Comenzo, Raymond L.

Background: The extent of cardiac involvement has a major impact on clinical outcomes in patients with newly diagnosed light chain (AL) amyloidosis. Here, we present the hematologic responses, major organ deterioration progression-free survival (MOD-PFS) and event-free survival (MOD-EFS), and organ responses by cardiac stage in patients with newly diagnosed AL amyloidosis treated with cyclophosphamide, bortezomib, and dexamethasone (VCd) with or without daratumumab subcutaneous (DARA SC) in the ANDROMEDA trial (NCT03201965). Methods: Key eligibility criteria included newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage I-IIIA (based on the European Modification of the Mayo staging system), eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to receive DARA-VCd or VCd alone. All patients received bortezomib (1.3 mg/m2 SC weekly), cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly [500 mg maximum]), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. DARA SC (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by injection weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter for up to 24 cycles. Disease evaluations occurred every 4 weeks (Cycles 1-6) and every 8 weeks (after Cycle 7) until major organ deterioration, hematologic progression, death, end of study, or withdrawal. The primary endpoint was overall (ie, at any time) hematologic complete response (CR) rate. Secondary endpoints included MOD-PFS, MOD-EFS, organ response rate, time to hematologic response, survival, and safety. Analyses of hematologic CR and MOD-PFS were performed on the intent-to-treat analysis set; cardiac response analyses were based on patients who were evaluable for cardiac response, defined as patients with baseline NT-ProNBP value ≥650 ng/L or baseline NYHA class 3 or 4 and received at least 1 administration of study treatment. Patients without a baseline assessment or post-baseline assessment were censored at randomization for the MOD-PFS analysis. Descriptive statistics were used to summarize overall CR rate and organ response rate. Hazard ratios and corresponding 95% confidence intervals were estimated based on Cox proportional hazard model. Results: A total of 388 patients were randomized to receive DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between treatment groups. The median age was 64 years and the proportions of patients with cardiac stage I, II, and III were 23%, 40%, and 37%, respectively. The median duration of treatment was 9.6 months for DARA-VCd and 5.3 months for VCd. Median follow-up was 11.4 months (range, 0.03-21.3+). Baseline characteristics were generally balanced across cardiac stages, except increasing cardiac stage was associated with older age (≥65 years), worse Eastern Cooperative Oncology Group performance status, more advanced renal failure (CrCl ≤30), and functionally worse heart failure (NYHA IIIA). Hematologic CR rates were higher in the DARA-VCd group than in the VCd group in patients with cardiac stages I, II, and III at baseline (Table). Cardiac and renal response rates at 6 months were also higher in the DARA-VCd group regardless of cardiac stage at baseline (Table). The hazard ratios (HRs) for MOD-PFS were 0.33, 0.55 and 0.66 for cardiac stages I, II and III, respectively, favoring DARA-VCd. Corresponding HRs for MOD-EFS were 0.24, 0.39, and 0.48, respectively. Rates of any grade adverse events (AEs) were similar in patients with and without cardiac involvement at baseline. Across both treatment arms, rates of serious treatment-emergent AEs were higher in patients with cardiac involvement at baseline than in those without. Conclusions: The benefit of DARA-VCd was retained over VCd alone across cardiac stages for hematologic CR, MOD-PFS, MOD-EFS, and organ responses. Disclosures Minnema: Kite, a Gilead Company: Speakers Bureau; Celgene: Other: travel support, Research Funding; Amgen: Consultancy; Servier: Consultancy. Dispenzieri:Alnylam: Research Funding; Intellia: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Comenzo:Unum: Consultancy; Prothena: Consultancy, Research Funding; Amgen: Consultancy; Sanofi: Consultancy; Caleum: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kastritis:Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Wechalekar:Takeda: Honoraria, Other: Travel; Celgene: Honoraria; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory. Witteles:Pfizer: Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Maurer:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ionis: Research Funding; Eidos: Research Funding; Akcea: Research Funding. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Jaccard:Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding; Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding.

