Hari, Parameswaran

8515 Background: AL is a clonal plasma cell (PC) disorder causing multiorgan dysfunction from amyloid fibril deposition. While bortezomib (B) induction has been used prior to AHCT recently, AHCT without prior induction has been a common practice. The primary objective of this study was to compare outcomes of AL patients who proceeded to AHCT without induction to those receiving pre-AHCT induction with B. Methods: Outcomes of 426 systemic AL AHCT recipients between 2014-2018 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) were reviewed. Patients receiving induction with therapy other than B, AHCT occurring > 9 months after diagnosis, no documented AL end-organ involvement, myeloma-defining events and conditioning other than melphalan (MEL) monotherapy were excluded. Multivariate analysis (MVA) was conducted to identify prognostic factors associated with relapse, PFS and overall survival (OS). Results: 286 patients received B induction therapy vs 140 patients receiving no induction. Age, gender, number and type of organs involved, and AL AHCT center volume were similar between the groups. Patients receiving induction had greater PC burden compared with no induction (PC ≥ 10%, 41% vs 11%, p < 0.01). Induction was B, cyclophosphamide and dexamethasone (D) in 83% followed by B, lenalidomide and D (10%) or B+D (7%). Median follow-up was 24.9 months. At 2 years, B induction vs. no induction was associated with 13% (95% CI 10-17%) vs 22% (95% CI 15-30%) relapse risk (p = 0.03); 83% (95% CI 79-87%) vs 74% (95% CI 66-81%) PFS (p = 0.04); 93% (95% CI 90-95%) vs 94% (95% CI 89-97%) OS (p = 0.7). On MVA, the B induction group had improved PFS (HR 0.46, 95% CI 0.3-0.7, p < 0.001) with similar OS (HR 0.6, 95% CI 0.3-1.2, p = 0.1) compared with no induction. Creatinine < 2 mg/dl (HR 0.55, 95% CI 0.3-0.9, p = 0.02) and Karnofsky score ≥90 (HR 0.51, 95% CI 0.33-0.78, p < 0.01) were also associated with improved PFS. MEL dose < 180 mg/m2 was associated with inferior PFS (HR 2.17, 95% CI 1.31-3.61, p < 0.01) and OS (HR 3.6, 95% CI 1.5-8.6, p < 0.01). No deaths were seen in the first 100 days post-AHCT. At last follow-up, 32 deaths occurred, 26 (81%) due to AL. Conclusions: Compared with prior CIBMTR analyses, B induction use has increased in AL AHCT recipients and a higher PC burden was the only clinical determinant. Furthermore, B induction was associated with lower relapse and improved PFS at 2 years with no OS difference despite higher proportion of patients with > 10% PC, which has been associated with poor outcomes.

Abstract Background: HLA associations for the risk of developing MM have been described in various non-Caucasian ethnic groups but have not revealed consistent results. Racial and genetic differences in cytokine polymorphisms linked to extended haplotypes; association of autoimmune disorders with HLA types; the proximity of the HLA Class I and II genes to TNF and other Class III genes responsible for complement and cytokines suggest that HLA polymorphisms may be associated with the risk of developing MM. Aim: We compared HLA-A,-B and -DRB1 2-digit allele and haplotype frequencies in patients with MM to the normal population in order to define HLA specificities associated with the risk of developing MM. Methods: A cohort of 1803 US Caucasian patients with MM were identified based on availability of HLA-A, B, DRB1 DNA-based typing or serologic typing converted to 2-digit alleles. These patients had either received a matched sibling allogeneic transplant for MM reported to the CIBMTR (N=174) or had HLA typing performed for an unrelated donor search conducted through the US National Marrow Donor Program (NMDP) (N=1629). HLA-A, B and DRB1 allele frequencies among patients were compared to A-B-DRB1 frequencies in HLA typed healthy US Caucasian controls (N= 433838) from the NMDP database. The most frequent alleles among patients and controls as well as HLA haplotype frequencies generated using the EM (expectation-maximization) algorithm were compared using Chi-Square analysis with Bonferroni correction for the number of comparisons. Results: Patients with MM had a median age of 49 (range 3–78) years and M/F ratio of 1.86 (1172/631). The controls had a median age of 44 (range 18–60) years and M/F ratio of 0.735 (183785/250053). Comparison of HLA-A, -B and –DRB1 single-locus allele frequencies between the myeloma patients and controls (those in the top 10 in either group) revealed similarity except for HLA-B*07 and B*44. B*44 was observed less frequently among the patients (a protective effect) frequency (f): 0.126 vs 0.145 (p= 0.005, Odds Ratio (OR): 0.848). On the contrary, HLA-B*07 was more common (a predisposing effect) among patients (OR: 1.135, p=0.047). Among the top 20 two locus (HLA-A-B and HLA-B-DRB1) haplotype frequencies in either group, B*44-DRB1*13 and B*07-DRB1*13 were significant: OR: 0.506 and 1.714 (p=0.003 and 0.007) respectively. A-B-DRB1 haplotype comparisons showed significance for: A*02-B*44-DRB1*04 (OR: 0.686, p=0.021), A*02-B*44-DRB1*13 (OR: 0.445, p=0.065) and A*02-B*07-DRB1*04 (OR: 1.968, p=0.029) confirming the single and B-DRB1 combination comparison results. Significantly different HLA-A, -B and -DRB1 single-locus allele or haplotype frequencies between patients and controls are shown in table 1. Conclusion: This is the largest epidemiologic study of HLA allele frequencies and the first study on HLA haplotype frequencies in MM. We observed a protective effect on the risk of developing MM with B*44 and a predisposing effect with B*07. Similar predisposing and protective haplotype associations were observed with A*02-B*07-DRB1*04 and A*02-B*44-DRB1*04 respectively. A revised analysis using a gender-matched control group is in progress. Further study including major histocompatibility region SNP mapping and candidate gene testing will help elucidate the genetic basis underlying this observation. Table 1. Allele/Haplotype Frequency Controls Frequency MM Odds Ratio (OR) P value (corrected) OR = odds of observing the allele/haplotype in patients compared to controls A*02-B*44-DRB1*13 0.00620 0.00277 0.445 0.065 B*44-DRB1*13 0.01359 0.00686 0.507 0.003 A*02-B*44-DRB1*04 0.02605 0.01813 0.686 0.021 B*44 0.14552 0.12618 0.848 0.005 B*07 0.13313 0.14836 1.134 0.047 B*07-DRB1*13 0.00814 0.01397 1.714 0.007 A*02-B*07-DRB1*04 0.00367 0.00721 1.968 0.029

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

Background: Novel agent induction and AHCT remains the preferred initial therapeutic strategy for transplant-eligible MM patients. Current prognostic tools in MM focus solely on disease-specific factors at diagnosis to determine patient prognosis-International Staging System (ISS) and revised-ISS (R-ISS). A major limitation to both, the ISS and R-ISS, is that they are not specific for HCT-eligible patients and do not take into account other patient factors that may enter into a decision to pursue AHCT. The data used to generate these staging systems were from broad populations with varying upfront treatment strategies and included patients who were ineligible for intensive therapy. Additionally, there is considerable interest in identifying the population that relapses early despite modern induction/AHCT approaches who are candidates for novel approaches for maintenance/consolidation. To address these problems, we used data from the Center for Blood and Marrow Transplant Research (CIBMTR) registry to identify disease-, patient-, and transplantation-specific variables that are associated with progression-free survival (PFS) in patients undergoing upfront AHCT (within 12 months of diagnosis). Methods: We used the outcomes of 2528 MM patients undergoing upfront AHCT from 2008-2017 reported to the CIBMTR. Patients were divided into training and validation sets with a 50% random split. High risk cytogenetics was defined as the presence of one or more of the following: t(4;14), t (14;16), t (14;20), del 13q, del 17p, 1q gain, or 1p deletion. We used a Cox multivariable model to identify factors prognostic of progression free survival (PFS) in a training subset. The regression coefficients of the final model was transformed into a risk score with an appropriate transformation. A weighted score using these factors was assigned to the training cohort (n = 917) and validation cohort (n=897) using subset that had all values that entered the final model. Kaplan-Meier estimates of the individual scores were used to classify patients into risk groups for both cohorts. Results: Baseline characteristics of these patients are shown in Table 1. No cytogenetic abnormality, VRD induction, pre-AHCT bone marrow plasma cells (BMPCs) &lt;10% and 1 line of induction chemotherapy were assigned 0 points. Pre-AHCT BMPCs ≥10% (hazard ratio HR, 1.47; 95% CI, 1.19-1.83), use of ≥2 lines of induction chemotherapy prior to AHCT (HR 1.32; 95% CI 1.06-1.64), standard cytogenetic risk vs. no abnormality (HR 1.41; 95% CI 1.13-1.77) and induction regimens (non-VRD regimens vs. VRD) (HR 1.4, 95% CI 1.17-1.74) were associated with increased hazard of progression and assigned 1 point in the scoring system. Presence of high-risk cytogenetics vs. no abnormality (HR 1.87; 95% CI 1.45-2.42) was assigned 2 points, and the use of thalidomide and dexamethasone (TD) as an induction regimen (HR 2.19; 95% CI 1.48-3.2) was assigned 3 points. A two-category system was created based on the scoring: low risk (0-3) and high risk (4-6). The scoring system was prognostic for PFS when applied to both cohorts. High-risk group was found to have significantly higher risk of progression and/or death compared to low risk in training (HR 2.2; 95% CI 1.74-2.86; p&lt;0.0001) and validation cohort (HR 1.7, 95% CI 1.30-2.22; p=0.0001) respectively (Table 2). The 3-year PFS in the training cohort was 60% (95% CI 56%-64%) in low risk and 27% (95% CI 17%- 36%) in high risk while in the validation cohort was 51% (95% CI 47%-55%) in low risk and 28% (95% CI 16%- 39%) in high risk (Figure 1A and 1B). Conclusions: We describe a prognostic model specifically for patients undergoing upfront AHCT in MM which can identify patients at very high risk for early relapse/progression. These patients should be ideal candidates for studies of immunotherapy or other interventions after AHCT aimed at reducing relapse. Disclosures Dhakal: Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Shah:Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Poseida: Research Funding; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Bioclinical: Consultancy; Genzyme: Other: Speaker. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:AbbVie: Consultancy, Honoraria; Cell Vault: Equity Ownership; Sanofi: Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Research Funding; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Background: Autologous hematopoietic cell transplantation (AHCT) is an effective treatment to achieve deep and durable remission in multiple myeloma (MM). Typically, AHCT is offered to patients &lt;70 years of age, although the median age of diagnosis of MM is 70 years. We compared the outcomes of upfront AHCT across age groups for newly diagnosed MM in the era of novel therapies using the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Methods: We analyzed the outcomes of 15,999 MM patients aged 20 years and older from the USA who received a single AHCT with melphalan conditioning within 12 months of diagnosis between 2013 and 2017 and reported to the CIBMTR. Multivariate analysis was performed for non-relapse mortality (NRM), relapse/progression (REL), progression-free survival (PFS) and overall survival (OS) using Cox proportional hazards model with age at transplant in decades as the main effect. Hazard ratio (HR) with 95% confidence intervals (CI) are reported. Because of the large sample size, a p-value of &lt;0.01 was considered significant a priori. Results: Table 1 shows patient, disease and treatment characteristics by age group at diagnosis. All age groups had similar distribution of gender, race, ethnicity, Karnofsky performance score (KPS), comorbidity index (HCT-CI), stage III by Durie-Salmon/International Staging System. There was a higher proportion of high-risk cytogenetics in patients ≥70 years (30%), compared to age group 40-49 years (24%) and 20-39 years (20%) in this population. Older patients were more likely to be White compared to younger patients: 85% ≥70 compared to 64% 20-39 years. While 82% of the overall population received melphalan 200 mg/m2, 58% of the ≥70% received Mel 140 mg/m2. There were more ASCT performed in the ≥70-year age group in 2017 (28%) compared to 2013 (15%). Univariate outcomes by age groups shown in Table 2 revealed that 100-day NRM was higher in ≥70 years at 1% compared to younger patients (p &lt;0.01) and 2-year OS was lower in ≥70 years at 86 (85-88)% compared to 60-69 years, 89 (88-89)% (p&lt;0.01). When adjusted for other variables (Table 3), compared to reference age group of 60-69 years, patients ≥70 had similar NRM (HR 1.3, 95% CI 1, 1.7, p 0.06), REL (HR 1.03, 95% CI 0.9, 1.1, p 0.6), PFS (HR 1.06, 95% CI 1, 1.2, p 0.2), and OS (HR 1.2, 95% CI 1, 1.4, p 0.02). The leading cause of death across all age groups was primary disease. Among the ≥70 years cohort, melphalan dose was a surrogate for worse outcomes including NRM at 100 days (Mel 140, 1 (1-2)% vs Mel 200 0 (0-1)%, p 0.003, PFS at 2 years Mel 140 64 (60-67)% vs Mel 200 69 (66-73)%, p 0.003, and OS at 2 years (Mel 140 85 (82-87)% vs Mel 200 89 (86-91)%, p 0.01) (Figure). Conclusions: This is the largest study of AHCT in older adults with MM. More MM patients ≥70 years are being transplanted in the US over time. While our data may highlight referral and access biases regarding which older patients may be referred for ASCT, our results confirm that patients ≥70 years can undergo transplant safely and achieve similar benefits as 60-69 years' old patients. Our results also suggest that melphalan 200 mg/m2 may be given safely in the ≥70 years population. While melphalan conditioning dose 140 mg/m2 in the ≥70 group is associated with worse outcomes, this is likely a surrogate for higher frailty and comorbidities in this cohort of patients. Our analysis confirms that AHCT has similar benefits in terms of disease control (REL and PFS) in both young and older MM patients. This benefit is seen even in a contemporaneous era where proteasome inhibitors and/or immunomodulator drugs are used in upfront treatment. Thus, AHCT remains a safe consolidation therapy across all age groups of MM patients. Disclosures Hari: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Shah:Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Genzyme: Other: Speaker; Bioclinical: Consultancy; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees.

