Laubach, Jacob P.

Introduction Multiple myeloma (MM), relapsed or refractory (R/R) to standard of care therapies, represents a treatment indication with a significant unmet clinical need. Transcriptional activation of c-MYC through bromodomain and extra-terminal (BET) proteins contributes to the malignant phenotype of the disease. RO is a novel thienodiazepine, small molecule, non-covalent inhibitor of the BET family of bromodomains. Preclinical studies with BET inhibitors have demonstrated significant single agent in vivo activity in myeloma, accompanied by down-regulation of MYC and MYC target gene expression. We report results of a monotherapy phase 1b study of RO in R/R MM (NCT03068351). Methods Eligible pts with R/R MM included those treated with at least three prior lines of multiple myeloma therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent. Primary refractory myeloma pts were only allowed in the dose escalation portion of the study. In the dose escalation (part I), pts received subcutaneous (SC) escalating doses of RO (0.30-0.65 mg/kg) in a standard 3 + 3 design on days 1 - 14 of 21-day cycles to determine both the maximum tolerated dose (MTD) and recommended dose (RD). In the expansion cohort (part II), pts received RO as monotherapy at the RD level. Primary endpoint was safety (DLT, MTD, RD) and secondary endpoints included evaluation of pharmacodynamics (CD11b expression) and preliminary efficacy assessments based on IMWG criteria. Results Between June 2017 and April 2019, a total of 24 pts were enrolled in the US, the UK and Australia. 13 pts were enrolled in the dose escalation and 11 pts in the expansion part. The median age of pts was 65.5 years (range: 46 - 82 years). The study population was heavily pretreated with a median of 6 (3-9) prior therapies. Pts were refractory to immunomodulatory drugs (63%), proteasome inhibitors (46%), both (46%), or daratumumab (42%). 57 total cycles were administered, with a median of 2 (1-6) cycles per patient (pt). Two DLTs occurred in one pt in the 0.65 mg/kg cohort (thrombocytopenia grade 4, angina pectoris grade 3). The recommended dose is 0.65 mg/kg. Grade 3 treatment emergent AEs in ≥ 5% of pts were thrombocytopenia (11 pts [45.8%]), anemia (7 pts [29.2%]), fatigue (3 pts [12.5%]), injection site reaction, malaise, decreased appetite, and hyponatremia (2 pts [8.3%] each). 3 pts (12.5%) experienced a total of 4 AEs leading to discontinuation of the study treatment; these AEs were left ventricular dysfunction, fatigue, sepsis, and staphylococcal bacteremia (the latter two AEs occurred in the same pt). A total of 8 deaths (33.3%) were reported in the study, all as a consequence of progressive disease. The best overall response recorded was partial response in 4 pts (16.7 %), 3 of whom having received prior daratumumab. One pt experienced a minimal response, and stable disease was reported in 12 out of 24 (50%). There was no evidence for a dose-related increase in efficacy, though data are very limited (Table). Responses obtained during treatment with RO6870810 were short-lived and lasted for appr. 6 weeks. As evidence of target engagement, pharmacodynamic profiling demonstrated decreases in CD11b levels in peripheral blood mononuclear cells (Figure). Conclusions Treatment of MM pts with the BET inhibitor RO as monotherapy resulted in a high incidence of cytopenias, especially grade 3-4 thrombocytopenia and grade 3 anemia. However, none of these events led to study drug discontinuation. Cytopenias are a known side effect of BET inhibitors, with thrombocytopenia frequently reported as a DLT in various pt populations. Pts with NUT carcinoma, other solid tumors, or diffuse large B-cell lymphoma treated in the First in Man trial of RO had a low rate of cytopenias, indicating that the underlying disease and the extensive pre-treatment in MM may play a role in their occurrence (publication submitted). In this heavily pretreated R/R MM population, we have established 0.65 mg/kg as the recommended monotherapy dose. Pharmacodynamics effects were evident at this dose, but as monotherapy in this R/R MM cohort, response rates were low and less durable. Future drug combination approaches may result in an improved benefit / risk ratio. Disclosures Ramasamy: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria. Nooka:Adaptive Technologies: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy; GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding. Quach:Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy; GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria; Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding. Htut:City of Hope Medical Center: Current Employment. Popat:AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees. Tuchman:Caelum: Honoraria; Sanofi: Honoraria, Research Funding; Amgen: Research Funding; Janssen: Research Funding; Oncopeptides: Consultancy; Roche: Research Funding; Karyopharm: Honoraria, Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Hertzberg:Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; BMS: Honoraria; Takeda: 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Demario:BioNTech SE: Current Employment, Current equity holder in publicly-traded company; Hoffmann-La Roche Ltd.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Nueesch:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Chesne:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Franjkovic:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Lechner:Roche Diagnostics GmbH: Current Employment, Current equity holder in publicly-traded company. Kornacker:Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company.

