Abstract Background: Anthracycline-induced cardiotoxicity (CT) is a growing concern for public health, with a growing incidence due to improved survival rates for patients with hematological malignancies due to diagnostic and therapeutic advances. Identification of patients at risk for anthracycline-induced CT is vital to develop preventive strategies. Methods: A single-center retrospective cohort study was conducted between 1 January 2017 and 15 February 2023. Medical records of patients with lymphoma treated with first-line anthracyclines were reviewed. Demographic data, cardiovascular risk factors, biomarkers of myocardial damage and echocardiographic information were collected. Results: A total of 200 patients were included. The incidence of CT was 17.4 % (35/200). Patients with CT were older than those without CT, with a mean age of 65.17 years vs 56.77 (p = 0.008). Dyslipidemia (DL) (31.4% vs 13.4% p = 0.017) and previous cardiovascular disease (40% vs 13.3%, p< 0.001) were more frequent in the group who developed an event. Mean baseline NT-proBNP levels in the subgroup with cardiovascular events were 388.73 kg /L ± 101.02, and 251.518 kg /L ± 26.22 in those who did not (p = 0.004). Differences in Troponin I levels were identified during and after treatment without exceeding the laboratory’s upper reference limit. Patients were followed for a median of 51.83 months (0.76-73.49). The presence of a CT event had a negative impact on overall mortality from any cause (HR = 2.23 (95% CI 1.08-2.93), p = 0.031). Conclusions: Early identification of risk factors is crucial to manage patients at risk for anthracycline-induced cardiotoxicity.

Background: PROMs have been included in cancer clinical trials, but it is yet to come in daily clinical practice. Different PROMs exist for assessing patients’ quality of life (QoL), physical functioning and symptom burden. Integrating PROMs in the healthcare of patients with cancer has the potential to improve their care delivery and outcomes. Aims: We hypothesize that patients subscribed to a PROMs program may benefit from a better self-perception of health status and might require fewer hospital admissions and emergency room visits, which might also allow a reduction in the costs of treatment. Methods: Patients (pts) with diagnosis of any type of lymphoma in the need of starting therapy in our hospital were included in our study between 1st Jan 2019 and 31st Dec 2020. Inclusion in “E-Res Salud”, the value-based healthcare program using PROMs was offered to patient starting intravenous treatment since 2020. Pts who started treatment in 2019 and those who refused to participate in 2020 were considered the control arm of our study. The principal endpoint was to compare physician and patient-reported adverse events through a standardized questionnaire such as PRO-CTCAE. Secondary endpoints included association between inclusion in PROMs program and reduction of hospital admissions and emergency room visits. Here, we present the preliminary results from answers given at the beginning of treatment. Results: A total of 142 pts were included in our study; 76 of them (53.5%) reported outcome in the PROMs program. There were no differences in pts characteristics with regards of age or sex. Most frequent diagnoses were diffuse large B-cell, follicular and Hodgkin lymphoma. Adverse events (AEs) most frequently reported by physicians were hematological (76.1%), general (73.9%) and gastrointestinal symptoms (59.9%) and infections (43.7%). When patients were asked to report AEs of higher intensity the most frequently reported were general (31.6%), genitourinary (26.3%), gastrointestinal (23.7%), neurological (15.8%) and cutaneous (13.2%) symptoms (Figure 1). Patients included in the PROMs program reported fewer general (64.5% vs. 84.8%; p<0.05) and infectious (30.3% vs. 59.1%; p<0.05) AEs than those in the control arm. Moreover, inclusion in the PROMs program was associated with fewer number of visits to Emergencies, with 34.2% of pts versus 60% of pts not enrolled in the PROM program (p=0.003). They only group of symptoms which would itself increase the risk of visiting Emergencies was cutaneous AEs (p=0.027). It is important to note that those patients reporting symptoms of higher intensity, frequency or impact in their QoL AEs had more visits than those reporting AEs of lower grade (p<0.05). None of the different types of AEs were associated to an increase in the number of admissions or outpatient consultations. With such a short follow-up we have not found association between any type of AE and survival. Image:Summary/Conclusion: Accurate assessment of patient-reported symptoms allows physicians to help cancer patients manage these issues and thereby, improve the survivorship experience and QoL. Our study establishes the association of PROMs with healthcare utilization among patients with different types of lymphoma. A longer follow-up and changes in PROMs during the treatment will be further analyzed.

