ABSTRACT
Immune thrombocytopenia (ITP) was reported as a rare complication of COVID-19 vaccines. We conducted a retrospective single-center analysis of all ITP cases detected in 2021 and compared the quantity with the pre-vaccination years, from 2018 to 2020. In 2021, a two-fold increase in ITP cases was identified compared to previous years; 11 of 40 cases (27.5%) were considered COVID-19-vaccine related. Our study highlights an increase in ITP cases at our institution, probably related to COVID-19 vaccinations. Further studies are needed to investigate this finding globally.
Subject(s)
COVID-19 Vaccines , COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Humans , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Immunization Programs , Incidence , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/epidemiology , Retrospective Studies , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology , Vaccination/adverse effectsABSTRACT
Introduction: The COVID-19 pandemic afects everyday life, hospital infrastructures and cancer care worldwide and in Germany. While current infection rates nationwide are decreasing, a continuous long-term infection rate is expected until vaccine development. First data from China suggested that cancer patients are particularly susceptible and at higher risk of a severe course of the disease. Despite more data being available now, many open questions remain regarding the course of COVID-19 in cancer patients and the impact of cancer treatment. To prospectively address these questions, we initiated a multicentric, observational trial including cancer patients with COVID-19 in the Hamburg metropolitan region and parts of Schleswig-Holstein. Method(s): Patients with diagnosis of cancer and COVID-19, who were treated in the University Cancer Center Hamburg (UCCH), its contracted partner network or at the University Cancer Centers Kiel and Lubeck are included into the trial, which was initiated in April 2020. Data are collected as available from routine clinical care and include demographic and biometric data, medical history, baseline infection data at inclusion as well as inpatient and intensive care unit admissions. Upon consent, patients provide peripheral blood samples for a prospective biobanking with the aim of investigating immune response, immunity and predictive outcome markers. Recruitment is planned for a one-year period. Result(s): As of June 30th 2020, 17 patients of which 13 were male were included afer signing informed consent. Median age was 64 years. 12 of the 17 patients had hematologic disease, mostly acute leukemia. Two patients had solid tumors and three patients had both hematologic and solid malignancy. In 71 % of included patients COVID-infection was diagnosed while being hospitalized due to their oncologic disease. Five patients required mechanical ventilation in the course of disease, one patient died due to the infection. Updated data will be presented at the meeting. Conclusion(s): The prospective registrational COVIDHELP trial will continuously include patients with malignant diseases and COVID-19 during the current pandemic. Our analysis will help to better understand the clinical course, potential impact of intrinsic and extrinsic factors as well as immune response to COVID-19 infection in cancer patients and thus facilitate clinical decision making concerning therapy discontinuation and identifcation of subgroups at specific risk.
ABSTRACT
Context: CARTITUDE-2 (NCT04133636) Cohort A is assessing cilta-cel in lenalidomide-refractory patients with progressive MM after 1-3 prior LOT. Objective(s): To present updated results from CARTITUDE-2 Cohort A. Design(s): Phase 2, multicohort study. Patient(s): Lenalidomide-refractory patients with progressive MM after 1-3 prior LOT (PI and IMiD included) and no previous exposure to BCMA-targeting agents. Intervention(s): Single cilta-cel infusion (target dose 0.75x106 CAR+ viable T-cells/kg) after lymphodepletion Main Outcome Measure(s): Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Management strategies were used to reduce risk of movement/neurocognitive adverse events (MNTs). Pharmacokinetics (PK) (Cmax/Tmax of CAR+T-cell transgene levels), cytokine release syndrome (CRS)-related cytokines over time, peak cytokine levels by response/CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+T-cell CD4/CD8 ratio by response/CRS/ICANS are being evaluated. Result(s): As of January 2022 (median follow-up [MFU] 17.1 months), 20 patients (65% male;median age 60 years;median 2 prior LOT;95% refractory to last LOT) received cilta-cel. Overall response rate was 95% (90% >=complete response;95% >=very good partial response). Median times to first and best response were 1.0 month and 2.6 months, respectively. All 16 MRD-evaluable patients achieved MRD negativity at 10-5. Median duration of response was not reached. At 12 months, event-free rate was 79% and progression-free survival rate was 75%. 95% of patients had CRS (gr3/4 10%);median time to onset was 7 days and median duration was 3 days. Neurotoxicity was reported in 30% of patients (5 gr1/2;1 gr3/4) and ICANS in 15% (all 3 gr1/2);1 patient had gr2 facial paralysis. No MNTs were observed. 1 death occurred due to COVID-19 (treatment-related), 2 due to progressive disease, and 1 due to sepsis (not treatment-related). Preliminary PK analyses showed peak CAR-T cell expansion at day 10.5;median persistence was 153.5 days. Conclusion(s): At MFU of 17.1 months, a single cilta-cel infusion resulted in deep and durable responses in lenalidomide-refractory MM patients with 1-3 prior LOT. We will present updated PK/cytokine/CAR-T subset analyses and clinical correlation to provide novel insights into biological correlates of efficacy/safety in this population. Copyright © 2022 Elsevier Inc.