Background Panobinostat (Pano), a pan-histone deacetylase inhibitor, is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (RRMM) in combination with bortezomib and dexamethasone (FVd) in patients who have received ≥2 prior lines of therapy, including bortezomib and an immunomodulatory agent (IMiD). The pivotal phase 3 PANORAMA 1 trial, which used intravenous (i.v.) bortezomib, demonstrated significant progression-free survival benefit with FVd compared with placebo-Vd; however, adverse events (AEs) were also more frequent (San-Miguel J. et al., Lancet Oncol. 2014). The randomized phase 2 PANORAMA 3 study was conducted to optimize FVd by comparing three regimens with varying dose and schedule of Pano and by incorporating subcutaneous (s.c.) bortezomib. Methods PANORAMA 3 (NCT02654990) was a randomized, open-label, international, multicenter phase 2 study conducted in compliance with the Declaration of Helsinki. Eligible patients were ≥18 years old with 1‒4 prior lines of therapy, including an IMiD. Patients refractory to bortezomib were excluded. Patients were randomized 1:1:1 to Pano 20 mg three times weekly (TIW; the currently approved dosing regimen; Days 1, 3, 5, 8, 10, 12), Pano 20 mg twice weekly (BIW; Days 1, 4, 8, 11), or Pano 10 mg TIW (Days 1, 3, 5, 8, 10, 12), all administered in 21-day cycles. Randomization was stratified by number of prior treatment lines (1 vs 2 vs 3 or 4) and by age at screening (≤75 vs >75 years). For Cycles 1-4, all patients ≤75 years old received s.c. bortezomib 1.3 mg/m2 BIW (Days 1, 4, 8, 11) and oral dexamethasone 20 mg (Days 1, 2, 4, 5, 8, 9, 11, 12). Patients aged ≤75 years from Cycle 5 onwards, and patients >75 years for all cycles, received bortezomib 1.3 mg/m2 weekly (Days 1 and 8) and dexamethasone 20 mg on Days 1, 2, 8, and 9. Patients were treated until progressive disease or death, or until discontinuation due to toxicity or withdrawal of consent. The primary endpoint was overall response rate (ORR; IMWG 2011 criteria) after up to 8 treatment cycles by Independent Review Committee assessment. Secondary endpoints included best response, time to response (TTR), duration of response (DOR) and safety. Results In total, 248 patients were randomized (Pano: 20 mg TIW, N=82; 20 mg BIW, N=83; 10 mg TIW, N=83) and 241 patients received treatment (Pano: 20 mg TIW, N=79; 20 mg BIW, N=82; 10 mg TIW, N=80). Mean (SD) age was 65 (9) years; 55% of patients were male. Overall, patients had a median (range) time since diagnosis of 49 months (7‒242) and a median (range) of 2 (1-4) prior lines of therapy; 17% and 2% of patients were refractory to lenalidomide and pomalidomide, respectively. In total, 68% of patients had relapsed and 32% had relapsed/refractory disease. High-risk molecular findings were present in 15% of patients, with either del(17p) or t (4;14) at screening by fluorescence in situ hybridization. For the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, median (range) number of treatment cycles completed was 9 (1; 50), 8 (1; 40) and 7 (1; 39); ORR (95% CI) after up to 8 treatment cycles was 62% (51; 73), 65% (54; 75), and 51% (39; 62); median TTR was 1, 2, and 3 months, with a median (95% CI) DOR of 22 (14, not estimable), 12 (9, 21), and 11 (6, 14.5) months. Best responses are presented in Table 1. In the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, treatment-related AEs Grade ≥3 were reported in 78%, 72%, and 54% of patients; serious AEs were reported in 54%, 48%, and 44% of patients; and discontinuations due to AEs occurred in 29.5%, 28%, and 15% of patients, respectively. Most common treatment-emergent AEs (≥20% patients) are presented in Table 2. Grade ≥3 diarrhea occurred in 11.5%, 10%, and 5% of patients, respectively. There were 14 (6%) on-treatment deaths during the study (20 mg TIW, n=5; 20 mg BIW, n=3; 10 mg TIW, n=6), with none causally related to therapy and with 12 of 14 directly attributable to progressive disease. Conclusion In patients with RRMM, the 20 mg TIW and 20 mg BIW dosing regimens provided favorable outcomes, with most durable and deepest responses observed in the 20 mg TIW arm. The rate of AEs, including diarrhea, with Pano 20 mg TIW was lower than those observed with the same dosing