AbstractWe studied 2,528 patients with upfront autologous haematopoietic cell transplantation (AHCT) for multiple myeloma (MM) from 2008–2017 to develop a prognostic model to predict outcomes. High‐risk cytogenetics included t(4;14), t(14;16), t(14;20), del13q on karyotype, del17p, +1q or 1pdel. A Cox model identified factors prognostic of progression/relapse in a training subset (n = 1,246). A weighted score using these factors was assigned to a validation cohort (n = 774). Presence of high‐risk cytogenetics [hazard ratio, (HR) 1·68 (1·3–2·17)] and pre‐AHCT bone marrow plasma cells (BMPCs) ≥10% [1·68 (1·33–2·12)] were assigned 4 points each; albumin at diagnosis <3·5 g/dl [1·31 (1·07–1·61)] 2; standard risk cytogenetics 1, and no cytogenetics abnormality, BMPCs <10% at AHCT and albumin ≥3·5 g/dl at diagnosis 0 points each. A three‐category system with low risk (0–3), intermediate risk (4–8) and high risk (9–10) showed 3‐year progression‐free survival in the low vs. intermediate vs. high risk of 58% (95% CI: 52–63) vs. 49% (95% CI: 43–56) vs. 31% (95% CI: 12–51), P < 0.001 respectively, and 3‐year OS in low vs. intermediate vs. high risk of 88% (95% CI: 84–91) vs. 81% (95% CI: 76–86) vs. 64% (95% CI: 39–80); P < 0·001. Our prognostic scoring system can identify MM patients at risk for early relapse after AHCT.

Background Systemic AL amyloidosis is a clonal plasma cell disorder in which amyloid fibrils are deposited in tissues and organs, leading to multi-system organ dysfunction. The most frequently involved organs are the heart and kidney (individually or together), with advanced cardiac involvement conferring particularly poor outcomes. Achievement of hematologic response and improved organ function result in better outcomes. There are currently no approved treatments for AL amyloidosis; multiple myeloma (MM) treatment strategies are used for these pts. Active, tolerable treatment options specific for AL amyloidosis are needed. The oral proteasome inhibitor (PI) ixazomib (ixa) is active and approved in combination with lenalidomide (L)-dexamethasone (Dex) for the treatment of MM pts who have received ≥1 prior therapy. Methods RRAL pts with measurable disease and major organ involvement (cardiac/renal) who required treatment after 1-2 prior therapies (and were not refractory to prior PI therapy) were randomized to ixa (4.0 mg, d 1, 8, 15) plus Dex (20 mg, d 1, 8, 15, 22) or physician's choice (Dex alone or plus melphalan [M], cyclophosphamide [C], thalidomide [T], or lenalidomide [L]) in 28-d cycles until disease progression or unacceptable toxicity (or best response plus 2 cycles or maximum 18 mos therapy/600 mg total dose for MDex). Randomization was stratified by cardiac risk stage, relapsed vs refractory disease, and prior PI exposure. Primary endpoints were 1) overall hematologic response rate (ORR) centrally adjudicated, and 2) death or vital organ deterioration at 2 yrs. Key secondary endpoints were overall survival (OS) and hematologic complete response (CR) rate; other secondary endpoints included hematologic/vital organ progression-free survival (PFS), time to vital organ deterioration or mortality, duration of hematologic response (DOR), and safety. Results 168 pts were randomized to ixa-Dex (n=85) or physician's choice (n=83; 47 LDex, 24 MDex, 10 CDex, 2 TDex); median age was 65 (range 38-84) vs 66 (33-82) yrs, 60% vs 55% were male, 56% vs 63% had cardiac and 66% vs 58% had renal involvement (33% vs 23% had both) at initial diagnosis (plus 9% vs 