienced drug-related AEs, including fatigue (n=12), diarrhea (n=10), nausea, vomiting (each n=8), thrombocytopenia (n=6), pyrexia, neutropenia, decreased appetite, and headache (each n=5). Twelve patients (46%) had drug-related grade ≥3 AEs, including neutropenia (n=4), thrombocytopenia, and diarrhea (each n=3). Three patients discontinued due to AEs of drug-related grade 3 neutropenia (2.34 mg/m2), drug-related grade 3 asthenia and grade 3 acute pre-renal failure, and unrelated grade 3 thrombocytopenia (both 3.11 mg/m2). Three patients reported drug-related serious AEs. Four patients reported drug-related peripheral neuropathy, all were grade 1 or 2. There was 1 on-study death due to respiratory failure, considered unrelated to MLN9708. PK analyses showed a dose-proportional increase in plasma exposure with increasing dose from 0.5 to 2.34 mg/m2 and a terminal half-life of 5.5–9 days after multiple dosing. There was a dose-dependent increase in maximal whole blood 20S proteasome inhibition. Of 22 response-evaluable patients (as of August 7, 2012), one achieved a complete response (CR; FL at 1.76 mg/m2, initial partial response [PR] at cycle 4, improved to CR at cycle 20, ongoing at cycle 24), and 3 achieved a PR (1 FL at 1.4 mg/m2, achieved at cycle 10, ongoing at cycle 30; 1 FL at 3.11 mg/m2, recently achieved at cycle 2 and ongoing at cycle 3; 1 PTCL at 2.34 mg/m2, achieved at cycle 4 but progressed at cycle 8). A further 4 patients had stable disease of ≥ 4 cycles. Conclusions: These phase 1 data suggest that once-weekly IV MLN9708 is generally well tolerated, with infrequent peripheral neuropathy, and shows signs of clinical activity in heavily pretreated relapsed/refractory lymphoma patients, particularly FL patients. Enrollment continues at the MTD; phase 2 studies with oral MLN9708 are planned. Disclosures: Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory lymphoma. Chang:Genentech: Research Funding; Celgene: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc./Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ONYX: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; INCYTE: Speakers Bureau; Amgen: Speakers Bureau. Hui:Millennium Pharmaceuticals, Inc.: Employment. Yu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc: Employment. Shou:Millennium Pharmaceuticals, Inc: Employment. Martin:Millennium Pharmaceuticals, Inc.: Speakers Bureau.

332 Background: The high response rates seen with the bortezomib, lenalidomide, and dexamethasone (VRD/RVD) regimen (Kumar S, et al. Blood 2012; Richardson PG, et al. Blood 2010) highlight the feasibility of combining a proteasome inhibitor with an immunomodulatory agent and a steroid in patients with previously untreated multiple myeloma (MM). MLN9708 is an investigational, oral, reversible proteasome inhibitor with promising anti-MM effects and favorable toxicity profile with low rates of peripheral neuropathy (PN). Here we report phase (Ph) 1 and preliminary Ph 2 results of the first study of MLN9708 in combination with lenalidomide and dexamethasone in patients with previously untreated MM (NCT01217957). Methods: Patients aged ≥18 yrs with measurable disease, ECOG performance status 0–2, and no grade ≥2 PN, received oral MLN9708 (days 1, 8, and 15) plus lenalidomide 25 mg (days 1–21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to twelve 28-day cycles, then maintenance therapy with MLN9708 (same schedule) every 28 days until progression. Patients could undergo stem cell collection after 3 cycles and discontinue for autologous stem cell transplant (ASCT) after 6 cycles. In Ph 1, dose escalation (1.68–3.95 mg/m2) proceeded using a standard 3+3 design, based on cycle 1 dose-limiting toxicities (DLTs). Ph 1 primary objectives were determination of safety, maximum tolerated dose (MTD), and recommended Ph 2 dose (RP2D); the Ph 2 primary objective was CR+VGPR rate. Secondary and exploratory objectives included characterization of MLN9708 pharmacokinetics (PK) and measurement of minimal residual disease using multiparameter flow cytometry. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded by NCI-CTCAE v4.02. Results: From 22 November 2010 (Ph 1) and 14 October 2011 (Ph 2) to data cut-off (June 27, 2012), 65 patients (36 male) have been enrolled, 15 in Ph 1 and 50 in Ph 2. Median age was 66 yrs (range 34–86); 43% and 13% had ISS stage II and III. Patients have received a median of 5 cycles (range 1–15) – 6 cycles (range 1–15) in Ph 1 and 5 cycles (range 1–8) in Ph 2. 42 (65%) patients remain on treatment, 4 (27%) in Ph 1 and 38 (76%) in Ph 2. At 10 August 2012, 22 patients have discontinued: 16 to receive ASCT, 4 due to AEs (3 drug-related, 1 not drug-related GI bleed), 2 for other reasons (1 disease progression, 1 due to investigator decision). Of those who have undergone stem cell mobilization, a median yield of 9.1 × 106 CD34+ cells/L was reported. MLN9708 MTD was established as 2.97 mg/m2 and RP2D was selected as 2.23 mg/m2; RP2D converts to a 4.0 mg fixed dose based on population PK results. At 27 June, all-grade AEs related to any regimen drug and seen in ≥25% of patients were fatigue (32%), nausea (31%), and vomiting (25%). Grade 3 any-drug-related AEs were reported in 26 (40%) patients, including erythematous rash, nausea and vomiting (5% each). Grade 4 any-drug-related AEs were end-stage renal disease (related to progressing MM) and deep vein thrombosis in 1 patient each. One patient experienced grade 3 PN at the RP2D. At 10 August, 3 patients discontinued due to drug-related AEs – 1 in Ph 2 who stopped due to grade 1 resting tremor, grade 2 occasional memory loss (neurologic work-up was negative), and grade 2 peripheral sensory neuropathy, 1 patient in Ph 2 due to drug-related RSV pneumonia who subsequently died on study due to this AE, and 1 patient in Ph 1 with syncope (a DLT). Among all 65 patients (at 10 August), median patient follow-up was 3.88 months (Ph 1: 9.03 months, Ph 2: 3.68 months). The overall response rate (ORR; ≥PR, confirmed/unconfirmed) was 88% (100% in Ph 1 and 84% in Ph 2); this includes 40% ≥VGPR (53% in Ph 1 and 36% in Ph 2) and 18% CR (33% in Ph 1 and 14% in Ph 2). Median cycle number is limited, but 50 patients have received ≥4 cycles: ORR was 96%, with 44% ≥VGPR and 26% CR. Analyses by cytogenetic status will be presented at the meeting. At data cut-off, 50 of 52 responders remained in response, with responses durable for up to 13.2+ months. Median time to first response was 0.92 months (range 0.89–6.44). Conclusions: The combination of weekly oral MLN9708 plus lenalidomide and dexamethasone appears generally well tolerated, with one grade 3 PN at the RP2D. Preliminary data show antitumor activity at the RP2D in patients with previously untreated MM, and at data cut-off, 96% of patients had achieved ≥PR, including a ≥VGPR rate of 44% and a CR rate of 26%, with responses consistent with those reported with VRD/RVD. Disclosures: Kumar:Millennium Pharmaceuticals, Inc.: Research Funding; Novartis: Research Funding; Genzyme: Research Funding; Cephalon: Research Funding; Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Off Label Use: A study of the investigational agent MLN9708 in combination with lenalidomide and dexamethasone for the treatment of patients with previously untreated multiple myeloma. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Lonial:Onyx: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Bristol-Meyers Squibb: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Hari:Celgene: Consultancy. Vescio:Millennium Pharmaceuticals, Inc.: Speakers Bureau. Berg:Millennium Pharmaceuticals, Inc.: Employment. Lin:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Richardson:Millennium Pharmaceuticals, Inc.: Membership on an entity9s Board of Directors or advisory committees; Janssen Pharmaceuticals and Janssen-Cilag: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees.

