Kansagra, Ankit

8036 Background: Ide-cel, a BCMA-directed CAR T cell therapy, showed promising efficacy in patients (pts) with RRMM in the KarMMa study with an ORR of 73% and a CRR of 33% across target doses of 150–450 × 106 CAR+ T cells (Munshi NC, et al. J Clin Oncol 2020;38[suppl 15]. Abstract 8503). Associations of neurotoxicity (NT) with pt and disease characteristics, pt management, and impact on outcomes in the KarMMa study are reported here. Methods: Enrolled pts were triple-class exposed and refractory to their last regimen, with ide-cel given at target doses of 150, 300, or 450 × 106 CAR+ T cells after lymphodepletion (NCT03361748). Investigator-identified NT events were captured under the single preferred term of neurotoxicity and graded according to NCI CTCAE v4.03. Events were managed with corticosteroids (CS), anakinra (ANR), and tocilizumab (Toci) as needed. Results: Of 128 pts treated with ide-cel, NT was reported in 23 (18%); 12 pts (9%) had maximum grade (gr) 1 NT, 7 (5%) had gr 2, and 4 (3%) had gr 3. No gr 4 or 5 NT occurred. Most baseline characteristics were similar in pts with and without NT, including stage III disease (22% and 15%), high-risk cytogenetics (39% and 34%), and extramedullary disease (35% and 40%); exceptions were high tumor burden (65% and 48%) and sex (48% and 62% men). NT (any gr/gr 3) occurred in 0%/0%, 17%/1%, and 20%/6% of pts at doses of 150, 300, and 450 × 106 CAR+ T cells. Median time to onset was similar regardless of gr, and there were no late-onset events (Table). NT was managed with CS in 10 pts (43%), Toci in 3 (13%), and ANR in 1 (4%). Median (range) time to first use of CS was 2 d (1–6). ORR and DOR were similar in pts with and without NT (Table). All NT occurred in the proximity of cytokine release syndrome (CRS) events with the start date of NT events either overlapping with or occurring within 1 wk of the start of a CRS event. Conclusions: NT occurred early in the KarMMa study, was generally of short duration, and was mostly gr 1/2 with no gr ≥4 events. All NT was proximal to CRS. Pts with NT had a favorable ORR after ide-cel treatment. These results continue to demonstrate the durable efficacy and tolerability of ide-cel in pts with RRMM. Clinical trial information: NCT03361748. [Table: see text]

Background: Multiple myeloma is typically characterized by clonal expansion of malignant plasma cells within the bone marrow compartment. Presence of extramedullary disease (EMD) either in the form of soft tissue plasmacytoma or circulating plasma cells can be seen at diagnosis but is more common in the relapsed and refractory patients. Presence of EMD is typically associated with a poor prognosis, both in the newly diagnosed and relapsed setting, but trials designed specifically for patients with EMD are sparse. Treatment of EMD can be challenging and the responses even when seen are often short lasting, highlighting the need for developing specific treatment approaches aimed at these patients. Based on initial trials suggesting activity of pomalidomide in the setting of EMD and the increased tissue distribution with the oral proteasome inhibitor ixazomib, we designed this trial to examine if the all oral combination of ixazomib, pomalidomide and dexamethasone can be effective in the setting of EMD. Patients and Methods: Patients with previously treated multiple myeloma, with adequate hematologic and organ function were enrolled if there was evidence, at study entry, of EMD defined as one or more plasmacytomas, outside the bone marrow that were non-contiguous with a bone lesion and had a single diameter of ≥2 cm OR as plasma cell leukemia, with circulating plasma cells > 5% of peripheral blood leukocytes or at least 0.5 X 109/L or 200 cells/150000 events by flowcytometry. Patients were treated on 28-day cycles, with ixazomib 4 mg on days 1, 8, and 15 along with pomalidomide 4 mg PO daily on days 1-21 and dexamethasone 40 milligrams weekly until disease progression or unacceptable toxicity. The goals of the study were to determine confirmed response rate (≥ PR), toxicities of this combination, differential response rates and progression-free survival (PFS). Confirmed response rate, differential response rates and PFS were estimated using Duffy and Santner approach, exact