Berdeja, Jesús G.

TPS8551 Background: Multiple myeloma (MM) remains an incurable disease, with estimated median survival of 8–9 months in patients with relapsed or refractory (R/R) disease (Kumar et al. 2014; Usmani et al. 2016). There is no uniform standard of care for R/R MM, and combinations used in later lines have diminishing responses, especially after re-exposure to previously received classes of therapy (Gandhi et al. 2019). New targets and treatment modalities are needed. Fragment crystallizable receptor-like 5 (FcRH5) is expressed on myeloma cells across lines of therapy, and is overexpressed by myeloma cells with 1q21 gain; expression in healthy tissue is restricted to the B-cell lineage, and is retained in plasma cells (Li et al. 2017). BFCR4350A is an IgG-based T-cell-dependent bispecific antibody that was specifically engineered to target the most membrane-proximal domain of FcRH5 on myeloma cells and cluster of differentiation 3 (CD3) on T cells, with dual binding resulting in efficient immune synapse formation and T-cell killing of myeloma cells. BFCR4350A demonstrates potent killing of plasma cells and patient-derived myeloma cells (including those with low levels of FcRH5 expression) in vitro, and complete depletion of bone marrow plasma cells in primates, without severe or prolonged cytokine release (Li et al. 2017). GO39775 (NCT03275103) is an open-label, multicenter Phase I dose-escalation and dose-expansion trial evaluating the safety, pharmacokinetics (PK), and activity of BFCR4350A monotherapy in patients with R/R MM. Methods: Patients must be aged ≥18 years and must have R/R MM for which no established therapies are available or appropriate, or be intolerant to those therapies. Patients with prior CAR-T therapy and/or prior BCMA-directed therapy are not excluded. BFCR4350A is administered by intravenous infusion, and q3w dosing with Cycle 1 single-step or multi-step dosing is being investigated in dose-escalation (Arms A and B, respectively). Enrolment into both arms is ongoing, with patients receiving up to 17 cycles of treatment until disease progression or unacceptable toxicity. Primary objectives are to evaluate safety (including the maximum tolerated dose and dose-limiting toxicities) and to identify a recommended Phase II dose. Secondary objectives include assessment of PK, activity, immunogenicity, and pharmacodynamic biomarkers. Clinical trial information: NCT03275103 .

8503 Background: Outcomes are poor in triple-class exposed RRMM patients (pts) who progress on immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and CD38 antibodies (mAbs). Ide-cel, a BCMA targeted CAR T cell therapy, showed promising tolerability and efficacy in RRMM pts in the phase I CRB-401 study ( NEJM2019;380:1726). We present primary efficacy and safety data from the pivotal phase II KarMMa trial of ide-cel in RRMM (NCT03361748). Methods: Enrolled pts had ≥3 prior regimens (including IMiD, PI, and CD38 mAb) and were refractory to their last regimen per IMWG criteria. After lymphodepletion (cyclophosphamide 300 mg/m2+ fludarabine 30 mg/m2 x 3), pts received 150─450 × 106 CAR+ T cells (target dose range). Endpoints included overall response rate (ORR; primary), complete response (CR) rate, duration of response (DoR), and PFS. Results: Of 140 pts enrolled, 128 received ide-cel. Median age was 61 y; median no. of prior regimens was 6; 84% were triple- and 26% were penta-refractory. Most pts (88%) had bridging therapy. At data cutoff (16 Oct 2019), median follow up was 11.3 mo. ORR was 73% and median PFS was 8.6 mo; both increased with higher dose (Table). All subgroups had an ORR ≥50%, including older and high-risk pts. Most common any-grade (Gr) toxicities were cytopenias (97%) and cytokine release syndrome (CRS; 84%). CRS was mainly Gr 1/2; 5 pts (5%) had Gr 3, 1 had Gr 4, and 1 had Gr 5 (at 300 × 106). Neurotoxicity developed in 23 pts (18%); 4 (3%) Gr 3 and 0 Gr ≥4. Median peak CAR+ T cell expansion occurred at 11 d. Expansion was higher in responders and parameters (AUC0−28d, Cmax) increased with higher dose, with exposure overlap across doses. Persistence was durable, with CAR+ T cells detected in 29/49 (59%) and 4/11 pts (36%) at 6 and 12 mo. Conclusions: Ide-cel demonstrated deep, durable responses in heavily pretreated RRMM pts. Efficacy and safety reflected prior reports and support a favorable ide-cel clinical benefit-risk profile across the target dose range. Clinical trial information: NCT03361748 . [Table: see text]

e19505 Background: CFZ combined with dexamethasone is approved to treat pts with RRMM, with CFZ given once-weekly at 70 mg/m2 (Kd70 QW) or twice-weekly at 56 mg/m2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW. We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION-1 trials. Methods: Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION-1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION-1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW. Results: Among BTZ non-refractory pts with 2–3 lines of prior therapy, median progression-free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well-tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69). Conclusions: This post hoc analysis suggests that once-weekly Kd70 has a comparable benefit-risk profile to twice-weekly Kd56. Clinical trial information: NCT02412878, NCT01677858, NCT01568866.