Abstract 2672 Background: MLN9708 is an investigational, potent, reversible, and specific 20S proteasome inhibitor. It is immediately hydrolyzed in vivo to MLN2238, the biologically active dipeptidyl leucine boronic acid. In preclinical studies, MLN2238 showed faster proteasome dissociation and greater tissue penetration than bortezomib. In OCI-Ly10 and PHTX22L mouse models of lymphoma, prolonged tumor proteasome inhibition and enhanced antitumor activity was seen with MLN2238 compared with bortezomib. Both intravenous (IV) and oral formulations are in clinical development. Here we report data from the first phase 1 study of IV MLN9708 in patients with lymphoma (ClinicalTrials.gov: NCT00893464). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and safety of MLN9708. Other objectives included characterization of the pharmacokinetic (PK)/pharmacodynamic (PD) profile, and assessment of antitumor activity and tumor biomarkers. Adults with lymphoma who had failed at least 2 chemotherapeutic regimens received IV MLN9708 on days 1, 8, and 15 of 28-day cycles for up to 12 cycles or until disease progression or unacceptable toxicity occurred. Patients had ECOG PS 0–2, adequate renal, hepatic, and hematologic function, and no grade ≥2 peripheral neuropathy. One patient was enrolled at the starting dose of 0.125 mg/m2; dose doubling proceeded with 1 patient at each dose level up to 1.0 mg/m2. Dose escalation then proceeded in ≤40% increments via a standard 3+3 scheme based on DLT occurrence in cycle 1. The MTD was defined as the highest dose resulting in DLT during cycle 1 in 0/3 or 1/6 patients. Adverse events (AEs) were graded using NCI-CTCAE v3.0. Blood samples were collected at multiple time points after dosing on days 1 and 15 of cycle 1 for PK/PD analysis. PK and PD parameters were calculated using noncompartmental methods (WinNonlin v5.3). Archived tumor specimens were used for biomarker analysis. Response was assessed using International Working Group criteria for lymphoma. Results: At data cut-off (July 8, 2011), 17 patients had been enrolled and treated: 1 each at 0.125, 0.25, 0.5, and 1.0 mg/m2, 4 at 1.4 mg/m2, 7 at 1.76 mg/m2, and 2 at 2.34 mg/m2. The median age was 53 years (range 23–78). Histologies were follicular lymphoma (n=6), diffuse large B-cell lymphoma (n=3), Hodgkin lymphoma (n=3), T-cell lymphoma (n=3), and other (n=2). The median number of prior therapies was 5, including radiation and stem cell transplant in 29% of patients each; 47% had received ≥6. Patients received a median of 2 cycles (range 1–16); treatment is ongoing in 3 patients. Two DLTs were seen (1.76 mg/m2, grade 4 neutropenia; 2.34 mg/m2, grade 3 neutropenia delaying cycle 2 by >1 week); the MTD has not yet been reached. Drug-related AEs included fatigue (n=8), diarrhea (n=5), nausea (n=5) and vomiting, pyrexia, neutropenia, thrombocytopenia, and headache (n=4 each). Drug-related peripheral neuropathy was reported in 3 patients (one grade 1, two grade 2 in patients with peripheral neuropathy at baseline). Grade ≥3 drug-related AEs were seen in 8 patients, including neutropenia (n=4) and thrombocytopenia (n=3). Two patients treated at 1.4 mg/m2 had SAEs (grade 3 increased creatinine, grade 2 pyrexia). There were no on-study deaths. One patient treated at 2.34 mg/m2 discontinued due to drug-related grade 3 neutropenia. Three patients treated at 1.76 mg/m2 required dose reductions. Of 16 response-evaluable patients, 3 achieved partial response and continue to respond (2/6 with follicular lymphoma at 1.4 and 1.76 mg/m2, 1/3 with T-cell lymphoma at 2.34 mg/m2); duration of response is >9 months in a patient with follicular lymphoma. Stable disease, durable for up to 3.7 months, occurred in 4 patients. MLN2238 plasma concentration decreased by 90% within 4 hours post dose. After multiple dosing, the terminal half-life ranged from 4–8 days. Plasma exposure appeared to increase proportionally with increasing dose from 0.5–2.34 mg/m2. Whole blood 20S proteasome inhibition was immediate, and maximal inhibition correlated with maximum plasma concentration. Conclusions: These data suggest that once-weekly MLN9708 is generally well tolerated and has early signs of clinical activity in some patients with heavily treated lymphoma. Dose escalation continues to determine the MTD; a total of 16 patients will be evaluated at the MTD. Updated data and analyses of patient stratification biomarkers will be presented. Disclosures: Off Label Use: Use of investigational agent MLN9708 for the treatment of relapsed/refractory lymphoma. Rifkin:Amgen: Speakers Bureau; Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hui:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Xi:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Martin:Millennium Pharmaceuticals, Inc.: Research Funding, Speakers Bureau.