12% liver, 12% vs 18% gastrointestinal tract, and 11% vs 10% peripheral nerve involvement), 47% vs 47% had prior bortezomib, and 47% vs 37% had prior transplant. Median time since diagnosis was 14.7 vs 15.9 mos. Hematologic responses were seen in 45 (53%) vs 42 (51%) pts receiving ixa-Dex vs physician's choice (odds ratio 1.10 [95% CI 0.60-2.01], p=0.762). Higher CR rates were seen with ixa-Dex vs physician's choice (26% vs 18%). Overall survival, overall/hematologic/vital organ PFS, time to vital organ deterioration/death, DOR, time to treatment failure, and time to subsequent therapy data all favored pts treated with ixa-Dex vs physician's choice (Figure). Vital organ response rates were 36% in the ixa-Dex arm vs 11% with physician's choice (cardiac response rate: 18% vs 5%; renal response rate: 28% vs 7%). At data cut-off, pts had received a median treatment duration of 11.7 vs 4.9 mos with ixa-Dex vs physician's choice, and 21% vs 6% of pts remained on treatment. Grade ≥3 adverse events (AEs) were seen in 59% vs 56% of pts, including 33% vs 41% with drug-related grade ≥3 AEs, 45% vs 33% had serious AEs, 25% vs 20% had AEs resulting in discontinuation, and there were 6% vs 5% on-study deaths. AEs of clinical importance included diarrhea (34% vs 30%), rash (33% vs 20%), cardiac arrhythmias (25% vs 15%), nausea (24% vs 14%), pneumonia (22% vs 16%), and peripheral neuropathy (20% vs 15%). Common (≥5% overall) grade ≥3 AEs were fatigue (9% vs 9%), anemia (2% vs 10%), cardiac failure, dyspnea (each 6% vs 4%), peripheral edema, and pneumonia (each 5% vs 5%). Conclusions Treatment with ixa-Dex significantly prolonged duration of composite survival and vital organ function, PFS, and time to subsequent therapy vs physician's choice. Moreover, ixa-Dex resulted in an improved CR rate and DOR and, although the primary endpoint of hematologic response was not met, all clinically relevant time-to-event endpoint data favored ixa-Dex vs physician's choice. Ixa-Dex was generally well tolerated and associated with a doubling of treatment duration vs physician's choice; no new safety signals were seen. TOURMALINE-AL1 is the first phase 3 trial in RRAL to show significant outcome improvements, suggesting ixa-Dex represents a new option for RRAL pts, who have limited access to therapies. Disclosures Dispenzieri: Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Wechalekar:Takeda: Honoraria; GSK: Honoraria; Celgene: Honoraria; Amgen: Research Funding; Janssen-Cilag: Honoraria. Schönland:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Landau:Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Suzuki:Takeda: Honoraria; BMS: Honoraria, Research Funding; Ono: Research Funding; Celgene: Honoraria; Janssen: Honoraria. Comenzo:Takeda: Research Funding; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myself: Patents & Royalties: Patent 9593332, Pending 20170008966. Berg:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Employment, Patents & Royalties. Liu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faller:Phoenicia Biosciences: Equity Ownership; Briacell Pharmaceuticals: Equity Ownership; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Viracta Pharmaceuticals: Equity Ownership; Boston University: Employment. Off Label Disclosure: Investigation of the oral proteasome inhibitor ixazomib in combination with dexamethasone versus physician's choice (of which there are no approved treatment options) for the treatment of relapsed/refractory primary systemic amyloidosis.