Background Primary plasma cell leukemia (pPCL) is a rare plasma cell neoplasm with a high mortality rate. There have been improvements in multiple myeloma (MM) outcomes with novel induction agents and use of hematopoietic cell transplantation (HCT) with maintenance, but similar progress has not been reported for pPCL. We examined the outcomes of pPCL patients receiving novel agents with autologous (autoHCT) or allogeneic (alloHCT) approaches as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) in the modern era. Methods From 2008 to 2015, 348 pPCL pts underwent HCT (N = 277 - autoHCT and 71 - alloHCT) with 45% and 48% having research level data available, respectively. Cumulative incidences of non-relapse mortality (NRM) and relapse/progression (REL), and probability of progression-free survival (PFS) and overall survival (OS) were calculated. Cox multivariate regression was used to model survival after autoHCT only. Median follow-up in autoHCT and alloHCT was 48 and 60 months, respectively. Results AutoHCT Cohort Median age was 60 years and 93% received HCT within 12 months of diagnosis with 76% after a single line of induction (Table 1). 35% had high risk cytogenetics. 23% received bortezomib, doxorubicin, cisplatin, cyclophosphamide, and etoposide (VDPACE). Moreover, 40% received bortezomib (BTZ) and immunomodulatory drug (IMIID)-based triplets. Disease status at HCT was VGPR or better in 47%. 27% received maintenance therapy. At 4 years post-HCT, NRM was 7% (4-11%), REL 76% (69-82%), PFS 17% (13-23%), and OS 28% (22-35%) (Figures 1A, 2A, 2B). Disease status ≥VGPR at HCT and Karnofsky Performance Score &gt;90 significantly predicted superior OS in multivariate analysis. AlloHCT Cohort Median age was 53 years and 89% received HCT within 12 months of diagnosis (Table 1). 61% received a single alloHCT, while 39% used auto-alloHCT tandem approach. 42% had high-risk cytogenetics. 61% received total body irradiation with 44% receiving myeloablative conditioning. Use of VDPACE was higher at 41% in this cohort. VGPR status at HCT was similar (48%), while maintenance was used less often (12%). Grade II-IV acute GVHD occurred in 30% and chronic GVHD in 45%. At four years post-HCT, NRM was 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%) (Figures 1A, 1B, 2A, 2B). There were no differences in outcomes based on type of HCT. A comparison of post-HCT outcomes of CIBMTR pPCL patients from 1995 to 2006 showed that PFS and OS outcomes are inferior despite lower NRM in this modern cohort (Mahindra et al. Leukemia. 2012). In addition, analysis of SEER (1995-2009) and CIBMTR databases showed that use of HCT increased from 12% (7-21%) in 1995 to 46% (34-64%) in 2009. Conclusion More newly diagnosed pPCL patients are receiving modern induction regimens translating into a higher proportion receiving HCT, but without significant further benefit post-HCT. Post-HCT relapse remains the biggest challenge and further survival in pPCL will likely need a combination of targeted and cell therapy approaches. This study provides a benchmark for future HCT studies for pPCL. Disclosures Girnius: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dhakal:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria. Shah:University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Bioclinical: Consultancy; Autolus: Consultancy; Genzyme: Other: Speaker. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria.

Abstract Background: Isatuximab (SAR650984) is a humanized IgG1 monoclonal antibody that binds selectively to a unique epitope on the human CD38 receptor. In the dose escalation part of the Phase I portion of the trial (NCT01749969), isatuximab ≥10 mg/kg IV given every other week (q2w) or 10 mg/kg weekly (qw) induced responses in 6/19 recipients (ORR 32%). Responses were noted at doses as low as 1 mg/kg q2w. The maximum tolerated dose (up to 20 mg/kg IV qw) was not reached. The most common treatment-emergent adverse events (TEAEs) were fatigue and nausea; few serious grade 3/4 TEAEs were reported (pneumonia 6%). The most common category of drug-related TEAE involved infusion-associated reactions (IARs) occurring in half of the patients, with grade 3/4 IARs in <5% of the patients. Based on promising Phase I activity, a Phase II dose finding study was added to investigate single-agent isatuximab in patients with relapsed or refractory myeloma (RRMM). Methods: In Phase II, eligible patients were originally randomly assigned (1:1:1) to one of 3 treatment groups: 3 mg/kg q2w, 10 mg/kg q2w, and 10 mg/kg q2w x 4 doses then q4w. A 4th treatment group was enrolled at a higher isatuximab dose with an optimized schedule of 20 mg/kg qw x 4 doses then q2w. Patient assignment was stratified by prior anti-myeloma therapy (Stratum 1: prior treatment with pomalidomide (POM) and/or carfilzomib (CAR); Stratum 2: no prior POM or CAR). Patients continued therapy until disease progression, unacceptable AEs or physician/patient decision. Eligible patients had measurable disease (serum M-protein >1 g/dL or urine M-protein ≥200 mg/24 h, or serum free light chain ≥10 mg/dL), prior exposure to ≥3 lines of anti-myeloma therapy or were double-refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), prior treatment with an alkylating agent, and adequate baseline bone marrow reserve and organ function. Enrollment of 24 patients was planned for each treatment group. An interim efficacy analysis is planned when all patients have completed ≥2 disease assessments, with central review of these data currently ongoing. Enrollment has now been completed and all patients who completed at least 1 cycle of isatuximab at the cutoff date (5/29/15) are included in this preliminary analysis. Results: Patient characteristics (n=96): median age 62.5 yrs (range 38-85); median time from initial diagnosis to study treatment 5.85 yrs (1.2-24.1); 76% had IgA/G MM; 24% had light-chain only disease; and 22%, 22%, and 44% had Stage I, II, and III disease, respectively. The median number of prior lines of therapy was 5 (2-14) with 100%, 99%, and 98% having prior exposure to PIs, IMiDs, and alkylator-containing therapy, respectively. Overall, 78% of patients had previously received POM and/or CAR; 55% had been exposed to both of these agents. At data cut-off, 36.5% of patients remained on therapy and 53.1%, 6.3%, and 4.2% had discontinued therapy due to disease progression, AEs, or other reason, respectively. The median number of cycles received was 3 (1-9), with a median duration of treatment of 11.7 wks. Approximately 17% of patients required at least 1 dose delay and 7.3% of isatuximab infusions were interrupted. TEAEs occurred in 93% of patients, with 51% being grade ≥3. Drug-related TEAEs occurred in 61% of patients (grade ≥3, 10%). The most common drug-related TEAEs (>5% of patients) were nausea (14.6%), chills (14.6%), dyspnea (13.5%), chest discomfort (10.4%), flushing (7.3%), headache (7.3%), cough (6.3%), and vomiting (5.2%). The majority of the symptoms occurred within 24 h of isatuximab infusion and were attributed to an IAR. IARs occurred in 50% of patients, were predominantly grade 1/2 (grade ≥3, 3.1%), and were mostly limited to Cycle 1 (2 patients had IARs in Cycle 2). Pneumonia (6.3%) and sepsis (5.2%) were the most common serious TEAEs. Six deaths have occurred within 30 days of last dose, 4 due to disease progression, and 2 due to serious AEs unrelated to study therapy (cardiopulmonary arrest and cerebral hemorrhage). Conclusion: Isatuximab administered to heavily pre-treated patients with RRMM appears well tolerated. IARs are common in Cycle 1, but typically do not recur. Results by treatment arm, including interim analysis response data, will be presented. Disclosures Martin: Sanofi: Research Funding. Richter:Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Vij:Millennium: Honoraria, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS, Amgen, Prothena, Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Kaufman:Spectrum: Consultancy; Merck: Research Funding; Onyx: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Millenium: Consultancy. Bensinger:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acetylon: Research Funding; Sanofi: 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, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millenium: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dimopoulos:Novartis: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria. San Miguel:Millennium, Celgene, Novartis, Janssen, Onyx, BMS, MSD: Membership on an entity's Board of Directors or advisory committees. Zimmerman:Onyx: Honoraria; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Hari:Celgene: Consultancy; Takeda: Consultancy; BMS: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Sanofi: Consultancy. Gasparetto:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Honoraria; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kumar:Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding. Hsu:Sanofi: Employment. Charpentier:Sanofi: Employment. Strickland:Alexion Pharmaceuticals: Other: Advisory Board Particpation; Amgen: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation; Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation. Mikhael:Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; AbbVie: Research Funding.

Background Multiple myeloma (MM), a malignant neoplasm of plasma cells in the bone marrow, accounts for up to 1.8% of all cancers in the U.S., most frequently affecting people 65-74 years old. A variety of therapies are available to manage MM, including stem cell transplantation (SCT), immunomodulatory drugs (IMiD), proteasome inhibitors (PI), monoclonal antibodies (mAB), and alkylating agents (alk). Given the heterogeneity of MM and the rapidly evolving therapeutic landscape, MM contemporaneous real-world treatment patterns are not well described. We examined the patient characteristics and first-line (LT1) treatment patterns in NDMM patients. Methods MM patients (≥18 years), diagnosed in April 30, 2015 - April 29, 2017 (early cohort) or in April 30, 2017 - April 30, 2019 (recent cohort), were followed retrospectively from MM diagnosis to last patient activity in the Flatiron Health database - a geographically-diverse, longitudinal electronic health record spanning over 280 community and academic cancer clinics in the U.S. LT1 regimens were described as: 1) containing an IMiD (thalidomide, lenalidomide [R], or pomalidomide), PI (bortezomib [V], carfilzomib, or ixazomib), alk (melphalan, cyclophosphamide [C], bendamustine), mAB (daratumumab, elotuzumab), or combinations of these; and 2) doublet/monotherapy (doublets-) vs. triplet or greater agent (triplets+) combinations. Treatment patterns were examined by SCT status and by cytogenetic risk (high: del17p, t(4;14) and/or t(14;16); standard: ≥1 cytogenetic tests without high cytogenetic risk) and age groups (<65, 65-74, ≥75). Duration of therapy (DOT) and time to next therapy (TTNT) were estimated using Kaplan-Meier methods in the early cohort with longer follow-up. Results Of 4,070 NDMM patients, 3,433 were non-SCT (nSCT: early cohort: n=1,736; recent cohort: n=1,697) and 637 had SCT (early cohort: n=407; recent cohort: n=230). In nSCT patients, mean age at diagnosis was 70 years (SD: 10); 46% were female; 36% had stage III (699/1916, among non-missing), and 15% (392/2574, among non-missing) had high risk MM (25% had unknown cytogenetics). SCT patients were younger at diagnosis (mean [SD]: 61 years [9]); 44% were female; 25% (117/470, in non-missing) had stage III, and 19% (102/547, in non-missing) had high risk MM (14% had unknown cytogenetics). Overall, proportions with known cytogenetic risk were similar within SCT status cohorts over time but were lower in the SCT group (nSCT early vs. recent cohort: 26% vs. 24% had unknown cytogenetics; and in SCT: 15% vs. 13%, respectively). In nSCT and SCT patients, respectively, most common regimens were VRd (d: dexamethasone; 44% and 58%), Rd (16% and 7%), Vd (13% and 1%), and VCd (12% and 4%). In nSCT patients, the use of VRd increased over time (37% [early cohort] to 51% [recent cohort]), while frontline therapy with Rd/Vd doublets (19% to 14%/16% to 9%) and with VCd (13% to 11%) decreased. In the nSCT recent cohort, VRd (51%) frontline therapy dominated, with a slightly higher proportion of patients in the high-risk group vs. standard and unknown risk receiving VRd (56% vs. 53% and 46%); use of doublet therapy with Rd/Vd was lower in the high risk (12%/5%) vs. standard risk group (14%/9%). Irrespective of age, VRd was the most common frontline regimen in the nSCT recent cohort, albeit its use was lower among patients 75+ years of age (43%) vs. younger patients (54% [<65 years] and 59% [65-74 years]); 75+ year old patients had a higher use of Rd/Vd doublets (19%/15%) vs. <65 (10%/5%) or 65-74 (10%/6%) years of age. Triplets+ were more commonly used than doublets- across all cohorts: 59% vs. 41% (nSCT early cohort); 74% vs. 26% (nSCT recent cohort); and 89% vs. 11% (SCT early cohort); 95% vs. 5% (SCT recent cohort). mAB use in the recent cohort was low: 1.4% nSCT and 2.2% SCT patients. In the nSCT early cohort, the median (95% CI) LT1 DOT was 10 months (9-11) and for TTNT was 14 months (13-16). Conclusions PI/IMiD treatment combinations were most commonly observed in both nSCT and SCT patients, with an increase in use from early (40%) to recent (56%) cohort in nSCT patients. Use of triplets, generally, is on the rise from early (60%) to recent cohorts (74%). LT1 TTNT was lower than has been shown in clinical trials. These findings indicate a notable change in treatment patterns over time in nSCT NDMM patients, highlighting the changing landscape of MM management. Disclosures Ailawadhi: Celgene: Consultancy; Takeda: Consultancy; Cellectar: Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding. Romanus:Takeda: Employment. Cherepanov:Takeda: Employment. Yin:Takeda: Employment. Cheng:Takeda: Employment. Hari:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria.

Introduction: Proteasome inhibitors (PI), immunomodulatory agents (IMiDs) and the CD38 monoclonal antibody daratumumab (dara) have transformed the management of MM, yet eventual refractoriness to these agents seems inevitable. Relapsed and refractory MM (RRMM) which becomes triple class refractory (TCR, i.e. refractory to a PI, an IMiD and Dara) uncommonly responds to further lines of therapy and survival is dismal. Selinexor is a selective inhibitor of nuclear export compound targeting exportin 1 (XPO1) which is overexpressed in MM cells and essential for their survival. In the STORM study, selinexor in combination with low-dose dexamethasone (Sd) demonstrated promising efficacy in TCR, penta-exposed (TCR-PE, i.e. exposed to lenalidomide, pomalidomide, bortezomib, carfilzomib and dara) MM. Establishing the natural history for outcomes in the TCR-PE population can help provide context to understand the outcomes observed with Sd in STORM. In the retrospective MAMMOTH study, we reported the outcomes of patients with RRMM after they became refractory to dara, including a subset of patients who were TCR. We further analyzed the MAMMOTH dataset to generate a cohort of patients similar to patients in STORM in order to compare conventional care vs. Sd. Methods: We included all patients in STORM who received Sd as the first line therapy after they achieved TCR-PE status (n=64). We extracted from the MAMMOTH dataset all patients who were not exposed to Sd in a subsequent line of therapy, became TCR-PE and who received subsequent MM-directed therapy (n=128). Overall response rate (ORR) was evaluated according to IMWG criteria. Overall survival (OS) was calculated from the time of initiation of next line of therapy after TCR-PE status until death or last follow-up. We compared OS in STORM vs. MAMMOTH utilizing cox-regression analysis with adjustment for covariables potentially influencing the outcome. Results: Baseline patient characteristics and prior therapies are per table. The two cohorts were similar in terms of age, number of prior lines of therapy and presence of high-risk cytogenetic abnormalities. STORM patients had longer time between MM diagnosis and post TCR-PE therapy with a higher proportion of refractoriness to carfilzomib. Patients in STORM had ORR to Sd of 32.8% vs 25.0% for patients receiving conventional care in MAMMOTH (P=0.078). In direct comparison, patients in STORM had better OS than patients in MAMMOTH (median 10.4 vs. 6.9 months) (P=0.043, figure). In multivariate analysis, STORM patients had lower risk of death in comparison with MAMMOTH patients (aHR=0.55, 95%C.I. 0.35-0.86, P=0.009). Refractoriness to carfilzomib (aHR=2.20, 95%C.I. 1.16-4.15, P=0.015) and high-risk cytogenetics (aHR-1.66, 95% C.I. 1.13-2.42, P=0.009) were also associated with inferior OS. Conclusion: Despite inherent limitations in comparison of trial enrollees vs. real world patients, this analysis suggests improved OS with Sd vs conventional care in patients with TCR-PE RRMM. Prognosis for these patients remains poor and underscores the need for therapeutic advancements. Disclosures Costa: Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hari:Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Tang:Karyopharm: Employment. Shah:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Jagannath:BMS: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy; Multiple Myeloma Research Foundation: Speakers Bureau. Chari:Oncoceutics: Research Funding; Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: 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, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, 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; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Ma:Karyopharm: Employment, Equity Ownership. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding. Lonial:BMS: Consultancy; Genentech: Consultancy; GSK: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Celgene Corporation: Consultancy, Research Funding; Karyopharm: Consultancy. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Malek:Adaptive: Consultancy; Amgen: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding. Fiala:Incyte: Research Funding. Usmani:Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. Kang:Takeda Oncology: Consultancy; InCyte Corportation: Research Funding. Cornell:Takeda: Consultancy; KaryoPharm: Consultancy.

Background: Patients ≥55 years of age with rel/ref AML who have failed to achieve complete remission (CR) after standard induction & salvage therapies do not routinely undergo allogeneic hematopoietic cell transplantation (HCT) due to inability to receive myeloablative conditioning and lack of efficacy. With the advent of recently approved targeted therapies (e.g. venetoclax, IDH inhibitors) more patients achieve CR, however durable responses in heavily pre-treated patient populations remain unsatisfactory with very few patients being transplanted. The SIERRA (Study of Iomab-B in Elderly Relapsed or Refractory AML) trial is a prospective, randomized, phase 3 trial designed to address this unmet need. We present the preliminary analysis of the first 50% of patients and analyze the proportion of patients who fail standard chemo and targeted therapies that can then successfully undergo HCT with Iomab-B-based conditioning. Study continues to enroll (N=150), primary end-point durable CR of ≥180 days. Methods: Eligible patients are ≥ 55 years with rel/ref AML (≥5% blasts), adequate organ function, and related/unrelated 8/8 HLA-matched donors. Patients are randomized (1:1) to receive Iomab-B followed 12-14 days later by reduced intensity conditioning (fludarabine(FLU)/TBI) and HCT, or to conventional care (CC). CC patients may receive investigator's choice of salvage therapy, including newly approved targeted agents such as venetoclax, IDH Inhibitors and may proceed to standard HCT if they achieve CR. If patients do not achieve CR, the study allows cross-over (CO) to Iomab-B with HCT. Results: Preliminary data are available from the first 75 patients enrolled on the SIERRA trial. Median age of 64 years (range: 55-77). All patients had active measurable disease (Table 1). Patients in this trial were heavily pretreated with 85% failing ≥2 induction therapies and 33% failing targeted therapies. Molecular and cytogenetics was 68% adverse risk. (NCCN, v1.2018) Following therapeutic dose of Iomab-B as a single agent, there was significant reduction of circulating blasts by day 3 (99%, p<0.0001), and peripheral blasts became undetectable by day 8 prior to FLU. All patients transplanted on the Iomab-B arm with data available showed median days to engraftment of ANC at 14 (range: 9-22) and platelets at 16 (range: 4-30) (Table 1). After randomization, 82% (31/38) patients in the CC arm failed salvage therapy and did not proceed to standard HCT. Significantly, 32% (12/38) of these patients received targeted therapy. 73% (8/11) of the patients receiving venetoclax with HMA or cytarabine did not adequately respond and did not proceed to standard HCT, 45% (5/11) crossed over to Iomab-B and received HCT. Following standard chemotherapies, 85% (22/26) were evaluated for CO. In total, 63% (19/30) received Iomab-B and HCT. The most common reason preventing crossover was disease progression. All crossover (Iomab-B) patients showed similar engraftment (Table 1). CC patients showed increased incidence of febrile neutropenia with grade 3 prior to CO evaluation or HCT, compared to Iomab-B patients prior to HCT (CC: 34%, Iomab-B: 8%). Iomab-B administration was generally well-tolerated with no grade 4 and 1 grade 3 infusion reaction. There were no Iomab-B-related deaths or 100 day non-relapse transplant related mortality deaths in patients on the Iomab-B arm (Table 1). Conclusion: 100% of the patients receiving HCT on the Iomab-B arm engrafted, despite a median of 29% BM blasts pre-Iomab-B. 82% of the patients on the CC arm failed to be eligible for standard of care transplant, including a high percentage of those receiving targeted therapies. On the CC arm, 63% of eligible patients crossed over to Iomab-B/HCT with robust engraftment despite a median of 35% BM blasts pre-Iomab-B. The incidence of grade 3 febrile neutropenia was higher in patients treated on the conventional care arm with salvage therapy vs. those treated on the Iomab-B arm prior to HCT. In conclusion, despite advanced age, active disease and heavily pre-treated patients, 68% (50/74) of all patients enrolled in the SIERRA trial were able to undergo HCT after reinduction and targeted conditioning with Iomab-B. These results show significant improvements in the current rates of transplantation in this patient population. This SIERRA trial is currently enrolling. For full study details see www.sierratrial.com or clinicaltrials.gov (NCT02665065). Disclosures Gyurkocza: Actinium Pharmaceuticals: Research Funding. Nath:Astellas: Consultancy; Actinium: Consultancy; Daiichi Sankyo: Consultancy. Stiff:Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Unum: Research Funding; Cellectar: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding. Tomlinson:Actinium Pharmaceuticals, Inc: Other: Travel Support. Abhyankar:Incyte: Speakers Bureau; Therakos: Other: Consulting, Speakers Bureau. Hari:AbbVie: Consultancy, Honoraria; Cell Vault: Equity Ownership; Sanofi: Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria. Al-Kadhimi:Seattle Genetics: Other: Stocks; Celldex Biotech: Other: Stocks. Foran:Agios: Honoraria, Research Funding. Orozco:Actinium Pharmaceuticals: Research Funding. Van Besien:Miltenyi Biotec: Research Funding. Sabloff:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding. Kebriaei:Pfizer: Honoraria; Kite: Honoraria; Jazz: Consultancy; Amgen: Research Funding; Pfizer: Honoraria; Kite: Honoraria; Jazz: Consultancy; Amgen: Research Funding. Levy:Takeda (Millennium Pharmaceuticals): Consultancy. Lazarus:Adaptive Biotechnologies: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Actinium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva Pharmaceuticals: Speakers Bureau; Biosight: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Pluristem Therapeutics, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Genentech: Speakers Bureau. Giralt:Novartis: Consultancy; Actinium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Kite: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy. Berger:Actinium Pharmaceuticals, Inc: Employment, Equity Ownership. Reddy:Actinium Pharmaceuticals: Employment. Pagel:Pharmacyclics: Consultancy; AstraZeneca: Consultancy; Gilead Sciences: Consultancy.