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Aim: To compare the efficacy of idecabtagene vicleucel (ide-cel, bb2121) versus conventional care (CC) in triple-class exposed relapsed and refractory multiple myeloma (RRMM) patients. Patients & methods: A matching-adjusted indirect comparison was conducted using individual patient-level data from the pivotal, phase II, single-arm KarMMa trial (NCT03361748) and aggregate-level data from MAMMOTH, the largest independent observational study of CC in heavily pretreated RRMM patients. Results: Ide-cel improved overall response rate (odds ratio: 5.30; 95% CI: 2.96–9.51), progression-free survival (hazard ratio: 0.50; 95% CI: 0.36–0.70) and overall survival (hazard ratio: 0.37; 95% CI: 0.25–0.56) versus CC. Conclusion: These results suggest ide-cel offers improvements in clinical outcomes relative to CC in this heavily pretreated RRMM population.

PDF file - 2561K, Treatment with CC214-1, leads to induction of autophagy in GBM39 cells and genetic inhibition of autophagy sensitizes U87EGFRvIII cells to apoptosis.

PDF file - 5321K, In vitro and in vivo pharmacological inhibition of autophagy sensitizes U87EGFRvIII cells and orthotopic xenografts to CC214-1/CC214-2 mediated apoptosis.

Purpose:Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma.Patients and Methods:Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5–3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide.Results:DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg.Conclusions:Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL.

PDF file - 2080K, Tunable expression of EGFRvIII in genetically modified models correlates with autophagy induction upon CC214-1 treatment.

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Supplementary Table S1. Summary of avadomide plasma pharmacokinetic parameters by day and dose level Supplementary Figure S1. Representative flow cytometry analysis of Aiolos degradation in peripheral B cells (A) and T cells (B). Supplementary Figure S2. IL-2 expression correlates with Aiolos degradation in treated primary human T cells in vitro.

PDF file - 5300K, CC214-1 synergizes at low doses with rapamycin. Quantification of the blots shown in Fig. 2B. PTEN detection on DEAL captured GBM39 cells upon CC214-1 treatment.

PDF file - 3457K, Time course dependent CC214-1 treatment in a panel of isogenic GBM cell lines, U87EGFRvIII, U251 and LN229.

PDF file - 1554K, Cap-dependent translation is enhanced by EGFRvIII expression and CC214-1 strongly inhibits P-4E-BP1 phosphorylation.

Purpose: mTOR pathway hyperactivation occurs in approximately 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here, we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacologic strategy to overcome it.Experimental Design: We conducted in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin-resistant signaling and blocking glioblastoma growth and a novel single-cell technology—DNA Encoded Antibody Libraries—was used to identify mechanisms of resistance.Results: Here, we show that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling, block mTORC2 signaling, and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes glioblastoma cells and orthotopic xenografts to CC214-1- and CC214-2–induced cell death.Conclusions: These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in glioblastoma, and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. In addition, this study also shows a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacologic strategy for overcoming it. Clin Cancer Res; 19(20); 5722–32. ©2013 AACR.

Purpose: Chronic myeloid leukemia (CML) can be responsive to T-cell–mediated immunity. K562/granulocyte macrophage-colony stimulating factor (GM-CSF) is a GM-CSF producing vaccine derived from a CML cell line that expresses several CML-associated antigens. A pilot study was developed to determine if K562/GM-CSF immunotherapy could improve clinical responses to imatinib mesylate (IM) in patients with chronic myeloid leukemia.Experimental Design: Patients with chronic phase CML who achieved at least a major cytogeneic response but remained with persistent, measurable disease despite one or more years on imatinib mesylate were eligible. Each was given a series of four vaccines administered in three-week intervals, with or without topical imiquimod, while remaining on a stable dose of imatinib mesylate. CML disease burden was measured serially before and after vaccination.Results: Nineteen patients were vaccinated, with a median duration of previous imatinib mesylate therapy of 37 (13–53) months. Mean PCR measurements of BCR-ABL for the group declined significantly following the vaccines (P = 0.03). Thirteen patients had a progressive decline in disease burden, 8 of whom had increasing disease burden before vaccination. Twelve patients achieved their lowest tumor burden measurements to date following vaccine, including seven subjects who became PCR-undetectable.Conclusions: K562/GM-CSF vaccine appears to improve molecular responses in patients on imatinib mesylate, including achieving complete molecular remissions, despite long durations of previous imatinib mesylate therapy. Clin Cancer Res; 16(1); 338–47

PDF file - 1694K, EGFRvIII expression sensitizes cells to CC214-1 mediated inhibition of proliferation and to autophagy.

Supplementary Data from K562/GM-CSF Immunotherapy Reduces Tumor Burden in Chronic Myeloid Leukemia Patients with Residual Disease on Imatinib Mesylate

CC-90002 is an anti-CD47 antibody that inhibits CD47-SIRPα interaction and enables macrophage-mediated killing of tumor cells in hematological cancer cell lines. In this first clinical, phase 1, dose-escalation and -expansion study (CC-90002-AML-001; NCT02641002), we evaluated CC-90002 in patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). CC-90002 was administered in escalating doses of 0.1–4.0 mg/kg, using a modified 3+3 design. Primary endpoints included dose-limiting toxicities (DLTs), non-tolerated dose (NTD), maximum tolerated dose (MTD), and recommended phase 2 dose. Secondary endpoints included preliminary efficacy, pharmacokinetics, and presence/frequency of anti-drug antibodies (ADAs). Between March 2016 and July 2018, 28 patients were enrolled (24 with AML and 4 with MDS) at 6 sites across the United States. As of July 18, 2018, all patients had discontinued, mainly due to death or progressive disease. The most common treatment-emergent adverse events were diarrhea (46.4%), thrombocytopenia (39.3%), febrile neutropenia (35.7%), and aspartate aminotransferase increase (35.7%). Four patients experienced DLTs (1 patient had grade 4 disseminated intravascular coagulation and grade 5 cerebral hemorrhage, 1 had grade 3 purpura, 1 had grade 4 congestive cardiac failure and grade 5 acute respiratory failure, and another had grade 5 sepsis). The NTD and MTD were not reached. No objective responses occurred. CC-90002 serum exposure was dose-dependent. ADAs were present across all doses, and the proportion of ADA-positive patients in cycle 1 increased over time. Despite no unexpected safety findings, the CC-90002-AML-001 study was discontinued in dose escalation for lack of monotherapy activity and evidence of ADAs. However, as other anti-CD47 agents in clinical trials are showing promising early results for AML and MDS, understanding preclinical and clinical differences between individual agents in this class will be of high importance.

Author(s): Munster, Pamela; Mita, Monica; Mahipal, Amit; Nemunaitis, John; Massard, Christophe; Mikkelsen, Tom; Cruz, Cristina; Paz-Ares, Luis; Hidalgo, Manuel; Rathkopf, Dana; Blumenschein, George; Smith, David C; Eichhorst, Barbara; Cloughesy, Tim; Filvaroff, Ellen H; Li, Shaoyi; Raymon, Heather; de Haan, Hans; Hege, Kristen; Bendell, Johanna C | Abstract: PurposeThis first-in-human Phase I study investigated the safety, pharmacokinetics (PK), pharmacodynamic profile, and preliminary efficacy of CC-115, a dual inhibitor of mammalian target of rapamycin (mTOR) kinase and DNA-dependent protein kinase.Patients and methodsPatients with advanced solid or hematologic malignancies were enrolled in dose-finding and cohort expansion phases. In dose-finding, once-daily or twice-daily (BID) ascending oral doses of CC-115 (range: 0.5-40 mg/day) in 28-day continuous cycles identified the maximum-tolerated dose for cohort expansion in 5 specified tumor types. Twelve additional patients with mixed solid tumors participated in a bioavailability substudy.ResultsForty-four patients were enrolled in the dose-finding cohort. Dose-limiting toxicity included thrombocytopenia, stomatitis, hyperglycemia, asthenia/fatigue, and increased transaminases. CC-115 10 mg BID was selected for cohort expansion (n=74) in which fatigue, nausea, and decreased appetite were the most frequent toxicities. Dose-proportional PK was found. CC-115 distributed to glioblastoma tissue (mean tumor/plasma concentration ratio: 0.713). Total exposure of CC-115 was similar under fasting and fed conditions. A patient with endometrial carcinoma remained in complete remission g4 years. Partial response (PR; n=2) and stable disease (SD; n=4) were reported in the bioavailability substudy; SD was reached in 53%, 22%, 21%, and 64% of patients with head and neck squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme, and castration-resistant prostate cancer, respectively. Chronic lymphocytic leukemia/small lymphocytic lymphoma showed 38% PR and 25% SD.ConclusionCC-115 was well-tolerated, with toxicities consistent with mTOR inhibitors. Together with biomarker inhibition and preliminary efficacy, oral CC-115 10 mg BID is a promising novel anticancer treatment.Clinical trial registrationNCT01353625.