Abstract Background: Amyloid light chain (AL) amyloidosis is caused by the deposition of misfolded light chain (LC) proteins, which may cause organ failure and death. Current treatments, which target the plasma cells that produce LC, induce organ responses in only 30% to 40% of patients. There is a substantial need for a safe and effective amyloid-directed therapy to improve recovery of organ function. NEOD001, a monoclonal antibody that targets misfolded LC, is hypothesized to neutralize circulating LC aggregates and to clear insoluble organ deposits. In an ongoing phase 1/2 study (NCT02613182; Gertz M et al. J Clin Oncol. 2016;34(10):1097-1103) in 27 patients with AL amyloidosis and persistent organ dysfunction, monthly NEOD001 infusions were well tolerated and produced no infusion-related hypersensitivity reactions. In a best response analysis of subjects who fulfilled eligibility criteria at baseline, 57% met cardiac and 60% met renal response criteria. Supported by these positive results, the current study (VITAL; NCT02312206) is a randomized, double-blind, placebo-controlled, phase 3 trial of NEOD001 in patients with cardiac AL amyloidosis. Here we present the study design for this trial in progress. Patients and Methods: Eligible patients (estimated enrollment, 236) with a diagnosis of AL amyloidosis (newly diagnosed, treatment naive) and cardiac dysfunction (N-terminal probrain natriuretic peptide [NT-proBNP] ≥650 and <8500 pg/mL, clinical signs of heart failure, left ventricular wall thickness >12 mm, or cardiac biopsy-detected amyloidosis) and with estimated glomerular filtration rate ≥30 mL/min/1.73 m2 will be randomly assigned (1:1) to receive NEOD001 (24 mg/kg q28d) plus standard of care (SOC) chemotherapy or placebo plus SOC therapy. Subjects will be stratified according to Mayo Clinic stage, renal stage, and 6-minute walk test (6MWT) distance. The primary end point is a composite, evidence-based measure consisting of all-cause mortality or cardiac hospitalization. Key secondary end points include cardiac response measured by NT-proBNP (as defined by Comenzo RL et al. Leukemia. 2012;26(11):2317-2325) and change in 6MWT distance, Short Form-36 Health Survey response, Neuropathy Impairment Score-Lower Limb and renal response (as defined by Palladini G et al. Blood. 2014;124(15):2325-2332). Disclosures Liedtke: Gilead: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Research Funding. Merlini:Takeda and Janssen-Cilag: Honoraria. Landau:Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees. Comenzo:Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Karyopharm: Research Funding. Sanchorawala:Prothena: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Weiss:Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Millennium: Consultancy, Other: Travel, accommodations; GlaxoSmithKline: Consultancy; Prothena: Other: Travel, accommodations, Research Funding; Novartis: Consultancy. Zonder:Array Biopharma: Consultancy; Prothena: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy. Walling:Stealth: Consultancy; KaloBios: Consultancy; Exelixis: Consultancy; Newgen: Consultancy; Mateon (was Oxigene): Consultancy; Apex: Consultancy; Corcept: Consultancy; Aduro: Consultancy; Prothena: Consultancy; BioMarin: Equity Ownership; Amgen: Equity Ownership, Patents & Royalties; NuMedii: Consultancy; Pharm-Olam: Consultancy; Crown Bioscience: Consultancy; Codexis: Consultancy; Upsher Smith: Consultancy, Patents & Royalties. Kinney:Prothena: Employment, Equity Ownership, Other: Leadership. Koller:Prothena: Employment, Equity Ownership, Other: Travel, accommodations. Gertz:Ionis: Research Funding; Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Annexon Biosciences: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria.

BACKGROUND: AL amyloidosis is a rare, progressive, and typically fatal disease caused by both soluble and insoluble (amyloid) forms of misfolded immunoglobulin light chain (LC) proteins, with no approved treatments. Production and tissue deposition of LC aggregates result in various organ system dysfunction (most commonly cardiac and renal), causing significant morbidity and mortality. NEOD001 is an investigational humanized IGg1 designed to directly neutralize soluble toxic aggregates of misfolded LCs and promote phagocytic clearance of amyloid deposits. AIM: To evaluate efficacy and safety of NEOD001 + standard of care (SOC) vs placebo + SOC in patients with AL amyloidosis by assessing time to all-cause mortality (ACM) or cardiac hospitalization (CH). METHODS: This Phase 3, double-blind, placebo-controlled study randomized 260 newly diagnosed, untreated AL amyloidosis patients (stratified by Mayo stage (Kumar et al., 2012), renal stage, & 6MWD) with cardiac involvement. Patients were randomized 1:1 to 24 mg/kg IV NEOD001 + SOC or placebo + SOC every 28 days. SOC was concomitant chemotherapy with a first line bortezomib-containing regimen. Primary endpoint (PE) was time to ACM or time to centrally adjudicated CH (CH: >90 days after first study drug infusion). Futility analysis based on 103 adjudicated events favored NEOD001 but was not statistically significant (HR 0.84, 95% CI 0.57-1.204, p=0.386). The study was terminated early and post hoc analyses were performed. To our knowledge, this study was the first randomized, placebo-controlled, Phase 3 study evaluating an amyloid-targeting agent in AL amyloidosis. RESULTS: Study arms were balanced with regard to demographics and baseline clinical characteristics. The final PE results (intent-to-treat, ITT) were consistent with the futility analysis: HR 0.835, 95% CI 0.5799-1.2011, p=0.330. Favorability of HR for NEOD001 was largely