regimen in PANORAMA 1, suggesting s.c. administration of bortezomib improves tolerability compared with i.v. administration. Moreover, all three regimens of FVd proved generally manageable; Pano 20 mg TIW had greatest efficacy, while 10mg TIW proved best tolerated. Disclosures Schjesvold: Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Oncopeptides: Consultancy. Wróbel:Roche: Honoraria, Research Funding; Takeda, Celgene, Janssen, Amgen, AbbVie, Teva, Sandoz: Consultancy, Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Beksac:Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goncalves:Janssen, Takeda, Amgen, Bayer, Novartis, Merck, Bayer, Celgene, GSK, BMS: Research Funding; Janssen: Consultancy, Speakers Bureau. Bladé Creixenti:Celgene: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Chari:Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Novartis: Honoraria; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Adaptive Biotechnology: Honoraria; Array BioPharma: Honoraria; Karyopharm: Consultancy; Glaxo Smith Kline: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; The Binding Site: Honoraria. Lonial:JUNO Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria. Spencer:Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; Secura Bio: Consultancy, Honoraria; Pharmamar: Other; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TheraMyc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Other: Grant/Research Support; Takeda: Honoraria, Other, Speakers Bureau; Antegene: Consultancy, Honoraria. Maison-Blanche:Chiesi Pharmaceutical, Sanofi, Novartis: Honoraria. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction: New targets and treatment modalities are needed for multiple myeloma (MM). Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed on B cells and plasma cells, and is found on myeloma cells with near 100% prevalence. BFCR4350A, a humanized immunoglobulin G-based T-cell-engaging bispecific antibody (bsAb), targets the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 on T cells. Dual binding facilitates efficient immunological synapse formation, resulting in T-cell activation and potent killing of myeloma cells (Li et al. Cancer Cell 2017). GO39775 (NCT03275103) is an ongoing, multicenter Phase I trial evaluating the safety, activity, pharmacodynamics, and pharmacokinetics of BFCR4350A monotherapy in pts with relapsed/refractory (R/R) MM. We present dose-escalation data from the single step-up dosing cohort (Arm A). Methods: All pts have R/R MM for which no established therapy is available, appropriate, or tolerated. Prior exposure to CAR-T cells, T-cell engaging bsAbs, and antibody-drug conjugates (ADCs), including those targeting BCMA, is allowed. In dose-escalation, pts receive BFCR4350A by IV infusion in 21-day cycles (Q3W). In Arm A, a single step-up dose is used in Cycle (C) 1 to mitigate the risk for cytokine release syndrome (CRS), with the step dose (0.05-3.6mg) given on C1 Day (D) 1 and the target dose (0.15-132mg) given on C1D8, and on D1 of each subsequent cycle. Results: At cut-off (April 13, 2020), 51 pts (median age: 62.0 years [range: 33-80]; high-risk [HR] cytogenetics [1q21, t(4;14), t(14;16), or del(17p)]: 28 pts) had been enrolled into Arm A. Median number of prior lines of therapy was 6 (range: 2-15). Prior treatments included: proteasome inhibitors (PIs), 100% (94.1% refractory); immunomodulatory drugs (IMiDs), 100% (98.0% refractory); anti-CD38 mAbs, 78.4% (92.5% refractory); autologous stem cell transplant, 86.3%. Overall, 66.7% of pts were triple-class refractory (≥1 PI, ≥1 IMiD, and ≥1 anti-CD38 mAb), and 94.1% of pts were refractory to their last therapy. At cut-off, 46/51 pts were evaluable for efficacy. Responses were observed at the 3.6/20mg dose level and above, in 15/29 pts (51.7%) (Table). Responses included 3 stringent CRs, 3 CRs, 4 VGPRs, and 5 PRs (Table). At the 3.6/20mg dose level and above, responses were observed in pts with HR cytogenetics (9/17), triple-class refractory disease (10/20), and prior exposure to anti-CD38 mAbs (11/22), CAR-Ts (2/3), or ADCs (2/2). Duration of response data are evolving, with 6/15 pts in response for >6 months at cut-off. Median follow-up for safety was 6.2 months (range: 0.2-26.3 months). Almost all pts (49/51) had ≥1 treatment-related AE. The most common treatment-related AE was CRS (Lee et al. 2014 criteria; 38/51 pts, 74.5%). CRS was Grade (Gr) 1 in 20 pts (39.2%), Gr 2 in 17 pts (33.3%), and Gr 3 in 1 pt (2%) (due to Gr 4 transaminase elevation). CRS was most common in C1 (38 pts) and was uncommon or absent in subsequent cycles (4 pts). Most CRS events (49/58, 84.5%) resolved within 2 days. 18/38 (47.3%) pts with CRS received tocilizumab and/or steroids. Other treatment-related AEs in ≥5 pts were neutropenia and lymphocyte count decreased (6 pts each, 11.8%), aspartate aminotransferase increased and platelet count decreased (5 pts each, 9.8%). Treatment-related Gr 3-4 AEs (20 pts, 39.2%) in ≥3 pts were lymphocyte count decreased (6 pts, 11.8%), neutropenia (5 pts, 9.8%), anemia and platelet count decreased (3 pts each, 5.9%). No treatment-related Gr 5 (fatal) AEs were observed. Treatment-related AEs leading to withdrawal of treatment were uncommon (1 pt, 2.0%). One DLT (Gr 3 pneumonia) was observed in the 3.6/90mg cohort, but the MTD was not reached. BFCR4350A PK was linear across the active dose levels tested and the estimated half-life was supportive of the Q3W dosing regimen. Conclusions: BFCR4350A monotherapy demonstrates promising activity in heavily pre-treated R/R MM, with deep and durable responses observed in pts with HR cytogenetics, triple-class refractory disease, and/or prior exposure to anti-CD38 mAbs, CAR-Ts, or ADCs. Toxicity was manageable, with C1 single step-up dosing effectively mitigating the risk for severe CRS and allowing escalation to clinically active doses. Updated data will be presented. Disclosures Cohen: Novartis: Other: Patents/Intellectual property licensed, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda,: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Haemalogix: Consultancy; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Krishnan:Sutro: Membership on an entity's Board of Directors or advisory committees; Z Predicta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Regeneron: Consultancy; Takeda: Speakers Bureau; Amgen: Speakers Bureau; BMS/Celgene: Consultancy, Other: Stock BMS, Speakers Bureau; Sanofi: Consultancy. Fonseca:Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Juno: Consultancy; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Forsberg:Celgene: Speakers Bureau; Genentech, Inc., Sanofi, Karyopharm, Abbvie: Research Funding. Spencer:AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; Celgene, Janssen and Takeda: Speakers Bureau. Berdeja:BMS: Consultancy, Research Funding; Glenmark: Research Funding; Genentech, Inc.: Research Funding; Bioclinica: Consultancy; Teva: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Cellularity: Research Funding; Acetylon: Research Funding; CURIS: Research Funding; Legend: Consultancy; Lilly: Research Funding; Constellation: Research Funding; EMD Sorono: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy; Poseida: Research Funding; Amgen: Consultancy, Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Bluebird: Research Funding; Karyopharm: Consultancy; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Kesios: Research Funding. Li:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment. Choeurng:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Vaze:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Samineni:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Sumiyoshi:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cooper:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Fine:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Trudel:Janssen: Honoraria, Research Funding; Sanofi: Honoraria; GSK: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Karyopharm: Honoraria; AstraZeneca: Honoraria; BMS: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Honoraria. OffLabel Disclosure: BFCR4350A is a humanized IgG-based T-cell-engaging bispecific antibody that targets the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 on T cells. Dual binding facilitates efficient immunological synapse formation, resulting in T-cell activation and killing of myeloma cells. BFCR4350A is an investigational agent.