8033 Background: MLN9708 is an oral, reversible 20S proteasome inhibitor. The feasibility of combining a proteasome inhibitor with an immunomodulatory drug and a steroid in previously untreated MM has been demonstrated with the RVD regimen. This is the first study of MLN9708 in combination with lenalidomide and dexamethasone (NCT01217957). Here we report the phase (Ph) 1 MTD and preliminary Ph 2 results. Methods: Pts with previously untreated MM, aged ≥18 yrs with measurable disease received oral MLN9708 (phase 1: 1.68–3.95 mg/m2) days 1, 8, and 15, lenalidomide 25 mg days 1–21, and dexamethasone 40 mg days 1, 8, 15, and 22, for up to twelve 28-day cycles. Primary objectives were determination of safety, MTD, and recommended phase 2 dose (RP2D) (Ph 1), and CR+VGPR rate (Ph 2). Results: At data cut-off (Dec 1, 2011), 29 pts had been enrolled (15 Ph 1, 14 Ph 2). Median age was 64 yrs (range 40–82); 69% ISS stage II/III. In Ph 1, the MLN9708 MTD was determined as 2.97 mg/m2 and the RP2D as 2.23 mg/m2; for Ph 2, the RP2D was converted to a 4.0 mg fixed dose based on population PK results. Ph 1 pts have received a median of 6 treatment cycles (range 1–11), 8 received ≥6 cycles; 6 stopped to receive ASCT, 7 are ongoing. Ph 2 pts received a median of 1 (range 1–2), all are ongoing. Grade ≥3 hematologic toxicity was reversible and included anemia (n=2) and thrombocytopenia (n=1). Grade ≥3 nonhematologic toxicity included erythematous rash, syncope, and vomiting (2 pts each). All-grade drug-related peripheral neuropathy was seen in 6 pts (21%), including grade 2 with pain in 2 (both Ph 1 at doses above the MTD). Two pts discontinued due to AE; there were 5 pts who had serious drug-related AE (all Ph 1). Of 19 response-evaluable pts (Ph 1 + Ph 2), all achieved ≥PR, including 5 CR (1 sCR), 4 VGPR, and 10 PR; all remain in response with duration of confirmed response of up to 9.5 months. Of 4 response-evaluable Ph 2 pts, 1 has achieved VGPR and 3 PR to date. Conclusions: Oral MLN9708 plus lenalidomide and dexamethasone appears well tolerated with manageable toxicity. These data show antitumor activity at the RP2D in pts with previously untreated MM, with ≥PR in all pts to date.

