Mailankody, Sham

Abstract Studies have reported conflicting findings regarding the contribution of germline variants or somatic genomic drivers to racial disparities in multiple myeloma. To comprehensively investigate somatic drivers in relation to inherited genetics in multiple myeloma, we combined newly sequenced whole-genome sequencing data with publicly available datasets (total n = 1,286). Overall, we did not identify germline or somatic genomic differences that explain the different risk of developing multiple myeloma between patients with genetic similarity to African (AFR) or European (EUR) reference populations. A difference in the detectability and timing of APOBEC-associated and germinal center mutational activity was observed. Integrating epidemiologic data and mutational signature-based temporal estimates, we challenge the assumption that individuals in the AFR group develop multiple myeloma at a younger age. Finally, we demonstrate that, with equal access to efficacious therapies, patients in the AFR and EUR groups have equivalent clinical outcomes. Significance: Multiple myeloma is reported to occur at higher rates in individuals who self-identify as non-Hispanic Black. In this large dataset, genomic drivers occur at the same rate among ancestry groups, except for APOBEC mutagenesis. With equivalent therapy, clinical outcomes did not differ for patients grouped by genetic ancestry similarity.

ABSTRACT Chimeric antigen receptor T-cell (CART) and T-cell engager (TCE) therapies targeting B-cell maturation antigen (BCMA) are transforming the treatment landscape for relapsed multiple myeloma (MM). However, despite impressive initial response rates, most patients eventually relapse. To investigate this unmet medical need, we applied whole-genome sequencing (WGS) to MM cells from cohorts of 102 relapsed patients treated with anti-BCMA CART and TCE therapies. Several genomic alterations were associated with clinical outcomes, particularly primary refractoriness, including high genomic complexity and mutations in genes regulating plasma cell identity, which predicted resistance to therapy. Single-cell RNA sequencing further revealed that MM cells from refractory patients exhibited high proliferation signatures and reduced expression of TNFRSF17 (encoding BCMA), while were less enriched for plasma cell–associated transcriptional programs, a phenomenon we term “plasma cell identity escape.” This profile was strongly associated with immune dysregulation of CD8 T cells including increased activation and exhaustion. This evolution of MM toward a more proliferative and lineage-divergent state, refractory to the anti-BCMA T-cell redirecting therapies, was functionally validated in preclinical MM mouse models. Collectively, our results comprehensively define the cellular and molecular mechanisms underlying primary resistance to anti-BCMA therapies.

Abstract Consumption of a Western diet and high body mass index (BMI) are risk factors for progression from premalignant phenotypes to multiple myeloma, a hematologic cancer. In the NUTRIVENTION trial (NCT04920084), we administered a high-fiber, plant-based diet (HFPBD; meals for 12 weeks, coaching for 24 weeks) to 23 participants with myeloma precursor states and elevated BMI. The intervention was feasible and improved quality of life and modifiable risk factors: metabolic (BMI, insulin resistance), microbiome (diversity, composition), and immune (inflammation, monocyte subsets). Disease progression trajectory improved (n = 2) or was stable. Findings were translated to Vk*MYC mice modeling the myeloma precursor state, in which a high-fiber diet (HFD) delayed disease progression through improved metabolism and microbiome composition, leading to increased short-chain fatty acid production that reinvigorated antitumor immunity and inhibited tumor growth. These effects from fiber consumption were independent of calorie restriction and weight loss. A HFD is a low-risk intervention that may delay progression to myeloma. Significance: A HFPBD in participants with precursor plasma cell disorders and an elevated BMI improved metabolic, microbiome, and immune biomarkers of disease. In a subset, it may delay progression to myeloma. In mouse models, a HFD delayed progression to myeloma independent of calorie restriction. See related commentary by Fairfield and Reagan, p. 623