binomial distributions and Kaplan Meier curves, respectively. The study was designed to accrue 30 patients. Results: This study was designed to enroll up to 30 patients but was closed after enrolling 17 patients due to slow accrual. The baseline characteristics are as indicated in Table 1. Eleven patients were enrolled with an extramedullary plasmacytoma while the remaining six patients had plasma cell leukemia. Median number of lines of prior therapy was 3 (range: 1, 7). Overall, 10 (58.8%) patients had progressive disease and 11 (64.7%) patients have died, median (range) follow-up for the live patients is 22.2 (2.1, 37.9) months. Patients were treated for a median of 2 (range 1-34) cycles. A grade 3+ AE, at least possibly attributed, was seen in 53%. Grade 3+, at least possibly related, hematologic toxicity was noted in 41%, with 29% experiencing grade 3+ neutropenia. Notable grade 3+ non-hematologic toxicities (regardless of attribution), with >10% incidence rate were anemia, hypoxia, infections and lung infection. The confirmed response rate in evaluable patients was 35% (1 CRs and 5 PRs), with a 90% CI of 6% - 37%. While 33% (4/12; 95% CI: 1-8%) of patients reported a biochemical response, 40% (2/5; 95% CI: 0-4%) of patients reported an extramedullary response. The median PFS was 4.5 (95% CI: 2-11.8) months. Conclusions: The combination of ixazomib, pomalidomide and dexamethasone resulted in disease response in a third of this group of high-risk patients with EMD; however, the responses were not very durable, with a median PFS of only 4.5 months. The trial highlights the feasibility of doing clinical trials specifically targeted towards this high-risk patient population. Future trials should explore combinations of novel agents, including monoclonal antibodies through multicenter collaborative efforts. Disclosures Kansagra: Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics: Other: Advisory Board. Witzig:Spectrum: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; AbbVie: Consultancy; MorphSys: Consultancy; Celgene: Consultancy, Research Funding. Kumar:Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genecentrix: Consultancy; Carsgen: Other, Research Funding; Cellectar: Other; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Adaptive Biotechnologies: Consultancy; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Sanofi: Research Funding; Tenebio: Other, Research Funding.

Introduction: Cytokine release syndrome (CRS) is an expected and potentially life-threatening toxicity associated with CAR T cell therapy. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, demonstrated promising efficacy in triple-class exposed and highly refractory patients with multiple myeloma in the pivotal phase 2 KarMMa study, with an overall response rate (ORR), complete response (CR) rate, median duration of response, and median progression-free survival of 73%, 33%, 10.7 months, and 8.8 months, respectively, across the target dose levels of 150−450 × 106 CAR+ T cells, and 82%, 39%, 11.3 months, and 12.1 months at the highest target dose of 450 × 106 CAR+ T cells (Munshi et al. J Clin Oncol. 2020;38[suppl, abstr]:8503). Identifying the patterns of CRS evolution, associations with baseline patient and disease characteristics, and the impact of interventions are key to understanding this adverse event in the context of ide-cel. In addition, a better understanding of lower-grade CRS, including maximum grade 1 events, is important as these are easier to manage and represent a lower burden on the healthcare system. We report results of an examination of CRS events in the KarMMa study. Methods: Patients in the KarMMa trial (NCT03361748) were required to have ≥3 prior regimens (including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody) and were refractory to their last regimen per International Myeloma Working Group criteria. Patients received ide-cel target doses of 150, 300, or 450 × 106 CAR+ T cells 2 days after lymphodepletion with cyclophosphamide 300 mg/m2 plus fludarabine 30 mg/m2 daily for 3 days. The primary endpoint was ORR. The key secondary endpoint was CR rate; other secondary endpoints included safety. CRS was graded according to criteria in Lee et al. (Blood. 