Abstract Combination of carfilzomib with dexamethasone (Kd) is approved for use in relapsed and/or refractory multiple myeloma (RRMM), with carfilzomib administered twice weekly at 56 mg/m 2 (Kd56 BIW) or once weekly at 70 mg/m 2 (Kd70 QW). Post hoc cross‐trial comparisons were performed to compare efficacy and safety profiles of Kd70 QW vs Kd56 BIW dosing schedules using data from three trials of patients with RRMM: A.R.R.O.W., CHAMPION‐1, and ENDEAVOR. To select for comparable patient populations, side‐by‐side efficacy and safety comparisons were performed in subgroups of patients with 2‐3 prior lines of therapy who were not refractory to bortezomib. The overall response rate (ORR) was 69.9% (95% confidence interval [CI], 61.7‐77.2) for Kd70 QW and 72.4% (95% CI, 65.9‐78.2) for Kd56 BIW. Median progression‐free survival (PFS) was 12.1 months (95% CI, 8.4‐14.3) for Kd70 QW and 14.5 months (95% CI, 10.2—not evaluable) for Kd56 BIW. Frequency of grade ≥ 3 adverse events (AEs) was 67.6% for Kd70 QW and 85.3% for Kd56 BIW. Regression analyses (adjusting for prognostic factors) of all patients in the trials who received Kd70 QW vs Kd56 BIW estimated a PFS hazard ratio of 0.91 (95% CI, 0.69‐1.19; P = .47) and an ORR odds ratio of 1.12 (95% CI, 0.74‐1.69; P = .61). These results suggest that Kd70 QW has a comparable efficacy profile compared with Kd56 BIW and represents a convenient and well‐tolerated treatment for patients with RRMM.

Introduction: Chimeric antigen receptor (CAR) T cell therapy directed against B cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM) in several phase 1 studies. Persistence of CAR T cells post infusion may be one determinant of duration of response. bb21217 is a next-generation anti-BCMA CAR T cell therapy based on investigational therapy idecabtagene vicleucel (bb2121) (Friedman 2018, Hum Gene Ther 29:585) that uses the same lentiviral CAR T design as bb2121, but adds the phosphoinositide 3-kinase inhibitor bb007 during ex vivo culture to enrich the drug product for memory-like T cells. Evidence suggests that CAR T cells with this phenotype may be more persistent and more potent than unselected CAR T cells. CRB-402 is a first-in-human study of bb21217 in patients with RRMM designed to assess safety, pharmacokinetics, efficacy and duration of effect. Methods: CRB-402 (NCT03274219) is an ongoing, multi-center phase 1 dose escalation trial of bb21217 planning to enroll 74 patients with RRMM who received ≥ 3 prior regimens, including a proteasome inhibitor and an immuno-modulatory agent, or are double-refractory to both classes. During dose escalation, enrollment is restricted to patients with ≥ 50% BCMA expression by IHC on malignant plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis and sent to a central facility for transduction, expansion and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive bb21217 as a single infusion. Planned dose levels are 150, 450, 800, and 1,200 x 106 CAR+ T cells and intermediate dose levels are allowed. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures are quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria, evaluation of minimal residual disease (MRD), progression-free and overall survival, and quantification of CAR+ T cells in blood. Results: Asof April 20, 2019, 22 patients (median age 63 [min;max 42 to 74]) have received bb21217 (12 at 150, 6 at 300 and 4 at 450). Eleven had high tumor burden, defined as ≥ 50% bone marrow plasma cells pre-infusion. Patients had a median of 7 (min;max 4 to 17) prior lines of therapy and 18/22 had prior autologous stem cell transplant; 7/22 had high-risk cytogenetics. Of the 22 patients, 19 received prior daratumumab, 13 received prior Bort/Len/Car/Pom/Dara. Median follow-up after bb21217 infusion was 23 weeks (<1 to 77 weeks). As of data cut-off, 13/22 patients developed cytokine release syndrome (CRS; 5 G1, 7 G2, 1 G3) and responded to supportive care, tocilizumab and/or corticosteroids. Five patients developed neurotoxicity [1 G1, 2 G2, 1 G3 (vertigo/dizziness), 1 G4 (encephalopathy, previously reported)]. For the 1 patient with G4 neurotoxicity, G3 CRS was also reported; both have resolved. A total of 18 patients were evaluable for response with ≥ 2 months of follow up or PD within 2 months. Fifteen (83%) patients demonstrated clinical response per IMWG criteria. Six of these subjects subsequently progressed. Nine patients remained in response, including 2 patients with ongoing response at