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Core Outcome Sets (COS) contain an agreed minimum set of outcomes to be measured and reported in all studies in a specific area, with the objective of standardizing outcome reporting. COS may minimize research waste by identifying outcomes important to key stakeholders, allowing for improved evidence synthesis, and facilitating translation of research findings to clinical practice. Over the past 5 years, there has been significant progress in developing COS relevant to studies of diabetes in pregnancy. This review summarizes work in this area, reviews the role of patient and public involvement in COS development, and suggests areas for future research.

Acellular bronchoalveolar lavage (BAL) proteomics can partially separate lung cancer from non-lung cancer patients based on principal component analysis and multivariate analysis. Furthermore, the variance in the proteomics data sets is correlated mainly with lung cancer status and, to a lesser extent, smoking status and gender. Despite these advances BAL small and large extracellular vehicles (EVs) proteomes reveal aberrant protein expression in paracrine signaling mechanisms in cancer initiation and progression. We consequently present a case-control study of 24 bronchoalveolar lavage extracellular vesicle samples which were analyzed by state-of-the-art liquid chromatography-mass spectrometry (LC-MS). We obtained evidence that BAL EVs proteome complexity correlated with lung cancer stage 4 and mortality within two years´ follow-up (p value = 0.006). The potential therapeutic target DNMT3B complex is significantly up-regulated in tumor tissue and BAL EVs. The computational analysis of the immune and fibroblast cell markers in EVs suggests that patients who deceased within the follow-up period display higher marker expression indicative of innate immune and fibroblast cells (four out of five cases). This study provides insights into the proteome content of BAL EVs and their correlation to clinical outcomes.

Abstract Background Patients with human papillomavirus–related oropharyngeal cancers have excellent outcomes but experience clinically significant toxicities when treated with standard chemoradiotherapy (70 Gy). We hypothesized that functional imaging could identify patients who could be safely deescalated to 30 Gy of radiotherapy. Methods In 19 patients, pre- and intratreatment dynamic fluorine-18-labeled fluoromisonidazole positron emission tomography (PET) was used to assess tumor hypoxia. Patients without hypoxia at baseline or intratreatment received 30 Gy; patients with persistent hypoxia received 70 Gy. Neck dissection was performed at 4 months in deescalated patients to assess pathologic response. Magnetic resonance imaging (weekly), circulating plasma cell-free DNA, RNA-sequencing, and whole-genome sequencing (WGS) were performed to identify potential molecular determinants of response. Samples from an independent prospective study were obtained to reproduce molecular findings. All statistical tests were 2-sided. Results Fifteen of 19 patients had no hypoxia on baseline PET or resolution on intratreatment PET and were deescalated to 30 Gy. Of these 15 patients, 11 had a pathologic complete response. Two-year locoregional control and overall survival were 94.4% (95% confidence interval = 84.4% to 100%) and 94.7% (95% confidence interval = 85.2% to 100%), respectively. No acute grade 3 radiation–related toxicities were observed. Microenvironmental features on serial imaging correlated better with pathologic response than tumor burden metrics or circulating plasma cell-free DNA. A WGS-based DNA repair defect was associated with response (P = .02) and was reproduced in an independent cohort (P = .03). Conclusions Deescalation of radiotherapy to 30 Gy on the basis of intratreatment hypoxia imaging was feasible, safe, and associated with minimal toxicity. A DNA repair defect identified by WGS was predictive of response. Intratherapy personalization of chemoradiotherapy may facilitate marked deescalation of radiotherapy.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (>5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as <10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