2014;124:188). Patient characteristics and CRS management were examined by CRS grade to identify variables associated with higher-grade CRS. Management of CRS included tocilizumab 8 mg/kg with the addition of corticosteroids and other agents as needed. Results: Of 128 patients treated with ide-cel, 107 (84%) experienced CRS; 61 patients (48%) had maximum grade 1 and 46 (36%) had maximum grade ≥2 CRS (grade 2, n=39; grade 3, n=5; grade 4, n=1; and grade 5, n=1). Baseline characteristics were generally balanced among patients with maximum grade 1 and grade ≥2 (Table). Thirty patients (65%) with maximum grade ≥2 CRS progressed from initial grade 1 events, whereas 16 (35%) had initial grade ≥2. Median time to onset of CRS was the same (1 day) regardless of initial or maximum grade (Table). Median duration was 5.0 days in patients with maximum grade 1, 5.5 days in patients with maximum grade 2, and 11.0 days in patients with maximum grade ≥3 CRS. Median duration was shorter in patients with maximum grade 1 CRS than in those with initial grade 1 events that progressed to grade ≥2 (5.0 days vs 7.0 days). Most patients (83%) with maximum grade ≥2 CRS received at least 1 dose of tocilizumab and approximately one-third (35%) received corticosteroids, compared with 48% and 5%, respectively, of patients with maximum grade 1 CRS. A higher percentage of patients with initial grade ≥2 vs initial grade 1 CRS received multiple doses of tocilizumab (50% vs 37%) or at least 1 dose of corticosteroids (50% vs 27%). Conclusions: Almost half of the patients treated with ide-cel experienced maximum grade 1 CRS. Baseline disease and patient characteristics were similar among patients experiencing grade 1 and higher-grade CRS events. CRS was effectively managed with tocilizumab and corticosteroids, and more frequent use of these interventions in patients with grade ≥2 CRS was not associated with prolonged CRS events. The time to onset of CRS was predictable and equivalent in patients with maximum grade 1 and higher-grade CRS events. Duration of CRS was similar in patients with maximum grade 1 and 2 but was longer in patients with maximum grade ≥3 CRS. These data demonstrate the feasible management of CRS and thus confirm the tolerability of ide-cel in patients with relapsed and refractory multiple myeloma. Table 1 Disclosures Kansagra: Karyopharm: Honoraria; Pharmacyclics: Honoraria; Alnylam: Honoraria; BMS: Honoraria; GSK: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Lin:Novartis: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gamida Cells: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Vineti: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding. Berdeja:BMS: Consultancy, Research Funding; Cellularity: Research Funding; Lilly: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Research Funding; Poseida: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bioclinica: Consultancy; Bluebird: Research Funding; Prothena: Consultancy; Legend: Consultancy; Kesios: Research Funding; Kite Pharma: Consultancy; Karyopharm: Consultancy; Constellation: Research Funding; Novartis: Research Funding; Teva: Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Glenmark: Research Funding; EMD Sorono: Research Funding; Vivolux: Research Funding; Genentech, Inc.: Research Funding; CURIS: Research Funding; Acetylon: Research Funding. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Oriol:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy. Yakoub-Agha:Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria. Einsele:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rambaldi:BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.. Truppel-Hartmann:bluebird bio, Inc: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); F. Hoffmann La Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Rowe:Bristol-Myers Squibb: Current Employment. Wang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Agarwal:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Lonial:Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Novartis: Consultancy, Honoraria, Other: Personal fees; Millennium: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Onyx: Honoraria; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Other: Personal fees; JUNO Therapeutics: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy.