attributable to time to all-cause mortality rather than cardiac hospitalization. Study termination was the primary reason for discontinuation (majority occurring after 12 months). The 12-month study period was defined as modified ITT (mITT). Further mITT analyses by prognostic Mayo staging categories suggest benefit favoring NEOD001 for both PE (HR=0.635) and ACM (HR=0.498) in stage IV patients (n=77), who have highest risk of early mortality. Median overall survival in stage IV (mITT) was 8.3 months for placebo + SOC and was not reached (>12 months) for NEOD001 + SOC. One or more treatment-emergent adverse events (TEAEs) were experienced by 257 patients. Of the 88 NEOD001-treated patients with a serious adverse event (SAE), the majority of SAEs (95.5%) were considered not related to study drug. The most common TEAEs (fatigue, nausea, peripheral edema, constipation, and diarrhea) were similar in both arms. Overall safety results were similar within and across Mayo stages. CONCLUSION: After study termination, further calculations supported that the VITAL study as designed would not have achieved statistical significance. No statistically significant differences between NEOD001 + SOC vs. placebo + SOC were observed for the PE. Overall, the incidence, severity, and seriousness of AEs were similar in each arm, suggesting that NEOD001 was generally safe and well tolerated. Post hoc analyses suggest a potential survival benefit of NEOD001 for AL amyloidosis patients with the highest risk of early mortality (Mayo stage IV). This population has historically been the most in need of therapy to improve outcomes, therefore additional clinical studies for NEOD001 are warranted. Disclosures Gertz: Ionis/Akcea: Consultancy; Alnylam: Consultancy; Annexon: Consultancy; Physicians Education Resource: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Medscape: Consultancy, Speakers Bureau; Appellis: Consultancy; Prothena Biosciences Inc: Consultancy; Spectrum: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; Johnson and Johnson: Speakers Bureau; Teva: Speakers Bureau. Cohen:Poseida Therapeutics, Inc.: Research Funding. Comenzo:Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myself: Patents & Royalties: Patent 9593332, Pending 20170008966; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Du Mond:Inclin, Inc.: Employment; Prothena: Consultancy. Kastritis:Genesis: Honoraria; Prothena: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Landau:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Libby:Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy; Akcea: Consultancy. Liedtke:Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; BlueBirdBio: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Celator: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Merlini:University of Pavia: Employment. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Takeda: Research Funding; Prothena: Research Funding; Celgene: Research Funding. Schönland:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wechalekar:Janssen-Cilag: Honoraria; GSK: Honoraria; Amgen: Research Funding; Celgene: Honoraria; Takeda: Honoraria. Zonder:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kinney:Prothena Biosciences Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: named inventor on multiple patents and patent applications related to NEOD001.

Background: Seventy percent of patients with light chain (AL) amyloidosis present with renal involvement. The phases of the disease include asymptomatic seeding, increasing proteinuria, and progression to end stage renal disease. In an attempt to identify genes relevant to renal reprogramming due to persistent disease,renal biopsies from treated AL patients were obtained for systematic histologic evaluation and transcriptional profiling. Correlates were sought between these two approaches. Methods: Renal biopsies from 10 patients with persistent proteinuria (>500mg/day) following hematologic responses to anti-plasma cell therapy were scored independently by 2 expert renal pathologists employing a novel histologic tool that assessed scarring, fibrosis and the distribution of amyloid, and were successfully evaluated by transcriptional profiling in the Michigan Kidney Translational Medicine Core lab. Clinical data and histologic scores (CSIC = composite scarring injury score, AS = amyloid score) were correlated to the expression profiles of specific tubular and glomerular gene sets. Results: Baseline characteristics and histologic scores are in Table 1. Using a false discovery rate corrected P-value of < 0.10, numerous genes of interest were identified (Table 2). Transcriptional profiling revealed 2 distinct patient clusters (G1 and G2) within the tubular and glomerular gene expression sets. The histopathologic features were different between G1 and G2; the amyloid score was significantly higher in G2 in both the tubular (7.0 vs. 4.25; p=0.03) and the glomerular (6.92 vs. 4.38; p= 0.04) compartments. The differential expression for the genes of interest between G1 and G2 were also determined (Table 2). Conclusion: This effort has generated multiple genes of interest. ICQD and PODXL, in particular, correlated with the distribution of amyloid in the capillaries and mesangium. We are currently comparing these expression profiles to those of other nephropathies to identify genes whose expression levels may be specific to AL nephropathy, hopefully leading to further novel histologic and protein-based investigations. Disclosures Comenzo: Takeda: Research Funding; Prothena Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myself: Patents & Royalties: Patent 9593332, Pending 20170008966.