Abstract 301 Background: The investigational agent MLN9708 is the first oral proteasome inhibitor (PI) to enter clinical investigation in MM pts. MLN9708 has shown antitumor activity in solid tumor and hematologic malignancy xenograft models, including in vivo models of MM. The primary objectives of this study (NCT00932698) were to determine safety/tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose of oral MLN9708 in pts with relapsed and/or refractory MM. Secondary objectives included evaluation of response rate and characterization of pharmacokinetics (PK, of MLN2238, the biologically active hydrolysis product) and pharmacodynamics (20S proteasome inhibition in blood). Methods: Pts aged ≥18 years with measurable disease and no grade ≥2 peripheral neuropathy (PN) were eligible. For the dose-escalation phase (3+3 design), pts required ≥2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids. Pts could have received other PIs. At the MTD, pts were enrolled to four expansion cohorts: relapsed and refractory cohort (progressive disease [PD] on therapy or Results: As of June 29 2011, 53 pts have been enrolled (53% male). Median age was 66 years (range 50–86), median time since initial MM diagnosis was 4.6 years (range 1.1–24.3), and median number of prior therapies was 4 (range 1–28); 55% of pts had received stem cell transplant, 92%, 80%, 56%, and 4% had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively, and 47% were refractory to last therapy, including 28% who were bortezomib-refractory. During dose escalation, 27 pts received MLN9708 0.24–2.23 mg/m2; the MTD was determined as 2.0 mg/m2. To date, 32 pts have been enrolled to the expansion cohorts (including 6 from the dose-escalation phase): 17, 11, and 4 to the relapsed and refractory, bortezomib-relapsed, and PI-naïve cohorts, respectively. Overall, pts have received a median of 3 cycles (range 1–17), with 6 (11%) receiving ≥12 cycles. At data cut-off, 58% of pts had discontinued, mainly due to PD (36%). Safety profiles appeared similar between dose-escalation and expansion cohorts. Overall, 87% of pts experienced drug-related AEs, the most common being fatigue (45%), thrombocytopenia (30%), nausea (26%), diarrhea (25%), vomiting, and rash (each 23%). Only four (8%) pts had drug-related PN (three grade 1, one grade 2); all had grade 1 PN (n=3) or paresthesias (n=1) at baseline. Overall, 58% had grade ≥3 AEs, 21% had dose reductions, and 6% discontinued due to AEs (thrombocytopenia, arthralgia, hypoxia). Two pts died on study due to PD and a cardiac disorder, considered unrelated. To date, of 36 evaluable pts, six have achieved minimal response or better, including two with partial responses (in the 1.2 and 2.23 mg/m2 cohorts), with duration of disease control of up to 11.3 months; all 6 pts remain in response. Another 22 pts have achieved stable disease, which also proved durable with stabilization for up to 9.9 months. MLN9708 was rapidly absorbed with MLN2238 Tmax of 0.5–1.25 hours and terminal half-life of approximately 4–5 days after multiple MLN9708 dosing. MLN2238 plasma exposure appeared to increase proportionally with increasing MLN9708 dose from 0.8–2.23 mg/m2. Maximal 20S proteasome inhibition in blood was immediate and dose-dependent. Conclusions: Current data suggest that single-agent MLN9708 may result in clinical activity in heavily pretreated relapsed and/or refractory MM pts, including durable disease control, and is generally well tolerated, with infrequent PN. Updated information for all cohorts, plus data from an analysis of candidate biomarkers of responsiveness to treatment with MLN9708, will be presented. Disclosures: Richardson: Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Baz:Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Orthobiotech: Research Funding. Wang:Millennium Pharmaceuticals, Inc.: Research Funding. Jakubowiak:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

