ALBERT

Description: Advances in novel agents and treatment combinations have improved prognosis and increased disease-free and overall survival for patients (pts) with multiple myeloma (MM). However, currently available data on disease presentation, treatment patterns, and outcomes for real-world MM pts at the global level are limited. This is due to several factors, including the overrepresentation of medically fit pts in clinical trials making generalization of outcomes challenging, the large number of treatment combinations, and varying global access/practice patterns. INSIGHT-MM (NCT02761187) is a global, prospective, non-interventional, observational study which aims to further understand disease and pt characteristics at presentation, treatment and clinical outcomes of real-world MM pts, as well as the association of treatment with tolerability, effectiveness, health-related quality of life (HRQoL), and healthcare resource utilization (HRU), on both a country-specific and global basis. As this is an observational study, no formal hypothesis will be tested. The INSIGHT-MM objectives are summarized in the Table. At least 5000 pts aged ≥18 yrs with newly diagnosed or relapsed/refractory MM will be enrolled over a 3-yr period and followed prospectively for ≥5 yrs, until death or end of study, whichever comes first. Pts not available for data collection for 〉9 mos will have follow-up for survival. No study drug or medications will be provided; no modification of standard of care pt management will be assigned per protocol. Choice of therapy for all pts will be decided by the treating healthcare provider independent of study participation. Baseline pt and MM-specific characteristics, diagnosis, comorbidities, and prior therapies will be recorded based on review of hospital/clinic records. MM management, disease status and safety data will be obtained as part of routine office visits and recorded quarterly by each site in electronic case report forms. Quarterly assessment of MM management will be done based on prior and current treatment and recorded reason for treatment changes. Effectiveness of therapy will be assessed based on response, progression status, time to next therapy, vital status, and date and cause of death. Treatment tolerability will be assessed based on serious and non-serious adverse events leading to treatment discontinuation or dose modification. Incidence of second primary malignancies will be recorded. HRQoL, a specific type of patient reported outcome (PRO), will be collected at study entry and at predefined intervals following initiation of therapy using a secure electronic data collection system. HRQoL will be collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the MM module (EORTC QLQ-MY20). To capture pt satisfaction with MM-directed therapy, including the dimension of convenience, the 9-item Treatment Satisfaction Questionnaire for Medication will be used. The 5-dimension, 5-level EuroQol (EQ-5D-5L) PRO instrument will capture self-reported preference-based measures of health status suitable for calculating quality-adjusted life year (QALY) data to inform health economic evaluations. Frailty will be assessed using the Charlson Comorbidity Index, the Katz Index of Independence in Activities of Daily Living, and the Lawton Instrumental Activities of Daily Living. HRU will be evaluated using inpatient and intensive care unit admissions, length of stay, outpatient clinic visits, and emergency room visits. Data for all participating pts will be extracted by healthcare professionals at the site level and entered into a central database; descriptive statistical analyses will be done to address the study objectives. Interim analyses are planned after 1000 and 5000 pts have been enrolled and a final analysis will be conducted within 1 year after the last pt entered has completed ≥5 yrs follow-up. Data will be analyzed biannually to address emerging clinical questions identified by investigators to increase understanding of real-world treatment patterns. INSIGHT-MM aims to promote better understanding of contemporary demographics, patterns of care, and outcomes for real-world MM pts to inform treatment practice, supportive care, and pt outcomes. The study is currently ongoing and recruiting pts; further details regarding study rationale and protocol will be provided. Table 1 Table 1. Disclosures Davies: Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Zonder:Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Girnius:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Costello:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Usmani:Array: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Omel:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Member of Takeda's "Patient Leadership Council". Token payment. Thompson:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: MDS/AML Registry; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AIM Specialty Health: Membership on an entity's Board of Directors or advisory committees; VIA Oncology: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Multiple Myeloma International Registry; Doximity: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shah:Array: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: 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. Schwartz:Bayer: Consultancy; Blue Cross and Blue Shield Associations: Consultancy; Pfizer: Consultancy; Takeda: Consultancy. Hajek:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Amgen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria. Hungria:Takeda: Consultancy; Roche: Consultancy; International Myeloma Foundation Latin America: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Bristol: Consultancy; Amgen: Consultancy. Mateos:Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cook:Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Leleu:Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; TEVA: Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Pashos:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Stull:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Romanus:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Cacioppo:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Bell:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Yu:Takeda Restricted Stock Unit (RSU), a publicly traded company: Equity Ownership; Takeda Development Center Americas, Inc., Deerfield, IL, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Luptakova:Takeda Oncology: Employment. Niculescu:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Noga:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Skacel:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Chari:Array Biopharma: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Pharmacyclics: Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Description: Introduction:The management of multiple myeloma has become increasingly complex, given late age of onset, underlying co-morbidities, plethora of drugs, and variable clinical presentation and natural history. Practice patterns likely vary based on practice type, physician experience, and geographic distributions. The Multiple Myeloma Research Foundation's (MMRF) CoMMpass Trial (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile) is a prospective, longitudinal, observation trial in NDMM with the primary goal of correlating patient data and response with molecular profiles. Here, we evaluate practice patterns in NDMM the CoMMpass Trial based on staging, high-risk features, and demographics. Methods: Clinical data were derived from MMRF's CoMMpass IA8, accessed in late July 2016 on https://research.themmrf.org/rp/explore. Independent categorical variables analyzed include International Staging System (ISS), Revised-ISS (R-ISS), LDH (normal vs. above upper limit of normal), Fluorescence-In-Situ Hybridization (FISH) (standard vs. high risk (t(4;14), t(14;16), t(14:20), del17p)), race, performance status (PS) (0-1, 2, 3-4), age (〉65, 65-75, 76-80, 〉80 years), and gender. Dependent variables include use of doublets vs. triplets, the use of triplets using combined immunomodulatory/proteosome inhibition (IMID/PI), receiving or not receiving an autologous stem cell transplantation (ASCT), and timing of transplant (10 months). For high-risk MM, defined as ISS 3, R-ISS 3, elevated LDH, or high risk FISH, patients receiving doublet therapy without an autologous stem cell transplantation were further analyzed for performance status and age. Descriptive statistics were used. Chi-square testing was used to compare variables, using STATA v14.1. Results: Data on 921 patients has been released and was reviewed. Although men and women had similar upfront therapy, including the use of triplet (57% vs. 61%, p=0.483) and IMID/PI combinations (56% vs. 62%, p=0.181), women were more likely to have an ASCT (44% vs. 34%, p=0.002). When compared to European Americans (EA), African-Americans (AA) were less likely to receive triplets (47% vs. 61%, p=0.004), IMID/PI combination (55% vs. 59%, p=0.001), and ASCT (30% vs. 40%, p=0.034). Patients with high-risk disease were not more likely to be treated more aggressively. Patients with ISS Stage 3 disease were less likely to receive triplets (50% vs. 64%, p=0.002), IMID/PI combinations (51% vs. 66%, p=0.001), or an ASCT (26% vs. 48%, p=

