Alsina, Melissa

8012 Background: Cilta-cel was FDA approved in 2022 for the treatment of RRMM. We evaluated the outcomes of patients treated with intended SOC cilta-cel. Methods: 12 US academic medical centers contributed data to this retrospective study. As of 12/31/2022, 177 patients were leukapheresed and 139 received cilta-cel. Results: The table describes the study population compared to the CARTITUDE-1 trial. More patients in our study had extramedullary disease (EMD, 35%) and high-risk cytogenetics (41%). 55% of the patients would not have met eligibility criteria for CARTITUDE-1. Common reasons for ineligibility were cytopenias (19%), prior BCMA therapy (14%), organ dysfunction (12%), oligosecretory disease (13%), and plasma cell leukemia (8%). 83% of the patients received bridging chemotherapy (overall response rate, ORR: 28%). Lymphodepletion included fludarabine (Flu) + cyclophosphamide (Cy): 81%, bendamustine: 11%, Cy: 4%, and cladribine + Cy: 4%. Median CAR-T cells infused were 0.6 million/kg (range: 0.1-0.9), and 19% of patients were treated on an expanded access protocol (EAP). Median follow-up was 2.3 months (range: 0-8). Cytokine release syndrome (CRS) was seen in 81% (≥ grade 3: 7%) and immune effector cell-associated neurotoxicity syndrome (ICANS) in 22% (≥ grade 3: 8%) of patients. Tocilizumab, steroids, and anakinra were used in 61%, 44%, and 10% of patients, respectively. Delayed neurotoxicity (NT) was seen in 9% (cranial nerve palsy: 8, Parkinsonism: 2, others: 3). Grade ≥ 3 cytopenias at day ≥ 30 were seen in 75% of patients. Infections were seen in 32% of patients. Day 30 (N=115) and best response rates (N=118) were: ≥ partial response (PR), 75/80%; ≥ very good PR, 44/62%; and ≥ complete response (CR), 26/40%, respectively. In the non-EAP FluCy population (N=88), best ORR/≥CR were 89/49%. 17 patients died by data cut-off, 4 due to disease progression and 13 (9%) due to non-relapse mortality (NRM) (grade 5 CRS: 3, infection: 6, CRS/infection: 1, grade 5 ICANS: 1, delayed NT: 2). Conclusions: Patients treated with intended SOC cilta-cel had a favorable ORR (80%) despite a larger proportion of patients having high-risk features relative to trial patients and limited follow-up. Response rates were higher in patients receiving conforming products with FluCy conditioning (89%). Delayed NT and NRM were seen in 9% of patients. Results will be updated with continued follow-up. D.K.H., K.K.P, M.J., Y.L. & S.S. contributed equally. [Table: see text]

e20021 Background: CAR T cell therapies are FDA approved for patients with triple refractory multiple myeloma (MM) and >4 lines of therapy. The median survival of this is group is less than 12 months so salvage therapies need to be implemented quickly. Real-world access to CAR T remains challenging due to supply chain limitations impacting manufacturing. The goal of this study was to evaluate how centers are handling the challenges of CAR T slot allocation. Methods: MM CAR T physician leaders at each CAR T treatment center certified for idecabtagene vicleucel across the US were surveyed. Results: We received responses from 15/20 centers. Summary of CAR T volumes and outcomes of patient on waitlists are shown in the table. The median time on the waiting list was 6 months with only 25% of patients receiving CAR T eventually. For patient selection, all centers reported using a committee of experienced CART physicians to ensure consistency. Selection committee included: primary MD (n=9), CAR T MD (n=12), social workers (n=3), CAR T RN (n=10), APP (n=2), pharmacists (n=2) and ethicists (n=1). To ensure transparency, centers have clear selection criteria (n=10), priority score (n=8) and selection timeline (n=11) . To ensure accountability, centers document priority scores (n=5) and have pre-specified criteria (n=9) for selection. Centers also reported using ethical principles for selection: a) equal treatment: time spent on waiting list (n=8); b) priority to the worst-off: limited therapeutic options (n=10), MM burden (n=7), ineligible for trials (n=2); c) maximize benefit: most likely to complete apheresis (n=8) or infusion (n=8) or achieve response (n=6) and d) social value: younger pts (n=2). Maximizing benefit was considered the most important criterion by 7 centers. Conclusions: More stringent GMP manufacturing requirements with FDA approved CAR T and real-world practice with broader patient demographics can present challenges to implementation of CAR T in standard of practice. Our study is the first attempt to evaluate and highlight existing issues with MM CAR T access and the variability and challenges in patient selection. Learning from other models of resource allocation (ex: UNOS) and sharing experience across centers can help providers optimize slot allocation to improve accrual. Increasing supplies of key reagents and novel manufacturing methods(eg: non-viral vectors and allogeneic CAR) could help overcome these limitations. [Table: see text]