ABSTRACT
Background: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is a standard of care for newly diagnosed multiple myeloma (NDMM). Belantamab mafodotin (belamaf) is a B-cell maturation antigen-binding antibody-drug conjugate that eliminates myeloma cells by a multimodal mechanism: direct cell kill and anti-myeloma tumor immune response. Belamaf has demonstrated deep and durable responses as a monotherapy in the DREAMM-2 study of patients (pts) with relapsed/refractory multiple myeloma (RRMM). Preclinical evidence of belamaf in combination with bortezomib or lenalidomide suggests enhanced anti-myeloma activity, providing rationale for this treatment combination. Aims: To evaluate the safety and tolerability of this combination in adult pts with transplant-ineligible (TI) NDMM and establish the recommended Phase III dose. Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open-label, randomized study of belamaf + VRd. The belamaf dose cohorts currently being evaluated are Cohort 1 (1.9 mg/kg Q3/4W), Cohort 2 (1.4 mg/kg Q6/8W), Cohort 3 (1.9 mg/kg Q6/8W), Cohort 4 (1.0 mg/kg Q3/4W), and Cohort 5 (1.4 mg/kg Q3/4W). Belamaf is given with VRd Q3W until Cycle 8, and with Rd Q4W thereafter. After evaluation of safety data for Cohort 1, Cohorts 2-5 were opened in parallel and enrolled pts were randomized 1:1:1:1. Primary endpoint is safety. Secondary endpoints include efficacy, tolerability, and pharmacokinetics (PK). Results: As of data cutoff (07 Dec 2021), 64 pts were analyzed across all cohorts. Median age (range) was 73.0 (51- 88) years, 55% were male, 80% were white, 8% had extramedullary disease, 59% were International Staging System stage II or III, 20% had amp1q, and 17% had high-risk cytogenetics (≥1 of: t(4;14), t(14;16), del17p). The median duration of follow-up varied: Cohort 1 (17.4 months [mo]), Cohort 2 (5.9 mo), Cohort 3 (6.1 mo), Cohort 4 (4.7 mo), Cohort 5 (5.8 mo). Median number of belamaf cycles were: Cohort 1 (6), Cohort 2 (3), Cohort 3 (3.5), Cohort 4 (4.5), and Cohort 5 (5). Most common adverse events (AEs) across cohorts included thrombocytopenia (49%), constipation (43%), diarrhea (32%), and peripheral sensory neuropathy (30%). AEs related to study treatment were experienced by 61 (97%) pts. Belamaf-related grade 3/4 AEs occurred in 24 (38%) pts. Belamaf dose reductions occurred in 11 (18%) pts, with dose delays in 10 (16%) pts. Three pts experienced a fatal severe AE (unrelated to study treatment);2 due to COVID-19 infection, 1 due to pancreatic adenocarcinoma. Early deep responses were observed;67-92% pts achieved ≥very good partial response (VGPR) (Table), with median time to VGPR of 2.1-2.9 months across cohorts. Of pts with ≥VGPR, 17 were minimal residual disease (MRD) negative, 10 in Cohort 1. As of data cutoff, 8-75% of pts achieved best response of complete response (CR) or stringent CR (sCR). Grade 3 corneal exam findings were reported in 25-58% of pts;grade 3 visual acuity changes were reported in 21-75% of pts. No grade 4 corneal exam findings or visual acuity changes were reported in pts receiving belamaf Q6/8W, compared with 0-17% and 0-8%, respectively, in the Q3/4W cohorts. Belamaf PK profile was similar to that in pts with RRMM, accounting for baseline characteristics. Image: Summary/Conclusion: Belamaf + VRd demonstrated high response rates in pts with TI NDMM, with a high rate of MRD negativity indicating deep responses. No new safety signals were observed relative to DREAMM-2. Study is ongoing to evaluate the safety and efficacy of variable dose intensities of belamaf in combination with VRd.
ABSTRACT
Background: Cohort A of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study is assessing ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy, in patients with multiple myeloma (MM) who received 1-3 prior lines of therapy (LOT) and were refractory to lenalidomide (len). This population is difficult to treat and has poor prognosis. Aims: To present updated results from CARTITUDE-2 Cohort A. Methods: All patients provided informed consent. Eligible patients had progressive MM after 1-3 prior LOT that included a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Patients were len-refractory and had no prior exposure to BCMA-targeting agents. Patients received a single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg) after lymphodepletion. Cilta-cel safety and efficacy were assessed. The primary endpoint was minimal residual disease (MRD) negativity at 10-5 by next generation sequencing. Patient management strategies were used to reduce the risk of movement and neurocognitive adverse events (MNTs). Other assessments included pharmacokinetic (PK) analyses (Cmax and Tmax of CAR+ T-cell transgene levels in blood), levels of cytokine release syndrome (CRS)-related cytokines (e.g., IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: As of January 2022 (median follow-up: 17.1 months [range: 3.3-23.1]), cilta-cel was administered to 20 patients (male: 65%;median age: 60 years [range: 38-75]). Median number of prior LOT was 2 (range: 1-3);median time since MM diagnosis was 3.5 years (range: 0.7-8.0). 95% of patients were refractory to their last LOT;40% were triple-class refractory. Overall response rate was 95%, with 90% of patients achieving ≥complete response and 95% achieving ≥very good partial response. Median time to first response was 1.0 month (range: 0.7-3.3);median time to best response was 2.6 months (range: 0.9-13.6). All MRD-evaluable patients (n=16) achieved MRD negativity at 10-5. Median duration of response was not reached. The 12-month progression-free survival rate was 75% and the 12-month event-free rate was 79%. CRS occurred in 95% of patients (grade 3/4: 10%), with a median time to onset of 7 days (range: 5-9) and median duration of 3 days (range: 2-12). 30% of patients had neurotoxicity (5 grade 1/2 and 1 grade 3/4). ICANS occurred in 3 patients (15%;all grade 1/2);1 patient had facial paralysis (grade 2). No MNTs were observed. 1 death due to COVID-19 occurred and was assessed as treatment-related by the investigator;2 deaths due to progressive disease and 1 due to sepsis (not related to treatment) also occurred. Based on preliminary PK analyses of CAR transgene by qPCR, peak expansion of CAR-T cells occurred at day 10.5 (range: 8.7-42.9);median persistence was 153.5 days (range: 57.1-336.8). Summary/Conclusion: A single cilta-cel infusion led to deepening and durable responses at this longer follow-up (median 17.1 months) in patients with MM who had 1-3 prior LOT and were len-refractory. Follow-up is ongoing. We will present updated and detailed PK, cytokine, and CAR-T subset analyses as well as clinical correlation to provide novel insights into biological correlates of efficacy and safety in this difficult-to-treat patient population, which is being further evaluated in the CARTITUDE-4 study (NCT04181827;enrollment concluded).
ABSTRACT
Background: Cohort A of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study is evaluating cilta-cel safety and efficacy in pts with MM who received 1-3 prior LOT and were len-refractory - a difficult- to-treat population with poor prognosis. We present updated results. Methods: Pts had progressive MM after 1-3 prior LOT, including a PI and IMiD, were len-refractory, and had no prior exposure to BCMA-targeting agents. A single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) was given post lymphodepletion. Safety and efficacy were assessed, and the primary endpoint was MRD negativity at 10-5. Management strategies were implemented to minimize risk of movement/neurocognitive AEs (MNTs). Pharmacokinetic (PK) analyses (Cmax and Tmax of CAR+ T-cell transgene levels in blood) are being conducted, as well as analyses of levels of CRS-related cytokines (eg, IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with ICANS, and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: As of January 2022 (median follow- up [MFU] 17.1 mo [range 3.3-23.1]), 20 pts (65% male;median age 60 y [range 38-75]) received cilta-cel. Pts received a median of 2 (range 1-3) prior LOT, and a median of 3.5 y (range 0.7-8.0) since MM diagnosis. 95% were refractory to last LOT, and 40% were triple-class refractory. ORR was 95%, 90% achieved CR or better, and 95% had ≥VGPR. Median times to first and best response were 1.0 mo (range 0.7-3.3) and 2.6 mo (range 0.9-13.6), respectively. 16 pts were MRDevaluable, all of whom achieved MRD negativity at 10-5. Median DOR was not reached and 12-mo event-free rate was 79%. The 12-mo PFS rate was 75%. Median time to onset of CRS was 7 d (range 5-9) and occurred in 95% of pts (gr 3/4: 10%), with median duration of 3 d (range 2-12). Neurotoxicity occurred in 30% of pts (5 gr 1/2;1 gr 3/4). 3 pts (15%) had ICANS (all gr 1/2);1 pt had gr 2 facial paralysis. No MNTs were seen. 1 death occurred due to COVID-19 (assessed as tx-related by the investigator), 2 due to progressive disease, and 1 due to sepsis (not related to tx). Preliminary PK analyses indicate that peak expansion of CAR-T cells occurred at d 10.5 (range 8.7-42.9) and median persistence was 153.5 d (range 57.1-336.8). Conclusions: At a longer MFU of 17.1 mo, a single cilta-cel infusion led to deepening and durable responses in pts with MM who had 1-3 prior LOT and were lenrefractory. Follow-up is ongoing. Updated and in-depth PK, cytokine, and CAR-T subset analyses and clinical correlation will be presented and provide novel insights into biological correlates of efficacy and safety in this pt population. This pt population is being further evaluated in the CARTITUDE-4 study (NCT04181827), which has concluded enrollment.
ABSTRACT
Background: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is a SoC for NDMM. Belamaf, a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate, demonstrated durable responses in patients with relapsed/refractory multiple myeloma. Preclinical studies of belamaf in combination with bortezomib/ lenalidomide suggest enhanced antimyeloma activity. We report preliminary findings of belamaf + VRd for patients with TI NDMM. Materials and Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open label, randomized, dose and schedule evaluation trial. Adults with TI NDMM and ECOG status 0-2 are eligible. VRd is administered Q3W until Cycle 8, followed by lenalidomide + dexamethasone (Rd) Q4W. Belamaf + VRd is administered until Cycle 8, and with Rd thereafter. The currently evaluated belamaf dose cohorts are: Cohort 1 (1.9 mg/kg Q3/4W), Cohort 2 (1.4 mg/kg Q6/8W), Cohort 3 (1.9 mg/ kg Q6/8W), Cohort 4 (1.0 mg/kg Q3/4W), and Cohort 5 (1.4 mg/kg Q3/4W). Primary endpoint is safety. Secondary endpoints include efficacy, tolerability, and pharmacokinetics (PK). Results: Overall 36 patients were treated across the 5 cohorts. The median (range) age was 74.0 (63-80) years;56% patients were male, 17 (47%) had stage 2 disease, 3 (8%) had extramedullary disease, 6 (17%) patients had high risk cytogenetic abnormalities;the median number of belamaf cycles ranged from 1-9. No new safety signals were observed. Across Cohorts 1-5, all patients experienced AEs related to study treatment;1 patient in Cohort 1 died due to COVID-19 infection. The most common AEs leading to dose modification were thrombocytopenia, neutropenia, and corneal events. Patients in Cohort 2 and 3 had the lowest number of Grade ≥3 corneal events (3 and 2 events, respectively). All 12 patients in Cohort 1, all 6 in Cohorts 3 and 5, and 5/6 patients in Cohorts 2 and 4 have responded to the treatment;≥half of patients in each cohort achieved very good partial response or better. As of data cut-off, 3/12 patients in Cohort 1, 2/6 in Cohort 4, and 1/6 patients each in Cohorts 3 and 5 remained in complete response. Belamaf PK profile was similar to that observed in patients with RRMM taking into consideration baseline patients characteristics. Conclusions: Preliminary data suggest addition of belamaf to VRd did not reveal new safety signals and demonstrates high response rates, albeit with short follow-up. The trial is ongoing to confirm safety and evaluate the efficacy of belamaf + VRd. .