Background: Chimeric Antigen Receptor (CAR) T-cell therapy has changed the treatment landscape for patients with Non-Hodgkin Lymphoma (NHL). Despite the excellent responses in relapsed or refractory (R/R) aggressive NHL (aNHL), the outcome of patients (pts) that fail CAR T-cell therapy remains poor, and there is not a clear path for management of their disease. Methods: We conducted a retrospective analysis of aNHL pts treated with axicabtagene ciloleucel (axi-cel) at the Mayo Clinic campuses in Arizona and Florida between June 2018 and August 2020. We evaluated the predisposing factors, management, toxicities, and response after CAR T-cell therapy failure. Statistical calculations using parametric tests were performed, and survival curves were estimated using the Kaplan-Meier method and compared statistically using the log-rank test and Pearson's correlation. Results: Thirty-four pts with aNHL received axi-cel. The median age was 53 years [IQR 42-63], and 62% were male. All pts received inpatient axi-cel infusions and the median length of hospital stay was 14 days (IQR: 11-17). Cytokine Release Syndrome (CRS) was observed in 91% of pts (3% grade ≥3), while Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) was observed in 41% (24% grade ≥3). At day 30 response assessment, 16 pts (47%) had complete responses (CR), 9 (26%) had a partial response (PR), 4 (12%) had stable disease (SD), 4 (12%) showed progression with primary refractory disease (PD) and 1 (3%) died before assessment due to grade 5 ICANS (Table 1). After a median follow-up of 178 days, we observed PD in 12 (35%) pts. The median time-to-progression was 72 days (IQR 58-93) and most of the pts (83%) progressed during the first 3 months. None of the patients with more than 5 months of sustained response developed progression of disease. The likelihood of progression during the first 6 months after axi-cel infusion was 19%, 57%, 50% for pts that initially achieved a CR, PR, SD, respectively. Expression of CD19 was observed in 66% (4/6) of pts with available biopsies after axi-cel suggesting a failure mechanism other than antigen escape. The mortality rate of the R/R aNHL group was 58% with a median survival time of 83 days (IQR: 50-109). There was no association between age, stage, number of previous therapies, time from previous therapy to axi-cel infusion, time from apheresis to infusion, use of tocilizumab, or steroids with progression of disease. Of note, no correlation between CRS or ICANS with progression of disease was found (2-way ANOVA test F (1, 4) = 3.802, p=0.1230). Maintaining a response to axi-cel treatment (CR, PR, or SD) for ≥ 3 months was a strong predictor of durable response with an HR of 0.05 (p= <0.0001). Eleven R/R pts received subsequent therapies with a median time to retreatment of 76 days. Those treatments included: Radiotherapy (n=7), pembrolizumab (n=3), polatuzumab-rituximab with (n=3) and without (n=1) bendamustine, obinutuzumab with (n=1) or without (n=1) lenalidomide, Hyper-CVAD (n=2), R-GemOx (n=1), rituximab with lenalidomide (n=1) and intrathecal methotrexate (n=1). Only 2 (17%) patients have responded to salvage therapy achieving PR (one patient treated with radiotherapy and the other with rituximab-lenalidomide after two other salvage therapies). Conclusion: Our experience demonstrates the majority of aNHL patients respond to axi-cel. If patients maintain their response for more than 3 months, the likelihood of progression is very low - 15%. Similar to what has been previously reported in the literature, our series showed that 35% of patients progressed after axi-cel, and subsequently have a poor prognosis with median survival after a relapse of only 83 days (IQR: 50-109). Therapy options following axi-cel were limited due to severe cytopenias, only 2 of 11 patients have responded to salvage therapy, suggesting that conventional treatments are probably not effective/safe in this high-risk group of patients. Interestingly, the majority of R/R pts with available biopsies showed persistent CD19 expression suggesting that CAR T-cell exhaustion, poor in vivo expansion, and inhibitory signals of the tumor microenvironment may contribute to resistance. Additional strategies for monitoring of axi-cel persistence and its immunophenotypic profile could be helpful for prognosis and management of CAR T-cell pts receiving axi-cel. Disclosures Kharfan-Dabaja: Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Castro:Fate Therapeutics: Research Funding; Kite Pharma: Research Funding; Pharmacyclics: Research Funding.