CT053 comprises autologous T cells genetically modified with a second-generation chimeric antigen receptor (CAR) incorporating a fully human B-cell maturation antigen (BCMA)-specific single-chain fragment variant (25C2) with high binding affinity. Twenty-four subjects have been treated in phase 1 studies with an 87.5% overall response rate (ORR), 79.2% complete response (CR), and a median duration of response of 21.8 months without inducing immunogenicity [Blood (2019) 134 (Supplement_1): 4435]. Here we present the ongoing phase 1b/2 study (LUMMICAR-2) conducted in North America (NCT03915184) to evaluate safety and clinical efficacy. Eligible subjects with relapsed/refractory multiple myeloma (RRMM) had received ≥3 prior lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody, and had measurable disease per International Myeloma Working Group (IMWG) criteria. All subjects received a lymphodepletion regimen of cyclophosphamide (500 mg/m2/day ×2 days) and fludarabine (25 mg/m2/ day × 3 days). A single infusion of CT053 at the targeted 1.5-3.0×108 CAR+ T-cell dose was administered after lymphodepletion. Primary objectives for phase 1b were to evaluate the safety and tolerability of CT053 and to identify the recommended phase 2 dose. Adverse events (AEs) were graded using CTCAE, v5.0; cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). The response was assessed per 2016 IMWG criteria, and minimal residual disease (MRD) was assessed by next generation flow cytometry or sequencing. As of July 28, 2020, 20 subjects have enrolled, and 14 subjects have received CT053 infusion in the phase 1b portion of the study, including 8 subjects who received 1.5-1.8×108 CAR+ T cells while 6 subjects received 2.5-3.0×108 CAR+ T cells. The treated subjects had a median age of 59 years (range 42-73), had received a median of 6 (range 3-11) prior lines of treatment, 93% were triple refractory to a PI, IMiD, and anti-CD38 antibody, and 64% were penta-refractory. In addition, 36% of the subjects had extramedullary disease at baseline, and 64% had high-risk cytogenetics. All subjects received bridging therapy. The most common ≥ grade 3 AE was hematological toxicity. All subjects experienced ≥ grade 3 neutropenia (100%) and leukopenia (100%), and 36% of subjects had ≥ grade 3 thrombocytopenia within 30 days of treatment. No grade 3 or higher CRS or neurotoxicity was observed. Twelve of 14 subjects (86%) experienced grade 1 or 2 CRS, including 2 subjects who experienced grade 2 CRS and 1 subject who had grade 2 neurotoxicity. CRS events had a generally predictable time to onset, occurring at a median of 2 days post infusion with a median duration of 4 days (range 1-6). Two subjects received tocilizumab, and one subject with grade 2 CRS received both tocilizumab and steroids. One subject experienced grade 2 neurotoxicity with complete resolution within 24 hours upon administration of dexamethasone. At the data cutoff, 10 subjects were evaluable for at least two months of efficacy assessment with a median follow-up of 4.5 months (range 2-8). A 100% ORR was observed, with 2 stringent complete responses, 2 CRs, 1 very good partial response, and 5 partial responses. Of the 12 subjects with evaluable bone marrow samples, 11 were MRD-negative at the 10-5 sensitivity level. Responses were independent of baseline bone marrow BCMA expression. CT053 transgene levels showed expansion and persistence in peripheral blood, with peak expansion at 7-14 days after infusion. All subjects showed similar kinetics of rapid declines in serum free light chains and soluble BCMA (sBCMA) levels within 1 month, and continued depletion in sBCMA suggests CT053-mediated pharmacodynamic activity. Serum C-reactive protein and cytokine levels (i.e., IL-6, IFNγ, IL-8, IL-10) increased post-infusion within 7 days and correlated with the onset of CRS symptoms. Collectively, these results demonstrate that CT053 at a target dose of 1.5-3.0×108 CAR+ T cells delivers early and deep responses, including MRD negativity, with an acceptable safety profile in subjects with heavily pretreated relapsed or refractory MM. The promising results from the ongoing LUMMICAR-2 study are consistent with the previous phase 1 studies and support the launch of a pivotal Phase 2 LUMMICAR-2 study. Updated results will be presented at the conference. Disclosures Kumar: Carsgen: Other, Research Funding; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Tenebio: Other, Research Funding; Genecentrix: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; MedImmune: Research Funding; Cellectar: Other; Merck: Consultancy, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; Novartis: Research Funding; Karyopharm: Consultancy. Baz:Sanofi, Karypharm, Janssen, Celgene: Other: Advisory board; Karyopharm, janssen, Bristol Myers Squibb, Celgene, Merck, Sanofi, Abbvie Inc.: Research Funding. Orlowski:Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Anderson:Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Ma:CARsgen Therapeutics Corp.: Current Employment. Bilgi:CARsgen Therapeutics Corp.: Other: Current shareholder in the company. Kansagra:Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics: Other: Advisory Board. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria; Amgen: Research Funding; Sanofi: Consultancy, Research Funding. Li:CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in private company. Brayer:Bristol-Myers Squibb, WindMIL Therapeutics: Research Funding; Janssen: Consultancy; Bristol-Myers Squibb, Janssen, Amgen: Speakers Bureau.

