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What is this summary about? This article provides a short summary of 5-year results from the iNNOVATE trial. The original paper was published in the Journal of Clinical Oncology in October 2021. People with Waldenström's macroglobulinemia (WM) were randomly divided into two groups of 75 people each. One group received a combination treatment composed of two drugs, ibrutinib plus rituximab, and the other group took placebo (“sugar pill”) plus rituximab. Ibrutinib (also known by the brand name Imbruvica®) is a drug that reduces cancer cells' ability to multiply and survive. Ibrutinib is an FDA-approved drug for the treatment of WM. Rituximab is a drug that helps the immune system find and kill cancer cells. Participants in the trial were treated and their health monitored for up to 5 years (63 months). What were the results? During the 5 years of monitoring, more people who took ibrutinib plus rituximab experienced an improvement in their disease and lived longer without their disease getting worse compared to those who took placebo plus rituximab. Side effects from ibrutinib and rituximab were manageable and generally decreased over time. Participants in both study groups reported improvements in quality of life, but those who took ibrutinib plus rituximab reported significantly greater improvement in their quality of life (as measured by FACT-An score) compared to those who took placebo plus rituximab. What do the results mean? These results show that ibrutinib plus rituximab is better than rituximab alone in people with WM and that ibrutinib plus rituximab is safe and effective in the long term. This information confirms the role of ibrutinib plus rituximab as a standard of care for WM. Clinical Trial Registration: NCT02165397 ( ClinicalTrials.gov )

The maximum tolerated dose of the panobinostat and carfilzomib combination in patients with relapsed/refractory multiple myeloma (RRMM) was not reached in our previous dose-escalation study. We report additional dose levels in the phase I/II, single-arm, multicenter, standard 3+3 dose-escalation expansion-cohort study (NCT01496118). Patients with RRMM were treated with panobinostat 30 mg, carfilzomib 20/56 mg/m2 (N = 3), or panobinostat 20 mg, carfilzomib 20/56 mg/m2 (N = 33). Treatment cycles lasted 28 days; panobinostat: days 1, 3, 5, 15, 17, 19; carfilzomib: days 1, 2, 8, 9, 15, 16. For dose level 6 (DL 6), median age was 63 years (range, 49-91 years), 60.6% were male, 42.4% were high risk. Patients received a median of two prior therapies (range 1-7); proteasome inhibitors (PI; 100%), immunomodulatory imide drugs (IMiD; 78.8%), and stem cell transplant (36.4%); 48.5%, 51.1% , and 24.2% were refractory to prior PI or prior IMiD treatment or both, respectively. Patients completed a median of seven (range 1-40) treatment cycles. Overall response rate (primary endpoint) of evaluable patients in the expansion cohort (N = 32): 84.4%; clinical benefit rate: 90.6%. With a median follow-up of 26.1 months (range, 0-72.5 months), median (95% CI) progression-free survival, time-to-progression and overall survival of patients was 10.3 (6.1, 13.9), 11.7 (5.6, 14.5), and 44.6 (20.8, N/A) months, respectively. Common adverse events (AEs) included thrombocytopenia (78.8%), nausea (63.6%), fatigue (63.6%), diarrhea (51.5%), and vomiting (51.5%). Seven patients had serious treatment-related AEs. There was one treatment-related death. In conclusion, panobinostat plus carfilzomib is an effective steroid-sparing regimen for RRMM. This article is protected by copyright. All rights reserved.

Introduction: CFT7455 is a highly potent and novel Ikaros Family Zinc Finger Protein 1/3 (IKZF1/3) degrader. In xenograft models, CFT7455 has more potent IKZF1/3 degradation compared to other degraders. Early observations from the FIH clinical trial (NCT04756726) along with supporting translational studies are presented here. Methods: Pre-clinical studies comparing CFT7455 and CC-92480 in both in vitro and xenograft models were performed. The pre-clinical studies’ results coincided with observations from the on-going clinical trial. The clinical trial is an open-label, Phase 1/2, multi-center, FIH study in heavily pretreated relapsed/refractory (R/R) MM and non-Hodgkin’s lymphoma (NHL) patients evaluating safety, tolerability, and PK of CFT7455. Eligible MM patients are R/R to therapy and are not candidates for regimens known to provide clinical benefit. A starting dose of 50 μg QD 21 days on/7 days off (21/7) in 28-day cycles was administered. Results: CFT7455 and CC-92480 showed similar cereblon binding profiles and in vitro IKZF1/3 degradation kinetics, translating into sub-nanomolar GI50 values in proliferation assays across a panel of MM cell lines. In the NCI-H929 xenograft model, 100 μg/kg/day of CFT7455 resulted in durable tumor regressions, while 1000 μg/kg/day of CC-92480 gave tumor stasis. Similar results were seen in a systemic model of MM, MM1.S. Both compounds achieved >95% IKZF3 degradation in tumors 4h post dose. At 48h post dose, CFT7455 was more effective than CC-92480 in maintaining IKZF3 degradation (65% vs. 6% respectively). When levels of CFT7455 and CC-92480 in plasma and tumor were compared, CFT7455 concentrations were > DC80 in tumor 48h post dose, while CC-92480 levels were undetectable in tumor and plasma, demonstrating CFT7455 has longer exposure resulting in sustained IKZF1/3 degradation in pre-clinical models. In cohort A, 5 heavily pre-treated MM patients (pts) received single agent CFT7455. 4 pts have received at least 3 cycles, with 2 pts receiving 5 cycles. Neutropenia (grade 4) was observed in 3/5 pts without coincident fever or infection. Additionally, a 2-4 fold accumulation in plasma CFT7455 exposure at steady state was observed. Early pharmacodynamic (PD) data demonstrates deep persistent degradation of IKZF3 (~100%) and serum free light chain reduction (up to 72%) in response to treatment. Stable disease has been observed in 34 pts, suggesting clinical benefit. Conclusions: While CFT7455 showed clinical benefit at 50 ug with deep target degradation, neutropenia was dose limiting. PK/PD modeling suggests alternative dosing regimens may result in increased tolerability with preserved efficacy, and evaluation of them is underway. Updated results will be presented at the meeting. Citation Format: Sagar Lonial, Shambavi Richard, Jeffrey V Matous, Andrew J. Yee, Urvi Shah, Neha Mehta-Shah, Thomas Martin, Eli Muchtar, Sikander Ailawadhi, Paul G. Richardson, Manisha Bhutani, Samantha Perino, Jason Kirby, Roman V. Agafonov, Prasoon Chaturvedi, Bradley Class, Matthew Schnaderbeck, Michael R. Palmer, Cathleen Gorman, Oliver Schoenborn-Kellenberger, Amanda Hoerres, Stewart L. Fisher, Roy M. Pollock, Adam Crystal, Michelle Mahler, Jesus Bardeja. Pharmacokinetic (PK) profile of a novel IKZF1/3 degrader, CFT7455, enables significant potency advantage over other IKZF1/3 degraders in models of multiple myeloma (MM) and the results of the initial treatment cohort from a first-in-human (FIH) phase 1/2 study of CFT7455 in MM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT186.

e19047 Background: Human Leukocyte Antigen (HLA) typing is a necessary but expensive process to identify suitable donors for allogeneic hematopoietic cell transplantation (HCT) for the treatment of bone marrow disorders and hematologic malignancies. The likelihood of a patient and sibling being fully HLA matched is 25%. An HLA-identical related donor remains the preferred source among HCT recipients due to superior outcomes when compared to unrelated, mismatched, haploidentical, or cord blood. Because of the high probability of finding an HLA matched donor among siblings, and the benefit of quick access to these donors, it had been standard procedure at our institute to test all siblings to identify potential matches. The estimated costs of HLA typing alone is approximately $300-$1000 and is contingent upon the lab utilized and resolution of typing. The costs of HLA typing, additional testing, and screening are significant to patients and health care systems. Methods: Our institution initiated a protocol to assess potential sibling donors prior to HLA typing as per the donor eligibility guidelines of the National Marrow Donor Program (NMDP). From 2018-2020 each sibling was given a questionnaire prior to HLA typing and screened for suitability. If a sibling was determined to be ineligible for donation based on the NMDP guidelines, HLA typing and work up for that sibling was not pursued. Results: Between 2018 and 2020 we identified 789 potential donors for HCT. All potential donors were sent eligibility questionnaires. Based on this screening, 568 potential donors were found to be eligible for donation whereas 221 were ineligible. HLA typing was pursued in all eligible donors. This resulted in and estimated cost savings of $66,000-$221,000 in HLA typing alone. This translated into a substantial health care cost savings for our institution as compared to our prior policy of typing all siblings. Conclusions: Identification and work up for potential HLA matched siblings is critical for identifying optimal donors for HCT. Our previous policy of universal sibling screening was found to be costly due to typing individuals who later were found to be ineligible to donate. We found that the initiation of a simple donor screening protocol that excluded ineligible sibling donors resulted in significant cost savings compared to our prior policy of HLA typing all potential sibling donors. Cost savings are a relevant consideration in all aspects of healthcare and this screening tool could be a practical component of the best practice guidelines for HLA matching and HCT.