Introduction: Iberdomide (IBER; CC-220) is a potent, novel cereblon (CRBN) E3 ligase modulator (CELMoD) agent under investigation in a phase 1/2 dose-escalation study in relapsed/refractory multiple myeloma (MM) (CC-220-MM-001; NCT02773030). IBER modulates CRBN to induce ubiquitination and proteasome-dependent degradation of Ikaros/Aiolos, resulting in anti-myeloma and immunomodulatory activity. Compared with immunomodulatory drugs (IMiDs), IBER binds to CRBN with 20-fold higher affinity and is more efficient at degrading Ikaros/Aiolos. Additionally, IBER can overcome IMiD drug resistance. Here, we evaluate the preclinical activity of IBER in combination with monoclonal antibodies (mAbs) and assess immune pharmacodynamic changes of IBER + daratumumab (DARA) among patients in the CC-220-MM-001 study. Methods: Preclinical analyses were performed on MM cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers. In co-culture assays, cell lines and immune cells were treated with clinically relevant concentrations of lenalidomide (LEN; 1 μM), pomalidomide (POM; 300 nM), and IBER (20 nM) alone, and in combination with DARA or elotuzumab (ELO). Clinical biomarker data were obtained from blood samples of patients enrolled in IBER + dexamethasone (DEX) and IBER + DARA + DEX cohorts of the CC-220-MM-001 study. Immune profiling was evaluated by flow cytometry on Cycle (C) 1 Day (D) 1, C2D15, C4D1, and C4D15. Results: Treatment of CD3-stimulated PBMCs with IBER increased cytokine secretion more potently than with IMiD drugs, promoting natural killer (NK) cell proliferation and increasing NK cell numbers by > 30% in cultures. Treatment of CD3-stimulated PBMCs with IBER also promoted immune-mediated killing of MM cell lines, and pretreatment of MM cell lines for 48 h followed by washout sensitized cells to immune-mediated clearance. IBER treatment of MM cells increased protein expression of CD38, but had no discernable effect on SLAMF7 expression. IBER in combination with DARA or ELO enhanced the immune-mediated killing of MM cell lines and resulted in deeper cell killing compared with LEN or POM when combined with the same mAbs. Analogous to preclinical data, immune profiling of patients treated with IBER + DEX demonstrated an immune-stimulatory effect, including increased proliferating NK and T cells. Notably, patients coming on trial directly after a DARA-containing regimen showed depleted NK cell counts, which rebounded by nearly 2-fold after 1 cycle of IBER + DEX. Additionally, the effects of IBER on T and NK cell proliferation were similar in patients treated with IBER + DEX + DARA and IBER + DEX, except for overall reduction in CD38-expressing NK and T cells in patients receiving DARA. Conclusions: IBER induced immune-stimulatory activity more potently than LEN or POM, enhancing cytokine release and NK cell proliferation. MM cells treated with IBER were also sensitized to immune-mediated clearance. These data suggest that IBER may enhance the activity of biologics that exert anti-malignant activity through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Accordingly, IBER enhanced the activity of DARA and ELO in co-culture. IBER also induced an immune-stimulatory effect on NK and T cells in vivo, confirming immune-stimulatory effects of IBER in patients with MM. Notably, the effect of IBER on NK cells was more pronounced in patients whose last treatment regimen contained DARA, suggesting IBER treatment may contribute to NK cell recovery after DARA treatment. Furthermore, immune changes observed by the addition of DARA to IBER + DEX were similar, suggesting IBER was the primary agent promoting immunomodulation in this triplet therapy. Together, these data support continued clinical development of IBER in combination with CD38- and SLAMF7-directed mAbs as well as other immune-directed therapies for the treatment of MM. Disclosures Amatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bjorklund:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ma:Bristol Myers Squibb: Current Employment. Wollerman:Bristol Myers Squibb: Current Employment. Pierceall:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lonial:JUNO Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Other: Personal fees; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Onyx: Honoraria; Millennium: Consultancy, Honoraria; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. van de Donk:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ferrer: Membership on an entity's Board of Directors or advisory committees. Popat:Celgene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Zonder:Intellia: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; BMS: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Research Funding; Prothena: Consultancy; Janssen: Consultancy, Other: Personal fees; Oncopeptide: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Caelum: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Minnema:Kite, a Gilead Company: Speakers Bureau; Servier: Consultancy; Amgen: Consultancy; Celgene: Other: travel support, Research Funding. Oriol:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Larsen:Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Rodriguez-Otero:Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Kite: Consultancy, Honoraria. Sonneveld:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Nguyen:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hong:Bristol Myers Squibb: Current Employment. Sorrell:Bristol Myers Squibb: Current Employment; Children's Oncology Group: Other: Non-member; Previous Study Chair AAML08B1. Thakurta:Bristol Myers Squibb: Current Employment; Oxford University: Other: Visiting professor.