MM remains incurable with most patients (pts) relapsing or becoming refractory to standard therapies, highlighting the need for novel agents. Talquetamab (Tal) is a bispecific antibody that binds to G protein-coupled receptor family C group 5 member D (GPRC5D), a receptor highly expressed on plasma cells with limited expression in healthy tissue, and CD3 to redirect T cells to GPRC5D-expressing MM cells. In the phase 1 MonumenTAL-1 study, an overall response rate of 70% at median 6.3-month follow-up was observed at the recommended phase 2 dose (RP2D) of Tal in pts with RRMM. Daratumumab (Dara) is a monoclonal antibody that targets CD38 and is approved for treatment of MM. In preclinical studies, Dara enhanced Tal-mediated lysis of MM cells, suggesting the potential to increase clinical activity in pts with RRMM when the agents are combined. We report initial findings for pts with RRMM who received Tal + Dara in the phase 1b multicohort TRIMM-2 study (NCT04108195). Eligible pts (≥18 years) had MM and received ≥3 prior lines of therapy (LOT; including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and an IMiD. Pts who received anti-CD38 therapy ≤90 days were excluded. The primary objectives were to identify the RP2D of Tal in combination with Dara and to characterize the safety at the RP2D. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] graded per ASTCT guidelines). As of Jul 23, 2021, 23 pts received SC Tal + Dara in separate cohorts: Dara 1800 mg + Tal 400 μg/kg weekly (n=8), + Tal 400 μg/kg biweekly (n=5), and + Tal 800 μg/kg biweekly (n=10). Median follow-up across the cohorts was 2.9 months (range 0.3–11.2). Median age was 68 years (range 44–81), and 52.2% of pts were male. Pts had a median of 6 prior LOT (range 3–18); 82.6% were triple-class exposed (82.6% had prior Dara and 8.7% had prior isatuximab) and 73.9% were penta-drug exposed. Most frequently reported AEs (≥30%) were dysgeusia (52.2%; all grade 1/2), neutropenia (39.1%; grade 3/4 30.4%), thrombocytopenia (39.1%; grade 3/4 21.7%), anemia (34.8%; grade 3/4 21.7%), CRS (34.8%; all grade 1/2), and skin exfoliation (30.4%; all grade 1/2). Grade 3/4 AEs were reported in 78.3%. Median time to CRS onset was 2.5 days (range 2–4), and median duration was 2 days (range 1–3). Infections occurred in 34.8% of pts (grade 3/4 17.4%). Skin disorders were reported in 65.2% of pts (grade 3/4 13.0%), including nail disorders in 17.4% (all grade 1/2). Two ICANS events were reported (grade 1 [concurrent with CRS] and grade 3); both resolved and did not recur. One pt in the Dara 1800 mg + Tal 400 μg/kg biweekly cohort died from disease progression. Responses are shown in the Table. The median time to first response across the cohorts was 1.0 month (range 0.9–2.4), and median duration of response was not reached. Tal pharmacokinetics was similar to that reported in the MonumenTAL-1 study. Proinflammatory cytokine production and T cell activation were observed after Tal + Dara treatment. The combination of Tal with Dara was well tolerated, with a safety profile comparable to the monotherapies. The combination showed promising efficacy in pts with RRMM, supporting further clinical development of Tal + Dara combination therapy.

Background: Talquetamab (tal; JNJ-64407564) is a first-in-class, bispecific IgG4 antibody that binds both to G protein-coupled receptor family C group 5 member D (GPRC5D), a receptor highly expressed on malignant plasma cells but with limited expression in healthy tissue, and CD3 to mediate T-cell–activated lysis of GPRC5D+ multiple myeloma (MM) cells. Daratumumab (dara) is an anti-CD38 mAb with direct on-tumor and immunomodulatory actions. Initial clinical results from the phase 1b multicohort TRIMM-2 study identified the recommended phase 2 doses (RP2Ds) of tal as 400 μg/kg weekly or 800 μg/kg Q2W and support the combination of tal + dara for the treatment of RRMM, with manageable safety, no overlapping toxicities, and promising efficacy. Aims: Here we report updated results for both RP2Ds of tal + dara in TRIMM-2 with additional patients (pts) and longer follow-up. Methods: Eligible MM pts (aged ≥18 years) had received ≥3 prior lines of therapy (LOT; including a PI and IMiD) or were double refractory to a PI and an IMiD, and could not have received anti-CD38 therapy within 90 days. Pts received dara SC 1800 mg per approved schedule and tal (400 μg/kg weekly or 800 μg/kg Q2W) with step-up dosing. The primary objectives were to identify the RP2D(s) of tal for combination therapy and evaluate safety of the combination. AEs were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Responses were assessed by IMWG criteria. Results: At data cutoff (Jan 13, 2022, N=46), median follow-up was 4.0 months (range 0.4-16.3), median age was 65 years (range 47-81), and 48% were female. Pts received a median of 5 prior LOT (range 2-16); 83% were triple-class exposed, 61% penta-drug exposed, 37% anti-BCMA non–CAR-T exposed, and 4% anti-BCMA CAR-T exposed. 96% of pts had ≥1 AE (gr 3/4: 67%). The most frequently reported AEs (≥30% across tal + dara cohorts) were CRS (65%; all gr 1/2; median time to onset: 2 days; median duration: 2 days), dysgeusia (57%), thrombocytopenia (35%; gr 3/4: 20%), anemia (39%; gr 3/4: 20%), and dry mouth (44%). Infections occurred in 50% of pts (gr 3/4: 13%). Skin disorders were reported in 72% of pts (gr 3/4: 11%): skin exfoliation in 26% (all gr 1/2) and nail disorders in 11% (all gr 1/2). Two ICANS events were reported in the 800 Q2W group (both gr 1 and resolved within 1 day). 3 pts discontinued due to AEs. Response rates were consistent across both RP2Ds supporting their equivalence (Table). Median time to first response across dosing cohorts was 0.95 months (range 0.9-9.7); median duration of response was not reached. Upregulation of CD38+/CD8+ T cells and proinflammatory cytokines was observed with tal + dara, supporting potential synergy of the combination in pts with prior anti-CD38 exposure. Updated results will be presented. Image:Summary/Conclusion: Longer follow-up with additional patients shows comparable efficacy and safety across both RP2Ds, with no new safety signals, strengthening the benefit-risk profile of tal + dara as a novel immunotherapy-based approach for heavily pretreated pts with RRMM.