Purpose: Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression. Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and long-term clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo. Results: DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription. Conclusions: Our data show that DNAPK drives prostate cancer progression through transcriptional regulation of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

BACKGROUND: Preclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma. METHODS: In this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses of 50×10(6), 150×10(6), 450×10(6), or 800×10(6) CAR-positive (CAR+) T cells in the dose-escalation phase and 150×10(6) to 450×10(6) CAR+ T cells in the expansion phase. Patients had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. The primary end point was safety. RESULTS: Results for the first 33 consecutive patients who received a bb2121 infusion are reported. The data-cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression-free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10(−4) nucleated cells). CAR T-cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion. CONCLUSIONS: We report the initial toxicity profile of a BCMA-directed cellular immunotherapy for patients with relapsed or refractory multiple myeloma. Antitumor activity was documented. (Funded by Bluebird Bio and Celgene; CRB-401 ClinicalTrials.gov number, NCT02658929.)

Idecabtagene vicleucel (ide-cel, bb2121), a chimeric antigen receptor (CAR) T cell therapy, has been investigated in patients with relapsed and refractory multiple myeloma (RRMM) who have received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 antibody in the single-arm phase 2 KarMMa clinical trial. Two therapies with distinct mechanisms of action - selinexor plus dexamethasone (Sd) and belantamab mafodotin (BM) - are currently approved in the United States for heavily pretreated patients, including those who are triple-class refractory. To compare ide-cel versus Sd and ide-cel versus BM, matching-adjusted indirect comparisons were performed. Ide-cel extended progression-free survival (PFS) and overall survival (OS) versus both Sd and BM (hazard ratio (HR); 95% confidence interval (CI)). PFS: ide-cel versus Sd, 0.46; 0.28-0.75; ide-cel versus BM, 0.45; 0.27-0.77. OS: ide-cel versus Sd, 0.23; 0.13-0.42; ide-cel versus BM, 0.35; 0.14-0.87. These results suggest ide-cel offers clinically meaningful improvements over currently approved regimens for patients with heavily pretreated RRMM. ispartof: LEUKEMIA & LYMPHOMA vol:62 issue:10 pages:2482-2491 ispartof: location:United States status: published

OBJECTIVE: To understand the experience of patients with relapsed and refractory multiple myeloma (RRMM) receiving idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, in the pivotal, phase 2 KarMMa trial. METHODS: Optional semi-structured interviews before leukapheresis (pre-treatment) captured expectations and after ide-cel infusion (1, 2, and 3 months post-treatment), assessed treatment experience, ide-cel advantages/disadvantages, and health and well-being. In a mixed-method analysis, treatment experiences were categorized by clinical response status, health and well-being, and self-reported recovery after infusion. RESULTS: Pre-treatment interviews indicated unmet treatment needs. In post-treatment interviews, most patients reported the positives of ide-cel outweighed negatives (69%, n = 27/39). Most common advantages of ide-cel were efficacy (18-64%), favorable side-effect profile (46-68%), and recovery time (13-18%); most common disadvantages were related to side effects (13-20%). When analyzed by clinical response, patients most often had stringent complete or very good partial response and improved health and well-being with mild or severe recovery from the infusion (27/58, 47%). Most patients with minimal clinical response reported mild infusion recovery (5/6, 83%). CONCLUSIONS: Patient interviews before ide-cel treatment showed unmet needs in triple-class exposed RRMM. Post-treatment experiences generally favored ide-cel versus previously received treatments. ispartof: LEUKEMIA RESEARCH vol:120 ispartof: location:England status: published

Background Patients (pts) with RRMM who were exposed to immunomodulatory agents, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) have poor outcomes with subsequent treatments. Ide-cel, a BCMA-directed CAR T-cell therapy, has shown frequent, deep, and durable responses in triple-class exposed pts with RRMM in the pivotal KarMMa study (NCT03361748; Munshi NC et al. N Engl J Med 2021). Here, we report updated results from this trial. Methods Eligible pts had received ≥3 prior regimens (including an immunomodulatory agent, a PI, and an anti-CD38 mAb) and had disease refractory to their last regimen per IMWG criteria. After 3 days of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2), pts received 150–450×106 CAR+ T cells (target dose levels). Primary endpoint was overall response rate (ORR); key secondary endpoint was complete response (CR) rate (CR + stringent CR). Other secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results In total, 128/140 enrolled pts received ide-cel. Data are presented for the treated pts. Median age was 61 y. Pts had received a median of 6 (range, 3–16) prior regimens, with 84% being triple-class refractory and 26% penta-refractory (lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab). Most pts (88%) had received bridging therapy. At data cutoff (Dec 21, 2020), the median follow-up among surviving pts was 24.8 mo. In total, 94/128 pts (73%) achieved an overall response, with a CR rate of 33%; median DOR and PFS were 10.9 mo and 8.6 mo, respectively. In pts who achieved ≥CR, median DOR was 21.5 mo and median PFS was 22.4 mo. Outcomes improved at higher doses, with ORR of 81%, CR rate of 39%, median DOR of 11.3 mo, and median PFS of 12.2 mo at 450×106 CAR+ T cells; in pts who achieved ≥CR at this dose, median DOR was not reached. Responses were observed in all subgroups, including difficult-to-treat subsets (eg, high tumor burden [ORR, 71%], extramedullary disease [70%], and R-ISS stage III disease [48%]). Median OS was 24.8 mo; the estimated 24-mo OS rate was 51%. The most common any-grade toxicities were neutropenia (91%) and cytokine release syndrome (CRS; 84%). CRS was mostly grade 1/2; 5 pts (4%) had grade 3, 1 pt each had grade 4 and 5 events (both at 300×106). Investigator-identified neurotoxicity was reported in 23 pts (18%); 5 (4%) had grade 3 and 0 had grade ≥4 events. Tocilizumab was used in 67 and 3 pts, and steroids were used in 19 and 10 pts with CRS and neurotoxicity, respectively. Conclusion Updated results from the KarMMa trial continue to demonstrate durable and deep responses with ide-cel in heavily pretreated, triple-class–exposed pts with RRMM. Efficacy and safety data are consistent with prior reports and support a favorable clinical benefit–risk profile for ide-cel across the target dose levels.

BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy., Relapse following BCMA targeted CAR T-cell therapy is frequently observed in patients with multiple myeloma (MM). Here, by single cell transcriptome profiling on serially collected bone marrow samples, the authors report biallelic loss of BCMA as the mechanism of resistance underlying both relapse and lack of response to a second CAR T infusion in a patient with MM.