Abstract Introduction: Idecabtagene vicleucel (ide-cel, bb2121) is the first chimeric antigen receptor (CAR) T cell therapy approved for the treatment of relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. bb21217 is a B-cell maturation antigen (BCMA) directed CAR T cell therapy which uses the same CAR molecule as ide-cel, with the addition of a PI3K inhibitor (bb007) during ex vivo culture to enrich the drug product (DP) for memory-like T cells and decrease the proportion of highly differentiated or senescent T cells. We hypothesize that DPs enriched for memory like CAR T cells will persist and function longer than non-enriched DPs and this increased persistence will positively influence duration of response (DOR). We previously demonstrated patients with sustained response are more likely to have drug product enriched for naïve gene signatures and depleted of effector gene signatures compared to patients without a sustained response. Methods: CRB-402 (NCT03274219) is a multi-center phase 1 trial of bb21217 in RRMM patients who received ≥3 prior lines of antimyeloma therapy, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory to both classes. In expansion, patients were required to have prior exposure to an anti-CD38 antibody and were required to be refractory to their last line of therapy. Patients underwent lymphodepletion with fludarabine (30 mg/m 2) and cyclophosphamide (300 mg/m 2) daily for 3 days, then received a single infusion of bb21217 at 150, 300 or 450 x 10 6 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures include overall response rate and DOR by IMWG Uniform Response Criteria. Exploratory analyses include correlation of outcome with the molecular characteristics of materials collected temporally through the treatment course, including PBMCs at apheresis, CAR+ T cells from drug product and CAR+ T cells collected from patients around the time of peak expansion. Results: Asof Feb 16, 2021, 72 patients received bb21217, 12 at 150, 14 at 300 and 46 at 450 x 10 6 CAR+ T cells; median follow up for all patients is 9.0 (<1-36) months (M). Patients had a median of 6 (3-17) prior lines of therapy with 49/72 (68%) triple refractory. Cytokine release syndrome (CRS) developed in 54/72 (75%) patients and was predominately G1/2 (51 pts), with 1 G3 event and 2 deaths (previously reported). Median time to first onset of CRS was 2 days (1-20); tocilizumab (38 pts) + corticosteroids (12 pts) was used to manage CRS. Eleven (15%) patients developed neurotoxicity [8 G1/G2, 2 G3, 1 G4] with median time to first onset of 7 (2-24) days. Response was assessed per investigator for 72 patients treated with bb21217 (Table). CAR+ T cells remained detectable in 30/37 (81%) patients and 9/15 (60%) patients at 6 and 12 M respectively, post bb21217 infusion. Of the 15 patients evaluable for MRD with ≥CR, 14 (93%) were MRD negative at 10 -5 by NGS. Analysis of peripheral blood samples collected 15 days post bb21217 infusion demonstrated patients with higher than the median number of CD8+ CAR+ T cells expressing CD27 and CD28 had significantly longer DOR (p=0.0024), compared to patients with lower than the median values. This suggests less differentiated, more proliferative CAR+ T cells at peak expansion are associated with prolonged disease response (median DOR in high vs low: 27.2M (95% CI; 16.8, NE) vs 9.4M (95% CI; 5.1, NE). Conclusions: Adverse events are consistent with known toxicities of CAR T cell therapies. Efficacy results are encouraging with a median DOR estimate of 17M, CR rate continues to mature. Patients with higher levels of proliferative, less differentiated memory like CAR+ T cells at peak expansion are more likely to experience prolonged DOR, continuing to support the hypothesis that the memory like T cell phenotype associated with bb21217 results in prolonged DOR. Figure 1 Figure 1. Disclosures Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Shah: Poseida: Research Funding; Precision Biosciences: Research Funding; Sanofi: Consultancy; Sutro Biopharma: Research Funding; Karyopharm: Consultancy; Janssen: Research Funding; Oncopeptides: Consultancy; Kite: Consultancy; Nektar: Research Funding; Indapta Therapeutics: Consultancy; GSK: Consultancy; CSL Behring: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; Amgen: Consultancy; Teneobio: Research Funding. Kaufman: BMS: Consultancy, Research Funding; Tecnofarma SAS, AbbVie: Honoraria; Incyte, celgene: Consultancy; Janssen: Honoraria; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Research Funding; Fortis Therapeutics: Research Funding; Novartis: Research Funding; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Sutro, Takeda: Research Funding; Genentech, AbbVie, Janssen: Consultancy, Research Funding. Siegel: Celularity: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau; Amgen Inc.: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria, Speakers Bureau. Munshi: Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Legend: Consultancy; Adaptive Biotechnology: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Karyopharm: Consultancy; Pfizer: Consultancy. Rosenblatt: Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Attivare: Consultancy; Wolters Kluwer Health Inc: Consultancy, Patents & Royalties. Lin: Sorrento: Consultancy; Takeda: Research Funding; Juno: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding; Vineti: Consultancy; Legend: Consultancy; Bluebird Bio: Consultancy, Research Funding; Novartis: Consultancy; Gamida Cell: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Jakubowiak: BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Timm: bluebird bio: Current Employment. Yeri: bluebird bio: Current Employment. Martin: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company. Finney: bluebird bio: Current Employment, Current equity holder in publicly-traded company. Truppel-Hartmann: bluebird bio: Current Employment. Petrocca: blue bird bio: Ended employment in the past 24 months. Berdeja: Abbvie, Acetylon, Amgen: Research Funding; Celularity, CRISPR Therapeutics: Research Funding; Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy; EMD Sorono, Genentech: Research Funding; GSK, Ichnos Sciences, Incyte: Research Funding; Lilly, Novartis: Research Funding; Poseida, Sanofi, Teva: Research Funding.

Abstract Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01680965.

Background: Smoldering multiple myeloma (SMM) represents an intermediate stage between monoclonal gammopathy of undetermined significance and active myeloma with a high risk of progression to active MM, especially during the initial years after diagnosis. Available clinical risk factors have enabled development of risk stratification systems that allow for identification of patients at the highest risk of progression, opening opportunities for early intervention. Two phase 3 trials using lenalidomide with dexamethasone or lenalidomide alone have both shown benefit for early intervention by decreasing the risk of progression and improving the overall survival in the former. It remains unknown if an approach using a single active drug to delay progression, or one that uses therapies like active myeloma, represent a better approach; both are being studied in phase 3 trials. We designed this phase 2 trial to examine if an intense but limited duration therapy can possibly provide a significant elimination of the tumour burden that can potentially lead to long term responses. Patients and Methods: Patients with SMM (per updated IMWG definition of SMM) with high risk disease (defined by the IMWG updated risk stratification criteria- presence of any two of the following: Serum M spike > 2 gm/dL OR an involved to uninvolved FLC ratio > 20 OR bone marrow PC% > 20%) or a score of ≥9 using the risk scoring system using FLC ratio, serum M spike, marrow plasma cell% and presence of high risk FISH were enrolled provided they had adequate marrow and organ function. Patients with significant comorbidities such as heart disease were excluded from the trial. Treatment consisted of three phases: induction, consolidation and maintenance. Patients received carfilzomib (36 mg/m2 twice weekly or as per updated protocol 56mg/m2 weekly for 2 weeks), lenalidomide (25 mg daily for three weeks), daratumumab (weekly for 8 doses, every other week for 16 weeks) and dexamethasone 40 mg weekly, in 4 week cycles for 6 cycles as part of induction, the same regimen was administered with daratumumab every 4 weeks and dexamethasone 20 mg weekly for another 6 cycles for consolidation. This was followed by 12 cycles of maintenance therapy with lenalidomide (10 mg daily for three weeks), daratumumab (day 1 every other cycle) of a 4-week cycle. Appropriate antiviral, and thrombosis prophylaxis were mandated. The primary endpoint of this trial is the rate of confirmed sCR as best response across all cycles of treatment. We plan to accrue 83 patients to this trial with one-stage binomial trial design to test the null hypothesis that the true success (sCR) proportion is at most 65% and the alternate hypothesis of 80%. Results: Forty-six patients have been accrued to the trial as of July 14, 2020. The median age of the study population is 63 years (range 47 - 76); 70% are male. Overall, 2% have completed the maintenance, 50% have completed the consolidation, 80% have completed the induction and 15% are in the induction phase; only two patients have gone off treatment. The reasons for going off treatment were patient preference. At least one patient needed a dose modification for each drug; 17%, 2%, 13% and 7% required dose reductions for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively. The relative median dose intensity for the drugs were 85%, 92%, 80% and 98% for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively across the delivered cycles. The adverse events seen in at least 5% of the patients are as shown in the figure. A grade 3 or higher AE was seen in 52% of patients. There were no treatment related deaths observed. Response rate and depth have been as expected for this regimen in myeloma and analysis is pending completed accrual. Figure 1 Disclosures Kumar: Adaptive Biotechnologies: Consultancy; Sanofi: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Novartis: Research Funding; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; 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; Janssen Oncology: 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; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Carsgen: Other, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Dhakal:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Other: AdvIsory Board, Research Funding; Janssen: Consultancy, Other: Advisory Board, Research Funding; Takeda: Consultancy, Other: Advisory Board; GSK: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding. Abonour:Celgene: Consultancy; Janssen: Honoraria, Research Funding; Takeda: Consultancy; BMS: Consultancy, Research Funding. Rosenbaum:Celgene: Honoraria; Akcea: Honoraria; Amgen: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Research Funding. Bensinger:GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bhutani:Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Introduction: Chimeric antigen receptor (CAR) T cell therapy directed against B-cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM). bb21217 is an anti-BCMA CAR T cell therapy that uses the same CAR molecule as idecabtagene vicleucel (bb2121), but adds the PI3K inhibitor bb007 during ex vivo culture to enrich the drug product (DP) for memory-like T cells, thereby reducing the proportion of highly differentiated or senescent T cells. To investigate whether DP properties correlate with clinical outcomes including duration of response (DOR), we conducted extensive molecular characterization of patient DPs. Methods: CRB-402 (NCT03274219) is an ongoing, multi-center phase 1 dose escalation trial of bb21217 in RRMM patients who received ≥3 prior regimens, including proteasome inhibitor and immunomodulatory agent, or are double-refractory to both classes. In the expansion cohort, patients additionally required prior exposure to an anti-CD38 antibody and were required to be refractory to last line. Planned enrollment is 74 patients, including 50 in the expansion cohort. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive a single infusion of bb21217 at 150, 300 or 450 x 106 CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures include overall response rate and DOR by IMWG Uniform Response Criteria. We profiled DP and apheresis starting material (PBMC) by RNAseq and cyTOF and correlated expression of memory/senescence markers from apheresis to DP with clinical outcomes, including DOR. Results: Asof March 1, 2020, 46 patients (median age 62 [33-74]) received bb21217, 24 in escalation (12 at 150, 6 at 300 and 6 at 450) and 22 in expansion (8 at 300 and 14 at 450); median follow up for all patients is 8.5 (<1-29) months. Patients had a median of 6 (3-17) prior lines of therapy with 26/46 (57%) triple refractory. Cytokine release syndrome (CRS) developed in 31/46 (67%) patients and included one death (14 G1, 15 G2, 1 G3 and 1 G5). Median time to first onset was 3 days (1-20); tocilizumab (18 pts) +/- corticosteroids (6 pts) was used to manage CRS. Ten (22%) patients developed neurotoxicity [5 G1, 2 G2, 2 G3, 1 G4] with median time to first onset of 7 (3-24) days. Response was assessed per investigator for 44 patients with ≥ 2 months of follow up or PD/death within 2 months. Twenty-four (55%) patients had confirmed response per IMWG criteria including 8 (18%) with ≥CR and 13 (30%) with VGPR. Median time to CR was 2.5 (1-24) months. The median DOR was 11.9 (95% CI: 8.1-17.0) months across target dose levels of 150-450 x106 CAR+ T cells. The 450 target dose was selected as the RP2D and dose expansion is ongoing. bb21217 DPs from 44 patients were characterized. Paired analysis of T cells from PBMC and DP showed bb21217 DP is significantly enriched for memory-like T cells (LEF1+, CD27+, CCR7+) and depleted of highly differentiated or senescent CD57+ T cells. Patients with DPs most enriched for early memory markers (LEF1+, CCR7+ and CD27+) and with low expression of effector/exhaustion markers (EOMES+, GZMA+, CD57+) were more likely to have higher peak CAR+ T cell expansion. To evaluate the association of these DP markers with DOR, we split the 24 responders (≥PR) on median marker expression (high vs low) and analyzed DOR in these exploratory subgroups. High CD127 expression, associated with long-lasting memory T cell formation, was positively correlated with DOR, while multiple markers associated with differentiated T cells (e.g. EOMES+, TBET+) were negatively correlated with DOR. Conclusions: The adverse events observed are consistent with known toxicities of CAR T cell therapies. Initial efficacy results with bb21217 are encouraging, with 48% of patients treated across target dose levels of 150-450 obtaining ≥VGPR. The presence of T cell markers associated with memory and the absence of T cells markers associated with differentiation/senescence in DP correlated positively with peak expansion and DOR. These preliminary correlative data support the mechanistic hypothesis that enrichment for memory like T cells in bb21217 DP may result in improved clinical outcomes. Data for approximately 14 additional patients at the 450 target dose will be presented. Disclosures Alsina: Janssen: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Amgen: Honoraria, Speakers Bureau; BMS: Consultancy, Research Funding. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Raje:Janssen: Consultancy; Celgene: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Astrazeneca: Consultancy; Bluebird, Bio: Consultancy, Research Funding; Karyopharm: Consultancy; BMS: Consultancy; Amgen: Consultancy. Jagannath:Karyopharm: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Madduri:Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy; Legend: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Kinevant: Consultancy; Foundation Medicine: Consultancy. Kaufman:Janssen: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Tecnopharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi/Genyzme: Consultancy, Honoraria. Siegel:Amgen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Celulatiry: Consultancy. Munshi:BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; C4: Current equity holder in private company; Janssen: Consultancy; Adaptive: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy. Lin:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Timm:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Turka:bluebird bio: Current Employment. Mao:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Martin:BMS: Current Employment, Current equity holder in publicly-traded company. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Hege:Arcus Biosciences: Divested equity in a private or publicly-traded company in the past 24 months; Mersana Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BMS: Current Employment, Current equity holder in publicly-traded company, Other: Travel, accommodations, expenses, Patents & Royalties: Numerous, Research Funding. Bitter:Novartis AG, Predicant Biosciences, Biospect, F Hofmann-La Roche: Ended employment in the past 24 months; bluebird bio: Current Employment, Current equity holder in publicly-traded company; Novartis: Ended employment in the past 24 months, Patents & Royalties. Petrocca:bluebird, bio: Current Employment, Current equity holder in publicly-traded company. Berdeja:Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; CURIS: Research Funding; EMD Sorono: Research Funding; Takeda: Consultancy, Research Funding; Servier: Consultancy; Teva: Research Funding; Prothena: Consultancy; Poseida: Research Funding; Novartis: Research Funding; Lilly: Research Funding; Legend: Consultancy; Kite Pharma: Consultancy; Kesios: Research Funding; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; Glenmark: Research Funding; Genentech, Inc.: Research Funding; BMS: Consultancy, Research Funding; Bioclinica: Consultancy; Bluebird: Research Funding; Acetylon: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Research Funding; Vivolux: Research Funding.

Abstract In an effort to identify novel genetic abnormalities in multiple myeloma (MM) we analyzed an initial set, as part of the Multiple Myeloma Research Consortium (MMRC) Genomics Initiative, of 94 MM patient samples on high-resolution array-based comparative genomic hybridization (aCGH) and gene expression profiling (GEP) technologies. The MMRC Genomics Initiative is a three-year research program spanning a full-spectrum of genomic technologies with the goal of analyzing 250 MM patient samples by 2009. Raw data from the Initiative are released in near real time through the MMRC Multiple Myeloma Genomics Portal. This initial aCGH dataset from the Agilent 244K platform represents the highest resolution gene copy number analysis with corresponding GEP released to date in MM. It has confirmed the cytogenetic definitions of MM with the data set being split between patients with hyperdiploid and non-hyperdiploid MM. Furthermore, the 244K platform has helped to refine minimal regions of change present on 1p, 1q, 6q, 8p, 13q, 14q, and 16q. A comprehensive screen of the dataset for genes residing in regions of homozygous deletion identified 105 genes. The most commonly affected gene was CDKN2C(p18) (8.3%) while 12 other regions were recurrently targeted. Several of these regions were recently implicated in the pathogenesis of MM but the large majority represents novel observations. The aCGH and GEP data were integrated using two different programs developed by the core institutions (The Broad Institute of Harvard & MIT and Translational Genomics Research Institute). First, Genomic Identification of Significant Targets in Cancer (GISTIC), which identifies highly significant regions of change and a limited set of candidate genes within these regions, was used to identify 285 genes associated with DNA content alterations. Second, Breakpoint Expression Correlation (BEC), which identifies dysregulated genes on either side of a copy number alteration, was used to identify 194 genes with expression changes associated with a breakpoint. This latter gene list includes all known IgH translocation target genes identified to date in myeloma. Overlapping the gene lists generated by GISTIC, BEC, and the homozygous deletion screen identified a number of genes previously implicated in MM such as CDKN2C(p18), CYLD, BIRC2/BIRC3, and two novel genes, FAM46C and RNF6. Ongoing data integration with RNAi and high content sequencing projects of the current Initiative holds great promise in furthering our understanding of MM. The MMRC Genomics Initiative and resulting efforts from the myeloma research community will increase our understanding of MM at the molecular level, help to identify new targets, and ultimately lead to the development of better, more effective therapies for myeloma.