Abstract Introduction: Systemic amyloidoses are a group of rare disorders characterized by the accumulation of misfolded proteins in tissue, resulting in the dysfunction of vital organs (eg, heart and kidneys). In amyloid light chain (AL) amyloidosis, the most common form of systemic amyloidosis, the amyloidogenic protein is a misfolded light chain (LC) or a fragment of an LC produced by clonal plasma cells. Current therapies used to treat AL amyloidosis limit LC production but do not directly target deposits underlying multiorgan failure. NEOD001, a monoclonal antibody, targets misfolded LC and is thought to neutralize circulating LC aggregates and to clear insoluble deposits. In an interim analysis of a phase 1/2 dose-escalation study in 27 patients with AL amyloidosis and persistent organ dysfunction (NCT01707264; EudraCT2012-002683-27), monthly infusions of NEOD001 were safe, well tolerated, and associated with renal and cardiac responses.1 Here we report updated results from the escalation phase and new results from the expansion phase of this study. Patients and Methods: Inclusion criteria for this trial were that patients complete ≥1 PCD treatment before enrollment, attain partial hematologic response (HR) or better to any previous therapy, and have persistent organ dysfunction. NEOD001 was administered intravenously every 28 days. During the dose-escalation phase, 27 patients received NEOD001 at 0.5, 1, 2, 4, 8, 16, or 24 mg/kg in a 3+3 study design. An additional 42 patients with renal, cardiac, or peripheral nerve involvement were enrolled and treated (24 mg/kg) in the expansion phase. We assessed safety/tolerability, pharmacokinetics, immunogenicity, cardiac and renal responses based on consensus criteria, and neuropathy responses using the Neuropathy Impairment Score-Lower Limb (NIS-LL). Results: The 42 additional patients enrolled in the expansion study included cohorts with renal (16 patients), cardiac (15 patients), and peripheral nerve (11 patients) involvement. In the overall population (n = 69), the median age was 60 years, and 61% of patients were men. Median (range) time since diagnosis was 2.8 (0.4-12.8) years, and 45% of patients underwent ≥3 previous plasma cell-directed regimens. The total number of infusions administered was 913 over a mean of 13.2 (range, 3-35) months. NEOD001 treatment was not associated with dose-limiting toxicities or discontinuations; patients did not develop antidrug antibodies or treatment-related serious adverse events. The most frequent treatment-emergent adverse events, regardless of relationship to study drug, were fatigue, upper respiratory tract infection, nausea, and diarrhea. In a best response analysis, 53% of cardiac-evaluable patients (N = 36) and 63% of renal-evaluable patients (N = 35) met respective criteria for organ response; no patients experienced disease progression. The median time to initial response was 2 months (cardiac) and 4 months (renal). After 9 months of treatment, 82% of patients with measurable peripheral neuropathy at baseline (N = 11) achieved a peripheral neuropathy response based on the NIS-LL score. Conclusions: Our interim results demonstrated that monthly NEOD001 infusions were safe and well tolerated and that organ response rates compared favorably with traditional chemotherapy. These updated results from the escalation phase and these new results from the expansion phase, including results from patients with peripheral nerve involvement, support the design of ongoing late-stage clinical studies. Antibody therapy may allow for effective treatment of patients with AL amyloidosis. Reference: 1. Gertz MA, Landau H, Comenzo RL, et al. First-in-human phase 1/2 study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction. J Clin Oncol. 