Abstract 816 Background: Proteasome inhibition is a very effective therapeutic strategy in multiple myeloma (MM). The investigational agent MLN9708 is an oral, specific, reversible inhibitor of the 20S proteasome that has shown antitumor activity in solid tumor and hematologic malignancy xenograft models. Phase 1 trials are evaluating both intravenous and oral formulations using different dosing schedules in a variety of tumor types. Here we report the findings from the dose-escalation portion of a phase 1 trial of once-weekly, orally administered MLN9708 in patients with relapsed and/or refractory MM (NCT00963820). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of MLN9708. Secondary objectives included determination of response rate, and characterization of the pharmacokinetics (PK, of MLN2238, the biologically active hydrolysis product) and pharmacodynamics (PD, 20S proteasome inhibition in blood) of once-weekly oral MLN9708. Patients with MM who had received ≥2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. Treatment consisted of MLN9708 administered orally on days 1, 8, and 15 of a 28-day cycle. Dose-escalation proceeded from 0.24 mg/m2 using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded by NCI-CTCAE v3. Response was assessed by modified EBMT/IMWG criteria. Blood samples were collected after dosing on days 1 and 15 of cycle 1 for PK and PD analyses; parameters were calculated using noncompartmental methods (WinNonlin software v5.3). Results: A total of 28 patients have been enrolled to date (data cut-off: June 29, 2011), including 3 each at dose levels of 0.24, 0.48, 0.80, and 1.20, 4 at 1.68, 3 at 2.23, 4 at 2.97, and 5 at 3.95 mg/m2. The median age was 63.5 years (range 40–76); 54% were male. The median number of prior regimens was 5 (range 2–15), and median time from diagnosis was 4.6 years. Nineteen (68%) patients had prior stem cell transplant, and 16 (59%) were refractory to their last prior therapy, including 7 (26%) to bortezomib and 11 (41%) to lenalidomide or thalidomide. The MTD has not been reached; the current cohort is receiving 3.95 mg/m2. No DLTs have been observed among 21 DLT-evaluable patients. Patients have received a median of 2 treatment cycles (range 1–11; mean 2.8). Four patients remain on treatment; discontinuation was mainly due to progressive disease (71%). All 28 patients are evaluable for toxicity; 26 (93%) experienced at least one AE, including 22 (79%) who experienced at least one drug-related AE. Drug-related AEs occurring in >20% of patients included fatigue (39%), thrombocytopenia (36%), nausea (32%), and diarrhea (29%). Two (7%) patients had drug-related peripheral neuropathy (PN, both grade 2); both had grade 1 PN at baseline. Ten (36%) patients experienced grade ≥3 AEs, 4 (14%) had AEs resulting in MLN9708 dose reductions, and 3 (11%) discontinued due to AEs. No on-study deaths have occurred. In 16 response-evaluable patients, one partial response has been seen, in a patient treated at 2.97 mg/m2 (who had three prior lines of therapy, thalidomide–dexamethasone, lenalidomide–dexamethasone –perifosine, and bortezomib–dexamethasone, to which the patient responded and relapsed); duration of response is 3.7 months, and the patient remains in response at cycle 8. A further five patients had a best response of stable disease, durable for up to 9.5 months. PK analyses showed that MLN9708 was rapidly absorbed, with MLN2238 Tmax of 0.5–2.0 hours and a terminal half-life after multiple dosing of approximately 7 days based on limited data (n=5). MLN2238 exposure appeared to increase proportionally with increasing MLN9708 dose over the range 0.8–2.97 mg/m2. Maximal 20S proteasome inhibition in blood was immediate and dose-dependent. Conclusions: Current data suggest that MLN9708 on a once-weekly schedule is generally well tolerated and has early signs of anti-tumor activity in this heavily pre-treated population with prior exposure to lenalidomide/thalidomide and bortezomib. To date, toxicity has been manageable, and no significant neuropathy signal has been observed. Updated data will be presented, with the MTD anticipated to be reached. Data from an analysis of candidate biomarkers of responsiveness to treatment with MLN9708 will also be presented. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Bensinger:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding; Array: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding. Reeder:Celgene: Institutional research funding; Millennium Pharmaceuticals, Inc.: Institutional research funding; Novartis: Institutional research funding. Zimmerman:Novartis: Expert witness; Celgene: Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc: Honoraria, Speakers Bureau. Berenson:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medtronic: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Niesvizky:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Research Funding.