Introduction Poor diet quality, elevated body mass index (BMI), insulin resistance, microbiome dysbiosis, inflammation as well as immune dysfunction have all been implicated in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to multiple myeloma (MM). Plant-based diets have been associated with reduced risk of MGUS and MM in epidemiological studies. Whether a dietary intervention can impact these modifiable risk factors and delay disease progression has not been investigated. Methods We conducted a pilot, single-arm trial providing controlled high fiber plant based dietary (HFPBD) intervention for 12 weeks and health coaching for 24 weeks in 20 patients with MGUS/SMM with BMI≥25 (NCT04920084). The primary endpoint was feasibility (adherence and BMI reduction). Secondary and exploratory endpoints included quality of life, metabolic markers (insulin, adiponectin, leptin, LDL cholesterol), microbiome (diversity and composition by 16S and shotgun sequencing) and immune profiling in peripheral blood (flow cytometry and Olink inflammation panel) and bone marrow (scRNAseq and ATACseq). We also conducted an in vivo study in transgenic Vk*MYC mice fed a high fiber or control diet at the phase of mouse(m)SMM. The mice were monitored for the progression to active mMM. Differences in microbiome and immune response profiles between high fiber- and control-treated mice were assessed via microbiome 16S sequencing and flow cytometry. Results The HFPBD intervention was safe, feasible, improved quality of life and addressed modifiable risk factors - metabolic profile (improved BMI, insulin resistance, adiponectin leptin ratio), microbiome profile (increased alpha-diversity and butyrate producers) and immune (decreased inflammation and increased anti-inflammatory classical monocyte) subsets. A reduction in long-term progression trajectory was observed in 2 patients. Consistently, the high fiber diet delayed progression from mSMM to mMM in Vk*MYC mice increasing median progression-free survival from 12 weeks in the control arm to 30 weeks in the high fiber diet intervention arm. Additionally, in the intervention arm 40% of mice did not progress to mMM during the study period whereas all mice in the control arm progressed. Both human and mouse data showed that HFPBD modulated gut microbiota composition favoring the expansion of butyrate-producing bacteria. Additionally, short-chain fatty acids were increased in the feces of mice fed a high fiber diet. Integrated analysis from human bone marrow and peripheral blood analysis indicated that the dietary intervention reduced inflammatory biomarkers and skewed the immune response towards T helper and CD14+ monocytes. Consistently, the bone marrow of Vk*MYC mice fed high fiber diet was more infiltrated by IFNg-producing T lymphocytes while displaying less exhausted T cells and immunosuppressive myeloid cells. Conclusion This is the first interventional clinical trial and in vivo study to show that a HFPBD intervention may delay progression from MGUS/SMM to MM. To our knowledge there has been no similar dietary interventional study in hematological cancers or solid tumors. Together our in vivo and clinical data support the beneficial anti-inflammatory role of a HFPBD providing a link between diet, microbiota, and immune modulation to delay disease progression in MGUS/SMM.

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

Abstract Background Allogeneic (off the shelf) chimeric antigen receptor (CAR) T-cell therapy addresses the logistical challenges, availability (including insufficient T-cell yields from low baseline absolute lymphocyte count), and variable product quality of autologous CAR T therapy. ALLO-715 is a genetically modified anti-BCMA AlloCAR T™ cell which uses Cellectis TALEN ® technology to disrupt the T-cell receptor alpha constant gene (TRAC) and the CD52 gene to reduce the risk of graft-versus-host disease (GvHD) and permit the use of ALLO-647, an anti-CD52 monoclonal antibody (mAb), for selective and transitory host lymphodepletion (LD). Methods UNIVERSAL is an open-label, Phase 1 trial (NCT04093596) in adults with relapsed/refractory (R/R) multiple myeloma who have received ≥3 prior lines of therapy including a proteasome inhibitor, immunomodulator, and anti-CD38 mAb. Patients (pts) must be refractory to their last treatment line. Pts receive LD followed by ALLO-715 at 1 of 4 dose levels (DLs) in a 3+3 dose escalation design: 40, 160, 320, and 480 x 10 6 CAR+ T cells. Several LD regimens are being evaluated: FCA39; FCA60; FCA90; and CA39; with fludarabine [F] 90 mg/m 2, cyclophosphamide [C] 900 mg/m 2, and ALLO-647 [A] 39, 60, or 90 mg divided over 3 days. Results As of June 21, 2021 data-cut, 47 subjects were enrolled; 42 were treated with ALLO-715; 5 progressed prior to treatment. Median time from enrollment to LD was 5 days and no treated pts required bridging therapy. Pts were heavily pretreated with a range of 3-11 prior lines of therapy; 42.9% were penta refractory. There were 19% ISS Stage III at screening, 34% had high risk cytogenetics, and 19% had extramedullary disease. The most common Grade (Gr) 3+ adverse events (AEs) included anemia, neutropenia, lymphopenia, and thrombocytopenia. Cytokine release syndrome (CRS) occurred in 52.4%, all Gr 1/2 except 1 pt with Gr 3. CRS was treated with tocilizumab (21.3%) and corticosteroids (12.8%). One pt (with Gr 2 CRS) experienced Gr 1 neurotoxicity that resolved. Gr 3+ infections occurred in 12.8% of pts, including 2 previously reported Gr 5 events (fungal pneumonia and adenovirus hepatitis). Early results from this trial have been presented previously (ASH 2020) and therefore the efficacy analysis on pts (n=26) treated at DL3 and DL4 with FCA LD, which are considered a more relevant cell dose and LD, is presented here (Table). In pts who received DL3 or DL4 (320 or 480 x 10 6 CAR T cells) (n=26), the ORR was 61.5% (95% CI: 40.6, 79.8); very good partial response or better (VGPR+) rate was 38.5% (95% CI: 20.2, 59.4). Median time to 1 st response was 16 days. The median follow-up for the DL3/DL4 pts was 7.4 months (95% CI: 3.6, 9.9) with a median duration of response of 8.3 months (95% CI: 1.5, not reached). Of the 10 pts with a best response of VGPR+, 8 were found to be negative by minimal residual disease (MRD) analysis. Conclusions UNIVERSAL demonstrates proof of concept for allogeneic CAR T therapy in multiple myeloma. ALLO-715 showed CAR T cell dose response relationship with higher doses (DL3/DL4) leading to clinically meaningful efficacy, including high VGPR+ rate of 38.5% and high MRD negativity without requiring leukapheresis or bridging therapy. ALLO-715 following LD with FCA has a tolerable safety profile. FCA induces a deep and durable window of lymphocyte depletion allowing CAR T cell expansion and persistence. A study using the next generation anti-BCMA CAR (ALLO-605) which supplies cytokine signaling to the CAR bearing cells is ongoing (IGNITE). The current UNIVERSAL trial continues to enroll, including a cohort with consolidation, and updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Mailankody: Allogene Therapeutics: Research Funding; Plexus Communications: Honoraria; Fate Therapeutics: Research Funding; Physician Education Resource: Honoraria; Bristol Myers Squibb/Juno: Research Funding; Jansen Oncology: Research Funding; Legend Biotech: Consultancy; Evicore: Consultancy; Takeda Oncology: Research Funding. Liedtke: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Sidana: BMS: Consultancy; Magenta Therapeutics: Consultancy, Research Funding; Allogene: Research Funding; Janssen: Consultancy, Research Funding. Chhabra: GSK: Honoraria. Oluwole: Janssen: Consultancy; Pfizer: Consultancy; Curio Science: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Kumar: Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Merck: Research Funding; Carsgen: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Sanofi: Research Funding. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Anwer: Janssen pharmaceutical: Honoraria, Research Funding; Allogene Therapeutics: Research Funding; GlaxoSmithKline: Research Funding; BMS / Celgene: Honoraria, Research Funding. Raje: Caribou: Other; Janssen: Other; bluebird bio: Other; Amgen: Other; Celgene: Other; BMS: Other. Siegel: Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Honoraria; GlaxoSmithKline: Honoraria, Speakers Bureau; Celularity: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria; Amgen Inc.: Honoraria; Janssen: Honoraria, Speakers Bureau. Karski: Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Crispr Therapeutics: Current equity holder in publicly-traded company; Nektar Therapeutics: Current equity holder in publicly-traded company. Lovelace: Allogene Therapeutics, Inc.: Current Employment. Lourbakos: Allogene Therapeutics, Inc.: Current Employment. Hari: Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau.