2016;34(10):1097-1103. Disclosures Gertz: Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Ionis: Research Funding; Annexon Biosciences: Research Funding. Comenzo:Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Landau:Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding. Sanchorawala:Celgene: Research Funding; Takeda: Research Funding; Prothena: Research Funding. Weiss:Prothena: Other: Travel, accommodations, Research Funding; GlaxoSmithKline: Consultancy; Millennium: Consultancy, Other: Travel, accommodations; Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy. Zonder:BMS: Consultancy; Celgene: Consultancy, Research Funding; Prothena: Consultancy; Array Biopharma: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy. Walling:Stealth: Consultancy; BioMarin: Equity Ownership; Apex: Consultancy; Pharm-Olam: Consultancy; NuMedii: Consultancy; Amgen: Equity Ownership, Patents & Royalties; Crown Bioscience: Consultancy; KaloBios: Consultancy; Exelixis: Consultancy; Newgen: Consultancy; Mateon (was Oxigene): Consultancy; Corcept: Consultancy; Prothena: Consultancy; Aduro: Consultancy; Codexis: Consultancy; Upsher Smith: Consultancy, Patents & Royalties. Kinney:Prothena: Employment, Equity Ownership, Other: Leadership. Koller:Prothena: Employment, Equity Ownership, Other: Travel, accommodations. Schenk:Prothena: Employment, Equity Ownership, Other: Leadership. Guthrie:Prothena: Employment, Equity Ownership, Other: Leadership. Liu:Prothena: Employment, Equity Ownership; Weston Brain Institute: Honoraria. Liedtke:Prothena: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding.

Abstract Introduction:In amyloid light chain (AL) amyloidosis, the most common form of systemic amyloidosis, misfolded light chain (LC) or a fragment of an LC produced by clonal plasma cells accumulates in tissue, resulting in the dysfunction of vital organs and systems (eg, heart, kidneys, nervous system). Current therapies used to treat AL amyloidosis limit LC production but do not directly target deposits underlying multiorgan failure. Approximately 75% of patients do not achieve organ responses and have persistent organ dysfunction. Amyloid-directed therapies may stabilize and potentially reverse organ damage by specifically targeting existing LC aggregates. NEOD001, a monoclonal antibody, targets misfolded LC and is thought to neutralize circulating LC aggregates and to clear insoluble deposits. We have previously reported that monthly infusions of NEOD001 were safe and well tolerated. In addition, NEOD001 was associated with renal and cardiac responses. Here we analyzed the association between organ response and depth and time since last plasma cell-directed (PCD) treatment in the entire cohort of 69 patients enrolled in both the dose-escalation and the expansion phases of the phase 1/2 study. Methods: Inclusion criteria for this trial were that patients complete ≥1 PCD treatment before enrollment, attain partial hematologic response (HR) or better to any previous therapy, and have persistent organ dysfunction. NEOD001 was administered intravenously every 28 days. During the dose-escalation phase, 27 patients received NEOD001 at 0.5, 1, 2, 4, 8, 16, or 24 mg/kg in a 3+3 study design. An additional 42 patients with renal, cardiac, or nerve involvement were enrolled and treated (24 mg/kg) in the expansion phase. We assessed cardiac and renal responses based on consensus criteria and neuropathy responses using the Neuropathy Impairment Score-Lower Limb (NIS-LL). For this analysis, we focused on the relationship between organ response after treatment with NEOD001 to the time since last or best HR and the depth of best and last HR. Results: A total of 69 patients were enrolled, 27 in the dose-escalation and 42 in the expansion cohorts. The entire population included 36 cardiac-evaluable patients, 35 renal-evaluable patients, and 11 patients evaluated for peripheral neuropathy; 39% were women, and the median age was 60 years. Time since diagnosis was 2.8 (0.4-12.8; median, range) years, and 45% of patients had undergone ≥3 previous PCD regimens. Of the patients evaluable for organ response, best response rates indicating organ response were observed in 53% of cardiac-evaluable patients (n = 19/36) and 63% of renal-evaluable patients (n = 22/35). NIS-LL scores indicated that 82% (n = 9/11) of patients met criteria for a peripheral neuropathy response to NEOD001. Cardiac and renal response rates for NEOD001-treated patients could not be attributed to previous PCD treatment regimens. For example, 37% of the NEOD001 cardiac responders and 35% of nonresponders received cyclophosphamide-bortezomib-dexamethasone. Similarly, for NEOD001 renal responders vs nonresponders, 27% vs 25% were treated with autologous stem cell transplantation and 