Introduction: Iberdomide (IBER; CC-220) is a potent, novel cereblon (CRBN) E3 ligase modulator (CELMoD) agent under investigation in a phase 1/2 dose-escalation study for relapsed/refractory multiple myeloma (MM) (CC-220-MM-001; NCT02773030). IBER modulates CRBN to induce ubiquitination and proteasome-dependent degradation of Ikaros/Aiolos, resulting in antimyeloma and immunomodulatory activity. Compared with immunomodulatory drugs (IMiDs); IBER binds to CRBN with 20-fold higher affinity and is more efficient at degrading Ikaros/Aiolos. Additionally, IBER can overcome IMiD drug resistance. Here, we compare the preclinical activity of IBER versus IMiD drugs + proteasome inhibitors (PIs), and assess the pharmacodynamic (PD) activity of IBER in patients treated with IBER + dexamethasone (DEX), IBER + DEX + bortezomib (BORT), and IBER + DEX + carfilzomib (CFZ). Methods: MM cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were analyzed. Cell lines treated with PIs (BORT and CFZ) were pulsed with drug for 1 h, and then treated with clinically relevant concentrations of lenalidomide (LEN; 1 μM), pomalidomide (POM; 300 nM), or IBER (20 nM). Biomarker data for PD analyses were obtained from blood samples of patients enrolled in the IBER + DEX, IBER + DEX + BORT, and IBER + DEX + CFZ cohorts of the CC-220-MM-001 study. Degradation of Ikaros/Aiolos in peripheral blood was analyzed on Cycle (C) 1 Day (D) 1, pre-dose, and post IBER/IBER + PI dose by flow cytometry. Immune profiling was evaluated by flow cytometry from peripheral blood at C1D1, C2D15, C4D1, and C4D15. Results : Proteasome inhibition in cell lines after 1 h pulse of PI was maintained after washout. However, substrate degradation by IBER was affected only minimally by combination with PIs, and was more potent than by LEN or POM. These results correlate with synergistic antiproliferative activity and more potent tumoricidal activity in cell lines treated with IBER + PI than IMiD + PI combinations. Furthermore, ex vivo treatment of PBMCs with IBER + PIs minimally affected cytokine induction by IBER. Analysis of patient samples from the CC-220-MM-001 study confirmed preclinical observations showing minimal inhibition of IBER PD with the addition of PIs to the treatment regimen. In patient T cells, Ikaros and Aiolos protein levels decreased by > 50% and > 70%, respectively, with IBER + DEX, and by > 30% and > 45% (at lower IBER doses) with IBER + DEX + BORT or IBER + DEX + CFX. In all cohorts, the nadir of substrate expression was determined to be 6 h. After repeated dosing (mid-C1) patients treated with IBER + PIs showed > 70% decreases in both Ikaros and Aiolos expression. Furthermore, immune profiling of patients showed that the addition of PIs to the IBER treatment regimen did not inhibit immune-stimulatory activity of IBER, including induction of NK and T cell proliferation. Conclusions: Preclinically, IBER induced substrate degradation in the presence of PIs, and treatment with IBER + PIs resulted in substantially increased tumoricidal activity. Deeper substrate degradation and increased apoptosis were also observed when PIs were combined with IBER versus IMiD drugs. Clinically, IBER led to rapid decreases in substrate levels, even in the presence of PIs, and levels were reduced further with repeated dosing, suggesting that concurrent administration of PIs minimally affects proteasomal degradation of substrates mediated by IBER. Furthermore, increases in NK and T cell proliferation in IBER-treated patients were consistent whether or not they also received a PI, further confirming that IBER has immune-stimulatory activity in combination with PIs. These data support continued clinical development of IBER in combination with PIs for the treatment of MM. Disclosures Amatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bjorklund:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kang:Bristol Myers Squibb: Current Employment. Mukhopadhyay:Bristol Myers Squibb: Other: Contract scientist, Research & Early Development. Jiménez Nuñez:CITRE, a Bristol-Myers Squibb Company: Current Employment. Wong:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pierceall:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lonial:Merck: Consultancy, Honoraria, Other: Personal fees; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Millennium: Consultancy, Honoraria; JUNO Therapeutics: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria. van de Donk:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Popat:GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. Zonder:Caelum: Consultancy; Intellia: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Alnylam: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Oncopeptide: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Research Funding; Janssen: Consultancy, Other: Personal fees; Prothena: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; BMS: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Minnema:Celgene: Other: travel support, Research Funding; Servier: Consultancy; Amgen: Consultancy; Kite, a Gilead Company: Speakers Bureau. Oriol:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Larsen:Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Rodriguez-Otero:Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Amgen: Consultancy, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Oncopeptides: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Sonneveld:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Nguyen:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Hong:Bristol Myers Squibb: Current Employment. Sorrell:Children's Oncology Group: Other: Non-member; Previous Study Chair AAML08B1; Bristol Myers Squibb: Current Employment. Thakurta:Oxford University: Other: visiting professor; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