In the phase 1 MajesTEC-1 trial, teclistamab (Tec), a B-cell maturation antigen × CD3 T cell redirecting bispecific antibody, showed an overall response rate of 65% at 6.1-month follow-up. Daratumumab (Dara) is a monoclonal antibody that targets CD38 and is approved for the treatment of MM. In MM cell lines, the lytic activity of Tec was enhanced by pretreatment and combination treatment with Dara; thus, the combination of both agents may improve efficacy in RRMM by targeting discrete yet complementary antigens. We present data on patients (pts) with RRMM who received Tec + Dara in the phase 1b TRIMM-2 study (NCT04108195). Eligible pts were ≥18 years of age, had a MM diagnosis, and received ≥3 prior lines of therapy (LOT; including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and IMiD. Receipt of anti-CD38 therapy ≤90 days was not allowed. The primary objectives were to identify the RP2D for the Tec + Dara combination and to assess safety of the combination. This analysis focuses on subcutaneous (SC) cohorts in the study. Responses were assessed by IMWG criteria and adverse events (AEs) by CTCAE v5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] were graded per ASTCT guidelines). 33 pts received SC Tec + Dara in different dosing cohorts: Dara 1800 mg + Tec 1500 μg/kg weekly (n=21), + Tec 3000 μg/kg weekly (n=5), + Tec 300 mg biweekly starting Cycle 3 Day 1 (C3D1; Tec 150 mg weekly in C1–C2; n=2), and + Tec 3000 μg/kg biweekly (n=5). 9 pts in the Dara 1800 mg + Tec 1500 μg/kg weekly cohort switched to Tec 3000 μg/kg biweekly dosing after C3D1. As of Jun 22, 2021, median follow-up across the cohorts was 3.6 months (range 0.1–10.4). Median age was 67 years (range 51–78) and 57.6% were female. Median number of prior LOT was 5 (range 2–16); 69.7% were triple-class exposed (prior Dara in all 69.7%) and 60.6% were penta-drug exposed. The most common AE was CRS (54.5%; all grade 1/2); median time to onset was 2 days (range 1–6), and median duration was 2 days (range 1–7). Other AEs (≥30%) were neutropenia (36.4%; all grade 3/4), thrombocytopenia (36.4%; grade 3/4 33.3%), anemia (36.4%; grade 3/4 24.2%), diarrhea (36.4%; grade 3/4 3.0%), nausea (30.3%; all grade 1/2), and pyrexia (30.3%; all grade 1/2). Overall, 66.7% of pts had grade 3/4 AEs. Infections occurred in 51.5% of pts (grade ≥3 24.2%). No ICANS events were reported. One pt in the Dara 1800 mg + Tec 3000 μg/kg weekly cohort died from treatment-unrelated bacterial pneumonia during C1, and 1 pt in the Dara 1800 mg + Tec 1500 μg/kg weekly cohort died from progressive disease. Responses are shown in the Table. Across the cohorts, median time to first response was 1.0 month (range 0–1.9). Median duration of response was not reached. Tec + Dara treatment led to proinflammatory cytokine production and T cell activation. The Tec pharmacokinetic profile was similar to that reported in the MajesTEC-1 study. The combination of Tec + Dara had a manageable safety profile and showed preliminary efficacy in pretreated pts with MM. These findings warrant further investigation, and the randomized phase 3 MajesTEC-3 study will evaluate Tec + Dara vs Dara, pomalidomide, and dexamethasone or Dara, bortezomib, and dexamethasone in pts with RRMM.

Background: CC-99282 is a novel, oral small molecule CELMoD® agent that co-opts cereblon to induce targeted degradation of Ikaros/Aiolos, transcription factors critical for development of B-cell malignancies. Compared with immunomodulatory drugs (IMiD®) and other CELMoD agents, CC-99282 had similar immunostimulatory effects and 10- to 100-fold stronger antiproliferative and apoptotic activity in preclinical models of diffuse large B-cell lymphoma (DLBCL). Aims: To evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), and preliminary efficacy of CC-99282 in pts with R/R NHL. Methods: CC-99282-NHL-001 (NCT03930953) is a 2-part multicenter first-in-human study comprising dose escalation of CC-99282 monotherapy (part A) and expansion with or without combination partners (part B). Part A includes pts with R/R DLBCL or follicular lymphoma (FL) who had progressed after ≥2 lines of therapy, including IMiD/CELMoD agents and chimeric antigen receptor T-cell (CAR-T) therapy, and pts with R/R DLBCL who received ≥1 line of standard therapy and are unfit for transplant. Pts receive oral CC-99282 0.2, 0.4, 0.6, or 0.8 mg once daily on 3 intermittent dosing schedules of 28-day cycles, with ≥3 pts per dosing cohort. Results: As of Oct 6, 2021, 50 pts were treated in part A (38 DLBCL, 12 FL; median age 66y; 58% male); 17 pts (34%) were ongoing and 26 pts (52%) discontinued due to progressive disease. Grade 3/4 CC-99282–related adverse events were reported in 32 pts (64%); the most common were neutropenia (29 pts [58%]), thrombocytopenia (4 pts [8%]), and anemia (4 pts [8%]). Correlation analysis showed that grade 4 neutropenia in the first month was more strongly associated with number of prior lines of alkylating agent and anti-CD20 therapy than with CC-99282 dose level or schedule. Neutropenia was manageable with CC-99282 dose modifications and granulocyte colony–stimulating factors. All dose-limiting toxicities were hematologic. The maximal recommended doses for schedules of interest were 0.6 mg on 7/14 days and 0.4 mg on 14/28 days. For doses ≥0.4 mg on schedules of interest, the overall response rate was 42% (15/36 evaluable pts; 6 FL, 9 DLBCL), with complete responses in 6 pts and partial responses in 9 pts. Responders included pts previously treated with CAR-T therapy and/or IMiD/CELMoD agents. Responses were durable, with median durations of 239 days (range 48–587; median follow-up [mFUP] 247 days [range 21–690]) and 112 days (range 63–414; mFUP 121 days [range 22–464]) for 7/14- and 14/28-day schedules, respectively. CC-99282 was absorbed rapidly and had a prolonged terminal half-life (median ~50 hours at doses ≥0.4 mg), with considerable distribution into the peripheral compartment. Increase in plasma CC-99282 and degradation of Ikaros/Aiolos in peripheral T cells occurred in a dose-dependent manner, and maximum degradation (>90%) occurred by day 4 of treatment at doses ≥0.4 mg. Within 2 weeks of initiating CC-99282, peripheral T-cell subsets showed a significant shift toward a more activated phenotype (P<0.05). Analysis of mutant circulating tumor DNA levels showed rapid reductions that correlated with response to CC-99282, suggesting strong tumor cell–intrinsic activity. Summary/Conclusion: CC-99282 monotherapy showed a manageable safety profile and demonstrated promising efficacy in heavily pretreated pts with R/R NHL. PK and pharmacodynamic data were consistent with robust and rapid CC-99282 antitumor activity. This study is ongoing, with patients actively being enrolled in the monotherapy and CC-99282+rituximab combination expansion cohorts.

Background: Teclistamab (JNJ-64007957) is a B-cell maturation antigen (BCMA) × CD3 T-cell redirecting bispecific antibody currently under investigation in patients with relapsed/refractory multiple myeloma (RRMM). Daratumumab is a CD38-targeting monoclonal antibody with direct on-tumor and immunomodulatory mechanisms of action. The preliminary results from the phase 1b multicohort TRIMM-2 study showed tolerable safety with no overlapping toxicities, and encouraging efficacy, supporting the combination of teclistamab with daratumumab for the treatment of RRMM. Aims: We report updated results from the TRIMM-2 study with additional patients and longer follow-up. Methods: Eligible patients were ≥18 years of age with a MM diagnosis and previously treated with ≥3 prior lines of therapy (including a proteosome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double-refractory to a PI and IMiD. Patients who had received anti-CD38 therapy ≤90 days prior were excluded. Written informed consent was obtained from all eligible patients. Patients received subcutaneous (SC) daratumumab 1800 mg per approved schedule and teclistamab SC 1.5–3 mg/kg once weekly or every 2 weeks. Primary objectives of the study were to identify the recommended phase 2 dose for the teclistamab and daratumumab combination and to assess safety of the combination. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0, except for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), which were graded per ASTCT guidelines. Results: At the Jan 13, 2022 data cutoff, the median follow-up was 7.2 months (range 0.1–16.6). Among the safety population (N=46), 52% were females, and the median age was 67 years (range 50–79). Patients received a median of 6 prior lines of therapy (range 2–17); 74% of patients were triple-class exposed; 63% were penta-drug exposed, and 15% were anti-BCMA exposed. Overall, 91% of patients had ≥1 AE of any grade; 78% had grade 3/4 AEs. The most common AE was CRS (61%; all grade 1/2); median time to onset was 2 days and median duration was 2 days. Other AEs included neutropenia (54%; grade 3/4 50%), anemia (46%; grade 3/4 28%), thrombocytopenia (33%; grade 3/4 28%), and diarrhea (33%; grade 3/4 2%). Infections occurred in 29 patients (63%; grade 3/4 28%). One patient had grade 1 ICANS that was fully resolved. Among 37 response-evaluable patients, the overall response rate was 78% (29/37); 27 patients (73%) had very good partial response (VGPR) or better (Table). While the median duration of response was not reached, median time to first response across dosing cohorts was 1.0 month (range 0.9–2.8). Upregulation of CD38+/CD8+ T cells and proinflammatory cytokines was observed after teclistamab dosing in combination with daratumumab, supporting potential synergy of the combination in patients with prior anti-CD38 exposure. Updated results will be presented. Image:Summary/Conclusion: Teclistamab in combination with daratumumab is a novel immunotherapy approach that may yield improved clinical efficacy in heavily pretreated patients with RRMM.

Background: Activated B-cell (ABC) lymphomas emerged as a distinct molecular subtype within Diffuse Large B-Cell Lymphoma (DLBCL). Canonical and non-canonical constitutive activation of nuclear factor kappa B (NF-kB) signaling pathway has been widely reported in the ABCs, and mainly implicates gain-of-function mutations in many players downstream of the BCR receptor. This molecular entity is normally associated with poor clinical outcome after standard immunochemotherapy. The discouraging results obtained in several clinical trials using proteasome inhibitors, tyrosine kinase inhibitors, or immunomodulators, lead to an intense search for new, potentially druggable biomarkers in DLBCL. Immunosuppressive microenvironment is a hallmark in many solid tumors as well as in DLBCLs. Aims: Herein, we searched for bioinformatic tools aim to repurpose drugs capable of modulating immune cells from transcriptomics dataset generated by RNA-seq analysis. Methods: RNA-seq was applied to RNA samples from FFPE blocks of DLBCL patients, 4 of whom were previously classified as GCB and the remaining 4 as ABC, based on NanoString-LST. All ABC were negative for the MYD88L265P mutation (ABC-MYD88non-L265P) determined by allele-specific PCR (AS-PCR). Median of age was 66.5 years (range 40-82) and 71.5 years (range 53-85) for GCB and ABC, respectively. Indexed samples were run together on a NextSeq 500 instrument (Illumina Inc.) with a 2 × 150-bp paired-end protocol. An average of 25.8 million mapped reads was generated per sample. Next, bioinformatic tool DREIMT was utilized to predict drugs for intratumor immunomodulation. DREIMT employ FGSEA ES and Pairwise ES calculations to calculate the enrichment score (ES). P-value estimation is calculated by adaptive multi-level split Monte-Carlo scheme and is P-adjusted using Benjamin correction. DREIMT apply a drug prioritization score (T, tau, ranging +100 to -100) following the approach described by LINCS L1000 team. To consider strong hypotheses for the drug profile-immune gene expression associations, we considered tau> 99 and selected top 26 candidates ranked by tau score. In the same way, we examined tau> -99 and chosen top 26 candidates ranked by tau score Results: We identified 79 differentially expressed genes (DEGs) obtained after RNA-seq analysis. GSEA showed two main enriched routes implicated in metabolism and immune pathways in the ABC lymphomas, tumor suppressor genes (TSGs) as MAPK10 and GRHL1 were downregulated while anti-inflammatory such as ALOX15B was upregulated. Triggers of Th2 response as CHIT1 and CHI3L-1 were upregulated, like serine protease inhibitors SERPINA1 and SERPINA5. The proto-oncogene FRG was upregulated. DREIMT applied on the 79 DEGs interestingly showed its capacity to selected drugs involved in augmenting anti-tumor immune response. Among them, Bucladesine, Labetalol or Glimepiride boost Th1 response and macrophages M1. On the other hand, Moracizine and Voriconazole inhibit of expression of genes encoding inflammatory molecules in monocytes Summary/Conclusion: RNA-sequencing-derived transcriptome described new tumor-resistant genes dysregulated in the ABC-MYD88non-L265P which promote the maintenance of tumor cells. DREIMT enables us to propose a prioritized list of drugs as the best theoretical therapeutic candidates to treat these patients in order to immunomodulating the oncogenic transcriptomic of ABC-DLBCLs. Of note, most of the proposed drugs are not being yet considered in the clinical practice of this cancer subtype opening up the approach of preclinical studies and new treatment possibilities

Background: CC-99282 is a novel, oral cereblon (CRBN) E3 ligase modulator (CELMoD) agent that co-opts CRBN to induce potent and targeted degradation of Ikaros and Aiolos, transcription factors that are known to be important for the normal differentiation and function of multiple types of hematopoietic cells. Non-Hodgkin lymphomas (NHL) comprise diverse lymphoma subtypes with varying genomic alterations and clinical outcomes. Despite treatment advances, management of aggressive relapsed or refractory (R/R) NHL remains challenging. The ability of CC-99282 to specifically target Ikaros and Aiolos for degradation provides a strong biological rationale for studying it for the treatment of patients with R/R B-cell NHL, both as a single agent and in combination with rituximab, an approved humanized anti-CD20 monoclonal antibody. CC-99282-NHL-001 (NCT03930953) is an ongoing, phase 1, multicenter, open-label, first-in-human study evaluating the safety, tolerability, and preliminary clinical activity of CC-99282 alone and in combination with rituximab in patients with R/R B-cell NHL. Methods: Eligible patients include those with R/R NHL, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma, or primary central nervous system lymphoma (PCNSL), who have relapsed on or are refractory to ≥2 lines of therapy (or who have received ≥1 prior line of standard therapy and are not eligible for any other therapy). This study is conducted in 2 parts: dose escalation (Part A) and dose expansion (Part B). Part A evaluates the safety and tolerability of escalating CC-99282 doses to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of CC-99282 monotherapy. In Part A, patients with R/R DLBCL or R/R FL receive oral CC-99282 once daily on intermittent schedules per 28-day cycle. Following the evaluation of the Bayesian logistic regression model recommendation as well as the safety and pharmacokinetic/pharmacodynamic data that are monitored continually, decisions on dose escalations are made by the safety review committee until the MTD/RP2D is reached. Part B will evaluate the safety and efficacy of CC-99282 administered at the RP2D alone or in combination with rituximab to confirm the RP2D of CC-99282. Treatment efficacy is assessed according to the Lugano Classification for NHL and the modified International PCNSL Collaborative Group criteria. Correlations between various biomarkers and clinical outcomes of treatment with CC-99282, alone or in combination with rituximab, will also be explored. Adverse events are monitored until 28 days following the final dose. Study treatments may be continued for up to 2 years, or until significant disease progression, unacceptable toxicity, or withdrawal. The research was funded by: Bristol Myers Squibb Keywords: Molecular Targeted Therapies, Ongoing Trials Conflicts of interests pertinent to the abstract Jean-M. Michot Consultant or advisory role: ASTEX, AstraZeneca, Bristol Myers Squibb Other remuneration: Investigator of clinical studies with Abbvie, Agios, ARGENX, Bristol Myers Squibb, Forma, Genentech, Janssen, Lilly, Roche, Sanofi, Xencor C. Carpio Consultant or advisory role: Novartis, Takeda, Regeneron Educational grants: Bristol Myers Squibb, Novartis, Gilead, Takeda L. Nastoupil Consultant or advisory role: ADC Therapeutics, Bristol Myers Squibb, Genentech, Janssen, Novartis A) Activation signature and B) fold increase in PF of tab- lots after EBV-specific activation. C) Representative alluvial plot illustrates the clonal expansion of TCRs associated with the-cel manufacturing process and that the clonal expansion of TCRs associated with the tab-cel manufacturing process and that the TCR repertoire of tab-cel is conserved within the functionally activated T-cell population Honoraria: Bayer, Epizyme, Kite/Gilead, Pfizer, TG Therapeutics Research funding: Bayer, Bristol Myers Squibb, Epizyme, Genentech, Janssen, Novartis, TG Therapeutics J. Chavez Consultant or advisory role: Kite/Gilead, Novartis, Kymera, Karyopharma, Abbvie, Janssen, ADC Therapeutics, Pfizer, TeneBio Other remuneration: Speakers Bureau: Beigene, Morphosys, Epizyme T. Feldman Consultant or advisory role: AstraZeneca, ADC Therapeutics, Janssen, Karyopharm, Kite, MorphoSys, AbbVie, Daiichi Sakyo Honoraria: AbbVie, ADC Therapeutics, AstraZeneca, Bristol Myers Squibb, Daiichi Sakyo, Janssen, Karyopharm, Kite, MorphoSys, Pharmacyclics, Seattle Genetics, Takeda Other remuneration: Speakers Bureau: AbbVie, Bristol Myers Squibb, Janssen, Pharmacyclics, Seattle Genetics, Takeda D. Morillo Honoraria: AbbVie, Takeda, Janssen Educational grants: AbbVie, Takeda, Janssen, Kite E. Bachy Consultant or advisory role: Roche, Bristol Myers Squibb Honoraria: Roche, Gilead, Novartis, Sanofi, Amgen Educational grants: AbbVie, Gilead, Sanofi Other remuneration: Provision of Writing Assistance: Roche A. Pinto Honoraria: Roche, Servier, Takeda, Bristol Myers Squibb, MSD J. Kuruvilla Consultant or advisory role: AbbVie, Bristol Myers Squibb, Gilead, Karyopharm, Merck, Roche, Seattle Genetics Honoraria: Amgen, Antengene, AstraZeneca, Bristol Myers Squibb, Gilead, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, Seattle Genetics, TG Therapeutics Research funding: Canadian Cancer Society, Leukemia and Lymphoma Society Canada, Princess Margaret Cancer Foundation, Janssen, Roche, AstraZeneca Other remuneration: Karyopharm (DSMB) T. J Buchholz Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb S. Kasibhatla Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb S. Carrancio Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb C. Guarinos Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb F. Wu Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb S. Li Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb P. Patah Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb M. Pourdehnad Employment or leadership position: Bristol Myers Squibb Stock ownership: Bristol Myers Squibb Other remuneration: Patents, Royalties, or Other Intellectual Property: Bristol Myers Squibb

Background: CC ‐ 99282 is a novel, oral cereblon (CRBN) E3 ligase modulator (CELMoD) agent that co ‐ opts CRBN to induce potent and targeted degradation of Ikaros and Aiolos, transcription factors that are known to be important for the normal differentiation and function of multiple types of hematopoietic cells. Non ‐ Hodgkin lymphomas (NHL) comprise diverse lymphoma subtypes with varying genomic alterations and clinical outcomes. Despite treatment advances, management of aggressive relapsed or refractory (R/R) NHL remains challenging. The ability of CC ‐ 99282 to spe-cifically target Ikaros and Aiolos for degradation provides a strong biological rationale for studying it for the treatment of patients with R/R B ‐ cell NHL, both as a single agent and in combination with rituximab, an approved humanized anti ‐ CD20 monoclonal multicenter, label, first in human study evaluating the safety, tolerability, and preliminary clinical activity alone and in combination with rituximab in patients with R/R B ‐ cell NHL. Methods: Eligible patients include those with R/R NHL, including diffuse large B ‐ cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma, or primary central nervous system lymphoma (PCNSL), who have relapsed on or are refractory to ≥ 2 lines of therapy (or who have received ≥ 1 prior line of standard therapy and are not eligible for any other therapy). This study is conducted in 2 parts: dose escalation (Part A) and dose expansion (Part B). Part A evaluates the safety and tolerability of escalating CC ‐ 99282 doses to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of CC ‐ 99282 monotherapy. In Part A, patients with R/R DLBCL or R/R FL receive oral CC ‐ 99282 once daily on intermittent schedules per 28 ‐ day cycle. Following the evaluation of the Bayesian logistic regression model recommendation as well as the safety and pharmacokinetic/pharmacodynamic data that are monitored continually, decisions on dose escalations are made by the safety review committee until the MTD/RP2D is reached. Part B will evaluate the safety and efficacy of CC ‐ 99282 administered at the RP2D alone or in combination with rituximab to confirm the RP2D of CC ‐ 99282. Treatment efficacy is assessed according to the Lugano Classification for NHL and the modified International PCNSL Collaborative Group criteria. Correlations between various biomarkers and clinical outcomes of treatment with CC ‐ 99282, alone or in combination with rituximab, will also be explored. Adverse events are monitored until 28 days following the final dose. Study treatments may be continued for up to 2 years, or until significant disease progression, unacceptable toxicity, or withdrawal. Background: Tabelecleucel (tab ‐ cel) is an investigational off ‐ the ‐ shelf, allogeneic Epstein ‐ Barr virus (EBV) ‐ specific T ‐ cell immunotherapy. Tab ‐ cel has shown clinical activity in patients with EBV + post ‐ transplant lymphoproliferative disease and other EBV ‐ associated diseases. We aim to comprehensively profile tab ‐ cel through high ‐ content immunophenotyping (IPT), T ‐ cell receptor (TCR) repertoire, cytokine polyfunctionality (PF), and differential gene expression patterns (GEP) using resting and EBV ‐ antigen stimulation states to model intrinsic effector responses associated with engagement of EBV + disease. Using this approach, we aim to identify corollaries associated with clinical outcomes. Methods: IPT was performed using targeted flow cytometry activation profiling (CD25/CD69), and 40 ‐ plex mass cytometry by time ‐ of ‐ flight (CyTOF). PF response and cytokine profiles were evaluated using the IsoLight single ‐ cell PF strength assay. TCR repertoires were assessed using TCR β immunoSEQ and GEP were evaluated using a custom Nanostring panel consisting of 333 T ‐ cell lineage gene targets. Results: Analyses for a subset of tab ‐ cel lots has been completed and are described here. This subset of tab ‐ cel lots varied in their CD4/CD8 composition, with the majority having proportionally higher CD8 + T cells ( > 70%). Baseline control expression of activation markers of 8.5 ± 2.1% increased to 65 ± 3.9% post ‐ activation with EBV + targets (Figure1A).BaselinecontrolPFwas0.58 ± 0.21%,anduponactivation tab ‐ cel demonstrated a 25.3 ‐ fold average induction of PF (Figure 1B). The resultant activated cytokine profiles are primarily comprised of effector and chemoattractive cytokines including IFN γ and MIP1 β . The tab ‐ cel manufacturing process effectively amplified and enriched for EBV ‐ specific TCRs that correspond back to a starting frequency of 0.52 ± 0.8% of the initial donor TCR repertoire (Figure 1C). Notably, cross comparison of tab ‐ cel enriched TCRs against publicly available databases (VDJdb, McPas ‐ TCR) identified previously curated EBV ‐ specific TCR β sequences as a component of the expanded repertoire. We are currently assessing the degree of convergence for TCR sequences against common antigen motifs across donors and corre-lationofIPTtopost ‐ activationPF.Analysis ofpost ‐ activation GEPand extended IPT by CyTOF are currently underway and will be reported at the time of presentation. Conclusions: The process for generating tab ‐ cel from unre-lated donors enriches for known EBV ‐ specific clones and results in a net amplification of EBV ‐ targeted T ‐ cell clonality. Upon activation, tab ‐ cel exhibits a multi ‐ factorial activation profile and demonstrates PF associated with secretion of effector and chemoattractive cytokines. Altogether this multi ‐ omics profiling will facilitate corollaries associated with clinical outcomes. EA – previously submitted to regional or national meetings (up to 1000 attendees) and EBMT 2021. The research was funded by: Atara Biotherapeutics to the abstract

Introduction: Allogeneic haematopoietic stem cell transplantation (alloHCT) is a potentially curative approach for patients (pts) with multiple myeloma (MM). The high transplant related mortality (TRM) rate with myeloablative conditioning has resulted in a shift to reduced intensity conditioning regimens (RIC). However, most MM pts who receive an alloRIC ultimately relapse and their treatment remains a challenge. Since alloHCT can modify the biology of the disease, including the immune environment, responses after alloHCT to rescue therapies previously used before alloHCT could be improved. Our main objective was to evaluate the efficacy of regimens including new drugs in MM pts relapsing after alloHCT comparing the efficacy achieved before and after alloHCT.