27% vs 31% were treated with bortezomib-dexamethasone. There was no relationship between NEOD001 cardiac, renal, or peripheral nerve organ response and time since last chemotherapy, time since last or best HR, or depth of last or best HR. Finally, an equivalent percentage of evaluable patients experienced renal or cardiac response regardless of whether they had received their most recent PCD treatment ≤6 months or >6 months before NEOD001 initiation. The median time since last PCD treatment to the start of NEOD001 intervention for all patients was 6.5 (range, 0.6-85.8) months and the median time to first cardiac response after NEOD001 treatment for all cardiac responders was 2 months. NEOD001 treatment was safe and well tolerated. Conclusions: Patients treated with monthly NEOD001 infusions had high organ response rates that were independent of time since previous chemotherapy, depth of hematologic response, or predominant type of PCD treatment. Ongoing studies of NEOD001 include VITAL (phase 3 in patients with newly diagnosed AL amyloidosis) and PRONTO (phase 2b in previously treated AL amyloidosis patients with persistent cardiac dysfunction). Disclosures Liedtke: Gilead: Research Funding; Prothena: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Research Funding. Comenzo:Takeda: Consultancy, Research Funding; Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Landau:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Sanchorawala:Prothena: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Weiss:Prothena: Other: Travel, accommodations, Research Funding; GlaxoSmithKline: Consultancy; Millennium: Consultancy, Other: Travel, accommodations; Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy. Zonder:Prothena: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Array Biopharma: Consultancy. Walling:Corcept: Consultancy; Stealth: Consultancy; Codexis: Consultancy; Exelixis: Consultancy; Newgen: Consultancy; Mateon (was Oxigene): Consultancy; Apex: Consultancy; Aduro: Consultancy; Prothena: Consultancy; Upsher Smith: Consultancy, Patents & Royalties; KaloBios: Consultancy; NuMedii: Consultancy; Pharm-Olam: Consultancy; Crown Bioscience: Consultancy; BioMarin: Equity Ownership; Amgen: Equity Ownership, Patents & Royalties. Kinney:Prothena: Employment, Equity Ownership, Other: Leadership. Koller:Prothena: Employment, Equity Ownership, Other: Travel, accommodations. Schenk:Prothena: Employment, Equity Ownership, Other: Leadership. Guthrie:Prothena: Employment, Equity Ownership, Other: Leadership. Liu:Prothena: Employment, Equity Ownership; Weston Brain Institute: Honoraria. Gertz:Annexon Biosciences: Research Funding; Ionis: Research Funding; Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria.

Abstract 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) 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-naïve 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 naïve. 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). Table.PI naïven=6PI exposed n=16TotalN=22Cycles received, median (range)12 (1–22)3.5 (1–16)5.5 (1–22)Dex added, n358Hematologic response-evaluable ptsn=5n=16N=21Response, n (%)ORR5 (100)6 (38)11 (52)CR2 (40)02 (10)VGPR3 (60)4 (25)7 (33)PR02 (13)2 (10)SD09 (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, %8341602 yr OS rate, %835157 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). 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.

Abstract 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 (<PR) after 3 cycles received dexamethasone (dex; 40 mg, days 1–4). Two expansion cohorts of PI-naïve and PI-exposed pts were enrolled at the MTD. The primary objectives were to determine the safety, tolerability, and MTD. Secondary objectives included analysis of plasma pharmacokinetic (PK) and whole blood pharmacodynamic effects of MLN9708, and assessment of overall hematologic response rate, time to and duration of hematologic and organ response. Adverse events (AEs) were graded using NCI-CTCAE version 4.03. Blood samples were collected at multiple timepoints pre- and post-MLN9708 dosing for PK analysis during cycle 1. Hematologic response and amyloid-related organ assessments were performed according to standardized criteria. 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.