Background: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoproliferative disorder characterized by expansion of clonal IgM-secreting cells (Advani P, et al. Hematol Oncol Stem Cell Ther. 2019;12:179-188). While ibrutinib is the only Bruton tyrosine kinase inhibitor (BTKi) currently approved by the US FDA and EMA for WM, other BTKi's are currently under investigation. More than 90% of patients with WM have somatic mutations in MYD88, and 30%-40% of these patients have activating mutations in CXCR4WHIM (Xu L, et al. Br J Haematol. 2016;172:735-744; Treon SP, et al. Blood. 2014;123:2791-2796). CXCR4WHIM in WM is associated with high serum IgM level, symptomatic hyperviscosity, earlier time to treatment, and inferior response to approved and investigational BTKi (Schmidt J, et al. Br J Haematol. 2015;169:795-803;Tam C, et al. Blood. 2020; 136:2038-2050). Inhibition of CXCR4 can sensitize CXCR4WHIM-expressing cells to ibrutinib (Cao Y, et al. Leukemia. 2015;29:169-176). Mavorixafor is an oral small-molecule antagonist of CXCR4. In vitro data have shown that mavorixafor inhibits CXCL12 binding and extracellular signal regulated kinase hyperactivation for CXCR4 mutations. Aims: To report on an early assessment of the safety and clinical response of mavorixafor in combination with ibrutinib after ≥6 months (6 cycles) of treatment in patients with MYD88 and CXCR4WHIM WM. Methods: This is an ongoing phase 1b, open-label, multicenter, single-arm study (NCT04274738) examining intrapatient dose escalation, safety, pharmacokinetics (PK), and pharmacodynamics of mavorixafor in combination with ibrutinib (target N=18). Eligibility includes age ≥18 years, clinicopathological WM diagnosis, consensus criteria indication for treatment, measurable disease, 0-3 prior therapies, and confirmed MYD88 and CXCR4WHIM mutations. Patients are initiated on mavorixafor 200 mg (low-dose) and ibrutinib 420 mg, both oral and once-daily. Mavorixafor escalation to 400 mg (mid-dose) occurs after 28 days if no dose-limiting toxicities (DLTs) are observed and to 600 mg (high-dose) after 400 mg is deemed safe ( Results: At data cutoff of June 15, 2021, 10 patients have enrolled, with 9 dosed and 9 continuing on study. Both 200-mg and 400-mg mavorixafor doses in combination with ibrutinib were deemed safe. Dosing at 600 mg is ongoing. Median duration of treatment was 198 days. A total of 107 AEs were observed (79% grade 1). Of 92 AEs with complete assessment for causal relationship to study drugs, 9 were deemed related to mavorixafor only, 13 to ibrutinib only, and 18 to the combination. One DLT was observed, consisting of grade 3 hypertension attributed to combination therapy. Two grade 2 AEs attributed to mavorixafor only led to drug interruption (7-8 days). Overall response rate for evaluable patients (minor response or better) was 100% (N=8). Four of 8 patients achieved major response; 1 of 8 patients achieved very good partial response. All 9 patients showed decrease in serum IgM while on treatment, with IgM levels normalizing in 1 patient after 4 months' treatment. For all patients treated for ≥6 months (N=7), median absolute serum IgM level decreased to 31.04 g/L at 6 months from pretreatment level of 46.23 g/L . Mean Hgb increased by >20 g/L, with Hgb approaching normal levels in these 7 patients. Mavorixafor and ibrutinib exposures were consistent with previous reports (de Jong J, et al. Cancer Chemother Pharmacol. 2015;75(5):907-916), and combination treatment increased peripheral lymphocytes, neutrophils, and monocytes in all 9 patients. Conclusion: Our findings as of June 2021 in patients with WM carrying both MYD88 and CXCR4WHIM mutations show that mavorixafor in combination with ibrutinib is well tolerated. Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, suggesting no drug-drug interactions, and mavorixafor exposures tracked with increases in key WBC counts. All evaluable patients demonstrated at least a minor response. Combination of mavorixafor with ibrutinib led to rapid, clinically meaningful, and durable decrease in IgM levels and increase in Hgb levels. These ongoing studies support the feasibility of combining ibrutinib with mavorixafor to improve responses in MYD88 CXCR4WHIM WM. Disclosures Treon: BMS: Consultancy, Research Funding; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; Pharmacyclics: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; Janssen: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; X4: Research Funding. Buske: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding. Thomas: Genentech: Research Funding; X4 Pharma: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Ascentage Pharma: Research Funding. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Branagan: CSL Behring: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dimopoulos: BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Amgen: Honoraria. Gavriatopoulou: Genesis: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; GSK: Honoraria. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Garzon: X4 Pharmaceuticals: Consultancy. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Seyffert: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Garg: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ali: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chen: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Matous: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Introduction : Daratumumab (Dara) is an anti-CD38 monoclonal antibody that is approved for use in patients with newly diagnosed and relapsed multiple myeloma (MM). We hypothesized that early therapeutic intervention with Dara in patients with high-risk MGUS (HR-MGUS) or low-risk SMM (LR-SMM) would lead to eradication of the tumor clone by achieving deep responses, resulting in prevention of progression to MM. We present results of our phase II, single arm study of Dara in HR-MGUS and LR-SMM. Methods : Patients enrolled on this study met eligibility for either HR-MGUS or LR-SMM. HR-MGUS is defined as 1.65, M protein ≥ 1.5g/dL or non-IgG M protein. LR-SMM is defined by one of the following 3 criteria: M protein ≥3g/dL, ≥10% bone marrow plasma cells, SFLC ratio 8. Dara (16mg/kg) was administered intravenously on a weekly schedule for cycles 1-2, every other week cycles 3-6, and monthly during cycles 7-20. The primary objective of this study was to determine the proportion of patients who achieve very good partial response (VGPR) or greater after 20 cycles of Dara. Secondary objectives included duration of response, safety, and rates of minimal residual disease (MRD)-negativity in VGPR or greater patients. Correlative studies included assessing changes in immune microenvironment, evaluating clonal heterogeneity using deep sequencing, and determining association of genomic aberrations correlating with either response to therapy or progression of disease. Results : At the time of data cutoff, a total of 42 patients were enrolled on this study from 2018 to 2020 with participation of 5 sites. The median age for all patients at enrolment was 60 years (range 38 to 76), with 22 males (52.4%) and 20 females (47.6%). Majority of patients enrolled were classified as LR-SMM (n = 37, 88.1%) and the remaining 5 patients had HR-MGUS (11.9%). 41 patients have started treatment and are included in toxicity assessment, and 40 patients have at least completed 16 cycles (range 6-20). Grade 3 toxicities were rare and only experienced in 5/41 patients including diarrhea (n =1/41; 2%), flu like symptoms (n = 1/41; 2%), headache (n=1/41; 2%), and hypertension (n=2/41; 5%). Most common toxicities of any grade included fatigue (n = 24/41, 51%), cough (n = 19/41, 46%), nasal congestion (n = 18/41, 44%), headache (n = 14/41, 34%), hypertension (n = 11/41, 27%), nausea (n = 13/41, 32%), and leukopenia (n = 13/41, 32%). No patients have discontinued therapy due to toxicity. Minimal response or better was observed in 82.9% of patients (34/41) and PR or better was observed in 51.2% of patients (21/41). This included overall CR (n = 4, 9.8%), VGPR (n = 1, 2.4%), PR (n = 16, 39.0%), MR (n = 13, 31.7%), and SD (n = 7, 17.1%). In the 40 patients who completed at least 16 cycles, response rates were as follows: MR or better 85% (34/40), PR or better 52.5% (21/40) and VGPR or better 12.5% (5/40). Median time to VGPR was 7 months. Median overall survival and progression-free survival have not been reached and no patients have progressed to overt multiple myeloma while on study. Conclusion : Dara is very well tolerated among patients with HR-MGUS and LR-SMM with minimal toxicities. Responses are seen in majority of patients. Early therapeutic intervention in this precursor patient population appears promising but longer follow up is required to define the role of single agent Dara in preventing progression to MM, therefore avoiding more toxic interventions in this low-risk patient population. Disclosures Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Yee: GSK: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Zonder: Caelum Biosciences: Consultancy; Amgen: Consultancy; BMS: Consultancy, Research Funding; Intellia: Consultancy; Alnylam: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy. Rosenblatt: Attivare Therapeutics: Consultancy; Imaging Endpoints: Consultancy; Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Wolters Kluwer Health: Consultancy, Patents & Royalties. Mo: AbbVIE: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sperling: Adaptive: Consultancy. Richardson: Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

Background: Despite many treatment options, multiple myeloma (MM) remains largely incurable with poor outcomes among patients who progress after treatment with a protease inhibitor, immunomodulatory imide drugs (IMiDs), and/or an anti-CD38 antibody. Multiple targeted therapies have been developed for different subtypes of non-Hodgkin lymphoma (NHL); however, these therapies are typically not curative for patients with relapsed/refractory (R/R) disease. IMiDs are a standard of care for treatment of MM and have shown activity in some NHL subtypes. However, given that many patients treated with these agents frequently develop disease progression, an unmet need remains. CFT7455 is a next-generation IKZF1/3 degrader, which is more potent and catalytically active than other approved agents targeting the cereblon E3 ligase complex that degrade IKZF1/3. CFT7455 is orally bioavailable and selective for IKZF1 (Ikaros) and IKZF3 (Aiolos). Depletion of these targets from malignant B cells result in tumor cell death, and depletion from the tumor microenvironment results in T-cell activation. In i n vitro and in vivo models of MM and NHL, including anaplastic large cell lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma (MCL), CFT7455 demonstrated greater activity than other agents in similar classes. These results provided rationale for a first-in-human, phase 1 study to evaluate CFT7455. Study Design: This is an open-label, multicenter, phase 1 clinical trial with dose escalation and dose expansion phases. The dose escalation phase, beginning with a starting dose of 50 mcg daily, may include single-participant cohorts at initial dose levels, after which 3-6 patients are enrolled per cohort using a Bayesian logistic regression model. After initial exploration of single-agent CFT7455 in a mixed cohort of patients with R/R MM or select NHLs, dose escalation is split to perform dose determination in R/R MM separate NHL. Once a safe dose of CFT7455 in R/R MM is determined, the combination of CFT7455 with dexamethasone will be explored in R/R MM. CFT7455 is dosed orally in 28-day cycles, on a 21-day on, 7-day off schedule, until disease progression or intolerable toxicity. Expansion cohorts of single-agent CFT7455 and CFT7455 plus dexamethasone in R/R MM, and single-agent CFT7455 for peripheral T-cell lymphoma and MCL are planned. Primary objectives include: safety and tolerability, randomized phase 2 dose (RP2D)/maximum tolerated dose (MTD) of CFT7455, and estimation of antitumor activity of CFT7455. Secondary objectives include assessment of pharmacokinetics. Exploratory objectives include characterization of target engagement and IKZF1/3 degradation and assessing the immunomodulatory effects of CFT7455. For MM patients, key inclusion criteria include histologically/cytologically-confirmed MM that is R/R. Patients must not be candidates for regimens known to provide clinical benefit, defined as having received ≥3 prior anti-myeloma regimens including ≥2 consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 antibody. Key exclusion criteria include the presence of central nervous system malignancy, recent venous thromboembolism or inability to undergo its prophylaxis. Plasma cell leukemia is excluded. For NHL patients, key inclusion criteria include histologically/cytologically-confirmed NHL that is R/R. Patients mustn't be candidates for regimens known to provide clinical benefit, defined as the requisite prior lines of therapy according to an indication-specific basis. Key exclusion criteria include the presence of central nervous system malignancy, recent venous thromboembolism or inability to undergo its prophylaxis. Several lymphoma subtypes less likely to benefit are excluded (eg, Richter transformation, Burkitt lymphoma, Sezary syndrome, and lymphoblastic lymphoma). Approximately 164 patients at approximately 13 US sites will be enrolled. This trial is registered with clinicaltrials.gov as NCT04756726, enrollment is ongoing. Disclosures Berdeja: Legend Biotech: Consultancy; Incyte: Research Funding; Ichnos Sciences: Research Funding; Genentech: Research Funding; GlaxoSmithKline: Research Funding; Lilly: Research Funding; SecuraBio: Consultancy; EMD Serono: Research Funding; Janssen: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; Amgen: Research Funding; Astex Pharmaceuticals: Research Funding; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Celularity: Research Funding; Celgene: Consultancy, Research Funding; Poseida: Research Funding; Acetylon: Research Funding; Teva: Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Abbvie: Research Funding; Takeda: Consultancy. Ailawadhi: GSK: Consultancy, Research Funding; Sanofi: Consultancy; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Xencor: Research Funding; Beigene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy; Takeda: Consultancy; Genentech: Consultancy; Medimmune: Research Funding. Horwitz: Millennium /Takeda: Consultancy, Research Funding; Kura Oncology: Consultancy; Janssen: Consultancy; Tubulis: Consultancy; Myeloid Therapeutics: Consultancy; Affimed: Research Funding; Aileron: Research Funding; Vividion Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Celgene: Research Funding; Acrotech Biopharma: Consultancy; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Trillium Therapeutics: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; SecuraBio: Consultancy, Research Funding; Shoreline Biosciences, Inc.: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Verastem: Research Funding. Matous: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Mehta-Shah: C4 Therapeutics: Consultancy; Kiowa Hakko Kirin: Consultancy; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Verastem: Research Funding. Martin: GlaxoSmithKline: Consultancy; Sanofi: Research Funding; Oncopeptides: Consultancy; Amgen: Research Funding; Janssen: Research Funding. Richardson: Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Secura Bio: Consultancy; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Protocol Intelligence: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; AbbVie: Consultancy; Janssen: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Richard: Karyopharm, Janssen: Honoraria. Bhutani: Sanofi: Consultancy; Amgen, BMS, Takeda: Speakers Bureau; Janssen, MedImmune, Takeda, Celgene, BMS, Cerecor, Celularity: Research Funding. Yee: Takeda: Consultancy; Adaptive: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Oncopeptides: Consultancy; GSK: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Janssen: Consultancy. Palmer: C4 Therapeutics: Current Employment. Gorman: C4 Therapeutics: Current Employment. Schoenborn-Kellenberger: C4 Therapeutics: Current Employment. Bilic: C4 Therapeutics: Current Employment. Crystal: C4 Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mahler: C4 Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lonial: Merck: Honoraria; Abbvie: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding.

Background Lenalidomide (LEN) with or without a proteasome inhibitor (PI) administered until disease progression is a standard treatment (Tx) approach for patients (pts) with newly diagnosed multiple myeloma (MM). Clinical trials investigating triplet therapies included few pts whose disease was relapsed/refractory to LEN after early-line Tx. The phase 2 MM-014 trial (NCT01946477) was designed to investigate outcomes with pomalidomide (POM)-based therapy immediately after first- or second-line LEN-based Tx failure in pts with relapsed/refractory MM (RRMM). In cohort B (n=112) of this trial, POM + dexamethasone (DEX) + daratumumab (DARA) demonstrated promising efficacy and safety with an overall response rate (ORR) of 78% and median progression-free survival (PFS) of 30.8 mo. Efficacy and safety in a subgroup of pts in cohort B previously exposed to LEN+PI are reported. Methods Pts with RRMM (1–2 prior Tx lines), LEN-based Tx for ≥2 consecutive cycles as most recent regimen, and disease progression during/after last line of Tx received POM+DEX+DARA (28-d cycles) until disease progression. POM 4 mg/d was given orally (PO) on d1–21; DEX 40 mg/d (20 mg/d in pts aged >75 y) PO on d1, 8, 15, and 22; and DARA 16 mg/kg IV on d1, 8, 15, and 22 of cycles 1–2, d1 and 15 for cycles 3–6, and d1 for cycles 7+. The primary endpoint was ORR; secondary endpoints included PFS and safety. Results In cohort B, 89/112 pts (79%; median age, 65 y) received prior LEN+PI. In this subgroup, 67 pts (75%) had LEN-refractory MM and 22 (25%) had LEN-relapsed MM; most pts (52 [58%]) received 1 vs 2 (37 [42%]) prior Tx lines. Median duration of Tx with POM, DEX, and DARA was 15.9, 14.0, and 16.1 mo, respectively. At a median follow-up of 28.4 mo (data cutoff Mar 2020), the ORR was 79% (≥very good partial response [VGPR], 55%). The ORR was 81% (≥VGPR, 63%) and 76% (≥VGPR, 43%) in pts with 1 vs 2 prior lines of Tx, respectively. Median duration of response and median PFS were not yet reached (1-y PFS rate, 74%). Infusion-related reactions occurred in 28% of pts and were primarily low grade (Gr). Overall, 98% of pts had ≥1 Gr 3/4 Tx-emergent adverse event. The most common Gr 3/4 hematologic events were neutropenia (64%; febrile, 12%), anemia (19%), and thrombocytopenia (13%). Gr 3/4 infections occurred in 40% of pts, including 16% with pneumonia. Conclusion POM+DEX+DARA administered immediately after LEN failure in a subgroup of pts previously treated with LEN+PI demonstrated a high response rate and a safety profile consistent with that in the overall cohort B population. Results support the use of POM-based therapy, integrating the monoclonal antibody DARA, as early as second line in pts with RRMM, potentially immediately after LEN Tx failure. Furthermore, the data support subsequent Tx with the same immunomodulatory agent class in a pt population with LEN-relapsed or -refractory MM. Previous presentation Bahlis NJ, et al. HemaSphere 2021;5:e482–483. EP1019.

Background Allogeneic (off the shelf) chimeric antigen receptor (CAR) T cell therapy addresses the logistical challenges, availability and variable product quality of autologous CAR T therapy. ALLO-715 is a genetically modified anti-BCMA AlloCAR Ttm cell product in which the TCR alpha constant gene is disrupted to reduce the risk of graft-versus-host disease (GvHD) and the CD52 gene is disrupted with Talen® technology to permit the use of ALLO-647, an anti-CD52 mAb, for selective and prolonged host lymphodepletion (LD). Methods This is an open-label, Phase 1 trial (NCT04093596) in adults with R/R multiple myeloma who have received ≥3 prior lines of therapy including a proteasome inhibitor, immunomodulator, and anti-CD38 mAb. Patients (pts) must be refractory to their last treatment line. Patients receive LD followed by ALLO-715 at 1 of 4 dose levels (DL) in a 3+3 dose escalation design: 40, 160, 320, and 480 x 106 CAR+ T cells. Several LD regimens are being evaluated. These include: FCA (fludarabine (F) 90 mg/m2, cyclophosphamide (C) 900 mg/m2, and ALLO-647 (A) 39 mg divided over 3 days), FCA+ (same F and C but ALLO-647 (A+) dose of 90 mg divided over 3 days); as well as CA (same C and A divided over 3 days, but no F given). Results As of 08 July 2020, 19 pts had enrolled and 15 had received ALLO-715 at 3 DLs: 3 pts at DL1 (3 FCA and 0 CA); 7 pts at DL2 (4 FCA and 3 CA); 5 pts at DL3 (3 FCA and 2 CA). As of the data cutoff, no pts had received FCA+ or ALLO-715 DL4. Patients were heavily pre-treated and in advanced stage of disease with a median of 5 (range 3-11) prior lines of therapy and 31.6% ISS Stage III at screening. All but 1 had a prior autologous stem cell transplant. 52.6% (10/19) of patients had high risk cytogenetics, and 26.3% (5/19) had extramedullary disease. The most common Grade ≥3 adverse events were anemia (41.2%), neutropenia (41.2%), lymphopenia (29.4%), and thrombocytopenia (29.4%). Four episodes of Grade ≥3 infections occurred in 4 pts. Three of these were Grade 3 and included parvovirus B19, staphylococcal bacteremia, and pneumonia, which resolved with treatment. The fourth was a Grade 5 episode that occurred on day 8 post-ALLO-715 infusion in a rapidly progressing, refractory myeloma pt who, on day 1, developed a non-neutropenic fever and multifocal pneumonia with negative blood and sputum cultures. The patient progressed to respiratory failure and only comfort care was pursued. This death was considered related to conditioning (CA). No DLTs to ALLO-715 had been reported as of the data cutoff. In addition, no neurotoxicity (ICANS) or GvHD had been reported as of the data cutoff. Cytokine release syndrome was reported in 4 pts (24%). Three episodes were Grade 1 and 1 was Grade 2 (Lee Grading); all resolved without tocilizumab or corticosteroids. Fifteen pts were efficacy evaluable (defined as receiving ALLO-715, and undergoing at least one response assessment or discontinuing prior to the first response assessment), with a median follow-up of 2 months (range 0, 10 months). A higher dose of ALLO-715 (DL3) was associated with greater anti-cancer activity with 3/5 pts responding per IMWG (60%, 95% CI 14.7, 94.7). In pts who received DL3 FCA, 2/3 responded (1 sCR and 1 VGPR, Table 1). All DL3 pts who responded experienced at least a VGPR and achieved MRD negative status by local MRD testing. All responses were initially observed at day 14. Four (80%) out of the 5 responders were still in response at the time of the data cutoff. ALLO-715 cell expansion by qPCR was observed at all dose levels. Conclusions These early data suggest that ALLO-715 and ALLO-647 have a manageable safety profile. ALLO-715 shows evidence of clinical activity in the allogeneic setting in pts with R/R multiple myeloma and suggests that higher cell doses are associated with greater anti-cancer activity. Enrollment is ongoing in cohorts with higher ALLO-715 (480M CAR+ T-cells) and ALLO-647 (90mg). Updated safety, efficacy, PK/PD data will be presented. Clinical trial information: NCT04093596. Disclosures Mailankody: Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Matous:Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Sidana:Janssen: Consultancy. Nath:Actinium: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria. Oluwole:Bayer: Consultancy; Spectrum Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy. Karski:Crisper Therapeutics: Current equity holder in publicly-traded company; Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Nektar Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Lovelace:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhou:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Nandakumar:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Balakumaran:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Merck: Ended employment in the past 24 months. Hari:BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; GSK: Consultancy; Incyte Corporation: Consultancy.

PURPOSE Observation is the current standard of care for smoldering multiple myeloma. We hypothesized that early intervention with lenalidomide could delay progression to symptomatic multiple myeloma. METHODS We conducted a randomized trial that assessed the efficacy of single-agent lenalidomide compared with observation in patients with intermediate- or high-risk smoldering multiple myeloma. Lenalidomide was administered orally at a dose of 25 mg on days 1 to 21 of a 28-day cycle. The primary end point was progression-free survival, with disease progression requiring the development of end-organ damage attributable to multiple myeloma and biochemical progression. RESULTS One hundred eighty-two patients were randomly assigned—92 patients to the lenalidomide arm and 90 to the observation arm. Median follow-up is 35 months. Response to therapy was observed in 50% (95% CI, 39% to 61%) of patients in the lenalidomide arm, with no responses in the observation arm. Progression-free survival was significantly longer with lenalidomide compared with observation (hazard ratio, 0.28; 95% CI, 0.12 to 0.62; P = .002). One-, 2-, and 3-year progression-free survival was 98%, 93%, and 91% for the lenalidomide arm versus 89%, 76%, and 66% for the observation arm, respectively. Only six deaths have been reported, two in the lenalidomide arm versus four in the observation arm (hazard ratio for death, 0.46; 95% CI, 0.08 to 2.53). Grade 3 or 4 nonhematologic adverse events occurred in 25 patients (28%) on lenalidomide. CONCLUSION Early intervention with lenalidomide in smoldering multiple myeloma significantly delays progression to symptomatic multiple myeloma and the development of end-organ damage.

Duvelisib, a potent δ- and γ-PI3K inhibitor, is a potential therapeutic for hematologic malignancies. Rituximab and bendamustine have demonstrated activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Combining duvelisib with either rituximab alone or rituximab and bendamustine may improve response rates and remission durability. We conducted this Phase one study in relapsed/refractory NHL and CLL patients. During expansion, each arm enrolled to disease-specific cohorts to assess efficacy. Arm one received rituximab 375 mg/m2 IV weekly for two 4-week cycles plus duvelisib until progression/intolerance. Arm two received rituximab 375 mg/m2 IV Day one, bendamustine 90 mg/m2 IV (NHL patients) or 70 mg/m2 IV (CLL patients) Days one-two for six cycles, plus duvelisib until progression/intolerance. Duvelisib doses of 50 mg and 75 mg BID were tested during dose escalation. Forty-six patients (27 NHL, 19 CLL) were treated. The adverse events of the drug combinations were consistent with single agent toxicities. The most common AEs were neutropenia (47.7%), fatigue (41.3%), and rash (41.3%). A duvelisib expansion dose of 25 mg BID was chosen based on the monotherapy phase one study, IPI-145-02, which confirmed that dose for further clinical development. Overall response rate was 71.8%. Median progression-free survival was 13.7 months. Median overall survival has not been reached, but 30-month overall survival probability was 62%. Duvelisib combined with rituximab, or bendamustine and rituximab did not appear to increase toxicities beyond the known safety profile of the individual agents. Further study is needed to determine if these combinations improve efficacy.

We examined the combination of the mammalian target of rapamycin inhibitor everolimus with bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM) in a phase I/II study. All patients received six cycles of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab followed by maintenance with everolimus until progression. Forty-six patients were treated; 98% received prior rituximab and 57% received prior bortezomib. No dose-limiting toxicities were observed in the phase I. The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs. Of these 36, 2 (6%) had complete response (90% confidence interval (CI): 1-16). In all, 32/36 (89%) of patients experienced at least a minimal response (90% CI: 76-96%). The observed partial response or better response rate was 19/36 (53, 90 CI: 38-67%). For the 36 FDT patients, the median progression-free survival was 21 months (95% CI: 12-not estimable). In summary, this study demonstrates that the combination of everolimus, bortezomib and rituximab is well tolerated and achieved 89% response rate even in patients previously treated, making it a possible model of non-chemotherapeutic-based combination therapy in WM.

Introduction: Daratumumab (DARA) is an anti-CD38 monoclonal antibody that is approved for use in patients with newly diagnosed and relapsed multiple myeloma (MM). We hypothesized that early therapeutic intervention with DARA in patients with high-risk MGUS (HR-MGUS) or low-risk SMM (LR-SMM) would lead to eradication of the tumor clone by achieving deep responses, resulting in prevention of progression to MM. This is a single-arm, phase II study evaluating efficacy and safety of using DARA in patients with HR-MGUS and LR-SMM. Methods: Patients enrolled on this study met eligibility for either: 1) HR-MGUS defined as 1.65, M protein ≥ 1.5g/dL or non-IgG M protein or 2) LR-SMM with one of the following 3 criteria: M protein ≥3g/dL, ≥10% bone marrow plasma cells, SFLC ratio 8. DARA (16mg/kg) was administered intravenously on a weekly schedule for cycles 1-2, every other week cycles 3-6, and monthly during cycles 7-20. The primary objective of this study was to determine proportion of patients who are in VGPR or greater after 20 cycles of DARA. Secondary objectives included duration of response, safety, and rates of MRD negativity in VGPR or greater patients. Correlative studies included assessing changes in immune microenvironment, evaluating clonal heterogeneity using deep sequencing, and determining association of genomic aberrations correlating with either response to therapy or progression of disease. Results: A total of 31 patients were enrolled on this study from January 2018 to June 2019 with participation of five sites. The median age for all patients enrolled was 59 years (range 41 to 76), with 16 males (52%) and 15 females (48%). Majority of patients enrolled were classified as LR-SMM (n = 29; 94%) and the remaining 2 patients had HR-MGUS (6%). Twenty-eight patients have started treatment and are included in toxicity assessment and 15 patients have at least completed cycle 6 (range 1-19). Grade 3 toxicities were rare and only experienced in 2/28 patients including diarrhea (n =1) and flu like symptoms (n = 1). Most common toxicities of any grade included fatigue (n = 13/28, 46%), cough (n = 11/28, 39%), nasal congestion (n = 10/28, 36%), headache (n = 8/28, 29%), hypertension (n = 8/28, 29%), nausea (n = 8/28, 29%), and white blood cell decreased (n = 8/28, 29%). All patients remain on treatment and none have discontinued therapy due to toxicity. Best overall responses were CR (n = 1, 3%), VGPR (n = 3, 11%), PR (n = 9, 32%, 2 unconfirmed), MR (n = 10, 36%), SD (n = 5, 18%, 1 unconfirmed), PD (n = 0, 0%), and NE (n = 1, 4%). Minimal response or better was observed in 82% of patients (23/28) and PR or better was observed in 46% of patients (13/28). In the 15 patients who completed at least 6 cycles, response rates were as follows: MR or better 93% (14/15), PR or better 73% (11/15) and VGPR or better 20% (3/15). Median time to VGPR was 3.2 months. Median overall survival and progression-free survival have not been reached. Thus far, no patients have progressed to MM. Conclusion: DARA is very well tolerated among patients with HR-MGUS and LR-SMM. Responses are seen in majority of patients and there has been no observed progression to MM to date. Early therapeutic intervention in this precursor patient population appears promising. Disclosures Nadeem: Celgene: Honoraria; Janssen: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Yee:Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy. Zonder:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rosenblatt:Partner Tx: Other: Advisory Board; Dava Oncology: Other: Education; Celgene: Research Funding; BMS: Research Funding; Parexel: Consultancy; Merck: Other: Advisory Board; BMS: Other: Advisory Board ; Amgen: Other: Advisory Board; Imaging Endpoint: Consultancy. Bustoros, MD:Takeda: Honoraria. Prescott:Janssen: Equity Ownership. Castillo:Abbvie: Research Funding; Janssen: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding. Munshi:Abbvie: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Oncopep: Consultancy; Takeda: Consultancy; Adaptive: Consultancy. Anderson:Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: 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, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Ghobrial:Janssen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Amgen: Consultancy; BMS: Consultancy; Sanofi: Consultancy. OffLabel Disclosure: Daratumumab has not been approved by the US Food and Drug Administration or any other regulatory agency worldwide for the uses under investigation.

Background: The introduction of novel agents such as proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs) with and without corticosteroids has revolutionized treatment (tx) and improved survival rates for MM. IMID/PI triplets such as VRD (bortezomib, lenalidomide, dexamethasone), VTD (bortezomib, thalidomide, dexamethasone), or KRD (carfilzomib, lenalidomide, dexamethasone) are preferred inductions for transplant-eligible patients (pts). Unfortunately, the PI often has unique safety events such as peripheral neuropathy (PN) or cardiac issues that can impact the quality of life. Elotuzumab is a mAb with a dual mechanism of action (tagging MM cells and activating NK cells by binding SLAMF7). The combination of elotuzumab, lenalidomide, and dexamethasone (ERd), is active, well-tolerated, and approved by the FDA for pts with relapsed MM. In this study, we will determine the feasibility of incorporating ERd into a transplant-eligible pt population. Methods: Pts with newly diagnosed MM requiring chemotherapy planning to undergo autologous stem cell transplantation (ASCT) were enrolled. Induction of elotuzumab at 10 mg/kg was administered IV on days (D) 1, 8, 15, 22 of the 1st 2 28-day cycles and days 1, 15 of the third and fourth 28-day cycles. Lenalidomide was dosed at 25 mg orally on D 1-21 of each 28 day induction cycle. Dexamethasone was administered IV concurrent with elotuzumab (28mg orally 3-24 hours prior to infusion and 8 mg IV with elotuzumab), with 40 mg orally administered on D 8 and 22 of cycles 3 and 4. After completion of the 4 induction cycles, pts proceeded to mobilization and ASCT though pts who refused transplantation were allowed to proceed directly to consolidation and maintenance if the investigator believed the pt was deriving benefit. 70-120 days after ASCT, 4 cycles of consolidation were administered (dosing similar to cycles 3-4 of induction but with lenalidomide at 15mg). Pts then went on to maintenance with elotuzumab 20 mg/kg IV on D 1, oral lenalidomide 10mg +/- 5 mg D 1-21 and dexamethasone 28mg oral/8 mg IV prior to elotuzumab infusion were dosed in 28-day cycles for up to 24 months. The primary endpoint was the induction feasibility rate (IFR) defined as the percentage of pts successfully completing 4 cycles of induction tx with ERd and able to start ASCT. Secondary end points were complete response rate (≥nCR), overall response rate (≥PR), progression-free survival (PFS) and overall survival (OS). AEs were assessed according to CTCAE V4 and responses were assessed using the revised IMWG criteria. Results: 52 pts were enrolled: 56% male, median age 61 ys, 12% RISS III, 21% high-risk cytogenetics [17p del, t(4;14), and/or t(14;16)]. To date, 26 (50%) pts remain on active tx. 4 pts refused transplantation despite being eligible and were excluded from the IFR calculation. The IFR was 69% and the best overall response rate (ORR) was 92% (69% ≥ VGPR). With a median follow up of 20 mos, median PFS and OS for all pts were not reached. The 18 mo PFS and OS were 83% and 89% respectively. The most common AEs were fatigue (59.6%), diarrhea (42.3%) and nausea (42.3%). PN was seen in 29%, and all events were ≤ G2. There were 28 SAEs in 20 pts, including 12 tx-related SAEs. There was 1 tx-related death due to heart failure in a pt with no history of prior cardiac issues who had subsequent therapy. 29% of pts met the high-risk (HR) criteria (defined as RISS III or high risk cytogenetics) and 29% of pts were considered standard-risk (RISS I and no high-risk cytogenetics). The best ORR was 87% (67% ≥ VGPR) for HR pts and 93% (53% ≥ VGPR) for SR pts and the IFR was 57% for HR pts and 64% for SR pts. The median PFS and OS were 20.5 mos and 22.0 mos respectively for HR pts and have not been reached for SR pts. Conclusions: ERd induction, consolidation and maintenance was feasible and well tolerated in conjunction with ASCT in transplant-eligible pts. Despite high ORR for all pts, HR patients had inferior PFS and OS. This study supports the continued evaluation of this regimen in SR pts. Disclosures Berdeja: Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; Poseida: Research Funding; 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. Gregory:Takeda: Speakers Bureau; Celgene: Speakers Bureau; Poseida: Research Funding; Amgen: Speakers Bureau. OffLabel Disclosure: Yes, this was an investigational clinical study of the combination of elotuzumab, lenalidomide, and dexamethasone in the induction, consolidation, and maintenance treatment of transplant-eligible patients newly diagnosed with multiple myeloma.

Background This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, Lenalidomide, and Dexamethasone in patients with high-risk smoldering multiple myeloma (SMM). ClinicalTrials.gov Identifier: NCT02279394. Aims The overarching objective of this trial is to determine progression free survival to symptomatic multiple myeloma (MM). Furthermore, the study examined whether genomic studies can help in determining patients who would benefit the most from this early therapeutic intervention. Methods Patients enrolled in this study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al, Blood 2014. Patients were administered weekly elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1-21. For cycles 3-8, patients were administered elotuzumab infusions on days 1, 8, and 15. dexamethasone (40mg) was given on days 1, 8 and 15 to 40 of the 50 enrolled patients. After 8 cycles or best response, patients were given the option to mobilize with either cyclophosphamide or plerixafor and collect stem cells for future transplant. Patients were then allowed to continue on maintenance therapy where they were administered elotuzumab (20 mg/kg) on day 1, in combination with lenalidomide days 1-21 of a 28-day cycle. Bone marrow (BM) samples of 32 patients were obtained before starting therapy for baseline assessment and whole exome sequencing (WES) of plasma cells. Results In total, 50 patients were enrolled on this study from January 2015 and completed accrual in December 2016, with the participation of eight sites. The median age of enrolled patients was 62 years (range, 29-79) with 18 males (36%) and 32 females (64%). Interphase fluorescence in situ hybridization (iFISH) detected high-risk cytogenetics (defined by the presence of 17p deletion, t(4;14), and 1q gain) in 20 patients. The median time to response was 2.8 months (range, 1.8-4.6). The most common toxicities were fatigue (92%), followed by diarrhea (72%), and hyperglycemia (62%). The most common grade 3 or more adverse events were hypophosphatemia (34%), neutropenia (26%), and lymphocyte count decreased (22%). Three patients (6%) had grade 4 hypophosphatemia during treatment. Additionally, grade 4 cholecystitis, cataract, lymphocyte count increase, hyperglycemia, neutropenia, and thrombocytopenia occurred in one patient (2%). Diabetic Ketoacidosis and sepsis led to death in a patient (2%). Stem cell collection was successful in all mobilized patients to date. As of this abstract date, the overall response rate is 84% (41/49). There were 3 complete responses (6%), 18 very good partial responses (37%), 20 partial responses (41%), 5 minimal responses (10%), 3 stable disease (6%), and 2 unevaluable patients. All the study participants except for three have finished treatment and are currently under follow up. None of the patients showed progression to overt MM to date. We continue to collect data for progression free survival. WES was performed on 32 samples at the time of initiation of therapy. Recurrent mutations in the MAPK pathway (KRAS, NRAS) and tumor suppressor gene, TP53, were detected in 40% of the cases (16% and 24%, respectively), while mutations in the NF-KB and plasma cell differentiation pathways were present in 13% of patients. Somatic copy number alterations (SCNAs) were called based on WES: 1q duplication, 13q, 17p, and 1p deletions were identified in 25, 31, 12, and 7% of cases, respectively. Interestingly, in 6 patients, high-risk SCNAs (1q gain and 17p deletion) were not reported in iFISH but were detected by WES. The analysis of these 32 samples showed that patients who are harboring mutations in the DNA repair pathway genes, had modest response to treatment. Finally, we are analyzing the transcriptomic profile of CD138 negative cells, which represent the BM microenvironment cells (immune and stromal cells) to characterize the BM microenvironment at baseline and end of treatment, and thus, elucidate the role of these cells in the differential response to therapy. Conclusion The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rate with no progression to overt MM to date. Correlation with genomic studies can help define patients who benefit the most from this early therapeutic intervention. Disclosures Ghobrial: Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy. Bustoros:Dava Oncology: Honoraria. Badros:GSK: Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Rosenblatt:Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Karyopharm: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Zonder:Celgene: Consultancy, Honoraria; Pharmacyclics: Other: DSMC; Janssen: Honoraria; Takeda: Honoraria; Alnylam: Honoraria; Coelum: Honoraria; BMS: Research Funding. Munshi:OncoPep: Other: Board of director. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; OncoPep: Equity Ownership, Other: Scientific founder; Millennium Takeda: Consultancy; Celgene: Consultancy. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Takeda: 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, Research Funding.

Background: Histone deacetylase inhibitors increase acetylation of proteins involved in multiple oncogenic pathways, including the aggresome protein degradation pathway (Blood 2006; 108:3441-9). Preclinical and clinical studies have shown synergism with the combination of proteasome inhibitors (PIs) and histone deacetylase inhibitors (HDACi) such as panobinostat.(PAN) (Cancer Lett 2009; 280:233-41; J Clin Oncol 2011; 29:8075) PAN was approved by the FDA in combination with bortezomib (BTZ) and dexamethasone based on the efficacy demonstrated in the PANORAMA1 trial (Lancet Oncol 2014;15:1195-206). We previously reported the combination of Carfilzomib (CFZ) and PAN in patients (pts) with relapsed and relapsed/refractory MM (Haematologica 2015;100:670-6). The maximum tolerated dose (MTD) of CFZ and PAN was never reached and we extended our original study to investigate higher dose levels. Here we present the final results of the second dose expansion (DL 6). Methods: Pts with MM who relapsed after ≥ 1 prior treatments (tx) were enrolled. PAN was administered orally on days 1, 3, 5, 15, 17, 19 of each 28-day cycle. CFZ was administered IV over 30 min on days 1, 2, 8, 9, 15, and 16. The initial dose escalation portion of the study used a standard 3+3 design to determine the maximum tolerated dose (MTD) of an initial 4 planned dose levels of the combination of CFZ and PAN. MTD was not reached and the maximum planned dose DL 4 (30 mg PAN and 20/45 mg/m2 CFZ) was expanded. The study was then revised to escalate to DL 5 (30 mg PAN plus 20/56 mg/m2 CFZ). Numerous PAN dose reductions resulted in a delivered PAN dose closer to 20 mg so DL 6 (PAN 20 mg and CFZ 20/56 mg/m2) was explored and eventually expanded. Tx continued until PD or intolerable toxicity. The primary efficacy endpoint was the overall response rate (ORR) (≥ PR). Secondary end points were time to progression (TTP), progression-free survival (PFS) and overall survival (OS), calculated using Kaplan-Meier methods. Adverse events (AEs) were assessed according to CTCAE V4 and responses were assessed using IMWG criteria (plus minimal responses (MRs) per the EBMT criteria). Results: Here we report the results of the second expansion cohort only (DL 6 (PAN 20 mg and CFZ 20/56 mg/m2). 33 pts were enrolled (61% male, median age 63 (range 49-91), 67% poor risk, 100% exposed to prior PIs, and a median of 2 prior therapies (range 1-7). 48% of pts were refractory to prior PI tx and 51% were refractory to prior immunomodulator (IMiD) tx. Pts completed a median of 7 tx cycles. There were CFZ dose reductions in 16 pts and PAN dose reductions in 21 pts, resulting in an average CFZ dose of 48.4 mg/m2 and average PAN dose of 14.7 mg. To date, 3 (9%) pts remain on active tx overall and 30 pts (91%) have discontinued due to disease progression (36%), toxicity (24%), stem cell transplant (15%), physician discretion or patient request (12%), and death (3%). The most common AEs are shown in Table 1. AEs of note were dyspnea (36%) and neuropathy (18%). There were 2 grade 3/4 cardiac toxicities, congestive cardiac failure and supraventricular tachycardia. There were 7 tx-related serious AEs (SAEs) in 6 pts and no tx-related deaths. 1 pt died on study of unrelated respiratory failure. The ORR was 82% and clinical benefit rate was 88% (6% complete response (CR)/near CR, 30% very good partial response, 47% partial response, 6% MR). ORR for pts refractory to prior PI was 75% and the CBR was 88%. ORR for pts refractory to prior IMiDs was 71% and the CBR was 82%. Median time to best response was 1.9 months (mos). With a median follow up (FU) of 19.6 mos (range 3.8-28 mos), median PFS was 9.69 mos, median TTP was 13.5 mos and median OS was 24.7 mos. Conclusions: The combination of PAN/CFZ is effective with an acceptable safety profile in this refractory population. Efficacy in this cohort (ORR 82%) was similar to the previously published expanded DL4 cohort (ORR 72%). A CFZ dose of 56 mg/m2 with PAN at 20mg as given in this schedule did not appear to result in increased cardiopulmonary toxicity, but dyspnea rates were higher in this cohort than previously reported. GI toxicity was manageable. Further evaluation of this combination at this dose level is warranted. Disclosures Berdeja: Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Gregory:Novartis: Honoraria. Faber:Cardinal Health: Honoraria; Gilead: Consultancy, Honoraria; Celgene: Speakers Bureau. Matous:Takeda Pharmaceuticals International Co.: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Hart:Onyx: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Flinn:Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership.

Background: Proteasome inhibitors (PI) such as bortezomib (BTZ) and carfilzomib (CFZ) have improved the treatment (tx) of MM; however, resistance invariably develops and MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM, and several histone deacetylase inhibitors (HDACi) are in clinical development. Panobinostat (PAN) is an oral pan-HDACi which has shown synergy with PIs through inhibition of the proteasome and aggresome pathways. It was recently approved by the FDA in combination with BTZ and dexamethasone based on the results of the PANORAMA1 study demonstrating efficacy, but significant G3 diarrhea (Lancet Oncol 2014;15:1195-206). We have previously reported the combination of CFZ and PAN in pts with relapsed and relapsed/refractory MM with encouraging results (Haematologica 2015;100:670-6). The maximum tolerated dose (MTD) of CFZ and PAN was never reached and we extended our original study to investigate higher dose levels. Here we present a comparison of the initial dose expansion (DL 4) and the subsequent dose expansion (DL 6). Methods: Ps with MM who had relapsed after ≥ 1 prior tx were enrolled. PAN was administered orally on days 1, 3, 5, 15, 17, 19 of each 28-day cycle. CFZ was administered IV over 30 min on days 1, 2, 8, 9, 15, and 16. In the initial dose escalation portion of the study a standard 3+3 design was used to determine the maximum tolerated dose (MTD) of an initial 4 planned dose levels of the combination of CFZ and PAN. The 4 dose levels tested were DL 1 (20 mg PAN and 20/27 mg/m2 CFZ); DL 2 (20 mg PAN and 20/36 mg/m2 CFZ); DL 3 (20 mg PAN and 20/45 mg/m2 CFZ), and DL 4 (30 mg PAN and 20/45 mg/m2 CFZ). MTD was not reached and the maximum planned dose DL 4 was expanded. We then revised the study in order to escalate to DL 5 (30 mg PAN plus 20/56 mg/m2 CFZ). Due to numerous PAN dose reductions resulting in a delivered PAN dose closer to 20 mg, we explored DL 6 (PAN 20 mg and CFZ 20/56 mg/m2). Tx continued until PD or intolerable toxicity. The primary efficacy endpoint was the overall response rate (ORR) (≥ PR). Secondary end points were time to progression (TTP), progression-free survival (PFS) and overall survival (OS), calculated using Kaplan-Meier methods. AEs were assessed according to CTCAE Version 4 and responses were assessed using IMWG criteria (plus MRs as per the EBMT criteria). Results: 80 pts were enrolled (50% male, median age 65 (range 41-91), 58% poor risk, and median of 4.5 prior therapies (1-9)). Prior PI or IMiD exposure and refractory status for all pts and expansion cohorts are shown in Table 1. 34 pts were in the 1st dose expansion (DL 4) and 33 in the 2nd (DL6). 13 (16%) pts remain on active tx overall, 6% of pts on DL 4 and 30% of pts on DL6. The most common all grade toxicities were thrombocytopenia (73%), nausea (69%), diarrhea (64%), and fatigue (51%). There were no significant differences in types or grades of toxicities between the 2 expansion cohorts except for decreased all grade diarrhea favoring DL 6 (71% v 49%). There was 1 tx related death due to heart failure in a pt with a prior history of hypertension and hyperlipidemia. The ORR was 75% (32% ≥ VGPR, 43% PR) for all pts, 72% (37% ≥ VGPR, 34% PR) for DL4 and 84% (34% ≥ VGPR, 50% PR) for DL 6 pts. With a median follow up (FU) of 14.5 mos for all pts, median PFS and TTP were 13.5 and 18.7 mos, respectively. Median OS was not reached. DL4 pts had a median FU of 24.3 mos, median PFS of 17.8 mo, median TTP of 19.5 mo, and median OS of 28.2 mo. The PFS and OS data of DL 6 pts is immature. Conclusions: The PAN/CFZ combination is effective with an acceptable safety profile in this heavily pretreated and highly refractory population. The results of this study compare favorably with the results of the PANORAMA-1 study in both efficacy and toxicity. An increase in CFZ from 45 to 56 mg/m2 did not appear to increase cardiopulmonary toxicity while a decrease in PAN from 30 to 20 mg appeared to have decreased the incidence of diarrhea. Both expansion dose levels tested were highly efficacious and well tolerated. Further evaluation of this combination in this schedule is warranted. Table 1. DL 4 (n=34) DL 6 (n=33) All Pts (n=80) Median # prior therapies, (range) 5 (1-9) 4 (1-9) 4.5 (1-9) Prior PIs 33 (97%) 33 (100%) 79 (99%) Prior IMiDs 31 (91%) 26 (79%) 69 (86%) Refractory to prior PIs 15 (44%) 19 (58%) 37 (46%) Refractory to prior IMiDs 17 (50%) 16 (48%) 42 (53%) Refractory to both prior IMiDs and PIs 8 (24%) 8 (24%) 20 (25%) Refractory to Last Therapy 23 (68%) 27 (81%) 57 (71%) Disclosures Berdeja: Acetylon: Research Funding; MEI: Research Funding; Array: Research Funding; Onyx: Research Funding; Takeda: Research Funding; Curis: Research Funding; Janssen: Research Funding; Celgene: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novartis: Research Funding. Gregory:Novartis: Speakers Bureau. Hart:Onyx: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mace:Spectrum Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Pfizer: Speakers Bureau. Flinn:Celgene Corporation: Research Funding.

Background: Duvelisib, a potent inhibitor of the δ and γ isoforms of phosphoinositide-3-kinase (PI3K) is being developed as a potential therapeutic in hematologic malignancies including chronic lymphocytic leukemia (CLL), as well as B and T cell lymphoma. Single agent bendamustine (B), rituximab (R), and their combination have demonstrated proven activity in iNHL and CLL. Combining duvelisib with bendamustine or rituximab alone or with both drugs may improve response rates and the durability of remission. The primary objective of this trial is to characterize the safety, maximum tolerated dose (MTD), and a preliminary efficacy profile of duvelisib given in combination with rituximab (Arm 1-DR), bendamustine plus rituximab (Arm 2-DBR) or bendamustine (Arm 3-DB) in subjects with select relapsed/refractory lymphoma or CLL. Methods: Pts with relapsed CLL or NHL, ECOG performance status (PS) ≤2, and adequate organ function were enrolled. The subject population during dose escalation was limited to relapsed NHL. During the dose expansion phase, each treatment arm enrolled to population specific cohorts to continue to assess efficacy. Arm 1 (DR) received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles plus duvelisib PO BID until disease progression or intolerance. Arm 2 (DBR)received rituximab 375 mg/m2 IV weekly for 2, 28 day cycles, bendamustine 90 mg/m2 IV for NHL pts or 70 mg/m2 IV for CLL pts on Days 1 and 2 of the first six cycles plus duvelisib PO BID until disease progression or intolerance. Arm 3 (DB) received bendamustine 120 mg/m2 IV on Days 1 and 2 of the first six cycles plus duvelisib PO BID up to 12 cycles. Three different dose levels of duvelisib, 25, 50, and 75 mg PO BID were initially explored. Pts were evaluated for response every 3 cycles according to specific criteria for their disease. Results: Between August 2013 and April 2015, 48 pts, median age 67 yrs (40-83) were enrolled; 12 NHL pts in the dose escalation portion and 36 pts (18 CLL, 18 NHL) in dose expansion. Pts had a median of 2 prior therapies (1-7). In arms 1 (DR) and 2 (DBR), no dose limiting toxicities were seen at the highest dose level of duvelisib (75 mg bid). In arm 3 (DB), with a higher dose of bendamustine, 1 pt developed a DLT at the 50 mg BID dose level of duvelisib (febrile neutropenia, neutropenia ≥ 7 days, thrombocytopenia ≥ 7 days, and liver toxicities which resulted in a treatment delay of ≥ 7 days). The MTD was not reached in this study but given recent data of single agent duvelisib showing no advantage in doses >25 mg BID, pts on the expansion phase were treated with 25mg BID. The AE profile of the drug combination is consistent with toxicities of the single agents (Table 1). There have been 2 potentially treatment-related deaths (cardiac arrest in a pt with history of hypertension and diabetes, and pneumonia), both on Arm 1. 38 pts were evaluable for response with an ORR of 74% (8% CR, 66% PR, 16% SD and 10% PD). The ORR of NHL and CLL pts were 64% and 92% respectively. With a median follow up of 16.25 mos, median progression free survival is 13.7 mos overall. Median overall survival (OS) has not been reached, but 15 mo OS probability is 82%. Pharmacokinetics analysis is consistent with the monotherapy Phase I trial of duvelisib (Figure 2) and is not effected by bendamustine. Conclusions: Analysis of duvelisib administered in combination with bendamustine and rituximab shows these combinations to be generally well-tolerated with encouraging response. Further follow-up is required to better characterize both response rates and durability of remissions. | | ARM 1 (N=28) | ARM 2 (N=18) | ARM 3 (N=2) | | | ------------------------------------ | --------------------- | --------------------- | -------------------- | ------- | ------- | | Preferred Term | G 1/2 | G 3/4 | G 1/2 | G 3/4 | G 1/2 | G 3/4 | Treated (N=48) | | RASH | 8 (29%) | 3 (11%) | 3 (17%) | 3 (17%) | | | 17 (35%) | | DIARRHEA | 8 (29%) | 3 (11%) | 2 (11%) | 1 (6%) | 1 (50%) | | 15 (31%) | | FATIGUE | 9 32%) | | 4 (22%) | 1 (6%) | 1 (50%) | | 15 (31%) | | NAUSEA | 5 (18%) | | 4 (22%) | | 1 (50%) | | 10 (21%) | | ALANINE AMINOTRANSFERASE INCREASED | 5 (18%) | 1 (4%) | 3 (17%) | | | | 9 (19%) | | NEUTROPENIA | 1 (4%) | 5 (18%) | | 3 (17%) | | | 9 (19%) | | ASPARTATE AMINOTRANSFERASE INCREASED | 4 (14%) | 1 (4%) | 3 (17%) | | | | 8 (17%) | | ANAEMIA | 3 (11%) | 1 (4%) | 2 (11%) | | 1 (50%) | | 7 (15%) | | PRURITUS | 3 (11%) | | 3 (17%) | | | | 6 (13%) | | UPPER RESPIRATORY TRACT INFECTION | 5 (18%) | | 1 (6%) | | | | 6 (13%) | | CONSTIPATION | 4 (14%) | | 1 (6%) | | | | 5 (10%) | | MUCOSAL INFLAMMATION | 3 (11%) | 1 (4%) | 1 (6%) | | | | 5 (10%) | Table 1. Treatment-related AEs (≥15% all pts) ![Figure 1.][1] Figure 1. Mean IPI-145 Concentration vs Time Plot with Tx Arms Overlaid for the First 6 Hours (Linear) Disclosures Flinn: Celgene Corporation: Research Funding. Berdeja: Curis: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Array: Research Funding; Acetylon: Research Funding; Takeda: Research Funding; Celgene: Research Funding; BMS: Research Funding; Onyx: Research Funding; MEI: Research Funding; Novartis: Research Funding. [1]: pending:yes

Although much is now known about the biological properties of the c-kit receptor and its ligand, stem cell factor (SCF), little is known of the structural basis for the binding and function of this hematopoietic cytokine. By analyzing the activities of chimeric interspecies and homologue muteins and epitope mapping of a monoclonal antibody (MoAb) to the human protein, we have found that three distinct regions of SCF are essential for full biological function. Homologue and interspecies swapping of polypeptide sequences between the amino terminus and G35, between L79 and N97, and between R121 and D128 reduced or eliminated the ability of the chimera to act in synergy with murine granulocyte- macrophage colony-stimulating factor (GM-CSF) to promote hematopoietic colony formation. Moreover, a nonconformation-dependent MoAb that neutralizes human, but not murine SCF, was found to bind to residues within the L79-N97 segment of the human homologue. As these three regions localize to the putative first, third, and fourth helices of the protein, findings remarkably similar to previous studies of cytokines as diverse as growth hormone, GM-CSF, and interleukin (IL)-4, our results suggest that cytokines of multiple classes share a common functional organization.

8026 Background: CFZ, a selective epoxyketone proteasome inhibitor, has potent, sustained action and lacks many BTZ-associated off-target activities. Durable activity has been observed in pts with advanced relapsed/refractory (R/R) MM, including those whose disease progressed on a BTZ-containing regimen. PX-171-004 is an ongoing phase (ph) II study of single-agent CFZ in pts with relapsed MM following 1–3 prior regimens. Here we present updated response, toxicity, and duration of response (DOR) data on BTZ-naive pts treated on this study. Methods: Pts in 2 sequential cohorts (Cohort 1 and Cohort 2) received IV CFZ on Days 1, 2, 8, 9, 15, 16 of every 28-day cycle (C), for up to 12 C. Both cohorts received 20 mg/m2 in C1; Cohort 2 dose escalated to 27 mg/m2 for C2–12. Primary endpoint was overall response rate (ORR) per IMWG criteria. Secondary endpoints were clinical benefit response (CBR), progression-free survival (PFS), DOR, overall survival (OS), time to progression (TTP), and safety. Results: 123 BTZ-...

IL-3 is a glycoprotein cytokine involved in the hematopoietic response to infectious, immunologic, and inflammatory stimuli. In addition, clinical administration of recombinant IL-3 augments recovery in states of natural and treatment-related marrow failure. IL-3 acts by binding to high affinity cell surface receptors present on hematopoietic cells. To determine the site(s) at which IL-3 binds to it receptor, we analyzed a series of interspecies chimera of the growth factor for species-specific receptor binding and biological activity. The results suggest that IL-3 binds to its receptor and triggers a proliferative stimulus through two noncontiguous helical domains located near the amino terminus and the carboxy terminus of the molecule. To corroborate these findings, we have also mapped the binding epitopes of 10 mAb of human or murine IL-3, and have defined four distinct epitopes. Two of these epitopes comprise the amino-terminal receptor binding domain. A third epitope corresponds to the carboxy-terminal receptor interactive domain, and the fourth epitope, apparently not involved in the interaction of IL-3 and its receptor, lies between these sites. And on the basis of sandwich immunoassays using pairs of these mAbs, the two receptor interactive regions appear to reside in close juxtaposition in the tertiary structure of the molecule. These results provide a correlation of the structure-function relationships of IL-3 that should prove useful in evaluating the details of IL-3-IL-3 receptor interaction and in the rational design of clinically useful derivatives of this growth factor.

8535 Background: This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 at days 1, 8, 15, 22, on cycles 1 and 4. Results: 37 pts (26 men and 11 women, median age 62 years, range 42 - 73) have been treated to date. The median number of lines of prior treatment was 3 (range 1 - 5). All patients had received prior rituximab and 5 pts received prior bortezomib. The median IgM at baseline was 3540 mg/dL (range 700-10,800). The median follow up is 12 months (range 5 - 26 months). Thirty-five pts are evaluable for response. Complete remission and near complete remission occurred in 2 (6%), partial remission in 17 (48%), and minimal response in 10 (29%). Progressive disease occurred in 1 (3%) and stable disease occurred in 5 (14%). Most patients achieved response rapidly within 3 months of therapy (2–7 months). Rituximab flare occurred only in 6 patients (20%). At 24 months of follow up, 8/35 pts have shown relapsed disease. The median time to progression and duration of response has not been reached. Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 2 pts. Grade 1 and 2 neuropathy occurred in 10 pts (26%). Other grade 3 and 4 toxicities included neutropenia in 5 patients, and anemia and thrombocytopenia in 4 patients. Grade 5 pneumonia and viral infection occurred in 1 patient who was within the first cycle of therapy and did not receive herpes zoster prophylaxis. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated. Conclusions: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates encouraging activity, with CR+ PR + MR in 83% of evaluable patients with relapsed WM. No significant peripheral neuropathy has been observed to date with this regimen. [Table: see text]