PURPOSE Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.

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 <1% gr 3). PN rates were 28% vs 21% (2% vs 2% gr 3), 35% vs 21% had rash events (4% vs 1% gr 3), 4% vs 6% had renal failure (2% vs 3% gr ≥3), and 4% vs 3% had heart failure (2% vs 2% gr ≥3). 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.

Abstract Abstract 2878 Poster Board II-854 Background: Significant advances have been made in the treatment of myeloma with the introduction of thalidomide, its analogue, lenalidomide, and the proteasome inhibitor bortezomib. While these new drugs have improved the outcome of patients with myeloma, the disease still remains incurable. Effectiveness of upcoming new therapies will need to be assessed in the context of anticipated outcome with the currently available therapies. However, given the rapid pace of development over the past decade, outcome of patients who have relapsed on the new therapies remain unclear. Methods: In order to further study this group of patients, we undertook a study of patients who have relapsed on or are refractory to one of the IMiDs (thalidomide or lenalidomide) as well as bortezomib. A total of 300 cases from 8 sites in the US, 5 sites in Europe and one site in Asia were identified for this study. Enrolled patients had relapsed and refractory multiple myeloma, per the EBMT or IMWG response criteria, after at least 2 prior treatments. Patients were refractory to bortezomib, defined as having no response on a prior bortezomib-containing regimen or experiencing disease progression within 60 days of a bortezomib-containing regimen. Patients also should have relapsed, refractory, intolerant, and/or ineligible in the opinion of the investigator, to other therapies, including an IMiD (thalidomide or lenalidomide). Clinical and laboratory data pertaining to the time of diagnosis and from the time of individual relapses were obtained from the clinical records. The date patients satisfied the above entry criteria was defined as time zero. Results: The current analysis includes the first 119 patients with complete data available. The median age at initial diagnosis was 59 years (range, 31-86 yr); 71% were males. The ISS stage distribution at diagnosis was 33%, 39% and 28% for stages 1, 2, and 3 respectively. 19 patients (37%) had high risk disease by FISH [t(4;14), t(14;16), del17p] or by cytogenetics [del 13, hypodiploidy]. The median time from diagnosis to time zero was 3.8 yrs (range 0.2-18.7 yr) and the median reported lines of therapy before time zero was 2. 74% patients had at least 1 autologous stem cell transplant prior to becoming eligible for the study. Following time zero, 77 (65%) pts had a treatment recorded, including an autologous SCT in 21 (18%), with the treatment regimen starting at a median of 1 month after time zero. A variety of treatment regimens were utilized beyond time zero (median=1; range 0-7). Thirty-two (27%) patients had a response any time following time zero, and only 8 had a subsequent response. Response to the first treatment, or supportive care for patients not treated, recorded following time zero included minor response or stable disease (n=14; 12%), PR (n=17, 14%), and VGPR or better (n=6, 5%). Patients treated with SCT had a higher rate of PR or better compared to patients receiving other treatments (85%; 17/20 vs. 26%; 15/57). In a multivariate analysis, the only significant predictor of a PR or better after time zero was younger age (<60 yrs). The median overall survival (OS) and event free survival (EFS) were 6 mos (95% CI, 4-7 mos) and 1 month (95% CI,1-2 mos) respectively. In a multivariate analysis normal creatinine predicted for a better overall survival and having an IgG M protein type predicted for better EFS. A complete analysis from all 300 patients will be presented at the meeting. Conclusions: This study confirms the poor outcome of patients once they become relapsed and refractory to agents that have become the mainstay of myeloma therapy. The findings highlight the incurable nature of the disease and urgent need to develop newer effective therapeutic agents for this group of patients, who currently do not have effective treatment options. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Jagannath:Merck: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Laubach:Novartis: . Palumbo:Ortho Biotech, Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. San Miguel:Millennium: Membership on an entity's Board of Directors or advisory committees; 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. Siegel:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Sonneveld:Janssen-Cilag: Honoraria. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

Abstract 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.