AbstractWe studied 2,528 patients with upfront autologous haematopoietic cell transplantation (AHCT) for multiple myeloma (MM) from 2008–2017 to develop a prognostic model to predict outcomes. High‐risk cytogenetics included t(4;14), t(14;16), t(14;20), del13q on karyotype, del17p, +1q or 1pdel. A Cox model identified factors prognostic of progression/relapse in a training subset (n = 1,246). A weighted score using these factors was assigned to a validation cohort (n = 774). Presence of high‐risk cytogenetics [hazard ratio, (HR) 1·68 (1·3–2·17)] and pre‐AHCT bone marrow plasma cells (BMPCs) ≥10% [1·68 (1·33–2·12)] were assigned 4 points each; albumin at diagnosis <3·5 g/dl [1·31 (1·07–1·61)] 2; standard risk cytogenetics 1, and no cytogenetics abnormality, BMPCs <10% at AHCT and albumin ≥3·5 g/dl at diagnosis 0 points each. A three‐category system with low risk (0–3), intermediate risk (4–8) and high risk (9–10) showed 3‐year progression‐free survival in the low vs. intermediate vs. high risk of 58% (95% CI: 52–63) vs. 49% (95% CI: 43–56) vs. 31% (95% CI: 12–51), P < 0.001 respectively, and 3‐year OS in low vs. intermediate vs. high risk of 88% (95% CI: 84–91) vs. 81% (95% CI: 76–86) vs. 64% (95% CI: 39–80); P < 0·001. Our prognostic scoring system can identify MM patients at risk for early relapse after AHCT.

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

Abstract Background and objective: Blood loss associated with total lower-extremity joint arthroplasty (TJA) often results in postoperative anemia and need for red blood cell transfusions (RBCT). We report the results of a quality improvement initiative to improve blood management and decrease transfusions in patients undergoing TJA in one tertiary hospital. Methods: Pre and post analysis after the implementation of a multifaceted intervention which included preoperative assessment for anemia, use of tranexamic acid, discouragement of autologous pre-operative blood collection and institution of more restrictive RBCT protocols. The results were stratified into three periods: I - pre-interventional (01/01/2013 -09/30/2013); II - peri-interventional (10/01/2013 -04/30/2014); and III - post-interventional (05/01/2014 -12/31/2014). We used fractional logistic regression with robust standard errors and regression modeling was configured using a segmented, or "piecewise", approach in which slope coefficients in each period were estimated. Results: During the study period 2511 patients underwent surgery. Compared with the pre-intervention period, the total number of RBC units transfused decreased from a total of 587 in the pre- to 107 in the post-intervention period (81.8% decrease). The percentage of patients receiving transfusion declined from 36.7% in pre-implementation period to 8.8% to post-intervention period. Depending upon the costing methodology used, annualized savings in RBC expenditure between time period 1 and 3 ranged from a low of $108,000 using the acquisition cost per unit (~$225/unit) to $480,000 when using activity based costing (~$1000/unit). Mean length of stay (days) and 30-day readmission rates remained stable during the study period. Conclusions: A multidisciplinary approach with proactive involvement of all the interested parties can be successful and sustainable in reducing RBCT and its associated costs, in patients undergoing TJA. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction Development of anti-CD38 monoclonal antibody therapies (MoABs), including daratumumab and isatuximab, have drastically changed the therapeutic landscape for management of relapsed and/or refractory multiple myeloma (RRMM). However, there is a paucity of information regarding response to treatment after progression on CD38 MoABs. This collaborative research study (MAMMOTH: Monoclonal Antibodies in Multiple Myeloma: Outcomes after Therapy Failure) investigates the therapeutic choices and outcomes of subsequent treatments after refractoriness to MoABs. Methods Patients from 14 US academic institutions with diagnosis of MM and refractory to daratumumab or isatuximab, administered alone or