Background and objectives: AL amyloidosis is a rare condition whose management is undergoing changes due to recent advances in diagnosis and treatment. We describe a contemporary series of patients with AL amyloidosis to analyze the features that enable early diagnosis and optimal management. Patients and methods: We recruited for analysis 32 patients (19 women; mean age, 63 years) treated consecutively at our center. Results: Eighty-four percent of the patients presented with asthenia, dyspnea or edema, with a previous duration of symptoms of 8 months (median). Cardiac (21/32) and renal impairment were the most common type (11/32). All of the patients, except one, had a monoclonal component in serum/urine or abnormal values for free light chains (78%, lambda). The bone marrow (BM) showed clonal plasmacytosis in 29 cases. All of the cardiac biopsies and 50% of the BM biopsies showed amyloid deposits. The results of the echocardiogram and/or cardiac resonance were abnormal in 27/30 cases. The median NT-proBNP value at diagnosis was 5200 ng/ml. Thirteen patients died due to heart failure, 2 due to rejection after heart transplantation, 2 due to pneumonia and 1 after a stroke. Ten patients did not undergo treatment, 12 were treated with bortezonnib and 5 were treated with alkylating agents. Five patients underwent heart transplantation and 4 underwent autologous bone marrow transplantation. Fourteen patients achieved a complete hematologic response and 10 achieved organ response. The median survival was 17 months. Conclusions: Cardiac involvement is the major determinant of prognosis. Yield of involved organ biopsy is high (100% heart biopsies). Antineoplastic treatment with bortezomib and/or autologous bone marrow transplantation achieves hematological responses with improvements in organ impairment. (C) 2014 Elsevier Espana, S.L.U. All rights reserved.

Resumen Antecedentes y objetivo La amiloidosis AL es una entidad rara cuyo manejo esta cambiando gracias a avances recientes en el diagnostico y tratamiento. Describimos una serie contemporanea de enfermos con amiloidosis AL, para analizar aspectos que permiten un diagnostico precoz y un manejo optimo. Pacientes y metodos Hemos reunido para su analisis 32 pacientes (19 mujeres, edad mediana 63 anos) atendidos consecutivamente en nuestro centro. Resultados El 84% de los enfermos comenzaron con astenia, disnea o edemas con una duracion previa de los sintomas de 8 meses (mediana). La afectacion cardiaca (21/32) y la renal fueron las mas frecuentes (11/32). Todos los enfermos, excepto uno, presentaban componente monoclonal en suero/orina o valores anormales de cadenas ligeras libres (78%, λ). La medula osea (MO) mostraba plasmocitosis clonal en 29 casos. El 100% de las biopsias cardiacas y el 50% de las de MO mostraron amiloide. El ecocardiograma y/o la resonancia cardiaca fueron anormales en 27/30 casos. La mediana de NT-proBNP al diagnostico fue de 5200 ng/mL. Trece enfermos fallecieron por insuficiencia cardiaca, 2 por rechazo tras trasplante cardiaco, 2 por neumonia y uno tras ictus. Diez enfermos no recibieron tratamiento; 12 recibieron bortezomib y 5 alquilantes. Cinco enfermos recibieron un trasplante cardiaco y 4, un autotrasplante de MO. Catorce enfermos alcanzaron respuesta hematologica completa y 10, respuesta de organos. La supervivencia mediana fue de 17 meses. Conclusiones La afectacion cardiaca es el principal determinante pronostico. La rentabilidad de las biopsias de organos afectados es alta (100% biopsias cardiacas). El tratamiento antineoplasico con bortezomib y/o autotrasplante de MO consigue respuestas hematologicas con mejoria de la afectacion de organos.