Abstract Abstract 1859 Genome wide RNA interference studies identified Aurora Kinase (AURK) A and B as lethal targets in Multiple Myeloma (MM) while suppression of these genes also sensitized MM to bortezomib (BTZ). MLN8237 is an oral inhibitor of AURKA. We therefore conducted a Phase I clinical trial of MLN8237 in combination with BTZ. The study enrolled a total of 19 patients at 5 institutions. 9 patients are still receiving active treatment as of the date of this report. Study Design: The phase I portion of this study uses a standard 3+3 design to determine the maximum tolerated dose (MTD) of MLN8237 and BTZ in patients with relapsed/refractory MM. Eligibility required a minimum of 1 and maximum of 4 lines of prior therapy. Patients who have received prior BTZ therapy were allowed on trial as long as they did not progress during prior BTZ or ≤ 60 days of therapy discontinuation. The following laboratory values were required £7 days prior to registration. ANC3 1000/mL, Hgb ≥9 g/dl, PLT3 100,000/mL, Total bilirubin £1.5 × upper limit of normal (ULN), Creatinine £ 2.5 × ULN, a baseline LVEF ≥45%. Patients were required to be able to take oral medication and to maintain a fast as required for 2 hours before and 1 hour after MLN8237 administration. Treatment Overview: The first 3 patients received MLN8237 at 25 mg po days 1–14 and BTZ at 1.3 mg/m2/dose iv. days 1, 4, 8, 11 on a 28 day schedule. Based on data from other concurrent trials an amendment changed dosing of MLN8237 to 20, 30, 40 or 50 mg po twice daily on days 1–7 and BTZ was given at 1.5mg/m2 iv weekly on a 28 day schedule. Results: Median age of patients was 64, 63% were male, 31% had high risk genetics, 84% had prior stem cell transplant, 53% of patients were relapsed and 47% were relapsed and refractory to therapy. No DLTs were observed even at the highest dose level tested. However, one patient at the highest dose level required a platelet transfusion in order to initiate treatment on time in Cycle 2. Thus, a further 3 patients accrued at the highest dose level before declaring the MTD and proceeding to phase II. The highest dose level (Dose Level 3: MLN8237 50 mg po twice daily on days 1–7; BTZ 1.5 mg/m2 iv. given on days 1, 8, 15, 22) was the final dose level tested (the MTD of single agent MLN8237 is 50mg as defined in other Phase I trials). The ORR was 26% (1 CR, 4 PR); when minor responses are included the ORR was 52%. Median follow up was 4.3 months (range 0.9–23.4) and PFS was 5.5 months. At last follow up 12 patients showed no progression and 7 had progressed. Toxicity: 63% of patients experienced a grade 3AE and 5% a grade 4 AE. Grade 3 or 4 toxicity seen in more than one patient was all hematologic with thrombocytopenia and neutropenia being common. Other toxicity of any grade regardless of attribution occurring in more than 20% of patients included neuropathy 63%, fatigue 63%, diarrhea 53%, nausea 47%,vomiting 26%, infection 32%, alopecia 21%, Conclusions: The MTD of the combination is MLN8237 50 mg po twice daily on days 1–7 and BTZ at 1.5mg/m2 iv weekly. Phase II testing is underway and updated results will be presented. Disclosures: Stewart: Millenium: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy. Vij:Millennium: Speakers Bureau. Hofmeister:Celgene: Advisory board Other, Honoraria.

