Le‐Rademacher, Jennifer

TPS3154 Background: Immune-related Adverse Events (irAEs) are rare but serious sequelae of treatment with immuno-oncology (IO) therapeutics. These therapeutics, including monoclonal antibodies targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have had transformative effects on outcomes for patients (pts) with advanced cancers. Although most pts tolerate the therapies well, a few experience irAEs ranging in severity up to life-threatening. These irAEs involve diverse organs including the heart, kidney, liver and lung, and gastrointestinal, musculoskeletal, central and peripheral nervous systems. Because of the relatively low incidence and wide variety of irAEs due to various immunotherapies for multiple tumor types, establishment of an efficient centralized repository for acquisition and organized distribution of well-annotated biospecimens is vital for translational studies that improve understanding of the molecular pathogenesis and treatment of these significant toxicities. Methods: This multi-institutional study is open at sites across the National Clinical Trial Network to pts who received ≥ 1 IO therapeutics (e.g., CTLA-4, PD-1 or PD-L1 inhibitor) and experienced 1) ≥ 1 serious (grade 3–5) adverse events that are likely immune-related, 2) rare infection or 3) tumor hyperprogression. IrAEs of interest include myocarditis, colitis, hepatitis, nephritis, myositis, pneumonitis, meningitis/encephalitis, dermatitis, endocrinopathies and neuropathy. Pts may be on an NCTN or non-NCTN IO trial or be receiving standard-of-care therapy. Registration must occur ≤ 72 hours after confirmation of the irAE event. Clinical data are collected at registration, 1 month after registration and for up to 1 year. Biospecimens (tumor blocks, biopsies of inflammatory tissues used to establish irAE diagnosis, and serial blood samples for isolation of plasma, serum and peripheral blood mononuclear cells) are collected at 1-2 timepoints. Stool samples are collected from pts experiencing colitis. Imaging data are collected for pts with hyperprogression or pneumonitis. Goal accrual is 240 pts. Biospecimens and data will be made available to investigators following future submission and approval of proposals. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180820 (ECOG-ACRIN); U10CA180888 (SWOG); U10CA180868 (NRG); https://acknowledgments.alliancefound.org; Clinical trial information: NCT04242095 .

Background/aims: The difference in mean survival time, which quantifies the treatment effect in terms most meaningful to patients and retains its interpretability regardless of the shape of the survival distribution or the proportionality of the treatment effect, is an alternative endpoint that could be used more often as the primary endpoint to design clinical trials. The underuse of this endpoint is due to investigators’ lack of familiarity with the test comparing the mean survival times and the lack of tools to facilitate trial design with this endpoint. The aim of this article is to provide investigators with insights and software to design trials with restricted mean survival time as the primary endpoint. Methods: A closed-form formula for the asymptotic power of the test of restricted mean survival time difference is presented. The effects of design parameters on power were evaluated for the mean survival time test and log-rank test. An R package which calculates the power or the sample size for user-specified parameter values and provides power plots for each design parameter is provided. The R package also calculates the probability that the restricted mean survival time is estimable for user-defined trial designs. Results: Under proportional hazards and late differences in survival, the power of the mean survival time test can approach that of the log-rank test if the restriction time is late. Under early differences, the power of the restricted mean survival time test is higher than that of the log-rank test. Duration of accrual and follow-up have little influence on the power of the restricted mean survival time test. The choice of restriction time, on the other hand, has a large impact on power. Because the power depends on the interplay among the design factors, plotting the relationship between each design parameter and power allows the users to select the designs most appropriate for their trial. When modification is necessary to ensure the difference in restricted mean survival time is estimable, the three available modifications all perform adequately in the scenarios studied. Conclusion: The restricted mean survival time is a survival endpoint that is meaningful to investigators and to patients and at the same time requires less restrictive assumptions. The biggest challenge with this endpoint is selection of the restriction time. We recommend selecting a restriction time that is clinically relevant to the disease and the clinical setting of the trial of interest. The practical considerations and the R package provided in this work are readily available tools that researchers can use to design trials with restricted mean survival time as the primary endpoint.

AbstractHistological transformation in Waldenström macroglobulinemia (WM) is an uncommon complication, with limited data, particularly regarding the impact of MYD88 L265P mutation on transformation. We examined risk factors and outcomes associated with transformation in WM, highlighting the role of MYD88 L265P mutation. Patients with WM seen at Mayo Clinic, Rochester, USA and University Hospital of Reims, France, between 01/01/1996 and December 31, 2017 were included; 50 (4.3%) of 1147 patients transformed to a high‐grade lymphoma, with median time‐to‐transformation of 4.5 (range 0‐21) years in the transformed cohort. The MYD88 L265P mutation status was known in 435/1147 (38%) patients (406 with non‐transformed WM and 29 patients in transformed cohort). On multivariate analysis, MYD88 WT status alone was an independent predictor of transformation (odds ratio, 7[95%CI: 2.1‐23]; P = .003). Additionally, the MYD88 WT status was independently associated with shorter time‐to‐transformation (HR 7.9 [95%CI: 2.3‐27; P = .001]), with a 5‐year transformation rate of 16% for MYD88 WT vs 2.8% with MYD88 L265P mutated patients. Patients with transformation demonstrated a significant increase in risk of death compared to patients who did not transform (HR 5.075; 95%CI: 3.8‐6.8; P < .001). In conclusion, the MYD88 WT status is an independent predictor of transformation and associated with a shorter time‐to‐transformation. Additionally, transformation conferred an inferior overall survival in patients with WM.

Background The phase 3 trial A041202 solidified the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib as a standard of care for older patients with previously untreated CLL by showing superior progression-free survival (PFS) as compared with bendamustine plus rituximab. While ibrutinib is highly effective in previously untreated CLL, there do remain disadvantages to this therapy, specifically the low rate of complete response (CR) and therefore the need for continuous administration, which increases cost and toxicity. In older patients especially, toxicities with ibrutinib are common; 17% of patients had atrial fibrillation and 29% had grade 3 or higher hypertension on the A041202 study. Thus, strategies to decrease the exposure time to ibrutinib are of interest. Venetoclax is an inhibitor of BCL2 that has shown efficacy as a single agent and in combination with monoclonal antibodies, specifically the anti-CD20 monoclonal antibody obinutuzumab for patients with previously untreated CLL. One significant advantage to venetoclax is the ability to produce CRs and minimal residual disease negative (MRD-) responses. In this study, we compare ibrutinib plus obinutuzumab (IO) to ibrutinib plus venetoclax plus obinutuzumab (IVO) with a response-dependent discontinuation. While other studies have been designed with the goal of discontinuation of ibrutinib through combinations with venetoclax, no other study has been presented using a response-dependent discontinuation strategy. Study Design and Methods A041702 is a randomized phase 3 study led by the Alliance for Clinical Trials in Oncology that is currently enrolling through the NCI National Clinical Trials Network (NCTN). CLL patients age 70 years or older who are previously untreated and in need of therapy are eligible. Previous treatment of autoimmune complications with steroids or rituximab is allowed. Patients must have intermediate- or high-risk Rai stage, ECOG performance status 0-2, ANC ≥ 1000/mm3 unless due to marrow involvement, and platelets ≥ 30,000/mm3. CrCl must be ≥ 40 mL/min and AST/ALT ≤ 2.5x upper limit of normal. Patients with hepatitis B must have undetectable viral load, and patients must not have an intercurrent illness that is expected to limit survival to < 5 years. Warfarin and strong inhibitors or inducers of CYP3A4/5 are not permitted. Patients are initially preregistered to the study and submit a peripheral blood sample for central FISH analysis of del(17p). Patients who are registered are randomized 1:1 to Arm 1 (IO) or Arm 2 (IVO), and are stratified by Rai stage and presence of del(17p). IO consists of I daily starting cycle 1 day 1, and O dosed as standard starting cycle 1 day 1 and continuing to cycle 6 day 1. IVO consists of IO as in Arm 1, with V starting cycle 3 day 1 with standard 5-week ramp-up and continuing until cycle 14 day 28. At the end of 14 cycles, patients in both arms undergo response evaluation with central peripheral blood and bone marrow MRD testing. Patients on IO then continue I indefinitely. Patients on IVO who are in a bone marrow MRD- CR discontinue all therapy, and those who are not continue I indefinitely. The primary objective of the study is to compare PFS between IO and IVO using the strategy of response-dependent discontinuation. There is 90% power to detect a hazard ratio for PFS of 0.55 (corresponding to 5-year PFS rates of 70% and 82.187% for IO and IVO, respectively), at a one-sided significance level of 0.025 by a log-rank test. This design requires 128 events and 431 total evaluable patients assuming uniform accrual over the course of 3 years and minimum follow-up of 5 years. The study includes two interim analyses for superiority when 50% and 75% of the expected number of events have been observed and three interim analyses for futility when 25%, 50%, and 75% of the expected number of events have been observed. Conclusions A041702 is an ongoing phase 3 clinical trial using a novel response-dependent discontinuation method. Results of this study have the potential to change the standard of care for older patients with previously untreated CLL. The study is expected to accrue for 3 years beginning January 2019, and we welcome participation from sites throughout the NCTN. Support: U10CA180821, U10CA180882, UG1CA189823, U24CA196171; U10CA180820 (ECOG-ACRIN); https://acknowledgments.alliancefound.org; ClinicalTrials.gov Identifier: NCT03737981 Disclosures Woyach: Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Lozanski:Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Ding:Merck: Research Funding; DTRM Biopharma: Research Funding. Hill:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stone:Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding; AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; BeiGene: Research Funding; Genentech: Research Funding; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau.

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: Currently, low molecular weight heparin is the guideline endorsed treatment of patients with cancer associated venous thromboembolism (VTE). While apixaban is approved for the treatment of acute VTE, there are limited data supporting its use in cancer patients. Methods: Patients with cancer associated acute VTE were randomly assigned to receive either apixaban 10 mg twice daily for 7 days followed by 5 mg twice daily or subcutaneous dalteparin (200 IU/kg for 1 month followed by 150 IU/kg once daily) for 6 months. The primary outcome was major bleeding. Secondary outcomes included VTE recurrence and a composite of major plus clinically relevant non-major bleeding. Results: Of the 300 patients who underwent randomization, 287 were included in the primary analysis. Of these, metastatic disease was present in 65.5% of subjects and 74% were receiving concurrent systemic cancer therapy. Colorectal, lung, pancreas, and breast cancers were the four most prevalent cancer types. Major bleeding occurred in 0 of the 142 patients (0%) in the apixaban group as compared with 3 of the 145 patients (2.1%) in the dalteparin group (p=0.9956). Recurrent VTE occurred in 5 patients (3.4%) in the apixaban group and 20 patients (14.1%) in the dalteparin group (difference in risk -10.7 percentage points) with a Hazard Ratio (HR) 0.26, (95% CI, 0.09 - 0.80, p = 0.0182). Major plus clinically relevant non-major bleeding were similar at 9% for both groups. There were no mortality differences comparing apixaban (15.9%) and dalteparin (10.6%) groups at 6 months (HR 1.36, 95% CI 0.79 - 2.35). Monthly quality of life surveys favored apixaban therapy for many measures including: concern for excess bruising, stress, irritation, burden of delivery, and overall satisfaction with anticoagulant therapy (p<0.05). Monthly bruising questionnaire favored apixaban at each interval (p<0.002). Conclusions: Oral apixaban therapy was associated with very low rates of bleeding and significantly lower VTE recurrence with superior quality of life outcome measures compared to parenteral dalteparin in the treatment of cancer associated VTE. These data support the clinical utility of apixaban for the acute treatment of VTE in this patient population. Table. Table. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: The preferred post-remission therapy for older patients (pts) with AML remains uncertain. We compared outcomes for older AML pts in CR1 receiving HCT reported to the CIBMTR to older AML pts achieving CR1 on National Clinical Trials Network induction and non-HCT consolidation therapy (CT) trials. Methods: This study focused on pts 60-75 years of age treated between 2004 to 2013. CT pts (n=211) underwent induction and consolidation on Alliance for Clinical Trials in Oncology, ECOG-ACRIN or SWOG clinical trials for initial therapy for newly diagnosed AML; the CIBMTR provided data for HCT pts (n=431). CT patients received at least one cycle of CT on study and were excluded if HCT occurred at any time. Time to event started at CR1 and pts entered at CT or HCT, respectively, using left-truncation to account for differential entry times. Results: For the CT cohort, first consolidation included standard therapy (e.g., cytarabine or a hypomethylating agent) and additional study drug (e.g., bortezomib, dasatinib, sorafenib, and Zosuquidar, gemtuzumab) or tipifarnib alone. Among HCT pts, the donor was a HLA-matched sibling or unrelated donor (URD) in 66% and the others were partially HLA-matched/mismatched URD (10%) or cord blood (24%). HCT pts were younger and more frequently had high-risk AML (high WBC, secondary AML and unfavorable cytogenetics) (Table). The median time from CR1 to HCT and CT was 3.2 and 0.5 months, respectively. Allogeneic HCT showed worse overall survival (OS) (HR=1.52, p=0.02) prior to 9 months and better OS thereafter (HR= 0.53, p <0.0001) relative to CT (figure 1A). Treatment-related mortality (TRM) was worse after HCT in the first 9 months (HR=2.8, CI: 1.5 -5.2, p=.0009), while relapse was less frequent beyond 9 months after treatment (HR = 0.42, CI: 0.29 to 0.61, p<.0001). Despite higher early TRM, HCT recipients went on to manifest superior OS [5 year OS: HCT 29% (24-34%), CT 13.8% (9 -22%)] (Figure 1A). The benefit of HCT for survival after 9 months was more prominent in those with unfavorable cytogenetics (Figure 1B). Multivariate analysis for OS showed no statistically significant effect of age or performance status, while unfavorable cytogenetics were detrimental (HR=1.74, p<.0001). Conclusions. Allogeneic HCT led to heightened early risks from TRM, but resulted in superior long-term survival in older AML pts receiving HCT relative to CT by reducing relapse. Efforts to attenuate early TRM after allogeneic HCT may further improve HCT outcomes for older pts. Disclosures Ustun: novartis: Speakers Bureau. Attar:Agios: Employment, Equity Ownership. Larson:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding. Roboz:Roche/Genentech: Consultancy; Eisai: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy; Bayer: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; Daiichi Sankyo: Consultancy; Celltrion: Consultancy; Novartis: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; AbbVie: Consultancy. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Stone:Fujifilm: Consultancy; Ono: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Arog: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Sumitomo: Consultancy; Amgen: Consultancy; Cornerstone: Consultancy. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Weisdorf:Seattle Genetics: Consultancy; Equillium: Consultancy; FATE: Consultancy; SL Behring: Consultancy; Pharmacyclics: Consultancy.

Abstract Abstract 824 There is no standard therapy for MM relapsing after autologous hematopoietic cell transplantation (AHCT). A second AHCT can result in additional progression-free survival (PFS). Nonmyeloablative/reduced intensity conditioning (NST/RIC) allogeneic transplantation (AlloHCT) has the advantages of a tumor-free graft and the potential of a graft-versus-myeloma (GVM) effect. Few studies have compared second AHCT vs. NST/RIC AlloHCT. We compared the outcome of second AHCT or NST/RIC AlloHCTafter relapse from prior AHCT in patients with MM reported to the CIBMTR from 1995–2008. Recipients of planned tandem transplants, AlloHCT for graft failure or second malignancies and myeloablative alloHCT were excluded. 137 patients underwent second AHCT and 152 underwent NST/RIC AlloHCT (32 HLA-identical sibling and 120 unrelated donor). The table below illustrates clinical characteristics and patient outcomes. AlloHCT recipients were significantly younger (median 53 years [yrs] of age vs. 56 yrs in the AHCT cohort (p < 0.001). The groups were similar in Karnofsky performance score (KPS) and gender. Conditioning regimens differed between groups. In the AHCT cohort, 85% were melphalan based. In the NST/RIC alloHCT cohort, 38% received melphalan + other drugs and 24% received total body irradiation +/− other drugs but no melphalan (p <0.001). Time from 1st to 2nd transplant was significantly shorter for the AlloHCT cohort (30 vs. 23 months, p = 0.014). Acute graft-versus-host disease (GVH) was 35% at 60 days while chronic GVHD was 44% at 36 months.Patient CharacteristicsAutologousAllogeneicP-valueNumber of patients137152Age at 2nd transplant, median (range), years56 (28–65)53 (32–65)0.001*Gender Male84 (61)90 (59)0.720Karnofsky Score pre-transplant ≥90%68 (50)76 (50)0.884Time from 1st to 2nd transplant, months, median (range)30 (6–122)23 (6–78)0.014* 6–24 months44 (32)78 (51)0.001* >24 months93 (68)74 (49)OutcomesTreatment-related Mortality (TRM)12 months2 (1–5)13 (8–19)<0.001*60 months4 (2–8)15 (10–21)<0.001*Relapse/Progression12 months51 (43–58)72 (64–79)<0.001*36 months82 (76–88)80 (73–86)0.655Progression-free survival12 months47 (40–54)15 (10–21)<0.001*36 months13 (9–19)6 (3–10)0.038*Overall Survival (OS)12 months83 (77–89)51 (42–58)<0.001*36 