Description: Background PI-based therapy is a standard of care for non-transplant NDMM pts. However, long-term treatment, which is associated with improved outcomes, is often challenging in the RW. This may be due to a number of factors, including the burden of repeated intravenous (IV)/subcutaneous (SC) administration, distance from treatment center, comorbidities, and toxicity (e.g. peripheral neuropathy [PN] with btz). With the aim of increasing PI-based treatment adherence and duration while maintaining quality of life (QoL), the US MM-6 RW, community-based study (NCT03173092) investigates a transition from IV/SC btz-based induction to all-oral ixazomib-based therapy (ixazomib-lenalidomide-dexamethasone, IRd). We report efficacy and safety, plus adherence and electronic pt-reported outcomes (ePRO) compliance data, for the first 55 pts. Methods Non-transplant NDMM pts (transplant-ineligible or transplant delayed 〉24 mos) with ≥stable disease (SD) after 3 cycles of a btz-based induction are being enrolled at 23 community sites to receive IRd (ixazomib 4 mg, d 1, 8, 15; lenalidomide 25 mg, d 1-21; dexamethasone 40 mg [20 mg in pts aged 〉75 yrs], d 1, 8, 15, 22) for up to 26 x 28-d cycles or until progression/toxicity. Pts complete ePROs every cycle to assess QoL/treatment satisfaction, and a monthly medication adherence survey via a wearable device/smartphone. The primary endpoint is progression-free survival (PFS); key secondary endpoints include partial (PR), very good partial (VGPR), and complete (CR) response rates, and duration of therapy. Results As of April 1 2019, 55 pts had been enrolled at 16 sites. Median age was 72 (range 49-90) yrs, with 76% classified as elderly (≥65 yrs); 47% were male. Key characteristics of this RW population are summarized in Table 1. Comorbidities/concurrent medical conditions at the start of IRd therapy were extensive and included hypertension (51%), anemia (44%), fatigue (42%), renal and urinary disorders (36%), gastroesophageal reflux disease (31%), cardiac disorders (27%), constipation (27%), nausea (24%), and PN (16%); 91% of pts were receiving concomitant medications. At data cutoff, with 40 (73%) pts remaining on therapy, median duration of PI therapy, including prior btz-based induction, was 6.9 mos (mean 8.4 mos) (Table 2). Median duration of IRd treatment was 4.0 mos (median 5 cycles; mean 5.6 mos, 6.6 cycles), with pts having received up to 17.3 mos (18 cycles) of therapy to date. After 3 cycles of btz-based induction, the ≥VGPR rate was 27%, with 4% ≥CR; overall response rate (ORR) was 62%. With IRd therapy, the ≥VGPR rate was 40%, with 22% ≥CR; ORR was 65% (15% not evaluable). Following transition from btz-based induction to IRd, 21 pts (36%) had deepened responses (18% increase in ≥CR rate), including 3 VGPR to CR, 3 PR to CR, 1 MR to CR, 4 SD to CR, 3 PR to VGPR, 1 SD to VGPR, 5 SD to PR, and 1 SD to MR (Figure). With limited follow-up, and enrollment ongoing, 3 pts had progressed and one had died at data cutoff. The preliminary 6-mo PFS rate (95% CI) was 91% (74-97%) from start of IRd and 96% (84-99%) from start of btz-based induction. Average compliance with completing issued ePRO questionnaires during IRd treatment was 96% (61 pts; data cutoff July 8, 2019). Patients recorded their monthly medication adherence for the previous 4 weeks; 81% of evaluable pts (n=32) in cycle 1, 81% in cycle 2 (n=27), 77% in cycle 3 (n=22), 96% in cycle 4 (n=24), and 94% in cycle 5 (n=18) (n2 pts. AEs led to study drug modification in 47% and discontinuation in 4% of pts; 29% had serious AEs. PN occurred in 25% (4% grade 3) and led to dose modification in 13% of pts. There were no on-study deaths (i.e. occurring

Description: Background Multiple Myeloma (MM) is a heterogeneous disorder of clonal plasma cells. Genetic aberrations are important in heterogeneity and have prognostic and perhaps therapeutic implications. Elevated Lactate Dehydrogenase (LDH) has been associated with drug resistance and short survival. The biologic basis of this observation is uncertain. In this study, we sought to define the genomic landscape of MM patients with high LDH to understand pathophysiology and identify therapeutic targets. Methods Utilizing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass database (IA12), which includes over 1000 newly-diagnosed MM patients with enriched tumor and matched constitutional samples analyzed using whole genome/exome and RNA sequencing (RNA-seq), we identified a cohort of patients with baseline LDH values and RNA-seq data available for inclusion. High LDH was defined as LDH greater than upper limit of normal (〉4.68 microkatals/L). The RNA-seq data was analyzed to predict differentially expressed genes, then gene set enrichment analyses using GSEA and ClueGO were performed to assess for highly enriched pathways and gene ontologies (GO). Thereafter we analyzed to see if there was an enrichment of high risk cytogenetic changes within the high LDH group. Overall survival (OS) was estimated by Kaplan Meier method and a log-rank test. Results We identified 871 patients who met inclusion criteria (High LDH N=143; Normal LDH N=728). LDH continued to remain a poor prognostic factor consistent with prior literature, with median survival 660 days vs 795 days (p=0.02852). Among the patients who underwent autologous transplant (N=385), LDH continued to be associated with poor prognosis with median overall survival (800.5 vs 878.8 days, p=0.01933). Patient characteristics and other clinical variables are submitted separately (Bal et al. ASH 2018). There was no difference in the non-synchronous mutations between the two groups when stratified by baseline LDH levels. To assess for enrichment of the known cytogenetic changes, we performed the hypergeometric test on the samples with both baseline LDH and cytogenetic information. Del(17p13) was significantly enriched (p=0.011) in the high LDH subset compared to normal LDH. (18.48% vs 10.36%) while there was no statistically significant difference in the presence of t(4;14) (p=0.16, 15.65% vs 11.8%) and t(14;16) (p=0.21, 6% vs 4%). GSEA detected 572 gene sets significantly up-regulated in the high LDH group (FDR q 〈 25%) compared to those with normal LDH including genes involved in the processing of capped intron containing pre-mRNA, recruitment of mitotic centrosome proteins and complexes, mRNA splicing and the proliferation signal in solid tumors leading to metastatic potential. No significantly down-regulated gene set was detected at same significance level. The ClueGO analysis using two separate sets of up-regulated DEGs (fold 〉 1.5x or fold 〉 2x, FDR 〈 0.05 for both) revealed upregulated molecular signatures in similar functional categories as the GSEA in patients with high LDH. The first gene set (fold 〉 1.5x) showed significant enrichments (p 〈 0.005) in cell cycle-related pathways, including microtubule cytoskeleton organization, polo-like kinase mediated events, regulation of cell cycle phase transition, regulation of nuclear division and kinesins which provide the myeloma cells with a proliferative advantage. The second gene set (fold 〉 2x) was strongly associated (p 〈 0.005) with sympathetic nervous system development (NELL2, NTRK1, and SOX11), collagen biosynthesis (ADAMTS family) and O-linked glycosylation (COL11A family). These genes play a role in lymphocyte differentiation, anti-apoptosis, local invasion, and metastasis. Conclusion Elevated LDH was confirmed as a poor prognostic factor in the MMRF CoMMpass cohort. Overrepresentation of Del17p in this population likely contributes to poor prognosis. In MM, the bone marrow microenvironment is crucial in the differentiation, migration, proliferation and survival. Overexpression of proteolytic and cell adhesion signatures, evasion/suppression of host immune system along with hyper-proliferative signatures via cell division and RTK pathways in MM patients with high LDH offers insight into the aggressive disease in these patients. Targeting tumor microenvironment and RTK pathways may provide novel therapeutic strategies in this subtype of MM Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Description: Background While survival of patients with multiple myeloma (MM) continues to improve, disparities in care are widely prevalent. While sex-based differences in cancer outcomes are apparent in several malignancies, these have not been studied as extensively in MM and consequently, the biology underlying these differences are unknown. Methods We utilized the Multiple Myeloma Research Foundation (MMRF) CoMMpass database (IA11) to evaluate the outcomes of MM by sex. The CoMMpass database includes over 1000 newly-diagnosed MM patients with enriched tumor samples analyzed using RNA sequencing (RNA-seq). Differentially expressed genes (DEGs) were predicted from RNA-seq data using the limma-voom method after TMM normalization, then gene set enrichment analyses using GSEA and WebGestalt and ClueGo were performed to assess for highly enriched pathways. We then performed multiple linear regression analysis using sex as the dependent variable. Other known high-risk prognostic markers were used as independent categorical or numeric variables. Categorical variables included age (65 years), beta2 microglobulin (〉5.5 mg/L), elevated LDH (〉ULN), presence of del 17p, t(4;14), t(14;16), gain chr 1q, del 1p and hyperdiploid status. Numeric variables included genes from the EMC-92 gene signature. Overall survival (OS) was estimated by Kaplan Meier method and log-rank test. Results Among patients with available data, females accounted for 44% (N=384) and males 56% (N=487) patients. Male sex is associated with inferior overall survival, with median survival (men 55 months vs women NR) (p=0.00024). GSEA detected 310 out of 668 gene sets to be up-regulated in the female cohort of which 69 gene sets were significantly up-regulated (FDR q

Description: Background Multiple Myeloma (MM) is a clinically heterogeneous disorder of clonal plasma cells. Elevated Lactate Dehydrogenase (LDH) has been shown to be an independent prognostic marker associated with drug resistance and shorter survival. Methods Utilizing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass database (IA12) which includes over 1000 newly-diagnosed MM (NDMM) patients with enriched tumor and matched constitutional samples analyzed using whole genome/exome and RNA sequencing, we identified patients with baseline LDH values. High LDH was defined as LDH greater than the upper limit of normal, (〉4.68 microkatals/liter). We compared baseline characteristics and outcomes with autologous stem cell transplant (ASCT), based on LDH as categorical variable. We sought to determine if there is enrichment of high and standard risk cytogenetic changes when stratified by LDH. Results We identified 871 patients with NDMM who had baseline LDH values. 143 patients had high LDH and 728 patients had a normal baseline LDH. Consistent with prior reports, high LDH was associated with shortened survival, 660 days vs 795 days (p=0.02852) in patients with normal LDH. 385 patients underwent ASCT (High LDH N=44; Normal LDH N=341). Those with high LDH had an inferior OS when compared with those with normal LDH (median OS 800.5 vs 878.8 days, p=0.019). In order to understand this difference, we examined baseline characteristics. Of the 44 patients with high LDH who underwent ASCT, median age was 60 years and ECOG performance status was 1. 61.36% were females, 77% were Caucasian, 11% were African American. Induction therapy consisted of 4 drugs or more in 16%, 3 drugs in 61%, and 2 drugs in 23%. Bortezomib and immune modulating agents (IMIDS) were combined in 72%. In those who did not receive an IMID, a bortezomib-based induction was used in 16% and carfilzomib-based induction was used in 11%. 93.18% underwent transplant in the consolidative setting with a median time to transplant was 178 days. 21 of the 44 patients (47.72%) received post-transplant maintenance. 10/21(48%) patients received triplet therapy (5/10 - lenalidomide, bortezomib, dexamethasone), 8/21 (38%) patients received lenalidomide alone. The median duration of maintenance was 217 days. Of the 341 patients with normal LDH who underwent ASCT, the median age was age 61 years, ECOG performance status was 1. 41.34% were females, 79% were Caucasian, 13% African American. Induction therapy consisted of 4 drugs in 8%, 3 drugs in 64%, 2 drugs in 24%. Combined Bortezomib-IMID in 76.24%, carfilzomib-IMID based therapy in 6%, and bortezomib-non-IMID based in 9.67%. 94.7% underwent an upfront consolidative with median time to transplant 164 days. Post-transplant maintenance was given in 213/341 (62.4%) of patients, in whom triplet therapy was given to 41/213 (19.2%), doublet therapy to 34/213 (16%), 130/213 (61%) received single agent. 107/213 (50%) received lenalidomide alone and 19/213 (6%) received bortezomib alone. Median duration of maintenance 266 days. There was no statistically significant difference in race, performance status, drug class and number of drugs used in induction therapy, time to transplant, whether or not patients received maintenance as well as maintenance duration between the groups when stratified by LDH. Female gender was enriched in the high LDH group (hypergeometric test, p=0.009). We used hypergeometric tests to assess for enrichment of high and standard risk cytogenetic changes. Del(17p13) was significantly enriched (p=0.011) in the high LDH subset where there were no statistically significant difference in the presence of t(4;14) (p=0.16) and t(14;16) (p=0.21). There was no difference in good risk hyperdiploid structural changes between the 2 groups. Conclusion Elevated LDH was confirmed as a poor prognostic factor in MMRF CoMMpass cohort. Among patients who underwent ASCT, those with high LDH have inferior survival, possibly driven by the presence of del(17p13). Since clinical outcomes remain poor despite the use of novel effective therapies and early consolidation with AHCT in patients with high baseline LDH, this group represents an unmet need for alternative therapy. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Description: 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 〉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.

Description: Background Long-term PI-based treatment is associated with improved outcomes in MM. Nonetheless, prolonged therapy with parenteral PIs (e.g. bortezomib) can be challenging in the real world, with median duration of therapy (DOT) of 4-7 months. Barriers to this long-term approach may include the burden of repeated intravenous/subcutaneous administration, difficulty travelling to/accessing treatment centers (e.g. due to environmental factors, travel restrictions, social/family situations), patient preference for treatment outside of a hospital or clinic setting, comorbidities, and toxicity. The US MM-6 study (NCT03173092) is investigating in-class transition (iCT) from parenteral bortezomib-based induction to all-oral ixazomib-based therapy (ixazomib-lenalidomide-dexamethasone; IRd) in the diverse US community population with the aim of increasing PI-based treatment duration while maintaining quality of life and improving outcomes. We report updated efficacy and safety for the first 101 patients. Methods Transplant-ineligible/delayed-transplant (〉24 months) NDMM patients with stable disease or better after 3 cycles of bortezomib-based induction are being enrolled at US community sites (including Veterans Affairs hospitals) to receive IRd (ixazomib 4 mg, days 1, 8, 15; lenalidomide 25 mg, days 1-21; dexamethasone 40 mg, days 1, 8, 15, 22) for up to 39 x 28-day cycles or until progression/toxicity. The primary endpoint is progression-free survival (PFS); key secondary endpoints include rates of partial (PR), very good PR (VGPR), and complete response (CR), and DOT. Results As of June 1 2020, 101 patients had been treated at 21 sites. Median age was 73 years (range 48-90), with 46% aged ≥75 years; 16% and 10% were of African American and Hispanic ethnicity, respectively. Table 1 summarizes the key characteristics of these real-world patients. A total of 95% of patients had ≥1 comorbidity at the start of IRd therapy including renal and urinary disorders (38%), cardiac disorders (29%), peripheral neuropathy (PN; 14%), and diabetes mellitus (13%) (Table 2). With 53 (52%) patients remaining on therapy and enrollment ongoing, mean duration of PI therapy from the start of bortezomib-based induction was 12.4 months, and mean duration of IRd therapy after iCT was 9.2 months (Table 3). Patients have received up to 29.4 months (31 cycles) of IRd to date. The overall response rate (ORR) after bortezomib-based induction was 62% (7% CR, 32% ≥VGPR). After iCT to IRd, the ORR increased to 71%, with the CR and ≥VGPR rates increasing to 29% and 53%, respectively (Figure); of 33 patients with stable disease following bortezomib-based induction, 14 (42%) achieved CR (n=10) or VGPR (n=4) after iCT. With a median follow-up of 12 months and enrollment ongoing, 13 patients had progressed and two had died during PFS analysis. The 12-month PFS rate was 84% (95% CI, 73-91) from the start of bortezomib-based induction and 80% (95% CI, 69-88) from the start of IRd. During IRd treatment to date, 91% of patients have had treatment-emergent adverse events (TEAEs) (54% grade ≥3). Grade 3 TEAEs (≥5% of patients) were diarrhea (8%), pneumonia (7%), and syncope (5%). TEAEs led to study drug modification in 52% of patients and discontinuation in 7% of patients; 37% had serious TEAEs. Diarrhea, nausea, and vomiting occurred in 43%, 23%, and 14% of patients (8%, 2%, 2% grade 3), and led to dose modification in 11%, 5%, and 2%. PN (not elsewhere classified; high-level term) occurred in 32% of patients (2% grade 3) and led to dose modification in 9%. There were three on-study deaths (i.e. occurring