months 15 and 18. MRD negative results at 10-5 nucleated cells or better were obtained by NGS in 10/10 evaluable responders at month 1. Overall, 6/8 patients evaluable at 6 months and 2/2 patients evaluable at 12 months had detectable CAR T cells in blood. Updated data from this study will be presented, including extended follow-up on the initial patients treated and early clinical and CAR T cell persistence data from at least 15 additional patients treated with up to 450 x 106 CAR+ T cells. Conclusions: The adverse events observed to date were manageable and consistent with known toxicities of CAR T therapies. Initial efficacy results with bb21217 CAR T therapy in heavily pretreated RRMM are encouraging, with 83% of patients demonstrating clinical response. Emerging data demonstrate long-term persistence of CAR T cells in long-term responders. Updated data to be presented will help determine whether treatment with bb21217 results in sustained CAR T cell persistence and durable clinical responses, and whether bb21217 is tolerated at higher doses. Disclosures Berdeja: AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Alsina:Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau. Shah:Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb 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. Jagannath:Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Merck: Consultancy. Madduri:Abbvie: Consultancy; Celgene: Consultancy; Takeda: Consultancy; undation Medicine: Consultancy. Kaufman:Janssen: Honoraria; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Winship Cancer Institute of Emory University: Employment; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Celgene: Consultancy. Munshi:Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Celgene: Consultancy; Adaptive: Consultancy; Abbvie: Consultancy. Rosenblatt:BMS: Other: Advisory Board ; Parexel: Consultancy; Imaging Endpoint: Consultancy; Partner Tx: Other: Advisory Board; Dava Oncology: Other: Education; BMS: Research Funding; Amgen: Other: Advisory Board; Celgene: Research Funding; Merck: Other: Advisory Board. Turka:bluebird bio: Employment. Lam:bluebird bio: Employment. Massaro:bluebird bio: Employment. Campbell:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees. Petrocca:bluebird bio: Employment. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy.

Background: Maintenance therapy with lenalidomide post-autologous stem cell transplantation (ASCT) has shown to improve progression-free survival (PFS) in multiple myeloma (MM), and has largely become the standard of care. However, toxicity leads to early discontinuation in nearly one-third of patients and additional options are needed (McCarthy, et al, JCO, 2017). Ixazomib is another maintenance option that has been shown to improve PFS; however, studies comparing lenalidomide and ixazomib are lacking. In this randomized phase 2 study, we analyzed the safety and efficacy of using lenalidomide and ixazomib as part of consolidation and maintenance therapies after ASCT (NCT02253316). Methods: Eligible patients, age 18-70 with newly diagnosed MM undergoing ASCT during first-line treatment, were consented prior to ASCT. Approximately 4 months following ASCT, patients received 4 cycles of consolidation therapy with IRd [ixazomib 4 mg on days 1, 8 and 15 of a 28-day cycle, lenalidomide 15 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8 and 15]. Primary data on IRd consolidation were presented at ASH 2018 (Abstract 109920). One month after the last consolidation cycle, patients were randomized (1:1) to maintenance therapy with single-agent ixazomib (4 mg on days 1, 8 and 15 of a 28-day cycle) or lenalidomide (10 mg daily months 1-3 followed by 15 mg for months 4+). The arms were stratified based on MRD-status post-consolidation. In total, 237 patients were enrolled from 10 US centers. This abstract coincides with planned interim analysis 3 which is the first comparison of ixazomib and lenalidomide maintenance. While the study was not powered to compare PFS between the two arms, the sample will provide a reasonable power to estimate non-inferiority. There is a planned stopping rule for non-inferiority set at a hazard ratio of >1.3 in favor of lenalidomide. Secondary end-points include MRD-negativity following 12 cycles and toxicity. Results: At time of abstract submission, 215 patients had completed IRd consolidation and 191 had begun maintenance. 90 were randomized to ixazomib and 94 to lenalidomide. 7 patients were not randomized due to toxicity during consolidation; data from these patients are not included in the analyses. The characteristics of the two arms are summarized in Table 1. Hematologic toxicity has been infrequent with ixazomib with neutropenia and thrombocytopenia occurring in 11% and 23% of patients. In comparison, neutropenia and thrombocytopenia occurred in 45% and 35% of patients on lenalidomide. The most common non-hematologic toxicities in both arms have been GI-related and infections, both expected events. 16% of patients on ixazomib have experienced Grade 3-4 non-hematologic toxicity compared to 34% on lenalidomide. No grade 3 or higher peripheral neuropathy has been reported in either arm. 11% of patients on ixazomib have discontinued due to toxicity and another 9% have required a dose reduction to 3mg. Lenalidomide toxicity has led to discontinuation in 15% of patients and another 12% were dose reduced to 5mg. Only 45% of patients receiving 4+ cycles of lenalidomide were able to titrate to the 15mg dose. After a median follow-up of 11.2 months from randomization (19.7 months post-ASCT), 30% of patients on ixazomib have discontinued treatment due to disease progression. After a median follow-up of 12.3 months from randomization (20.2 months post-ASCT), 18% patients on lenalidomide have discontinued treatment due to disease progression. Conclusion: Ixazomib and lenalidomide maintenance have been well tolerated to date. A comparison of PFS is currently being conducted as part of interim analysis 3 and final results will be presented, representing the first report directly comparing lenalidomide and ixazomib maintenance. Table 1: Disclosures Vij: Genentech: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria; Sanofi: Honoraria. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Fiala:Incyte: Research Funding. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Kaufman:Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Janssen: Honoraria; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Takeda: Consultancy. Hofmeister:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Berdeja:AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, 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, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding; Oncoceutics: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosko:Vyxeos: Other: Travel support.

Abstract Background: Guadecitabine SC (SGI-110) is a dinucleotide next generation HMA resistant to degradation by cytidine deaminase resulting in extended in vivo exposure to its active metabolite decitabine. A Phase 1 established 60 mg/m2 QDx5 as the biologically effective dose (BED), and 90 mg/m2 QDx5 as the Maximum tolerated dose (MTD) in MDS patients given in 28-day cycles (Issa et al, 2015, Lancet Oncology). Phase 2 is conducted to evaluate dose response between the BED and MTD in both untreated MDS patients, and patients previously treated with other HMAs. M ethods: Int, or HR MDS, and CMML patients who were either treatment-naïve (TN) or relapsed/refractory to other HMAs (r/r) were randomized to either 60 mg/m2 or 90 mg/m2 QDx5 every 28 days. Efficacy was evaluated by the clinical responses of CR, PR, marrow CR (mCR), and Hematological Improvement (HI) based on the International Working Group Criteria 2006, as well as transfusion-independence, and overall survival (OS). Adverse events (AEs) were graded by the CTCAE v4 criteria. Results: The study completed target enrolment with 102 patients: 53 r/r MDS, and 49 TN MDS. Fifty three patients were randomized to 60 mg/m2 and 49 patients to 90 mg/m2 QDx5 with a median follow up of 3.2 years (IQR 2.8-3.5 years). Median age was 72 and 71 years for r/r and TN MDS respectively. Most baseline patient characteristics were well balanced between the 2 treatment dose groups except that more CMML patients were randomized to the 60 mg/m2 group (28%) vs. 14% in the 90 mg/m2 group, and more patients with baseline BM blasts >5% were in the 90 mg/m2 group (67%) vs. 38% in the 60 mg/m2 group. Most patients were RBC transfusion-dependent at baseline (57%). In the r/r MDS cohort, most patients (58%) received their last HMA treatment <3 month before enrolment, and most of them received ≥6 months of prior HMA treatment (77%). Median number of treatment cycles was 5 for both r/r and TN MDS (range 1-37 in r/r MDS and 1-49 in TN MDS). In the TN MDS cohort CR was achieved in 11 (22%) of patients with no