2537 Background: Orva-cel is a B-cell maturation antigen–targeted chimeric antigen receptor (CAR) T cell therapy being evaluated in the phase 1/2 EVOLVE study (NCT03430011) in pts with RRMM who had at least 3 prior lines of therapy (Tx). We previously reported safety and efficacy in the phase 1 study and established the recommended dose (RD) of orva-cel as 600 × 106 CAR+ T cells (Mailankody et al, ASCO 2020). Cytokine release syndrome (CRS), a dominant toxicity of CAR T cell therapy, is mediated in part by IL-1. We explore the role of ppx with AKR, an IL-1 signaling inhibitor, on reducing the incidence of grade (G) ≥2 CRS after orva-cel treatment at the RD. Methods: Fourteen pts were enrolled sequentially for AKR ppx and treated with orva-cel at the RD. The non-AKR ppx control group comprised the remainder of the phase 1 pts receiving orva-cel at the RD (n = 19). The median follow-up (range) was 3.0 mo (1.8–6.2) for the AKR ppx group and 8.8 mo (5.3–12.2) for the non-AKR ppx group. AKR was administered as 100 mg SC the night before orva-cel infusion, 3 h before the infusion (Day 1), and q24 h on Days 2–5. Dosing was increased to q12 h if CRS developed. CRS was graded by Lee (2014) criteria. Tocilizumab (T) and steroids (S) were used per protocol-specified treatment management guidelines. Results: Disease characteristics and outcomes are shown in the table. In AKR ppx and non-AKR ppx groups, median number of prior regimens was 6 and 5, and bridging Tx was used in 57% and 68% of pts, respectively. The total frequency of CRS was similar in the 2 groups, but with less G 2 in the AKR ppx pts; relative risk (95% CI) = 0.54 (0.21, 1.38). No G ≥3 CRS was seen in either group. The incidence of neurological events (NE), G ≥3 infection, and macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) was similar. T and S use was numerically lower with AKR ppx. Orva-cel expansion kinetics were similar in the 2 groups. All pts had a 2-month efficacy assessment, with ORR in 100% of AKR ppx and 95% of non–AKR ppx pts. Conclusions: In this nonrandomized evaluation of AKR ppx with orva-cel treatment, the incidence of G ≥2 CRS was lower in pts receiving AKR ppx. The use of AKR ppx produced no adverse effect on the incidence of NE, infection, or MAS/HLH, nor on orva-cel expansion or disease response. These results warrant further study of AKR ppx in CAR T cell therapy. Clinical trial information: NCT03430011. [Table: see text]