months46 (37–54)20 (14–27)<0.001*60 months29 (21–38)9 (5–15)<0.001**Significant difference The most common cause of death in both cohorts was progression of MM. On multivariate analysis risk of death was higher for alloHCT (HR 2.38, p < 0.001), KPS < 90 (HR 1.96, p < 0.001), and year of transplant (2004 or earlier, HR 1.77, p = < 0.001). AlloHCT was associated with significantly higher risk of TRM (HR 7.14, p < 0.001). Durie-Salmon Stage III was associated with a higher risk of relapse (HR 2.70, 95% CI: 1.93–3.80, P<0.001) and treatment failure in the alloHCT group (HR 3.05, 95% CI: 2.20–4.22, p < 0.001). We conclude that patients with MM who underwent NST/RIC alloHCT after AHCT failure experienced higher TRM and lower probability of survival compared with those who received second AHCT. Because genetic risk data were not available for these patients, we cannot exclude the possibility that the alloHCT population was a higher risk population. Despite this limitation, our data demonstrate that the value of alloHCT after relapse from prior AHCT is limited. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 504 Background: There is limited data on the outcomes of AHCT for MM as a salvage approach following relapse after an initial (upfront) AHCT. We analyzed the outcomes of second salvage AHCT for relapsed MM. Methods: From the CIBMTR database we identified 187 patients (63% male) who had second AHCT (AHCT2) as salvage for MM relapsing after a prior AHCT (AHCT1). Planned tandem AHCT and AHCT2 within 6 months after AHCT1 were excluded. Cumulative incidence of relapse, non-relapse mortality (NRM) and the probabilities of progression-free (PFS) and overall survival (OS) were analyzed and multivariate analysis performed using proportional hazards models. Results: Median age at transplant was 57 (range 28–72) and 59 years (range 28–74) respectively at AHCT1 and AHCT2 respectively. Median follow up after AHCT2 was 47 months (range: 3–97). The proportion of IgG, IgA and free light chain subtypes was 48, 20 and 18% respectively. Durie Salmon stage at diagnosis was stage I (6%), II (21%), III (59%) respectively. Seven and 13% had serum creatinine > 1.5 mg/dl at AHCT1 and AHCT2 respectively. Conditioning regimen was single agent melphalan was in 78% and 84% for AHCT1 and AHCT2 respectively. At the time of AHCT2, majority (60%) were chemotherapy resistant compared with 80% patients with sensitive disease prior to AHCT1. Median time from AHCT1 to relapse was 18 months, with 32% relapsing within the first year, 29% in the second year, 19% in the third year and 19% beyond the third year after AHCT1. There was heterogeneity in the time to AHCT2 after relapse although 67% had AHCT2 within a year after relapse (median 7 months). Median between AHCT1 and AHCT2 was 32 months with the majority (69%) beyond 24 months. After AHCT2, day 28 engraftment rates of neutrophils and platelets were 96% (95% CI: 93–98) and 88% (95% CI: 83–92). Complete remission (CR) rates after AHCT1 were 43% whereas it was only 25% following AHCT2. After AHCT2, cumulative incidence of relapse at 1, 3 and 5 years was 51, 82, and 91% respectively. After AHCT2, one year NRM was 2%. PFS was 47%, 13% and 5% and OS was 83%, 46% and 29% at 1, 3 and 5 years respectively. In multivariate analysis, those relapsing within 36 months of AHCT1 had a higher risk of relapse (HR 1.58, p = 0.036) and higher risk of treatment failure and inferior PFS (HR1.52, p= 0.04). Mortality was higher for those relapsing early after AHCT1 (<36 months, HR 1.91, p = 0.02). OS was superior and mortality lower for AHCT2 performed after 2004-08 (HR 0.61, p=0.02). Conclusion: AHCT2 can be safely performed in relapsed MM with the best outcomes observed in later relapses (>36 months from AHCT1). OS has improved since 2004, but NRM, relapse and PFS after AHCT2 were not impacted by year of AHCT2. Thus the improved OS likely reflects greater availability of novel agents for post AHCT progression. Disclosures: No relevant conflicts of interest to declare.