8016 Background: Patients (pts) with RRMM previously exposed to immunomodulatory agents, proteasome inhibitors (PIs), and CD38 antibodies (mAbs) have poor outcomes with subsequent treatments. Ide-cel, a BCMA-directed CAR T cell therapy, showed frequent, deep, and durable responses in heavily pretreated pts with RRMM in the pivotal KarMMa trial (Munshi NC, et al. J Clin Oncol 2020;38[suppl 15]. Abstract 8503). Here, we present updated data. Methods: Pts with ≥ 3 prior regimens (including immunomodulatory agent, PI, and CD38 mAb) and refractory to their last regimen per IMWG criteria were eligible (NCT03361748). Pts received 150─450 × 106 CAR+ T cells (target dose range) after 3 days of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2). Endpoints included overall response rate (ORR; primary) and complete response (CR) rate (key secondary). Additional secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: KarMMa enrolled 140 pts, and 128 received ide-cel. Pts had a median age of 61 years and a median of 6 (range, 3-16) prior regimens; 84% were triple-class refractory, and 26% were penta-class refractory (lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab). Most pts (88%) had bridging therapy. Median follow-up was 15.4 mo (data cutoff, 7 Apr 2020). ORR was 73% and median PFS was 8.8 mo in all treated pts; both increased with higher dose (Table). At the highest target dose (450 × 106 CAR+ T cells), the ORR was 81%, the CR rate was 39%, and the median PFS increased to 12.2 months with longer follow-up. Responses were observed in all subgroups including difficult-to-treat subsets (eg, extramedullary disease [ORR, 70%], high tumor burden [71%], and R-ISS stage III disease [48%]). OS continues to mature and the median has not been reached; the 15-month event-free rate for OS was 71%. Cytopenias (97%) and cytokine release syndrome (CRS; 84%) were the most common any-grade toxicities. CRS was mostly grade 1/2; 5 pts (4%) had grade 3, 1 had grade 4 (at 300 × 106), and 1 had grade 5 (at 300 × 106). Investigator-identified neurotoxicity was reported in 23 pts (18%); 4 pts (3%) had grade 3 and 0 had grade ≥ 4. Tocilizumab was used in 67 and 3 pts with CRS and neurotoxicity, respectively. Conclusions: Updated results from the KarMMa trial continue to demonstrate deep, durable responses with ide-cel in heavily pretreated pts with RRMM. Efficacy and safety reflect prior reports and support a favorable clinical benefit-risk profile for ide-cel across the target dose range. Clinical trial information: NCT03361748. [Table: see text]

BACKGROUND Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigendirected chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma. METHODS In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulating agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 x 10(6) to 450 x 10(6) CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses). RESULTS Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (

B cell maturation antigen (BCMA) is a target for various immunotherapies and a biomarker for tumor load in multiple myeloma (MM). We report a case of irreversible BCMA loss in a patient with MM who was enrolled in the KarMMa trial ( NCT03361748 ) and progressed after anti-BCMA CAR T cell therapy. We identified selection of a clone with homozygous deletion of TNFRSF17 (BCMA) as the underlying mechanism of immune escape. Furthermore, we found heterozygous TNFRSF17 loss or monosomy 16 in 37 out of 168 patients with MM, including 28 out of 33 patients with hyperhaploid MM who had not been previously treated with BCMA-targeting therapies, suggesting that heterozygous TNFRSF17 deletion at baseline could theoretically be a risk factor for BCMA loss after immunotherapy. Biallelic loss of BCMA caused a patient with multiple myeloma to relapse after anti-BCMA CAR T cell treatment. Baseline heterozygous BCMA deletions might be a risk factor for this form of resistance.

Purpose: Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma. Patients and Methods: Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5–3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide. Results: DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg. Conclusions: Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL.

While CD19-directed CAR T cells can induce remissions in patients with B cell acute lymphoblastic leukemia (ALL), a large subset relapse with CD19-negative disease. Like CD19, CD22 is broadly expressed by B-lineage cells and thus serves as an alternative immunotherapy target in ALL. Here we present the composite outcomes of two pilot clinical trials (NCT02588456 and NCT02650414) of T cells bearing a 41BB-based CD22-targeting CAR in patients with relapsed or refractory ALL. The primary endpoint of these studies was to assess safety, and the secondary endpoint was anti-leukemic efficacy. We observed unexpectedly low response rates, prompting us to perform detailed interrogation of the responsible CAR biology. We found that shortening of the amino acid linker connecting the variable heavy and light chains of the CAR antigen-binding domain drove receptor homo-dimerization and antigen-independent signaling. In contrast to CD28-based CARs, autonomously signaling 41BB-based CARs demonstrated enhanced immune synapse formation, activation of pro-inflammatory genes and superior effector function. We validated this association between autonomous signaling and enhanced function in several CAR constructs, and based on these observations designed a new short-linker CD22 scFv for clinical evaluation. Our findings suggest that tonic 41BB-based signaling is beneficial to CAR function and demonstrate the utility of bedside-to-bench-to-bedside translation in the design and implementation of CAR T cell therapies.

Introduction : CD47, a cell-surface ligand overexpressed in various malignancies, binds to SIRPα on effector macrophages to promote tumor cell evasion of phagocytosis. Blockade of the CD47-SIRPα interaction provides a pro-phagocytic signal which enhances phagocytosis mediated by tumor-targeting antibodies such as rituximab. Agents targeting CD47 in combination with rituximab have demonstrated promising clinical activity in R/R NHL; however, the broad expression of CD47 leads to frequent on-target, off-tumor toxicities, including treatment-emergent hemolytic anemia. CC-95251 is a novel, fully human immunoglobulin G1 antibody that binds to SIRPα on monocytes and macrophages to potently block the CD47-SIRPα interaction. Here we report interim results from a phase 1 study evaluating CC-95251 combined with rituximab in patients (pts) with R/R NHL. Methods: CC-95251-ST-001 (NCT03783403) is a multicenter, open-label, phase 1, dose-escalation and expansion study of CC-95251 in pts with advanced solid tumors and CD20+ R/R NHL. The primary objectives of the dose-escalation stage presented here are to evaluate the safety and tolerability of escalating doses of CC-95251 combined with rituximab and to define the maximum tolerated dose (MTD) and/or recommended phase 2 dose for the combination in pts with R/R NHL. Pts with CD20+ NHL who had progressed on standard anticancer therapy or for whom no approved conventional therapy was available were eligible for inclusion. Dose-escalation was conducted using an adaptive, 2-parameter Bayesian logistic regression model with overdose control. Pts were treated in 28-day cycles with CC-95251 administered intravenously at 3, 10, or 20 mg/kg every week (QW) and rituximab 375 mg/m 2 given on days 1, 8, 15, and 22 of cycle 1, on day 1 of cycles 2-5, and on day 1 of every other cycle from cycle 6 to 24 until disease progression or unacceptable toxicity. Results: As of April 30, 2021, 18 pts were enrolled and 17 had received ≥ 1 dose of CC-95251 and rituximab. Median age of the enrolled study population was 69 (range 30-84) years. Treated pts had received a median of 4 (range 1-7) prior systemic therapies, including 14/17 (82%) pts with confirmed prior rituximab exposure. Enrolled tumor types included R/R diffuse large B-cell lymphoma in 14 (78%) pts, follicular lymphoma in 2 (11%), and mantle cell lymphoma and marginal zone lymphoma in 1 (6%) pt each. Of the pts with available response data for prior lines of therapy (LOT), 7 (41%) had disease confirmed to be refractory to any prior LOT, including 5 (29%) refractory to rituximab-containing regimens, and 5 (29%) to their last LOT. Pts received a median of 3 (range 1-12) cycles of CC-95251, with a median duration of treatment of 14.1 (range 1.1-47.3) weeks. There were no CC-95251 dose reductions. Five (29%) pts experienced ≥ 1 treatment-emergent adverse events (TEAEs) leading to CC-95251 dose interruption. To date, the MTD has not been reached for the combination of CC-95251 and rituximab. The most common (≥ 30%) TEAEs of any grade were neutropenia (11/17 [65%]), infections (9/17 [53%]), hypokalemia (6/17 [35%]), and hypomagnesemia (6/17 [35%]; Table). Grade ≥ 3 TEAEs reported in ≥ 2 pts were neutropenia (9/17 [53%]) and infections (4/17 [24%]). No treatment-related anemia, a notable toxicity of some anti-CD47 therapies, was reported with CC-95251 and there were no treatment-related deaths. The overall response rate was 41% (7/17), with 2/17 (12%) pts achieving a complete response (Figure). The median time to response was 7.6 weeks. Median duration of response has not been reached as responses are ongoing. Pharmacokinetic (PK) analysis showed that CC-95251 exhibited dose-proportional increases in exposure at doses > 3 mg/kg QW indicating saturation of nonlinear clearance pathways or target saturation. Full receptor occupancy on peripheral monocytes was achieved at doses > 3 mg/kg QW. The estimated terminal half-life when in the linear range of clearance was approximately 12 days. No substantial differences in PK were observed at the given dose levels for CC-95251 monotherapy versus CC-95251 combined with rituximab. Conclusions: CC-95251, a novel anti-SIRPα antibody, demonstrated a manageable safety profile and promising efficacy in combination with rituximab in pts with heavily pretreated CD20+ R/R NHL. The study continues to enroll in the dose-expansion phase. Updated safety and efficacy data will be presented. Figure 1 Figure 1. Disclosures Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. Hawkes: Regeneron: Speakers Bureau; Specialised Therapeutics: Consultancy; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Antigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Ghosh: Karyopharma: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Adaptive Biotech: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Genentech: Research Funding; AbbVie: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau. Tuscano: BMS, Seattle Genetics, Takeda, Achrotech, Genentech, Pharmacyclics, Abbvie: Research Funding. Chu: Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; BI: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Eli Lilly: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Merck KgaA: Other: DSMB. Patel: Bristol Myers Squibb: Current Employment. Burgess: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hege: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Chhagan: Bristol Myers Squibb: Current Employment. Boyanapalli: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Day: Tracey Day: Current Employment. Shen: Bristol Myers Squibb: Current Employment. Mehta: Affirmed; Kite/Gilead; Roche-Genetech; Celgene/BMS; Oncotartis; Innate Pharmaceuticals; Seattle Genetics; Incyte; Takeda; Fortyseven Inc/Gilead; TG Therapeutics; Merck; Juno Pharmaceuticals/Bristol Myers Squibb: Research Funding; Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics; Incyte; TG Therapeutics: Consultancy.