Abstract Introduction: IgM-secreting myeloma is rare, encompassing about 1% of all the myeloma cases. Given its rarity, the characteristics and survival of these patients have not been extensively studied. Therefore, we carried out a multicenter retrospective study in patients with IgM myeloma. Methods: The study protocol was reviewed and approved by the Institutional Review Board of each participating institution. Clinical data were gathered and included age, sex, hemoglobin, calcium, LDH, estimated glomerular filtration rate (GFR), presence of lytic bone lesions, International Staging System score, cytogenetic abnormalities, final outcome and overall survival (OS) time. OS was defined as the time in months from diagnosis to last follow-up or death. The Chi-square and the rank-sum tests were used to compare categorical and continuous variables, respectively. The Kaplan-Meier method was used to estimate OS and the log-rank waas used to compare groups. The Cox proportional-hazard regression method was used to fit univariate and multivariate survival models, reported as hazard ratio (HR) with 95% confidence intervals (CI). All reported p-values are two-sided, and were considered significant if less than 0.05. Results: A total of 159 patients with IgM myeloma from 20 centers from Europe, USA and Latin America were included in this analysis. Patients were diagnosed between 1996 and 2015. The median age at diagnosis was 65 years (range 37-86 years) with a male predominance (68%). The median serum IgM level was 2510 mg/dl (range 27-12,100 mg/dl) with 25% of patients having a serum IgM within normal limits but an IgM monoclonal spike detectable in serum electrophoresis. Hemoglobin levels <10 g/dl were seen in 49 patients (32%), serum calcium was elevated in 24 (16%), estimated GFR of 60 ml/min or less in 56 (37%), lytic lesions were detected in 86 (58%), and serum LDH was elevated in 28 (24%). ISS scores of 1, 2 and 3 were seen in 53 (36%), 63 (43%) and 31 (21%) of patients, respectively. Although immunohistochemistry and/or flow cytometry data were limited, CD20 expression was seen in 15/26 (58%) and cyclin D1 in 10/15 (67%) patients. The most common cytogenetic abnormalities were t(11;14) in 26/67 (39%), del13q in 25/76 (33%) and del17p in 6/76 (8%) patients. 149 patients (94%) received at least one line of systemic therapy for myeloma of which 13 (9%) received rituximab as part of initial therapy. After a median follow-up of 47 months, 74 patients (47%) have died. The median OS was 62 months (95% CI 51-79 months). Cause of death was known in 38 patients, and the most common was myeloma progression (74%). IN the univariate analysis, prognostic factors associated with a worse OS were age (HR 1.03, 95% CI 1.01-1.06; p=0.01) and ISS score (ISS 2: HR 1.43, 95% CI 0.83-2.48; p=0.2, and ISS 3: HR 3.03, 95% CI 1.54-5.98; p=0.001, using ISS 1 as reference group), while male sex was associated with a better OS (HR 0.56, 95% CI 0.34-0.90; p=0.02). Hemoglobin, calcium, estimated GFR and lytic lesions were not associated with OS. In the multivariate analysis, male sex was associated with a better OS (HR 0.57, 95% CI 0.35-0.95; p=0.03) and ISS with worse OS (ISS 2: HR 1.57, 95% CI 0.89-2.74; p=0.12, and ISS 3: HR 2.76, 95% CI 1.38-5.55; p=0.004, using ISS 1 as reference group). Conclusion: Patients with IgM myeloma apparently present with similar clinical characteristics as patients with non-IgM myeloma. Pathologically, CD20 and cyclin D1 expression is common. The most common cytogenetic abnormalities identified were t(11;14) and del13q. Survival does not appear shorter than non-IgM myeloma patients, and the ISS appears to have similar prognostic value. Disclosures Castillo: Millennium: Research Funding; Janssen: Honoraria; Otsuka: Consultancy; Biogen: Consultancy; Abbvie: Research Funding; Pharmacyclics: Honoraria. Ghobrial:Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Noxxon: Honoraria; Amgen: Honoraria. Hájek:Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; BMS: Honoraria; Takeda: Consultancy. Hungria:International Myeloma Foundation Latin America: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Consultancy; Roche: Consultancy; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding, Speakers Bureau. Reagan:Alexion: Honoraria; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees. Spicka:Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria. Gertz:Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Annexon Biosciences: Research Funding.

AbstractObjectivesTo evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation.MethodsData were pooled from four NDMM phase I/II studies; patients received induction therapy with once‐ or twice‐weekly ixazomib plus lenalidomide‐dexamethasone (IRd), melphalan‐prednisone (IMP), or cyclophosphamide‐dexamethasone (ICd), followed by single‐agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity.ResultsA total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice‐weekly IRd, n = 18; weekly or twice‐weekly IMP, n = 35; weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drug‐related adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance.ConclusionsIxazomib maintenance following ixazomib‐based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long‐term administration. Phase III investigation of ixazomib maintenance is ongoing.