Background: Multiple myeloma (MM) occurs most commonly among the older population, with a median age of 69 years at diagnosis. Advanced age has been shown to negatively affect prognosis and limit treatment options for patients with hematologic malignancies, including MM. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, demonstrated deep and durable responses in the pivotal phase 2 KarMMa study of patients with triple-class exposed relapsed and refractory MM (RRMM; Munshi et al. J Clin Oncol. 2020;38[suppl, abstr]:8503). The overall response rate (ORR), complete response (CR) rate, median duration of response (DOR), and median progression-free survival (PFS) were 73%, 33%, 10.7 months, and 8.8 months, respectively, among all 128 patients treated across the target dose levels of 150-450 × 106 CAR+ T cells, and 82%, 39%, 11.3 months, and 12.1 months at the highest target dose of 450 × 106 CAR+ T cells. The safety profile of ide-cel was consistent with the mechanism of action of CAR T cell therapies, with the most common toxicities across all dose levels being cytopenia (97%) and cytokine release syndrome (84%). In the present analyses, the efficacy and safety of ide-cel in elderly patients in the KarMMa study were evaluated. Methods: Patients enrolled in the KarMMa trial (NCT03361748) were required to have ≥3 prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody, and were refractory to their last regimen per International Myeloma Working Group (IMWG) criteria. Patients received ide-cel at target doses of 150, 300, or 450 × 106 CAR+ T cells after 3 days of lymphodepletion with cyclophosphamide (300 mg/m2/day) and fludarabine (30 mg/m2/day) followed by 2 days of rest. The primary endpoint was ORR, and the key secondary endpoint was CR rate. Additional secondary endpoints included DOR, PFS, and safety. Patients were classified into ≥65 years and ≥70 years subgroups for analysis. Responses were assessed according to IMWG guidelines, and DOR and PFS were analyzed using Kaplan-Meier methods. Results: Of the 128 patients treated with ide-cel, 45 (35%) were aged ≥65 years and 20 (16%) were aged ≥70 years. The median age within these age groups was 69 years (range, 65-78) and 73 years (range, 70-78), the median number of prior antimyeloma regimens was 6 and 5, and the median time since initial diagnosis was 6.7 years and 6.1 years, respectively. Baseline characteristics were generally similar between age groups with the exception of tumor burden. Response rates for both age groups were comparable with those of the overall ide-cel treated population, with ORRs of 84% to 90% and CR rates of 31% to 35% (Table). Likewise, median DOR among responders in both age groups (10.9 months in patients aged ≥65 years and 11.0 months in patients aged ≥70 years) was similar to that of the overall ide-cel treated population. Median PFS was 8.6 months (95% CI, 4.9-12.2) in patients aged ≥65 years and 10.2 months (95% CI, 3.1-12.3) in patients aged ≥70 years. At the time of analysis, overall survival data were still immature. No new safety signals were observed in either of the older age groups compared with those in the overall ide-cel treated population (Table). Conclusions: These results demonstrate deep and durable responses with ide-cel treatment together with a manageable safety profile in triple-class exposed patients with RRMM aged ≥65 years and ≥70 years. Outcomes were comparable with those observed in the overall ide-cel treated population. These data suggest ide-cel is safe and effective in older patients and provide further evidence supporting ide-cel as a promising treatment option in RRMM. Figure 1 Disclosures Berdeja: Karyopharm: Consultancy; Kite Pharma: Consultancy; Cellularity: Research Funding; Acetylon: Research Funding; Genentech, Inc.: Research Funding; Prothena: Consultancy; Teva: Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Lilly: Research Funding; Janssen: Consultancy, Research Funding; EMD Sorono: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Glenmark: Research Funding; Kesios: Research Funding; Legend: Consultancy; Vivolux: Research Funding; Abbvie: Research Funding; Bioclinica: Consultancy; Bluebird: Research Funding; CURIS: Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Poseida: Research Funding. Raje:Takeda: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Immuneel: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Caribou: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Research Funding; Amgen: Consultancy. Siegel:Karyopharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Celulatiry: Consultancy. Lin:Gamida Cells: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy; Vineti: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding. Anderson:Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Rodriguez-Otero:Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Kite: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Manier:Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene/BMS: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Jenssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GSK: Consultancy; Takeda: Consultancy. Einsele:Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau. Cavo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Truppel-Hartmann:bluebird bio, Inc: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); F. Hoffmann La Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Rowe:Bristol-Myers Squibb: Current Employment. Sanford:BMS: Current Employment, Current equity holder in publicly-traded company. Wang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Campbell:BMS: Current Employment, Current equity holder in publicly-traded company. Jagannath:Takeda: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria.