Hofmeister, Craig C.

Background: Multiple myeloma (MM) is characterized by somatic mutations involving cancer-associated genes. The MyDRUG trial was initiated to explore the efficacy of specific molecularly-targeted therapies in combination with a standard triplet combination in MM. Methods: MyDRUG (NCT03732703) is a genomically-guided umbrella trial for patients with functional high-risk MM, defined as early relapse following primary therapy (3 years for transplant with maintenance, 18 months without), with specific genetic abnormalities. Patients with no actionable mutation or mutations with allelic burden below 30% were randomly assigned to one of the “non-actionable” arms. Here we present the data for the Y3 arm which combines selinexor (60mg po days 1,8,15), ixazomib (4mg po days 1,8,15), pomalidomide (3mg po days 1-21) and dexamethasone (40mg po weekly) (Seli-IPD), given on a 28-day cycle. The primary objective of the Y3 sub-protocol was to evaluate the overall response rate (ORR) according to the International Myeloma Working Group consensus criteria. Secondary objectives included assessment of adverse events (AEs). Results: 17 patients were enrolled into the Y3 arm. The average age was 62 (51-79), 65% were male with a median of 29 months since initial diagnosis and a median of 2 prior lines of therapy. The ORR (> PR) was 52.9% with a clinical benefit rate (> MR) of 58.8%. The median progression free survival was 10.2 months ( 95% CI: 3.9; 12.9) with a median overall survival which has not yet been reached; with all 17 patients still alive at the current data cutoff. No dose-limiting toxicities were seen. Eight patients (47.1%) experienced a serious AE with 2 patients (11.8%) experiencing an AE leading to treatment discontinuation. Two patients (11.8%) required dose reductions. The most common non-hematologic AEs were fatigue, nausea and constipation; all of which were grade 1 and 2. Conclusions: In this platform study of patients with relapsed, functionally high-risk MM, patients who received Seli-IPd exhibited significant efficacy and a manageable AE profile. Furthermore, this provides an all-oral option for patients wishing to minimize their office visits and parenteral therapy administrations.

Abstract Waldenstrom macroglobulinemia (WM) and its precursor IgM gammopathy are distinct disorders characterized by clonal mature IgM-expressing B-cell outgrowth in the bone marrow. Here, we show by high-dimensional single-cell immunogenomic profiling of patient samples that these disorders originate in the setting of global B-cell compartment alterations, characterized by expansion of genomically aberrant extrafollicular B cells of the nonmalignant clonotype. Alterations in the immune microenvironment preceding malignant clonal expansion include myeloid inflammation and naïve B- and T-cell depletion. Host response to these early lesions involves clone-specific T-cell immunity that may include MYD88 mutation–specific responses. Hematopoietic progenitors carry the oncogenic MYD88 mutations characteristic of the malignant WM clone. These data support a model for WM pathogenesis wherein oncogenic alterations and signaling in progenitors, myeloid inflammation, and global alterations in extrafollicular B cells create the milieu promoting extranodal pattern of growth in differentiated malignant cells. Significance: These data provide evidence that growth of the malignant clone in WM is preceded by expansion of extrafollicular B cells, myeloid inflammation, and immune dysfunction in the preneoplastic phase. These changes may be related in part to MYD88 oncogenic signaling in pre–B progenitor cells and suggest a novel model for WM pathogenesis. This article is highlighted in the In This Issue feature, p. 549

Abstract Objectives Two pilot studies of AR‐42, a pan‐histone deacetylase inhibitor, in human neurofibromatosis type 2 (NF2), vestibular schwannomas (VS), and meningiomas are presented. Primary endpoints included safety, and intra‐tumoral pharmacokinetics (PK) and pharmacodynamics (PD). Methods Pilot 1 is a subset analysis of a phase 1 study of AR‐42 in solid tumors, which included NF2 or sporadic meningiomas. Tumor volumes and treatment‐related adverse events (TRAEs) are reported (NCT01129193). Pilot 2 is a phase 0 surgical study of AR‐42 assessing intra‐tumoral PK and PD. AR‐42 was administered for 3 weeks pre‐operatively. Plasma and tumor drug concentrations and p‐AKT expression were measured (NCT02282917). Results Pilot 1: Five patients with NF2 and two with sporadic meningiomas experienced a similar incidence of TRAEs to the overall phase I trial. The six evaluable patients had 15 tumors (8 VS, 7 meningiomas). On AR‐42, tumor volume increased in six, remained stable in eight, and decreased in one tumor. The annual percent growth rate decreased in eight, remained stable in three, and increased in four tumors. Pilot 2: Four patients with sporadic VS and one patient with meningioma experienced no grade 3/4 toxicities. Expression of p‐AKT decreased in three of four VS. All tumors had higher AR‐42 concentrations than plasma. Conclusions AR‐42 is safe. Tumor volumes showed a mixed response, but most slowed growth. On a 40‐mg regimen, drug concentrated in tumors and growth pathways were suppressed in most tumors, suggesting this may be a well‐tolerated and effective dose. A phase 2 study of AR‐42 for NF2‐associated tumors appears warranted. Level of Evidence 1b, 4.

Abstract Background There is increasing evidence for the clinical benefit of long-term, continuous therapy for NDMM pts. Proteasome inhibitors (PIs) form a backbone of therapy in MM; however, long-term therapy with some PIs may be limited due to toxicity and the need for regular parenteral administration, increasing the treatment burden. Ixazomib, the first oral PI, has been studied in NDMM pts in 4 phase 1/2 studies in which approximately 1 year of induction therapy with once- or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd) was followed by single-agent ixazomib maintenance. Here we report an integrated analysis of pts from these studies who did not undergo autologous stem cell transplant (ASCT) and received ixazomib maintenance therapy. Methods Pts from 4 studies were included: 1) weekly IRd, 12x28-d cycles IRd (weekly ixazomib 1.68-3.95 mg/m² in phase 1, recommended phase 2 dose [RP2D] 4.0 mg; C16005, NCT01217957; ASCT-eligible/-ineligible pts); 2) twice-weekly IRd, 16x21-d cycles IRd (twice-weekly ixazomib 3.0-3.7 mg in phase 1, RP2D 3.0 mg; C16008, NCT01383928; ASCT-eligible/-ineligible pts); 3) IMP, 9x42-d or 13x28-d cycles IMP (weekly/twice-weekly ixazomib 3.0-5.5/3.0-3.7 mg in phase 1, RP2D of weekly ixazomib 4.0 mg; C16006, NCT01335685; ASCT-ineligible pts); 4) ICd, 13x28-d cycles ICd (weekly ixazomib 4.0 mg; C16020, NCT02046070; ASCT-ineligible pts). In all 4 studies, pts completing induction without progressive disease (PD) and, in the IRd studies, not withdrawn for ASCT, could receive single-agent ixazomib maintenance at the last tolerated dose during induction until PD or unacceptable toxicity. Results 121 pts received ixazomib maintenance (25, 18, 35, and 43 in weekly IRd, twice-weekly IRd, IMP, and ICd studies, respectively). Median age was 72 yrs (range 34-90 yrs; 83% aged ≥65 yrs), 62% had IgG myeloma, 47/34/19% had ISS disease stage I/II/III, 40/49% had Eastern Cooperative Oncology Group performance status 0/1. Combined median progression-free survival (PFS) was 33.8 months from time of study entry and 21.4 months from start of maintenance (Figure). Median PFS from the start of maintenance seemed to be longer for the two IRd studies than for IMP, while median PFS for ICd had not yet been reached. 4-yr OS from time of study entry/3-yr OS from the start of maintenance was 82%. Overall response rate was 93% after induction and 94% after maintenance. Best response rate of CR+VGPR after induction was 57% (22% CR), which increased to 63% (35% CR/sCR) after maintenance; 24 pts (20%) improved their response during maintenance (4 pts with CR improved to sCR; 14 VGPR to CR/sCR; 5 partial response [PR] to VGPR/CR; 1 stable disease to PR). Combined mean dose intensity during maintenance was 89.1%. At time of analysis, median duration of maintenance therapy was 2.2 yrs for weekly IRd, 1.0 yr for twice-weekly IRd, and 0.9 yr for IMP and ICd; maximum duration was 4.8, 3.8, 3.9, and 1.6 yrs respectively. 78% of pts had discontinued maintenance, primarily due to PD (55%), and only 7% due to adverse events (AEs). 15% of pts had ixazomib dose reductions during maintenance. Grade ≥3 AEs (48% vs 74%), drug-related grade ≥3 AEs (24% vs 62%), serious AEs (SAEs; 21% vs 43%), and drug-related SAEs (5% vs 19%) were less common during maintenance than during induction. Common grade ≥3 AEs are shown in the Table. Other AEs of clinical interest were also generally similar or less common during maintenance than during induction, including cardiac arrhythmias (13% vs 21%), pneumonia (12% vs 17%), acute renal failure (7% vs 8%), hypotension (4% vs 7%), myocardial infarction (0 vs <1%), and heart failure (2% vs 2%). Only 6 pts (5%) reported a new primary malignancy. There was only 1 on-study death during maintenance, which was not considered related to ixazomib; due to pulmonary edema in an 81-yr old pt with a history of cardiovascular co-morbidities. Conclusions In this integrated analysis, single-agent ixazomib maintenance therapy following an ixazomib-based induction regimen was associated with deepening of responses and good long-term outcomes in NDMM pts not undergoing ASCT. Single-agent ixazomib is feasible for long-term administration, with limited new-onset grade ≥3 AEs. These outcomes appear similar to other studies involving maintenance approaches in NDMM and support the ongoing phase 3 investigation of ixazomib maintenance therapy. Disclosures Dimopoulos: Novartis: Consultancy, Honoraria; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Genesis Pharma: Research Funding. Laubach: Novartis, Takeda, Celgene, Onyx: Research Funding; Novartis, Takeda, Celgene: Consultancy. Hofmeister: Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Roche: Research Funding; Karyopharm: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding. San Miguel: Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kumar: Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy; Skyline: Honoraria. Lu: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng: Array Pharmaceuticals: Equity Ownership; AMAG Pharmaceuticals: Equity Ownership; Gilead Science: Equity Ownership; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Liu: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Byrne: Oncopeptides AB: Consultancy; Takeda: Consultancy. Berg: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. van de Velde: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson: Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees.

TPS8057 Background: Multiple myeloma (MM) is the second most prevalent blood cancer, representing approximately 1% of all cancers. Although overall survival has improved in recent years due to new approved agents, the vast majority of MM patients (pts) ultimately stop responding to treatment. Moreover, about a quarter of MM pts characterized as “high risk” experience limited benefit from existing treatments. Seminal genomic sequencing research efforts, such as the MMRF CoMMpass study, have highlighted that a large number of MM cases harbor potentially actionable oncogenic molecular alterations and published reports on small numbers of cases suggest that Precision Medicine (PM) interventions clinically targeting such actionable drivers may benefit MM pts. These results suggest that PM approaches in MM are possible and should be further studied clinically. To that end, we have launched MyDRUG, a master protocol aimed at developing new myeloma regimens based on individual pt’s genomics. Methods: This study is a Phase I-II, multicenter master protocol in functional high risk MM patients (i.e patients having progressed from baseline treatment within 18 months without maintenance or 3 years on maintenance) with 1-3 prior lines of therapy. Patients are screened for actionable genomic alterations on the CLIA-grade MI-ONCOSEQ platform. Patients with actionable alterations are assigned to the appropriate targeted agent used in combination with a backbone regimen ixazomib, pomalidomide and dexamethasone (IPd), whereas patients without such alterations go on an immune arm (see Table). Inclusion criteria include measurable disease (as measured by M-protein and FLC) and acceptable hematologic and metabolic functions. A maximum of 12 evaluable pts will be accrued onto the phase I portion of each arm and an additional 21 evaluable phase II pts will be accrued onto each arm for a total of 27 evaluable pts at the MTD combination dose. The primary objective of the study is to evaluate ORR per IMWG consensus criteria. Secondary objectives are to assess adverse events (AEs), progression-free survival, and overall survival (OS). Experimental correlative aims include assessing molecular or clonal response, molecular and immune signatures of resistance/response, MRD. Clinical trial information: NCT03732703. [Table: see text]

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.

Introduction. Our previous flow cytometry-based comparison of HIV(+) and HIV(-) autologous hematopoietic stem cell transplant (auto-HSCT) recipient immunomes at 56, 180 and 365 days post-transplant to each other and to healthy controls (HCs) showed that both sets of auto-HSCT recipient immunomes approached HCs over time, but retained significant differences. HIV(+), but not HIV(-), auto-AHCT recipients retained pro-inflammatory features consistent with chronic HIV infection. Here, we report the results of a quantitative and functional analysis of immune reconstitution in HIV(+) patients treated with allogeneic hematopoietic stem cell transplant (allo-HSCT), in comparison with HIV(+) auto-HSCT recipients and HCs. Methods. Blood samples were collected for analysis at days 56, 180 and 365 post-transplant from HIV(+) transplant recipients and at 1 time point from HCs. Whole blood analysis was performed by five-color flow cytometry across 100 immune marker combinations. Comparisons were made between HIV(+) allo-HSCT recipients (n=17, acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, Hodgkin and non-Hodgkin lymphoma that received myeloablative or reduced intensity conditioning on the BMT-CTN-0903/AMC-080 trial), HIV(+) auto-HSCT recipients (n=36, aggressive B cell non-Hodgkin lymphoma or Hodgkin lymphoma that received myeloablative conditioning on the BMT-CTN-0803/AMC-071 trial) and 71 HCs. Unsupervised principal component analysis (PCA) examined differences in immune cell proportions, identified by flow cytometry across 100 cell subsets at each time point. Wilcoxon rank-sum tests compared median absolute counts and median proportions of cell subsets. An independent feature importance score analysis (FIS) identified contributions of immune cell populations expressing specific immune marker combinations to the differences between HIV(+) auto-HSCT recipients, HIV(+) allo-HSCT recipients and HCs. Functional responsiveness of HIV(+) allo-HSCT recipients' T cells to stimulation with CD3- and CD28-directed antibodies, NK cells to stimulation with IL-12 and IL-18 and monocytes to stimulation with lipopolysaccharide (LPS) was assessed in a preliminary mass cytometry on peripheral blood mononuclear cells isolated at the same time points (n=2) and compared to HCs (n=2). Results. PCA showed that immunomes of HIV(+) allo-HSCT recipients and HIV(+) auto-HSCT recipients clustered together with each other, but away from HCs at all time points throughout the post-transplant year. FIS identified: 1) 13 cell subsets that defined the difference between HIV(+) allo-HSCT recipients (all visits) and HCs, and 2) 11 immune cell subsets that defined the difference between HIV(+) auto-HSCT recipients (all visits) and HCs; in both of these comparisons, activated CD3+/HLA-DR+ T cells had the greatest impact on the difference between HIV(+) and HC immunomes. At 1 year, both HIV(+) transplant recipient cohorts had higher absolute numbers of activated T cells, effector T cells and CD8+ T cells than HCs (Wilcoxon rank-sum test, p<0.0031). HIV(+) autologous and allogeneic HSCT recipients also had lower numbers of CD4+ T cells, naïve T cells and activated NK cells compared to HCs (p<0.0031). FIS also identified 20 immune cell subsets that defined the difference between HIV(+) autologous and allogeneic HSCT recipients immunomes at 1 year, with CD8+/CD27- effector T cell subset exerting the highest impact on the difference. Preliminary functional mass cytometry analysis of 2 HIV(+) allo-HSCT recipients and 2 HCs showed that: 1) IFNʏ production by CD8+ T cells was increased above that of HCs at all time points. 2) Expanded populations of CD4+/T-bet+ cytotoxic cells expressing granzyme B and perforin, and CD8+ cytotoxic T cells expressing granzyme B and perforin, persisted in HIV(+) allo-HSCT recipients at all time points, but not in HCs. 3) NK cells retained an ability to produce IFNʏ in response to stimulation with IL-12 and IL-18 in HIV(+) allo-SCT recipients. 4) Monocytes showed an enhanced production of TNFα in response to stimulation with LPS in HIV(+) allo-HSCT recipients compared to HCs at 1 year post-HSCT. Conclusion. Chronic HIV infection confers the pro-inflammatory immune features on the phenotypic and functional profiling of the T lymphocyte immunome of stem cell transplant recipients, irrespective of allogeneic or autologous stem cell donor source. Disclosures Devine: Bristol Myers: Other: Grant for monitoring support & travel support; Kiadis Pharma: Other: Protocol development (via institution); Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Hofmeister:Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Navarro:Atara Biotherapeutics: Employment, Equity Ownership. Behbehani:Fluidigm corporation: Other: Travel funding. Lozanski:Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Baiocchi:Prelude: Consultancy.

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.