in combination, were evaluated. Patients were considered refractory to a CD38 MoAB if treated with at least 4 weeks of therapy and had evidence of progressive disease (PD) while on therapy or within 60 days after last dose. Time of progression was defined as time zero (T0). Data was collected by electronic platform and submitted to peer-based quality check for completeness and internal consistency. Results Two hundred and seventy-five patients with MM refractory to CD38 MoAB were evaluated; 249 (90.5%) of those patients who received at least one subsequent line of therapy were included in this analysis. The median age at T0 was 65 years (range 27-90) and 54% were male. At the time of diagnosis, 28% had ISS stage III disease and 29% had high-risk cytogenetics. Patients were heavily pre-treated at T0 with a median of 5 lines of therapy (range 2-17); most (74%) underwent a prior autologous stem cell transplant. The majority of patients were refractory to other anti-myeloma therapies including lenalidomide (78%), pomalidomide (65%), bortezomib (69%) and carfilzomib (45%). In total, 97.1% of patients were exposed to at least one immunomodulatory agent (IMiD) and one proteasome inhibitor (PI), 79.3% were ≥ triple-refractory (refractory to 1 IMiD, 1 PI and 1 CD38 MoAB), while 25.3% were penta-refractory (refractory to 2 IMiDs, 2 PIs and 1 CD38 MoAB). Responses to the next subsequent line of therapy after progression with CD38 MoAB are shown (Table). The overall response rate (ORR; ≥PR) of first regimen post-T0 was 31% with a median progression free survival (PFS) of 3.4 mo and median overall survival (OS) of 9.3 mo. Carfilzomib-based therapy resulted in an ORR of 32% with median PFS 4.2 mo and overall OS of 10.9 mo. The addition of an IMiD to daratumumab yielded an ORR of 37% with median PFS 4.5 mo and OS 12.6 mo. The addition of a PI to daratumumab yielded no responses. Elotuzumab-based therapy had an ORR of 21% with median PFS 2.6 mo and OS 8.3 mo. By multivariate analysis, alkylator-based therapies were found to have the highest ORR (OR 3.1, 95% CI 1.8-5.7, p<0.001), however, resulted in median PFS of only 3 mo and OS of 7.7 mo. Multivariate analysis evaluating for PFS and adjusting for refractoriness to prior therapies found lower risk of progression with carfilzomib-based therapy (HR 0.60, 95% CI 0.42-0.85, p=0.004, Figure 1) and with the addition of an IMiD to daratumumab (HR 0.64, 95% CI 0.43-0.94, p=0.02). The benefit of IMiD + daratumumab was essentially restricted to patients previously refractory to CD38 MoAB as monotherapy. These patients demonstrated improved PFS with subsequent daratumumab-combination therapy at time of progression compared with patients refractory to CD38 MoAB combination therapy (log-rank p=0.02, Figure 2). No particular regimen was associated with improved OS compared with the rest. Conclusions After progression on CD38 MoAB, treatment with carfilzomib-based regimens and the addition of an IMiD to daratumumab-monotherapy resulted in a higher ORR and PFS compared with other regimens. Alkylating agents resulted in the highest ORR but relatively short PFS and OS. The use of elotuzumab and the addition of a PI to daratumumab monotherapy resulted in relatively low response rates. Overall, progression after CD38 MoAB therapy is associated with a poor prognosis and innovative therapeutic strategies are needed. Disclosures Malek: Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau. Paul:Bristol Myer Squibb: Other: Stock and pension plan (past employee). Neppalli:Celgene: Consultancy; Amgen: Consultancy. Liedtke:Amgen/Onyx: Consultancy, Honoraria, Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Research Funding; Gilead: 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; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; celgene: Research Funding; BlueBirdBio: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:Takeda: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Kite Pharma: Consultancy, Honoraria; Sanofi: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Honoraria. Vij:Bristol-Myers Squibb: Honoraria, 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. Costa:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Sanofi: Honoraria. Kumar:Roche: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract History of prior cancer is a widespread exclusion criterion in cancer trials. Up to 80% of NCI-sponsored and 80% of industry-sponsored lung cancer trials exclude patients with a prior cancer. We suspect this exclusion is commonly applied in other cancer trials, although no definitive data exist. Prior cancer is especially common among older patients and those with certain cancer types. Among patients >65 years, 15.1% overall have prior cancer. In Multiple Myeloma, the most common plasma cell disorder (PCD), prevalence of prior cancer is as high as 17.4%. Examining the prior cancer exclusion criterion is important because the number of US cancer survivors is large and rapidly growing. Arbitrarily excluding cancer survivors from trials is not evidence-based and exclusion presumably arises from assumptions that higher mortality of patients with prior cancer could hinder study conduct and bias trial outcomes. However, few data exist to support this assumption of higher mortality. In fact, we demonstrated that lung cancer patients with a prior cancer have similar or lower mortality risk, compared to those without prior cancer. In this abstract, we reviewed prior cancer related eligibility criteria in three of the most common PCD (Multiple Myeloma, Amyloidosis and Waldenström Macroglobulinemia) clinical trials sponsored or endorsed by 5 major Co-Operative groups in North America (Table 1). We use descriptive statistics (n, %) and Fisher's exact tests to describe characteristics of trials with and without exclusion criteria. Of 33 trials, 26 (79%) excluded patients with prior cancer as follows - active cancer (12%), within 2-3 years of PCD diagnosis (9%), or within 5 years of PCD diagnosis (55%). Many trials had exceptions to prior cancer exclusion. Specifically, 67% of trials allowed non-melanoma skin cancer, 58% allowed in-situ cervical cancer, 12% allowed early stage prostate cancer. Table 2 shows the association between clinical trial characteristics and prior cancer exclusion. There was no association between prior cancer exclusion and phase of study, transplant studies, or survival end point. Exclusion criteria varied across year of activation (p=0.01); for example, 75% of studies activated 1990-1999 excluded prior cancer, compared to 100% of studies activated after 2010. Type of PCD was marginally associated with exclusion criteria (p=0.08); 74% of Multiple Myeloma trials excluded patients with prior cancer compared to 100% of the Amyloidosis and Waldenström Macroglobulinemia trials. Conclusion: A substantial proportion of potential participants may be excluded from PCD clinical trials because of a history of prior cancer. This practice impacts accrual, generalizability, and fair access to cutting-edge treatments and the highest level of clinical care. As treatment outcomes for other cancers continue to improve, it is likely that the prevalence of multiple primary cancers will increase. This exclusion criterion is applied widely across studies, including more than two-thirds of those with non-survival endpoints. Our study is the first to examine the prevalence and potential impact of prior cancer exclusion in PCD clinical trials. Using population-based cancer registry data, we plan to undertake further research to understand the appropriateness and ramifications of this standard exclusion policy in PCD cancer trials. Disclosures Collins: Agios: Research Funding; Bristol Myers Squibb: Research Funding; Celgene Corporation: Research Funding; Arog Pharmaceuticals: Research Funding. Devine:Kiadis Pharma: Consultancy. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy. Anderson:Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Kumar:Janssen: 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; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: 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; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.