Background: Ide-cel, a BCMA-directed CAR T cell therapy, showed tolerability and promising efficacy in patients with relapsed and/or refractory multiple myeloma (RRMM) in the first-in-human phase 1 CRB-401 study (Raje et al. N Engl J Med. 2019;380:1726) and the pivotal phase 2 KarMMa study (Munshi et al. J Clin Oncol. 2020;38[suppl, abstr]:8503). Ide-cel demonstrated a favorable benefit-risk profile with an overall response rate (ORR) of 85%, a complete response (CR) rate of 45%, and a median progression-free survival (PFS) of 11.8 months in the first 33 patients treated in CRB-401. Reported here are updated safety and efficacy results for 62 patients who received ide-cel in the ongoing CRB-401 study. Methods: CRB-401 (NCT02658929) is a 2-part, phase 1 dose-escalation and -expansion study. The expansion phase enrolled patients who had received ≥3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody, and were refractory to their last line of therapy. Eligibility criteria for the dose-escalation phase were described previously (Raje et al. N Engl J Med. 2019;380:1726). After lymphodepletion with fludarabine (30 mg/m2/day) and cyclophosphamide (300 mg/m2/day) for 3 days followed by 2 days of rest, patients received ide-cel at target doses of 50, 150, 450, or 800 × 106 CAR+ T cells in the dose-escalation phase and 150 to 450 × 106 CAR+ T cells in the dose-expansion phase. The primary endpoint was safety. Secondary endpoints included tumor response according to the International Myeloma Working Group criteria. Exploratory endpoints included PFS, overall survival (OS), and minimal residual disease (MRD). Results: As of January 14, 2020, 21 patients had received ide-cel in the dose-escalation phase, and 41 patients received ide-cel in the dose-expansion phase. The median age was 61 years, and 44% of patients had high tumor burden (≥50% bone marrow CD138+ plasma cells). Of the 62 patients, 45% received >6 prior regimens, 90% were daratumumab-exposed, and 77% were daratumumab-refractory. As of the cutoff date, 13 patients were ongoing, and 49 patients had discontinued the study. Reasons for study discontinuation were progressive disease (58%), withdrawal by patients (10%), and death (10%). Based on safety and efficacy in the dose-escalation phase, target dose levels of 150 to 450 × 106 CAR+ T cells were selected for the dose-expansion phase. The most frequent adverse events (AEs) were neutropenia (92%), cytokine release syndrome (CRS; 76%), anemia (76%), and thrombocytopenia (74%). The most frequent grade 3/4 AEs were neutropenia (89%), leukopenia (61%), anemia (57%), and thrombocytopenia (57%). Most CRS events were grade 1 or 2 (Table). Four patients (7%) had grade 3 CRS; there were no grade >3 CRS events. The incidence of CRS generally increased with target dose level. Neurologic toxicity (NT; clustered term) occurred in 27 patients (44%) and was primarily grade 1/2 with 1 patient having grade 3 and 1 patient having grade 4 NT. Among all 62 patients in the dose-escalation and -expansion phases, the ORR was 76%, including 24 patients (39%) with a CR or better and 40 patients (65%) with a very good partial response or better. The median duration of response was 10.3 months. Of 37 responders evaluable for MRD, 30 were MRD negative (≤10−4 nucleated cells) at 1 or more time point, and 7 responders were MRD positive. With a median follow-up of 14.7 months for all patients in the dose-escalation and dose-expansion phases, median PFS was 8.8 months and median OS was 34.2 months. Overall, a dose-dependent effect was observed on responses and survival outcomes, with greater efficacy reported at ≥150 × 106 CAR+ T cells (Table). Conclusions: Ide-cel demonstrated deep and durable responses in heavily-pretreated RRMM patients. Efficacy and safety reflect prior reports and support a favorable clinical benefit-risk profile for ide-cel at target dose levels ≥150 × 106 CAR+ T cells. Table Disclosures Lin: Novartis: Consultancy; Janssen: Consultancy, Research Funding; Vineti: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gamida Cells: Consultancy; Takeda: Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Raje:Caribou: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Bluebird, Bio: Consultancy, Research Funding; Takeda: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Astrazeneca: Consultancy; Amgen: Consultancy. Berdeja:Abbvie: Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Vivolux: Research Funding; Genentech, Inc.: Research Funding; Bluebird: Research Funding; Lilly: Research Funding; Constellation: Research Funding; Glenmark: Research Funding; Janssen: Consultancy, Research Funding; Legend: Consultancy; Novartis: Research Funding; Poseida: Research Funding; Prothena: Consultancy; Teva: Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Bioclinica: Consultancy; EMD Sorono: Research Funding; Acetylon: Research Funding; Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Kesios: Research Funding; CURIS: Research Funding; Kite Pharma: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Siegel:Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy. Jagannath:Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Madduri:Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Celgene: Consultancy, Honoraria; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Foundation Medicine: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau. Liedtke:Pfizer: Honoraria; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees. Rosenblatt:Celgene: Research Funding. Maus:arcellx: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; kite: Consultancy, Research Funding. Massaro:bluebird, bio: Current Employment, Current equity holder in publicly-traded company. Petrocca:bluebird, bio: Current Employment, Current equity holder in publicly-traded company. Caia:Celgene a BMS company: Current Employment, Current equity holder in publicly-traded company. Yang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Celgene: Ended employment in the past 24 months. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Hege:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties: numerous, Research Funding; Celgene (acquired by Bristol Myers Squibb): Ended employment 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; Arcus Biosciences (Former Board of Directors): Divested equity in a private or publicly-traded company in the past 24 months. Munshi:BMS: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Adaptive: Consultancy; Janssen: Consultancy; C4: Current equity holder in private company; Amgen: Consultancy; Legend: Consultancy. Kochenderfer:Celgene: Patents & Royalties, Research Funding; bluebird, bio: Patents & Royalties; Kite, a Gilead company: Patents & Royalties, Research Funding.