major difference between the 2 dose groups (19% in the 60 mg/m2 group vs 27% in the 90 mg/m2 group). Overall CR+mCR was achieved in 18 patients (37%) in TN MDS patients and median OS was 23.4 months. In the r/r MDS cohort, CR was achieved in 4% of patients in each of the 2 dose groups. Overall CR+mCR in the r/r MDS cohort was achieved in 17 patients (32%), with a median duration of response of 7.9 months, and median OS of 11.7 months. No significant difference in response or OS between the 2 dose groups was observed. In patients who were RBC transfusion-dependent at baseline, transfusion independence for at least 8 weeks was achieved in 42% of TN MDS, and 15% in r/r MDS patients. In the overall population of 102 TN and r/r MDS patients there were no major differences in OS based on DNMT3A or TET2 mutation status while patients with TP53 mutations had worse median OS (7.4 months) compared to those without TP53 mutations (22.6 months). Other baseline prognostic factors for worse OS were BM blasts >5%; RBC transfusion-dependence; IPSS High Risk; and ECOG Performance Status of >1. Overall incidence of Grade ≥3 AEs regardless of relationship to treatment was reported in 83 vs. 96% for 60 and 90 mg/m2 dose groups respectively. There was a slightly higher but non-significant difference in Grade ≥3 thrombocytopenia (57 vs 41.5%); neutropenia (51 vs 39.6%); febrile neutropenia (43% vs 32%); and pneumonia (32.7 vs. 26.4%) for the 90 mg/m2 compared to 60 mg/m2 dose group. Early 30, 60, and 90-day all-cause mortality was observed in 0, 3.7%, and 5.7% in the 60 mg/m2 dose group respectively; and in 2%, 4%, and 12% in the 90 mg/m2 dose group respectively. Conclusions: Guadecitabine at both dose groups is a well-tolerated novel HMA with clinical activity in the treatment of both TN and r/r Int and HR MDS, and CMML patients. In TN MDS patient CR rate of 22% and median OS of 23.4 months compare well with first generation HMA efficacy (Fenaux et al, 2009, Lancet Oncology). Activity in r/r MDS who previously failed prior HMAs is particularly promising (CR+mCR in 32% of patients with median duration of response and overall survival of almost 8 and 12 months respectively). A phase 3 trial (ASTRAL-3) of guadecitabine vs Physician Treatment Choice in r/r MDS and CMML patients previously treated with azacitidine or decitabine is actively enrolling (ClinicalTrials.gov ID: NCT02907359). Disclosures Ritchie: NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kropf:Celegene: Consultancy; Takeda: Consultancy. Daver:Pfizer: Consultancy; Sunesis: Consultancy; Pfizer: Research Funding; ImmunoGen: Consultancy; ARIAD: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Otsuka: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Alexion: Consultancy; Incyte: Consultancy; Karyopharm: Research Funding; BMS: Research Funding; Kiromic: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Yee:Celgene, Novartis, Otsuka: Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, GSK, Onconova, Genentech/Roche: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Griffiths:Alexion Inc.: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Celgene, Inc: Honoraria, Research Funding; Novartis, Inc.: Research Funding; Pfizer, Inc.: Research Funding. Podoltsev:Astex Pharmaceuticals: Research Funding; LAM Therapeutics: Research Funding; Sunesis Pharmaceuticals: Research Funding; Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Daiichi Snakyo: Research Funding; Astellas Pharma: Research Funding; Pfizer: Research Funding; Celator: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Berdeja:Genentech: Research Funding; Bluebird: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Glenmark: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Teva: Research Funding; Sanofi: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Roboz:Orsenix: Consultancy; Roche/Genentech: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Celltrion: Consultancy; Bayer: Consultancy; Orsenix: Consultancy; Pfizer: Consultancy; Astex Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Sandoz: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Janssen Pharmaceuticals: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Celgene Corporation: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Argenx: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Aphivena Therapeutics: Consultancy; AbbVie: Consultancy; Aphivena Therapeutics: Consultancy; AbbVie: Consultancy; Cellectis: Research Funding.

Abstract Background: Maintenance therapy post-autologous stem cell transplantation (ASCT) has shown to improve progression-free and overall survival in multiple myeloma (MM) and has largely become the standard of care. Consolidation therapy, a brief duration of more-intensive chemotherapy administered prior to maintenance, has been shown to further deepen responses and may improve long-term outcomes. Ixazomib, lenalidomide and dexamethasone (IRd) is an all oral regimen that has been shown to be active in newly diagnosed MM as well as relapsed disease. In this study, we are analyzing the safety and efficacy of IRd as consolidation therapy after ASCT (NCT02253316). Methods: Eligible patients, age 18-70 with newly diagnosed MM undergoing ASCT during first-line treatment, are being consented prior to ASCT. Approximately 4 months following ASCT, patients receive 4 cycles of consolidation therapy with IRd [ixazomib 4 mg on days 1, 8 and 15 of a 28-day cycle, lenalidomide 15 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8 and 15]. The primary end point is minimal residual disease (MRD) status. MRD is being assessed by ClonoSEQ where possible and by multi-color flow where not. Toxicity, IMWG response rate, PFS, and OS are secondary end points. One month after the last consolidation cycle, patients are randomized (1:1) to maintenance therapy with single-agent ixazomib (4 mg on days 1, 8 and 15) or lenalidomide (15 mg daily). In total, 240 patients will be enrolled on the trial. This presentation coincides with planned interim analysis 2 which included data from the consolidation phase only. Results: As of July 2018, 172 patients with NDMM have been enrolled from 10 centers within the US. The median age was 57 (range 28-70) and 67% were male. 76% were white, 10% African-American/Black, and 13% were another race. 39% were ISS Stage I, 30% were Stage II, and 20% were Stage III. All patients received proteasome inhibitors and/or IMIDs as front-line induction and melphalan as conditioning for ASCT. IRd consolidation started at a median of 110 days post-ASCT (range 80-138). IRd has been well tolerated. Only 4% (6/154) of patients have been unable to complete the 4 cycles of consolidation to date due to toxicity. Grade 3 hematologic toxicity has been uncommon; 4% neutropenia, 3% thrombocytopenia, and 2% anemia. There has been no grade 4 hematologic toxicity. Non-hematologic grade 3-4 toxicities have included: infection (8%), nausea/vomiting/diarrhea (3%), and transaminitis (1%). No grade 3-4 peripheral neuropathy has been reported. One case of grade 5 pneumonia was reported but was not considered related to study treatment. Following ASCT, the MRD-negative rate was 26% and this improved to 37% following consolidation. In the subset of patients with Clonoseq results available, the MRD negative rate improved from 19% to 27%. Clinical response rate improved similarly; prior to consolidation the VGPR or better rate was 76% including 39% CR/sCR. Following consolidation, the VGPR or better rate was 85% including 56% CR/sCR. 137 patients went on to receive maintenance with either ixazomib (n = 71) or lenalidomide (n = 66). At time of submission, the median follow-up from start of IRd is 14 months and 28 patients have relapsed/progressed and 6 have expired. An interim analysis is planned for 2019, representing the first comparison of ixazomib and lenalidomide maintenance. Conclusion: IRd consolidation following ASCT appears to be safe and effective. The all oral regimen is convenient for patients which greatly simplifies follow-up in the peri-transplant period. Study enrollment is scheduled to complete in Q1 of 2019. Disclosures Vij: Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees. Martin:Amgen: Research Funding; Sanofi: Research Funding; Roche: Consultancy. Deol:Kite Pharmaceuticals: Consultancy; Novartis: Consultancy. Kaufman:Janssen: Consultancy; Karyopharm: Other: data monitoring committee; BMS: Consultancy; Abbvie: Consultancy; Roche: Consultancy. Hofmeister:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Gregory:Poseida Therapeutics, Inc.: Research Funding. Berdeja:Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Bluebird: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; Novartis: Research Funding; Teva: Research Funding; Sanofi: Research Funding. Chari:Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; The Binding Site: Consultancy.

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