Introduction: Patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies have poor clinical outcomes. Idecabtagene vicleucel (ide-cel, bb2121) is a chimeric antigen receptor (CAR) T cell therapy under development for this patient population. The ide-cel construct includes a single-chain variable fragment anti-B-cell maturation antigen (BCMA) recognition domain, a CD3-zeta activation domain, and a 4-1BB T-cell activation domain. An ongoing, single-arm phase 2 study to evaluate the efficacy and safety of ide-cel in RRMM (KarMMa; NCT03361748) reported an overall response rate (ORR) of 73%, a complete response rate of 31%, a median duration of response of 10.6 months, median progression-free survival (PFS) of 8.8 months, and a median overall survival (OS) of 19.4 months in the treated population (Munshi NC, et al. J Clin Oncol 2020;38:8503). A systematic literature review of published efficacy data for triple-class-exposed patients with RRMM identified MAMMOTH, a large, retrospective observational study (Gandhi UH, et al. Leukemia 2019;33:2266-2275). Patients in both MAMMOTH and KarMMa were triple-class exposed. In MAMMOTH, patients received a variety of regimens corresponding to conventional care (CC) following progression on anti-CD38 antibodies. This analysis aimed to compare efficacy outcomes observed with ide-cel treatment in KarMMa and CC in MAMMOTH. Methods: Individual patient-level data (IPD) with a median follow-up of 13.3 months were available for KarMMa (data cutoff January 14, 2020) while study-level data were available for MAMMOTH. Unanchored matching-adjusted indirect comparisons (MAICs) were conducted to compare efficacy outcomes from the 2 studies. These analyses were performed on data from 128 patients who received ide-cel (target dose 150, 300, or 450 × 106 CAR+ T cells) in KarMMa, and 249 patients who received CC therapies after progression on an anti-CD38 antibody in MAMMOTH. IPD from MAMMOTH were reconstructed based on published Kaplan-Meier curves for time-to-event outcomes. The most relevant differences in patient characteristics between the studies were identified for adjustment based on published literature and clinical expertise. These included the number of prior lines of treatment, proportion of patients refractory to specific prior treatments, and time since diagnosis. Propensity score models were used to weight the treated population from KarMMa to match the baseline characteristics of treated patients in MAMMOTH in order to predict outcomes for ide-cel in a population corresponding to those evaluated in MAMMOTH. The effective sample size (ESS) was calculated as a measure of the amount of overlap between the study populations included in the MAIC. Odds ratios (ORs) were calculated for ORR using weighted logistic regression models. Hazard ratios (HRs) were calculated for PFS and OS using weighted Cox proportional hazards models. Results: Ide-cel was associated with a significantly higher ORR compared with CC in a population matched to the treated MAMMOTH population (OR 5.11, 95% confidence interval [CI] 2.92-8.94, P < 0.001) (Table 1). Similarly, ide-cel significantly extended PFS (HR 0.55, 95% CI 0.42-0.73, P < 0.001) and OS (HR 0.36, 95% CI 0.24-0.54, P < 0.001) versus CC. Results were generally consistent for patients in the ITT population and those who received the target dose of 450 × 106 CAR+ T cells who experienced efficacy gains exceeding those receiving lower target doses. In MAMMOTH, the individual CC regimens involving targeted therapies (carfilzomib, daratumumab, and elotuzumab) were associated with a median OS of between 8.3 and 12.7 months. The weighted median OS times for ide-cel are consistently longer than those associated with the individual CC regimens in MAMMOTH (Table 2), similar to the results for the overall treated population. Limitations of this inter-study comparison include a tighter window of OS evaluation in the ide-cel arm, which may have underestimated the true difference. More broadly, there is also a risk of bias given limited reporting on potential confounders. Conclusion: Ide-cel provides clinically and statistically significant efficacy benefits over current CC, including combination regimens involving targeted agents. Disclosures Shah: GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Ayers:PRECISIONheor: Current Employment. Davies:Adaptive Biotech: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cope:PRECISIONheor: Current Employment. Mojebi:PRECISIONheor: Current Employment. Parikh:BMS: Current Employment, Current equity holder in publicly-traded company. Dhanda:BMS: Current Employment, Current equity holder in publicly-traded company. Hari:Amgen: Consultancy; Janssen: Consultancy; GSK: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy; BMS: Consultancy. Patel:BMS: Current Employment. Huang:BMS: Current Employment, Current equity holder in publicly-traded company. Hege:BMS: Current Employment, Current equity holder in publicly-traded company, Other: Travel, accommodations, expenses, Patents & Royalties: Numerous, Research Funding; Mersana Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Divested equity in a private or publicly-traded company in the past 24 months. Dhanasiri:BMS: Current Employment, Current equity holder in publicly-traded company.

Introduction: Identifying prior therapy exposures that affect the patient or their peripheral blood mononuclear cell (PBMC) material is one strategy to optimize outcomes to CAR T cell therapy. Alkylating agents commonly used in multiple myeloma management, such as cyclophosphamide, have been reported to impair the proliferative capacity of T lymphocytes and to blunt their functional activity (Ercolini et al. J Exp Med. 2005;201:1591; Banissi et al. Cancer Immunol Immunother. 2009;58:1627; Litterman et al. J Immunol. 2013;190:6259). In the pivotal phase 2 KarMMa trial (NCT03361748) investigating the BCMA-directed CAR T cell therapy idecabtagene vicleucel (ide-cel, bb2121) in triple-class exposed patients with RRMM, 80% of patients had a history of prior anticancer treatment with ≥1 alkylating agents. In this retrospective analysis, patient and PBMC characteristics associated with time from last dose of alkylating agent(s) until apheresis of PBMCs for CAR T cell manufacture were identified. Methods: PBMCs isolated from patient apheresis material, which serves as starting material for CAR T cell manufacturing, were immunophenotyped by polychromatic flow cytometry for markers associated with T cell differentiation, memory, senescence, and exhaustion. Data from relevant prespecified clinical and exploratory endpoints were collected, and a novel implementation of left-censored time-to-event analysis (Ware et al. Biometrics. 1976;32:459) was used to identify statistically significant relationships between washout time after prior alkylator exposure (encompassing 14 individual drugs) and patient and PBMC variables. Dose intensity of prior alkylators was not considered due to sparse annotations in the patient histories. Optimal cutpoints were identified for each variable that maximized the proportional hazard of receiving an alkylator between patients above and below the cutpoint, and P values were adjusted for testing multiple cutpoints. Relationships were verified by nonparametric correlation, in which alkylator washout was encoded as 1/log(−washout). Results: More recent exposure to an alkylating agent (after diagnosis but before apheresis) was associated with patients receiving more prior therapies per year to manage their disease (hazard ratio [HR]=2.63, ρ=−0.54, P Conclusions: Associations between patient characteristics and alkylator washout suggest that patients who more recently received alkylating agents to manage their myeloma had a more aggressive disease course, having progressed more quickly through prior regimens, and had lower weight and elevated systemic inflammation. Although these factors suggest a suboptimal patient profile, the depletion of T cells by alkylator therapy may be especially disadvantageous for autologous CAR T cell therapies (Wang et al. Mol Ther Oncolytics. 2016;3:16015; Perica et al. Biol Blood Marrow Transplant. 2018;24:1135). Our analysis found that the use of alkylators prior to CAR T cell therapy exhibits a detrimental effect on the apheresis PBMC material up to 6-9 months after the last dose. Figure 1 Disclosures Rytlewski: Adaptive Biotechnologies: Current equity holder in publicly-traded company; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Madduri:Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria. Fuller:BMS: Current Employment. Campbell:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Mashadi-Hossein:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; NanoString Technologies: Ended employment in the past 24 months. Thompson:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Jiang:Bristol Myers Squibb: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol Myers Squibb company: Current Employment. Martin:BMS: Current Employment, Current equity holder in publicly-traded company. Sangurdekar:bluebird bio: Current Employment, Current equity holder in publicly-traded company; Biogen: Ended employment in the past 24 months. Finney:bluebird bio: Current Employment, Current equity holder in publicly-traded company; Seattle Childrens Research Institute: Ended employment in the past 24 months. Bitter:Novartis: Ended employment in the past 24 months; Novartis AG: Patents & Royalties; bluebird bio: Current Employment, Current equity holder in publicly-traded company; F Hofmann-La Roche: Patents & Royalties; Predicant Biosciences: Patents & Royalties; Biospect: Patents & Royalties. Agarwal:BMS: Current Employment, Current equity holder in publicly-traded company. Kaiser:BMS: Current Employment, Current equity holder in publicly-traded company. Hege:Arcus Biosciences (Former Board of Directors): 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; Celgene (acquired by Bristol Myers Squibb): Ended employment in the past 24 months; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties: numerous, Research Funding. Hause:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

Background: Approximately 40% of patients (pts) with non-Hodgkin lymphoma (NHL) have disease that will relapse or is refractory to chemotherapy and/or immunotherapies; management of these pts remains a challenge. Although follicular lymphoma (FL) generally responds well to first-line treatment (tx), this disease is characterized by frequent relapses with shorter intervals between tx lines. Pts with early relapse (ER) (progressive disease Methods: CC-122-NHL-001 (NCT02417285) is an ongoing, open-label, phase 1b study of avadomide in combination with obinutuzumab conducted at 8 sites in 3 European countries with dose-escalation and dose-expansion parts in R/R FL. Eligible pts (age ≥18 y) had histologically confirmed, CD20-positive R/R NHL. Pts with FL (grade 1, 2, or 3a) had ≥1 prior standard regimen. Avadomide active ingredient in capsule (1.0-4.0 mg) or formulated capsules (3.0 or 4.0 mg) was administered orally once daily on days 1-5 followed by 2 days off (5/7-day schedule) every week of each 28-day cycle. Obinutuzumab 1000 mg was given intravenously on days 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-8. Primary objectives were to determine the safety and tolerability of the combination, including the non-tolerated dose, maximum tolerated dose, and recommended phase 2 dose (RP2D). Response was assessed using Cheson 2007 criteria every 2 cycles to cycle 6, then every 3 cycles to cycle 12, and every 6 cycles thereafter. Median duration of response (mDOR) and median progression-free survival (mPFS) were assessed by Kaplan-Meier estimates. Results: As of January 10, 2020, 73 pts with R/R NHL were enrolled and treated, including 19 with R/R diffuse large B-cell lymphoma, 1 with marginal zone lymphoma, and 53 with R/R FL; all 35 pts in the dose-expansion part of the study had R/R FL. The median age among treated pts was 61 y (range, 26-83), the median number of prior antilymphoma therapies was 3 (range 1-11), and 26 pts (36%) had prior autologous stem cell transplantation. As of July 14, 2020, tx was ongoing in 3/38 pts (8%) in dose-escalation (all ongoing in cycle >24, 1 pt ongoing in cycle >40). In the dose-expansion, tx was ongoing in 15/35 pts (43%); of these pts, all were ongoing in cycle >21 and 1 was ongoing in cycle 30. The RP2D of avadomide was established as 3.0 mg formulated capsule. In the expansion part of the study, pts received a median of 15 tx cycles (range, 1-33), and median tx duration was 60 wk (range, 1-132). The most common (≥10%) grade 3/4 TEAEs were neutropenia, reported in 19 pts (54%) and thrombocytopenia, reported in 7 pts (20%). Sixteen pts (46%) had a serious TEAE; only pyrexia (11%) and sepsis (9%) occurred in >2 pts. The objective response rate (ORR) among the 35 pts with R/R FL in the dose-expansion part of the study was 71%, including 40% with a complete response (CR). The mDOR was 14.6 mo (95% CI, 14.6-not estimable [NE]), and mPFS was 16.4 mo (95% CI, 8.3-NE). The median duration of PFS follow-up in dose-expansion was 14.4 mo (range, 0.8-30.3). Two pts had CRs lasting 13.7 mo and 15.3 mo before discontinuation owing to receiving allogeneic stem cell transplantation. Response rates were similar among all 53 R/R FL pts in both parts of the study (dose escalation and dose expansion) and in high-risk (ER and/or DR) FL pts (Table). Conclusions: Long-term follow-up results demonstrate that avadomide plus obinutuzumab has a manageable safety profile and durable responses in patients with R/R FL. The antitumor activity of cereblon modulators plus next-generation anti-CD20 antibodies in heavily pretreated R/R NHL warrants further investigation as a novel chemotherapy-free option. Disclosures Michot: Genentech: Research Funding; Abbvie: Research Funding; Forma: Research Funding; Eisai: Research Funding; Debiopharm: Research Funding; Daiichi Sankyo: Research Funding; Kyowa: Research Funding; AstraZeneca: Other, Research Funding; Gustave Roussy: Honoraria, Other: Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 bio, Research Funding; Janssen: Other, Research Funding; Celgene: Other; Mundi Pharma: Other; Eos: Research Funding; AZD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Medimmune: Research Funding; Lytix Biopharma: Research Funding; Lysarc: Research Funding; Lilly: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Argen-x: Research Funding; Amgen: Research Funding; Agios: Research Funding; Xencor: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other; Exelixis: Research Funding. Doorduijn:Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Boccomini:SC Ematologia, ASOU Città della Salute e della Scienza di Torino, Turin, Italy: Current Employment. Kersten:Takeda: Research Funding; Miltenyi Biotech: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen/Cilag: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); MSD: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Chiappella:Servier: Honoraria; Takeda: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead-Kite: Honoraria; Celgene: Honoraria; Iqone: Honoraria. Zinzani:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salles:Abbvie, Autolus, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Epizyme, Janssen, Karyopharm, Morphosys, Novartis, F. Hoffmann-La Roche, Takeda: Consultancy; Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, Roche, Takeda: Other: Participation to educational events; Abbvie, Autolus, BMS/Celgene, Debiopharm, Genmab, Kite/Gilead, Epizyme, Janssen, Karyopharm, Morphosys, Novartis, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie, Amgen, Celgene, Gilead, Janssen, Kite, Morphosys, Novartis, F. Hoffmann-La Roche, Takeda: Honoraria. Hentrup:Neuronetics, Inc: Current equity holder in publicly-traded company, Ended employment in the past 24 months; BMS Consultant: Current Employment. Rhee:I own stocks for publicly-traded companies: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current Employment. Hagner:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Klein:Roche: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Pourdehnad:Celgene: Ended employment in the past 24 months, Patents & Royalties: Various CC-122 patents; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Various CC-122 patents. Hege:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties: numerous, Research Funding; Celgene (acquired by Bristol Myers Squibb): Ended employment 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; Arcus Biosciences (Former Board of Directors): Divested equity in a private or publicly-traded company in the past 24 months. Dobmeyer:BMS: Consultancy. Nikolova:Celgene, A Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Ribrag:nanostring: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; gustave roussy comprehensive cancer center: Current Employment; servier: Consultancy; pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; argenX: Research Funding; epizyme (EPZ): Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; EPZ: Honoraria, Membership on an entity's Board of Directors or advisory committees; AZD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: This is a phase I study evaluating the safety and efficacy of avadomide in combination with obinutuzumab in patients with R/R B-cell NHL. Avadomide is an investigational agent and has not yet been approved in the US.

Background: Patients (pts) with relapsed and refractory multiple myeloma (RRMM) experience unsatisfactory outcomes with established treatment modalities. In the pivotal phase 2 KarMMa study (NCT03361748), idecabtagene vicleucel (ide-cel, bb2121) demonstrated frequent, deep, and durable responses in triple-class exposed pts with RRMM, with an overall response rate (ORR) of 73% and a complete response rate of 33% (Munshi et al. J Clin Oncol. 2020;38[suppl, abstr]:8503). The overall safety profile of ide-cel was also manageable. The median time to onset and duration of cytokine release syndrome (CRS) were 1 d and 5 d, respectively, and the median time to onset and duration of neurotoxicity (NT) were 2 d and 3 d; the frequencies of higher-grade CRS and NT were low. Evaluated here are the T cell phenotypes, soluble factors, and cytokines associated with ide-cel activation, CRS, NT, and tumor responses over time in pts who received ide-cel in the KarMMa study. Methods: After longitudinal sampling of peripheral blood post-ide-cel infusion in the KarMMa study (N=128), plasma was analyzed for levels of proinflammatory cytokines and inflammation-related soluble factors; serum was evaluated for soluble BCMA (sBCMA) as a peripheral surrogate measure of tumor burden, and peripheral blood mononuclear cells were assessed by flow cytometry for memory phenotypes of CAR T cells. Associations between these features over time after ide-cel infusion were evaluated in the context of ORR, ongoing response at 9 mo, and grade ≥2 CRS and NT. Response at 9 mo was selected for analysis because this visit was proximal to the median progression-free survival (PFS) reported in all ide-cel-treated pts in KarMMa. The 9-mo responders were defined as pts with assessments >8 mo postinfusion and no progression before 10 mo postinfusion. Results: The levels of both CD4+ and CD8+ populations of CAR T cells increased to a greater degree postinfusion in responders and were skewed towards a higher fraction of CD8+ cells through peak expansion. Cell expansion in responders was characterized by an increased proportion of TEM in CAR T cells (CCR7−/CD45RA−) for both CD4+ and CD8+ subsets. Congruent with dominant TEM expansion, characteristic TEM-associated proinflammatory cytokines, such as IFN-ɣ and IL-6, were consistently upregulated early after infusion. Peak IFN-ɣ and IL-6 levels occurred a median of 4 d postinfusion, and 90% of pts (5th−95th percentile) had IFN-ɣ and IL-6 peaks 21 d and 15 d postinfusion, respectively, which was in line with the observed early onset of CRS and NT. Pharmacodynamic responses, shown by decreases in sBCMA after infusion, also occurred consistently early after infusion, and the sBCMA nadir occurred in 90% of pts 7 d−85 d postinfusion (5th−95th percentile; median, 31 d). Early sBCMA clearance below the limit of detection of the assay was associated with longer responses, and median PFS was significantly longer in pts with undetectable sBCMA vs detectable sBCMA at 2 mo (12.3 mo [95% CI, 11.6−17.7] vs 2.9 mo [95% CI, 1.9−3.1]; P Conclusions: Postinfusion expansion of ide-cel was characterized by a TEM-dominant phenotype with expansion of both CD4+ and CD8+ CAR T cell populations. The relative magnitudes of the increase in both populations were substantially greater in responders vs nonresponders, with a bias toward a higher proportion of CD8+ CAR T cells in responders. The induction of effector cytokines followed by return to baseline levels occurred predictably and early after infusion and was consistent with both the observed early onset and resolution of CRS and early sBCMA clearance in pts who received ide-cel in the KarMMa study. Disclosures Martin: BMS: Current Employment, Current equity holder in publicly-traded company. Thompson:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Brown:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Finney:bluebird bio: Current Employment, Current equity holder in publicly-traded company; Seattle Childrens Research Institute: Ended employment in the past 24 months. Rytlewski:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Adaptive Biotechnologies: Current equity holder in publicly-traded company. Jiang:Juno Therapeutics, a Bristol Myers Squibb company: Current Employment; Bristol Myers Squibb company: Current equity holder in publicly-traded company. Sangurdekar:bluebird bio: Current Employment, Current equity holder in publicly-traded company; Biogen: Ended employment in the past 24 months. Wang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. 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. Hause:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hege:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties: numerous, Research Funding; Celgene (acquired by Bristol Myers Squibb): Ended employment 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; Arcus Biosciences (Former Board of Directors): Divested equity in a private or publicly-traded company in the past 24 months. Kaiser:BMS: Current Employment, Current equity holder in publicly-traded company.

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 ( 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.

Introduction: Idecabtagene vicleucel (ide-cel, bb2121) is a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T cell therapy under investigation in the KarMMa trial as a treatment for patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies. In the phase 2 KarMMa trial, ide-cel demonstrated a favorable benefit-risk profile in this patient population (Munshi NC, et al. J Clin Oncol 2020;38:8503). Ide-cel also demonstrated clinically meaningful improvements in the key health-related quality of life (HRQoL) symptoms associated with MM (Delforge M, et al. HemaSphere 2020;4:EP1000). Translating HRQoL data to health state utility values (HSUVs)/HRQoL weights is key to understanding the HRQoL impact of a treatment in relation to that of a healthy general population and is an important consideration in clinical decision making and health technology assessments. HSUVs are scored between 0 and 1, where 0 is death and 1 is perfect health. In the general population, individuals of a similar age range to patients with MM have HSUV scores of 0.83 in the USA, 0.80 in the UK, and 0.84 in Canada (Guertin JR, et al. CMAJ 2018;190:E155-161; Janssen MF, et al. Eur J Health Econ 2019;20:205-216). This analysis aimed to determine HSUVs for patients treated in the KarMMa study according to their progression status. Methods: HRQoL assessment in the KarMMa study (NCT03361748) included the European Quality of Life-5 dimensions 5 levels (EQ-5D-5L) health state classifier performed at specified time points: prior to receiving lymphodepleting chemotherapy (baseline), day of infusion (Day 1), Months 1, 2, 3, 6, 9, 12, and 15, inclusive of disease progression/relapse or complete remission. Using US, UK, and Canadian weights, HSUVs were estimated for the KarMMa trial at an aggregate level. A longitudinal mixed-effects model was used with health state as a fixed effect, and a random intercept term. Three models were run using different health states. Model 1 considered 3 health states: baseline, pre-progression, and post-progression. In Model 2, the pre-progression health state was split into 2 time periods: Day 1 to the end of Month 1, and Month 2 onward. In Model 3, 2 pre-progression health states were defined based on the quality of response to treatment, thus capturing the difference in HRQoL for patients achieving at least a very good partial response (≥ VGPR) or patients who did not achieve a VGPR (< VGPR). Results: The HSUVs derived from the 3 different models using US, UK, and Canadian tariffs are summarized (Table). In all 3 models, patients in the pre-progression state experienced an increase in HRQoL from baseline. In Model 1, the increment ranged from +0.05 to +0.08. On progression, patients experienced a decrement (−0.01 to −0.03), but their HSUV remained above the baseline value by +0.04 to +0.05, indicating that ide-cel treatment was associated with an improvement in HRQoL, with some of the benefit remaining even upon disease progression. When HSUV in the pre-progression state was analyzed in Model 2 at Month 1 and then Month 2 onward, patients also experienced an increase in their HRQoL from baseline. While this increase was small in Month 1 (+0.02 to +0.04), the subsequent increase from baseline (i.e. from Month 2 onward) was more pronounced (+0.07 to +0.10) reflecting the benefits of a one-off administration of ide-cel and the associated treatment-free interval. A further analysis of the pre-progression HSUV by the quality of response in Model 3 showed that patients who achieved ≥ VGPR had a greater improvement in HRQoL (+0.08 to +0.11) than patients who achieved < VGPR. Both response levels were associated with an improvement in HRQoL compared with baseline, with HRQoL for patients achieving ≥ VGPR approaching that of the general population (Figure). Conclusions: Results of this analysis indicate that ide-cel provides clinically meaningful improvements in HRQoL for patients with triple-class-exposed RRMM. The benefit is particularly marked in patients who achieve ≥ VGPR, in whom HRQoL approaches that of the general population. Disclosures Delforge: Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Rodriguez-Otero:Celgene-BMS: Consultancy, Honoraria; Mundipharma: Research Funding; Janssen, BMS: Other: Travel, accommodations, expenses; BMS, Janssen, Amgen: Honoraria; Janssen, BMS, AbbVie, Sanofi, GSK, Oncopeptides, Kite, Amgen: Consultancy, Honoraria. Hari:Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy; BMS: Consultancy; Incyte Corporation: Consultancy; Takeda: Consultancy. Braverman:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Trigg:Adelphi Values: Current Employment. Patel:BMS: Current Employment. Huang: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. Dhanasiri:BMS: Current Employment, Current equity holder in publicly-traded company.

Re-directing T cells via chimeric antigen receptors (CARs) was first tested in HIV-infected individuals with limited success, but these pioneering studies laid the groundwork for the clinically successful CD19 CARs that were recently FDA approved. Now there is great interest in revisiting the concept of using CAR-expressing T cells as part of a strategy to cure HIV. Many lessons have been learned on how to best engineer T cells to cure cancer, but not all of these lessons apply when developing CARs to treat and cure HIV. This mini review will focus on how early CAR T cell studies in HIV paved the way for cancer CAR T cell therapy and how progress in cancer CAR therapy has and will continue to be instructive for the development of HIV CAR T cell therapy. Additionally, the unique challenges that must be overcome to develop a successful HIV CAR T cell therapy will be highlighted.

Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are limited, with no standard of care; prognosis is poor, with 4- to 6-month median survival. Avadomide (CC-122) is a cereblon-modulating agent with immunomodulatory and direct antitumor activities. This phase 1 dose-expansion study assessed safety and clinical activity of avadomide monotherapy in patients with de novo R/R DLBCL and transformed lymphoma. Additionally, a novel gene expression classifier, which identifies tumors with a high immune cell infiltration, was shown to enrich for response to avadomide in R/R DLBCL. Ninety-seven patients with R/R DLBCL, including 12 patients with transformed lymphoma, received 3 to 5 mg avadomide administered on continuous or intermittent schedules until unacceptable toxicity, disease progression, or withdrawal. Eighty-two patients (85%) experienced ≥1 grade 3/4 treatment-emergent adverse events (AEs), most commonly neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). Discontinuations because of AEs occurred in 10% of patients. Introduction of an intermittent 5/7-day schedule improved tolerability and reduced frequency and severity of neutropenia, febrile neutropenia, and infections. Among 84 patients with de novo R/R DLBCL, overall response rate (ORR) was 29%, including 11% complete response (CR). Responses were cell-of-origin independent. Classifier-positive DLBCL patients (de novo) had an ORR of 44%, median progression-free survival (mPFS) of 6 months, and 16% CR vs an ORR of 19%, mPFS of 1.5 months, and 5% CR in classifier-negative patients (P = .0096). Avadomide is being evaluated in combination with other antilymphoma agents. This trial was registered at www.clinicaltrials.gov as #NCT01421524.

Chimeric antigen receptor (CAR) T-cell therapy targeting B cell maturation antigen (BCMA) has provided deep (73% - 100%) responses in relapsed/refractory multiple myeloma (MM). However, median PFS has been less than 12 months, and amongst the small number of patients retreated at the time of progression with the same CAR T product, responses have been infrequent. This highlights development of resistance that may preclude effectiveness of the 2ndinfusion, and may also underly relapse following response to the initial CAR-T cell therapy. Here, we have investigated one of the resistance mechanisms using longitudinal single cell transcriptomic and bulk genomic analysis. This patient had relapsed/refractory IgG lambda MM with hypodiploidy and a complex karyotype with t(8;12) (q24;q14), clonal t(11;14) (q13;q32), and clonal deletion 13. Patient received 150x106CAR+ T cells (ide-cel) and achieved partial response, with duration of response of 8 months. The patient was retreated with 450 x106CAR+ T cells at relapse, but with no response. To delineate the resistance mechanism, we evaluated the bone marrow (BM) niche using 37658 cells from eight time points from before 1st CAR T cell infusion to 2 months after 2nd CAR T cell infusion, and identified 13 clusters consisting of hematopoietic cells and MM/plasma cells. Using RT-PCR based detection, we observed engineered CAR T cells only at 2 weeks after first infusion, when maximal CAR T cell expansion was observed. We did not observe infused CAR T cells with single cell RNAseq after 2ndinfusion, but a limited expansion was confirmed using RT-PCR.Re-clustering of the T cell cluster showed an increased proportion of CD4+ helper and T regulatory cells (Treg) 2 weeks after 1st infusion. In contrast, TREG proportion remained constant at the 2nd infusion, suggesting other causes for lack of expansion of CAR-T cells. We also did not identify any significant increase in the proportion of cells expressing immune check point inhibitory markers or in accessory cell types with immune inhibitory function in MM BM. Since we did not delinate a role of the BM milieu mediating suppression of CAR-T cell expansion and function following 2ndinfusion, we next explored tumor intrinsic factors. Soluble BCMA level (produced predominantly by MM cells) was high before the first CAR T cell infusion and dropped significantly to a very low level coinciding with the clinical response; however, it remained low even at the time of relapse with increase burden of MM, indicating a lack of BCMA production by MM cells. We therefore investigated genomic changes in MM cells at the time of relapse. Our single cell analysis of BM samples identified 3 samples (at the time of relapse and post 2ndCAR T cell infusion) with significant numbers of MM cells, evidenced by expression of CD138 and XBP1 (marker of plasma cells), CCND1 (upregulated in this patient with t(11;14)) and lack of RB1 (downregulated in this patient with del13). Imputation of copy number alterations scRNAseq showed that the majority of MM cells had a deletion of 16p, including the BCMA locus located on 16p13.13. We further validated these findings using deep whole exome sequencing (WES) of purified CD138+ cells collected after the second CAR T infusion. Before first CAR T cell infusion, 4% MM cells showed deletion 17p, while after second infusion both WES and scRNAseq prediction showed that del17p and del16p were clonal, and longitudinal scRNAseq analysis indicated that del17p and del16p co-occurred in the same clone. Moreover, WES identified a subclonal nonsense mutation (p.Q38*) in BCMA that creates an early stop codon in the BCMA gene. This biallelic BCMA deletion, acquired with one copy loss and a 2ndloss-of-function mutation, provides the molecular basis for lack of BCMA expression in MM cells at the time of relapse. Our data showed that both TP53 and BCMA had deletion in one allele and mutation in the second allele. These results identify biallelic loss of BCMA locus as a potential resistance mechanism to BCMA targeting therapy. Our results highlight the need to investigate sBCMA as a potential indicator of BCMA loss at relapse, and to carry out detailed transcriptomic or genomic analysis to confirm mutations. Moreover, these data also demonstrate the ability of MM cells to survive without BCMA expression. With the growing number of BCMA targeting therapeutic modalities under development, we would expect to see such occurrences more commonly in the future. Disclosures Fulciniti: NIH: Research Funding. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Petrocca:bluebird, bio: Current Employment, Current equity holder in publicly-traded company. Hege:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties: numerous, Research Funding; Celgene (acquired by Bristol Myers Squibb): Ended employment 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; Arcus Biosciences (Former Board of Directors): Divested equity in a private or publicly-traded company in the past 24 months. Kaiser:BMS: Current Employment, Current equity holder in publicly-traded company. Anderson:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.. Munshi:C4: Current equity holder in private company; Legend: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy.

155 Background: Outcomes remain poor in triple-class exposed (to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody) patients (pts) with relapsed and refractory multiple myeloma (RRMM), and there is no standard of care. Ide-cel, a BCMA-directed CAR T cell therapy, showed deep, durable responses in heavily pretreated RRMM pts in the pivotal phase 2 KarMMa trial ( J Clin Oncol 38:2020. Suppl; abstr 8503). Limited data are available on pts’ experience with prior therapies and expectations on ide-cel. By embedding pt interviews in KarMMa, we assessed pts’ initial knowledge of and expectations on ide-cel beyond pt-reported outcome measures prior to ide-cel therapy. Methods: This qualitative study was conducted in triple-class exposed pts refractory to their last regimen who entered the KarMMa trial (NCT03361748). Pts were invited to participate in the optional interview component that included up to 11 interviews. We present results of the first interviews that occurred between initial consent and leukapheresis. The interview topics were pts’ initial knowledge of ide-cel, decision making, expectations, hopes, and concerns, and current well-being. All interviews were recorded, transcribed, and coded. Results: Forty-seven pts from 14 clinical sites participated in the interviews. Most pts were able to describe the overall process of CAR T cell therapy and one third first heard about the therapy from their local healthcare professionals. According to patients, key decision-making factors were potential outcomes with ide-cel, recommendation from a doctor, and lack of other options. The most frequently perceived differences between ide-cel and prior treatments are shown (Table). Pt hopes were mostly focused on remission and improved quality of life. Most pts reported some restrictions on their daily activities due to the disease. Conclusions: RRMM pts need new treatment options. Most pts reported the limitations of prior therapies, expectations on ide-cel, impact of the disease, and differentiated ide-cel from other treatments. The ongoing interviews will further assess pt experience during and after ide-cel therapy. Clinical trial information: NCT03361748 . [Table: see text]