ABSTRACT
Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell (CAR-T) therapy expressing two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies. The multicohort, open-label, phase 2 CARTITUDE-2 study (NCT04133636) is assessing cilta-cel in patients (pts) with multiple myeloma (MM) under various clinical settings and evaluating the suitability of outpatient administration. Updated results of CARTITUDE-2 cohort A are presented here. Methods: Cohort A pts had progressive MM after 1-3 prior lines of therapy (LOT;included proteasome inhibitor [PI] and immunomodulatory drug [IMiD]), were lenalidomide-refractory, and had no previous exposure to BCMA-targeting agents. A single cilta-cel infusion at a target dose of 0.75×106 CAR+ viable T cells/kg was given 5-7 d after start of lymphodepletion (cyclophosphamide [300 mg/m2] and fludarabine [30 mg/m2] for 3 d). The primary endpoint was minimal residual disease (MRD) negativity at 10-5 at any time point. Secondary endpoints were overall response rate (ORR), duration of response (DOR), time and duration of MRD negativity, and incidence and severity of adverse events (AEs). Response was assessed per International Myeloma Working Group criteria and AEs were graded by Common Terminology Criteria for Adverse Events version 5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] by American Society for Transplantation and Cellular Therapy). Results: As of April 15, 2021 (median follow-up of 9.7 mo), 20 pts (65% men;median age 60 y [range 38-75]) received cilta-cel, with 1 pt treated in an outpatient setting. Pts had a median of 2 prior LOT (range 1-3);60% had 1-2 prior LOT and 40% had 3 prior LOT. All pts were exposed to a PI, IMiD, and dexamethasone;95% were exposed to alkylating agents and 65% to daratumumab. 95% of pts were refractory to last LOT;40% were triple-class refractory. ORR was 95% (95% CI 75.1-99.9);85% (95% CI 62.1-96.8) had ≥complete response (CR), and 95% (95% CI 75.1-99.9) had ≥very good partial response (Figure). Median time to first response was 1.0 mo (range 0.7-3.3) and median time to ≥CR was 2.6 mo (range 0.9-7.9). Median DOR was not reached;progression-free survival (PFS) at 6 mo was 90% (95% CI 65.6-97.4). Of 13 MRD-evaluable pts, 92.3% (95% CI 64.0-99.8) were MRD-negative at 10-5. Hematologic AEs (≥20% of pts) were neutropenia (95%;grade [gr] 3/4: 95%), thrombocytopenia (80%;gr 3/4: 35%), anemia (75%;gr 3/4: 45%), lymphopenia (65%;gr 3/4: 60%) and leukopenia (55%;gr 3/4: 55%). 95% of pts had CRS (gr 3/4: 10%);median time to onset was 7 d (range 5-9) and median duration was 4 d (range 2-11). Four pts (20%) had CAR-T neurotoxicity (all gr 1/2). Three pts (15%) had ICANS (all gr 1/2);median time to onset was 8 d (range 7-10) and median duration was 3 d (range 1-3). One pt had facial paralysis (gr 2) with time to onset of 29 d and duration of 51 d. No movement and neurocognitive treatment-emergent adverse events (TEAEs) were reported. One death due to COVID-19 was assessed as treatment-related. Safety was manageable in the pt treated in an outpatient setting. Conclusions: A single cilta-cel infusion led to early and deep responses in pts with MM who had 1-3 prior LOT and were lenalidomide-refractory. No movement and neurocognitive TEAEs occurred, suggesting successful implementation of monitoring and pt management strategies across phase 2/3 studies in the CARTITUDE program.
ABSTRACT
Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell (CAR-T) therapy expressing two B-cell maturation antigen (BCMA)-targeting, singledomain antibodies. The multicohort, open-label, phase 2 CARTITUDE-2 study (NCT04133636) is evaluating ciltacel in patients (pts) with multiple myeloma (MM) in various clinical settings and assessing the suitability of outpatient administration. Updated results from CARTITUDE-2 cohort A are presented here. Cohort A pts had progressive MM after 1-3 prior lines of therapy (LOT;included proteasome inhibitor [PI] and immunomodulatory drug [IMiD]), were lenalidomide-refractory, and had no previous exposure to agents targeting BCMA. A single cilta-cel infusion at a target dose of 0.75 × 106 CAR+ viable T cells/kg was given 5-7 days after start of lymphodepletion (cyclophosphamide [300 mg/m2 ] and fludarabine [30 mg/m2 ] for 3 days). The primary endpoint was minimal residual disease (MRD) negativity at 10 -5 at any time point. Secondary endpoints were overall response rate (ORR), duration of response (DOR), time and duration of MRD negativity and adverse events (AEs). Response was assessed by International Myeloma Working Group criteria and AEs were graded by Common Terminology Criteria for Adverse Events version 5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] by American Society for Transplantation and Cellular Therapy). As of April 15, 2021 (median follow-up 9.7 months), 20 pts (65% men;median age 60 years [range 38-75]) received ciltacel, with 1 pt treated in an outpatient setting. Pts had a median of two prior LOT (range 1-3);60% with 1-2 prior LOT and 40% with three prior LOT. All pts were exposed to a PI, IMiD and dexamethasone;95% were exposed to alkylating agents and 65% to daratumumab. 95% of pts were refractory to last LOT;40% were triple-class refractory. ORR was 95% (95% CI 75.1-99.9);85% (95% CI 62.1-96.8) had ≥complete response (CR), and 95% (95% CI 75.1-99.9) had ≥very good partial response. The median time to first response was 1.0 months (range 0.7-3.3) and the median time to ≥CR was 2.6 months (range 0.9-7.9). The median DOR was not reached;progression-free survival (PFS) at 6 months was 90% (95% CI 65.6-97.4). Of MRD-evaluable pts ( n = 13), 92.3% (95% CI 64.0-99.8) were MRD-negative at 10 -5 . Haematological AEs (≥20% of pts) were neutropenia (95%;grade [gr] 3/4: 95%), thrombocytopenia (80%;gr 3/4: 35%), anaemia (75%;gr 3/4: 45%), lymphopenia (65%;gr 3/4: 60%) and leukopenia (55%;gr 3/4: 55%). Ninety-five percent of pts had CRS (gr 3/4: 10%);median time to onset was 7 days (range 5-9) and median duration was 4 days (range 2-11). Four pts (20%) had CAR-T neurotoxicity (all gr 1/2). Three pts (15%) had ICANS (all gr 1/2);median time to onset was 8 days (range 7-10) and median duration was 3 days (range 1-3). One pt had facial paralysis (gr 2) with time to onset of 29 days and duration of 51 days. No movement and neurocognitive treatment-emergent adverse events (TEAEs) occurred. One death occurred due to COVID-19 (assessed as treatment-related). Safety was manageable in the pt treated in an outpatient setting. Lenalidomide-refractory pts with MM and 1-3 prior LOT showed early and deep responses with a single cilta-cel infusion. No movement and neurocognitive TEAEs were reported, suggesting utilisation of successful monitoring and pt management strategies across phase 2/3 studies in the CARTITUDE program.
ABSTRACT
Objectives: Cilta-cel is a CAR-T cell therapy that expresses 2 BCMA-targeting single-domain antibodies, designed to confer avidity. In the multicohort, phase 2 CARTITUDE-2 study (NCT04133636), the safety and efficacy of cilta-cel in various clinical settings and suitability of outpatient administration was explored in patients with multiple myeloma. Material and methods: Patients enrolled in Cohort A had progressive MM after 1–3 prior lines of therapy (LOT), including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), were lenalidomide refractory, and were naïve to BCMA-targeting agents. A single cilta-cel infusion (target dose: 0.75 × 106 CAR+ viable T cells/kg) was given 5–7 days after start of lymphodepletion (daily cyclophosphamide [300 mg/m2] and fludarabine [30 mg/m2] for 3 days). The primary outcome was minimal residual disease (MRD) 10-5 negativity. Secondary outcomes were response rates (per IMWG criteria) and safety (per CTCAE;CRS and ICANS by ASTCT). Results: As of the February 2021 data cutoff (median follow-up: 5.8 months [2.5–9.8]), 20 patients (65% male;median age 60 years [38–75]) received cilta-cel;1 patient was treated in an outpatient setting. Patients (n = 12: <3 prior LOT;n = 8: 3 prior LOT) received a median of 2 (1–3) prior LOT. All patients were exposed to PI, IMiD, and dexamethasone, 95% to alkylating agents, and 65% to daratumumab. The majority (95%) were refractory to the last LOT;40% were triple-class refractory. Overall response rate was 95% (95% CI: 75–100), 75% (95% CI: 51–91) achieved stringent CR/CR, and 85% (95% CI: 62–97) achieved ≥VGPR. Median time to first response was 1.0 month (0.7–3.3);median time to best response was 1.9 month (0.9–5.1). Median duration of response was not reached. All patients (n = 4) with MRD-evaluable samples at 10-5 at data cutoff were MRD-negative. Hematologic AEs ≥20% were neutropenia (95%;grade 3/4: 90%), thrombocytopenia (80%;grade 3/4: 35%), anemia (65%;grade 3/4: 40%), lymphopenia (60%;grade 3/4: 55%), and leukopenia (55%;all grade 3/4). 85% of patients had CRS;10% were grade 3/4. Median time to CRS onset was 7 days (5–9), with a median duration of 3.5 days (2–11). CAR-T cell neurotoxicity occurred in 20% of patients (all grade 1/2). Three patients had ICANS (n = 1: grade 1;n = 2: grade 2);median time to onset was 8 days (7–11) and median duration was 2 days (1–2). One patient had grade 2 facial paralysis;time to onset was 29 days with a duration of 51 days. One death occurred due to Covid-19 (assessed as treatment-related by investigator). The safety profile was manageable in the patient who was treated in an outpatient setting. Discussion: Updated efficacy and safety findings will inform suitability of outpatient treatment in this and other cohorts of CARTITUDE-2 as well as the CARTITUDE-4 study. Conclusion: A single cilta-cel infusion at the recommended phase 2 dose led to early and deep responses with a manageable safety profile in patients with MM who had 1–3 prior LOT.
ABSTRACT
Introduction: There are several treatment options for patients (pts) with progressive multiple myeloma (MM) who are refractory to lenalidomide but most pts relapse shortly after receiving salvage treatment. Cilta-cel is a CAR-T therapy expressing 2 BCMA-targeting, single-domain antibodies that demonstrated early, deep, and durable responses in pts with MM who had received ≥3 prior lines of therapy (LOT) in the phase 1b/2 CARTITUDE-1 study (Berdeja, Lancet, 2021). The multicohort, open-label, phase 2 CARTITUDE-2 study (NCT04133636) is evaluating cilta-cel safety and efficacy in various clinical settings for pts with MM and exploring suitability of outpatient administration. Initial analysis (median follow-up 5.8 mo) of pts in CARTITUDE-2 cohort A (lenalidomide-refractory with 1-3 prior LOT) demonstrated an overall response rate (ORR) of 95%, with 75% of pts achieving complete response or better (≥CR) and 85% achieving very good partial response or better (≥VGPR). Here, we present updated results for this population. Methods: Pts had progressive MM after 1-3 prior LOT, including a PI and immunomodulatory drug (IMiD), were lenalidomide-refractory, and had no prior exposure to BCMA-targeting agents. Bridging therapy was allowed after apheresis. A single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) was given 5-7 d after start of lymphodepletion (daily cyclophosphamide [300 mg/m 2] and fludarabine [30 mg/m 2] for 3 d). The primary endpoint was minimal residual disease (MRD) negativity at 10 -5. Secondary endpoints were ORR, duration of response (DOR), time and duration of MRD negativity, and incidence and severity of AEs. MRD was assessed by next-generation sequencing, response was assessed per IMWG criteria, and adverse events (AEs) were graded using CTCAEv5.0 (CRS and ICANS by ASTCT). Results: Initial results from this cohort were published at ASCO 2021. Here we report data as of the April 15, 2021, data cutoff (median follow-up 9.7 mo: range 3.3-13.4). 20 pts (65% male;median age 60 years [range 38-75]) received cilta-cel;1 pt was treated in an outpatient setting. Pts received a median of 2 prior LOT (range 1-3);60% received 1 or 2 prior LOT and 40% received 3 prior LOT. All pts were exposed to a PI, IMiD, and dexamethasone, 95% to alkylating agents, and 65% to daratumumab. In all, 95% of pts were refractory to the last LOT;40% were triple-class refractory. ORR was 95% (95% CI 75.1-99.9);85% (95% CI 62.1-96.8) of pts had ≥CR, and 95% (95% CI 75.1-99.9) had ≥VGPR (Figure). Median time to first response was 1.0 mo (range 0.7-3.3);median time to best response was 3.3 mo (range 0.9-7.9);median time to ≥CR was 2.6 mo (range 0.9-7.9). Median DOR was not reached;6-mo PFS rate was 90% (95% CI 65.6-97.4). Of MRD-evaluable pts (n=13), 92.3% (95% CI 64.0-99.8) were MRD-negative at 10 -5. Hematologic AEs in ≥20% of pts were neutropenia (95%;grade [gr] 3/4: 95%), thrombocytopenia (80%;gr 3/4: 35%), anemia (75%;gr 3/4: 45%), lymphopenia (65%;gr 3/4: 60%) and leukopenia (55%;gr 3/4: 55%). CRS occurred in 95% of pts (gr 3/4: 10%). Median time to CRS onset was 7 d (range 5-9), with a median duration of 4 d (range 2-11). CRS resolved within 7 d in 90% of pts. CAR T-cell neurotoxicity occurred in 4 pts (20%;all gr 1/2). Three pts (15%) had ICANS (all gr 1/2);median time to onset was 8 d (range 7-10) and median duration was 3 d (range 1-3). One pt had other neurotoxicities (gr 2 facial paralysis);time to onset was 29 d with a duration of 51 d. No movement and neurocognitive TEAEs were observed. One death occurred due to COVID-19 (assessed as treatment-related by the investigator). Safety profile was manageable in the pt treated in an outpatient setting. Conclusions: At a longer median follow-up of 9.7 mo, a single cilta-cel infusion led to early and deep responses in pts with MM who had 1-3 prior LOT and were lenalidomide-refractory. ORR in this cohort was consistent with the CARTITUDE-1 study in heavily pretreated pts;responses deepened over time, with 92% of MRD-evaluable pts achievi g MRD 10 -5 negativity. The safety profile was manageable;CRS was mostly gr 1/2, and no movement and neurocognitive TEAEs occurred, suggesting the efficacy of monitoring and pt management strategies that were implemented across phase 2/3 studies in the CARTITUDE program. Follow-up is ongoing, including additional enrollment in this cohort;this pt population is being further evaluated in the CARTITUDE-4 study (NCT04181827). [Formula presented] Disclosures: Cohen: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Karyopharm: Research Funding;neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cohen: Janssen: Consultancy;Takeda: Consultancy;AstraZeneca: Consultancy;GlaxoSmithKline: Consultancy, Research Funding;BMS/Celgene: Consultancy;Novartis: Research Funding;Oncopeptides: Consultancy;Genentech/Roche: Consultancy. Delforge: Amgen, Celgene, Janssen, Sanofi: Honoraria, Research Funding. Hillengass: Adaptive: Membership on an entity's Board of Directors or advisory committees;Beijing Medical Award Foundation: Speakers Bureau;Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees;Beijing Life Oasis Public Service Center: Speakers Bureau;Curio Science: Speakers Bureau;Oncopeptides: Membership on an entity's Board of Directors or advisory committees;Oncotracker: Membership on an entity's Board of Directors or advisory committees;Axxess Network: Membership on an entity's Board of Directors or advisory committees;Sanofi: Membership on an entity's Board of Directors or advisory committees;GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees;Skyline: Membership on an entity's Board of Directors or advisory committees. Goldschmidt: GSK: Honoraria;Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding;Adaptive Biotechnology: Consultancy;BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding;Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding;Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding;Incyte: Research Funding;Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding;Johns Hopkins University: Other: Grant;Molecular Partners: Research Funding;MSD: Research Funding;Mundipharma: Research Funding;Novartis: Honoraria, Research Funding;Dietmar-Hopp-Foundation: Other: Grant;Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding;Takeda: Consultancy, Research Funding. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;GSK: 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, Research Funding;Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Karyopharm: Consultancy Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Abbvie: Consultancy;Novartis: Honoraria;Pfizer: Honoraria. Raab: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Honoraria;Celgene: Membership on an entity's Board of Directors or advisory committees;BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Roche: Consultancy;Sanofi: 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, Research Funding;GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees. Scheid: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, 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, Research Funding;Abbvie: Honoraria;Roche: Consultancy;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schecter: Janssen: Current Employment, Current holder of stock options in a privately-held company. De Braganca: Janssen: Current Employment. Varsos: Janssen: Current Employment. Yeh: Janssen: Current Employment. Vogel: Janssen Global Services, LLC: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock optionsin a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Corsale: Janssen: Current Employment. Akram: Legend Biotech USA: Current Employment. Pacaud: Legend Biotech: Current Employment. Nesheiwat: Legend Biotech USA: Current Employment. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved.
ABSTRACT
Introduction: Patients with hematological malignancies and concomitant SARS-CoV-2 infection suffer from a more severe course of their infection than patients without underlying concomitant disease. Similar observations have been made for concomitant influenza infections. The aim of this retrospective study is to compare the clinical courses of COVID-19 and seasonal influenza in patients with hematological malignancies. Methods: In this retrospective, single center analysis all patients with hematological malignancies aged 18 years and older were included with a laboratory confirmed SARS-CoV-2 or influenza A or B infection who were admitted or were already under treatment at the Department of Oncology and Hematology or at the Department of Stem Cell Transplantation at the University Medical Center Hamburg-Eppendorf, Germany, between January 2012 and January 2021. Primary and secondary endpoints of this study are the rate of acute respiratory distress syndrome (ARDS) and virus-associated 30- and 90-day mortalities. The retrospective data collection was performed in accordance with local legal requirements and was reviewed and approved by the Ethics Committee of the Medical Council of Hamburg. Results: A total of 79 patients were included in this study. 29 patients had laboratory confirmed SARS-CoV-2 infection and 50 patients had influenza A or B infection. 69% in the COVID-19 group and 68% in the influenza group were male. Median age in the COVID-19 group were 59 years vs 58.5 years in the influenza group. Distribution of hematological malignancies in the COVID-19 group was as follows: 59% had acute leukemia (AL), 24% malignant lymphoma, 14% multiple myeloma (MM) and 3% myelodysplastic syndrome (MDS). 89% of the patients with concomitant SARS-CoV-2 diagnosis were currently under treatment with chemotherapy, CD20 or CD38 antibody-therapy, underwent allogeneic stem cell transplantation (SCT) or received CAR-T-cells shortly before (< 2 months) or during SARS-CoV-2 positivity. In the influenza group, 60% had AL, 8% lymphoma, 24% MM and 8% MDS or myeloproliferative neoplasm. 84% of these patients were under treatment with chemotherapy, CD33-, CD38- or SLAMF7-directed antibodies or underwent allogeneic SCT shortly before or during infection with seasonal influenza. At the time of infection, 41% of all SARS-CoV-2 positive patients were in refractory or relapsed setting compared to 42% in the influenza group whereas 28% in the COVID-19 and 36% in the influenza cohort were in complete remission. At the time of SARS-CoV-2 detection 38% of patients had grade IV neutropenia (defined as neutrophil count <0.5 x 10 9/L) with a median duration of 3.5 days which is comparable to 33% of patients and a median neutropenia duration of three days in the influenza group. The incidence of ARDS was significantly higher in the COVID-19 group compared to the influenza group (48% vs. 14%, p = 0.001). Furthermore, virus infection related 30-day and 90-day mortality was significantly higher in the COVID-19 group (28% vs. 8%, p = 0.026 and 41% vs. 12%, p = 0.005). In the COVID-19 group, a duration of aplasia ≥ 7 days had no negative impact on 90-day mortality or development of an ARDS (p = 0.599 and 0.982 respectively) whereas in the patients infected with influenza A or B, an aplasia ≥ 7 days had a negative impact on 90-day mortality and development of ARDS (p < 0.001 each). Conclusion: Based on our results, we conclude that comparable to the general population, infections with SARS-CoV-2 result in a significantly higher rate of ARDS and a significantly higher 30- and 90-day mortality compared to influenza A or B infections in patients with underlying hematological malignancies. Disclosures: Weisel: Adaptive: Consultancy, Honoraria;Amgen: Consultancy, Honoraria, Research Funding;BMS: Consultancy, Honoraria;Celgene: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding;GSK: Consultancy, Honoraria;Karyopharm: Consultancy, Honoraria;Takeda: Consultancy, Honoraria;Sanofi: Consultancy, Honoraria, Resear h Funding. Bokemeyer: Gilead Sciences: Research Funding;Bayer Schering Pharma: Consultancy;Merck Serono: Consultancy, Other: Travel accomodation;AOK Health insurance: Consultancy;Alexion Pharmaceuticals: Research Funding;Agile Therapeutics: Research Funding;ADC Therapeutics: Research Funding;Abbvie: Research Funding;GSO: Consultancy;Lilly/ImClone: Consultancy;Amgen: Research Funding;Apellis Pharmaceuticals: Research Funding;Astellas: Research Funding;BerGenBio: Research Funding;Blueprint Medicine: Research Funding;Boehringer Ingelheim: Research Funding;Celgene: Research Funding;Daiichi Sankyo: Research Funding;Eisai: Research Funding;Gylcotope GmbH: Research Funding;GlaxoSmithKline: Research Funding;Inside: Research Funding;IO Biotech: Research Funding;Isofol Medical: Research Funding;Janssen-Cilag: Research Funding;Sanofi: Consultancy, Honoraria, Other: Travel accomodation;Merck KGaA: Honoraria;Roche: Honoraria, Research Funding;Merck Sharp Dohme: Consultancy, Honoraria;AstraZeneca: Honoraria, Research Funding;BMS: Honoraria, Other: Travel accomodation, Research Funding;Bayer: Honoraria, Research Funding;Karyopharm Therapeutics: Research Funding;Lilly: Research Funding;Millenium: Research Funding;MSD: Research Funding;Nektar: Research Funding;Rafael Pharmaceuticals: Research Funding;Springworks Therapeutics: Research Funding;Taiho Pharmaceutical: Research Funding;Pfizer: Other. Fiedler: Novartis: Honoraria;Pfizer: Consultancy, Honoraria, Research Funding;Daiichi Sanyko: Consultancy, Other: Meeting attendance, Preparation of information material;Stemline: Consultancy;Servier: Consultancy, Other: Meeting attendance, Preparation of information material;MorphoSys: Consultancy, Honoraria;Jazz: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material;Celgene: Consultancy, Honoraria;Ariad/Incyte: Honoraria;Amgen: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material, Patents & Royalties, Research Funding;Abbvie: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material. Modemann: Teva: Other: Travel accomodation;Novartis: Other: Travel accomodation;Jazz Pharmaceuticals: Other: Travel accomodation;Gilead: Other: Travel accomodation;Incyte: Other: Travel accomodation;Servier: Honoraria, Other: Travel accomodation;Pfizer: Other: Travel accomodation;Amgen: Other: Travel accomodation;Daiichi Sankyo: Research Funding;Abbvie: Honoraria, Other: Travel accomodation.
ABSTRACT
Introduction: Despite recent advances, MM remains incurable and new therapeutic options are needed, particularly for pts with RRMM. IBER is a novel, potent oral cereblon E3 ligase modulator (CELMoD ®) compound with enhanced tumoricidal and immune-stimulatory effects compared with immunomodulatory (IMiD ®) agents. Preclinically, IBER demonstrated marked synergy with DEX and with other standard myeloma treatments. CC-220-MM-001 (NCT02773030) is an ongoing phase 1/2 study evaluating IBER with different treatment combinations in independent cohorts of pts with RRMM;in phase 1, the recommended phase 2 dose of IBER, when given in combination with DEX, was determined at 1.6 mg (Lonial S, et al. Blood 2019;134[suppl 1]:3119). Here we report results from the dose expansion of IBER + DEX in pts with heavily pretreated, triple-class exposed (including ≥ 1 IMiD agent, ≥ 1 proteasome inhibitor [PI], and ≥ 1 anti-CD38 monoclonal antibody [mAb]) RRMM. Methods: Eligible pts had RRMM;had received ≥ 3 prior lines of therapy, including lenalidomide (LEN), pomalidomide (POM), a PI, a glucocorticoid, and an anti-CD38 mAb;had experienced disease progression within 60 days of last myeloma therapy;and were refractory to an IMiD agent, a PI, a glucocorticoid, and an anti-CD38 mAb. Pts with central nervous system involvement were not eligible. Pts who had received prior anti-BCMA therapy were excluded, but included in a supportive cohort for safety and preliminary efficacy assessment. IBER (1.6 mg) was given orally on days (D) 1-21, in combination with DEX (40 mg;20 mg if > 75 years of age) on D1, 8, 15, and 22 of each 28-day cycle. Thrombo-embolism prophylaxis was mandatory for all pts. Primary objective was to determine efficacy expressed as overall response rate (ORR). Secondary endpoints included additional efficacy and safety assessments. Exploratory endpoints included evaluation of health-related quality of life (HRQoL). Results: As of June 2, 2021, 107 pts had received IBER + DEX. Median age was 64 (44-83) years;median time since initial diagnosis was 6.9 (1.6-24.5) years. Extramedullary plasmacytomas were present in 25.2% of pts;29.9% of pts had high-risk cytogenetics. Median number of prior regimens was 6 (3-23). All pts were triple-class exposed;prior therapies included autologous stem cell transplantation (78.5%), PIs (100%), IMiD agents (LEN [100%] and POM [100%]), and anti-CD38 mAbs (100%);99.1% of pts were refractory to last myeloma regimen and 97.2% of pts were triple-class refractory. Median follow-up was 7.69 (0.5-17.5) months, with a median number of 4 (1-17) cycles received and 13 (12.1%) pts continuing treatment. Main reason for discontinuation was progressive disease (69.2%). ORR was 26.2%, with 1 (0.9%) stringent complete response, 8 (7.5%) very good partial responses, and 19 (17.8%) partial responses (Table);the clinical benefit rate (≥ minimal response) was 36.4% and disease control rate (≥ stable disease) was 79.4%. Median duration of response was 7.0 (4.5-11.3) months (Table), median progression-free survival was 3.0 (2.8-3.7) months, and median overall survival was 11.2 (9.0-not reached) months. Similar response rates were observed among a cohort of pts also exposed to BCMA therapies (N = 24, Table). Grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) were reported in 88 (82.2%) pts. Most frequent (≥ 20% pts) hematologic Gr 3-4 TEAEs were neutropenia (44.9%;and 4.7% febrile neutropenia), anemia (28.0%), thrombocytopenia (21.5%), and leukopenia (20.6%). Gr 3-4 infections were reported in 27.1% of pts;Gr 3-4 pneumonia and COVID-19 occurred in 10.3% and 4.7% of pts, respectively. Occurrence of other Gr 3-4 non-hematologic TEAEs was generally low, including gastrointestinal disorders (5.6%), fatigue (2.8%), rash (1.9%). Fifty-six (52.3%) pts and 20 (18.7%) had IBER dose interruptions and reductions due to TEAEs, respectively. Five (4.7%) pts discontinued due to TEAEs. No pt discontinued IBER due to neutropenia. Overall, HRQoL was maintained in these pts. Conclusions: IBER + DEX demonst ated promising efficacy in pts with heavily pretreated, triple-class exposed and refractory RRMM, as well as in pts who had previously received anti-BCMA therapy;this combination was generally well tolerated and TEAEs were manageable with dose reductions and interruptions. These results support the further development of IBER in MM, including phase 3 trials in combination regimens. [Formula presented] Disclosures: Lonial: Abbvie: Consultancy, Honoraria;AMGEN: Consultancy, Honoraria;Takeda: Consultancy, Honoraria, Research Funding;GlaxoSmithKline: Consultancy, Honoraria, Research Funding;TG Therapeutics: Membership on an entity's Board of Directors or advisory committees;Merck: Honoraria;BMS/Celgene: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding. Popat: GlaxoSmithKline: Consultancy, Honoraria, Research Funding;Abbvie, Takeda, Janssen, and Celgene: Consultancy;Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES;AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria;Janssen and BMS: Other: travel expenses. Hulin: Sanofi: Honoraria;Celgene/BMS: Honoraria;Janssen: Honoraria;Takeda: Honoraria;abbvie: Honoraria. Jagannath: Legend Biotech: Consultancy;Bristol Myers Squibb: Consultancy;Karyopharm Therapeutics: Consultancy;Janssen Pharmaceuticals: Consultancy;Sanofi: Consultancy;Takeda: Consultancy. Oriol: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: 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. Richardson: Karyopharm: Consultancy, Research Funding;Regeneron: Consultancy;AbbVie: Consultancy;Celgene/BMS: Consultancy, Research Funding;Oncopeptides: Consultancy, Research Funding;GlaxoSmithKline: Consultancy;Protocol Intelligence: Consultancy;Janssen: Consultancy;Secura Bio: Consultancy;Takeda: Consultancy, Research Funding;Sanofi: Consultancy;AstraZeneca: Consultancy;Jazz Pharmaceuticals: Consultancy, Research Funding. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Abbvie: Consultancy;Novartis: Honoraria;Pfizer: Honoraria. Minnema: Cilag: Consultancy;Janssen: Consultancy;Alnylam: Consultancy;Celgene: Other: Travel expenses;Kite/Gilead: Consultancy;BMS: Consultancy. Badros: J&J: Research Funding;Janssen: Research Funding;BMS: Research Funding;GlaxoSmithKline: Research Funding. Knop: BMS/Celgene: Consultancy, Honoraria, Research Funding;Amgen: Research Funding;Janssen: Consultancy;Oncopeptides: Consultancy;Pfizer: Consultancy;Sanofi: Consultanc . Stadtmauer: Janssen: Consultancy, Honoraria;Takeda: Consultancy, Honoraria;Abbvie: Consultancy, Honoraria;Amgen: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Chen: Bristol Myers Squibb: Current Employment. Nguyen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Amin: Bristol Myers Squibb: Current Employment. Kueenburg: Celgene a BMS company: Current Employment. Peluso: Celgene, a Bristol-Myers Squibb Company: Current Employment. van de Donk: BMS/Celgene: Consultancy, Honoraria;Janssen: Consultancy, Research Funding;Amgen: Consultancy, Research Funding;Cellectis: Research Funding;Takeda: Consultancy;Roche: Consultancy;Novartis /bayer/servier: Consultancy.
ABSTRACT
Introduction: Up to now,reliable results regarding the efficacy of anti-SARS-CoV-2 vaccines in patients with multiple myeloma (MM), especially under current myeloma-directed therapy, are scarcely available. Here, we report an analysis describing the level of post-vaccination antibody titers after the 1 stand 2 ndanti-SARS-CoV-2 vaccination depending on therapy, remission status, and B- and T-cell numbers in patients with MM and related plasma cell neoplasia. Methods: This observational single-center study included patients aged ≥18 years with diagnoses of MM, monoclonal gammopathies of clinical significance (MGCS), or systemic light-chain amyloidosis (AL) who were eligible for Anti-SARS-CoV-2 vaccination according to the International Myeloma Society recommendations. Patients with prior COVID-19 infections were excluded. Samples were analyzed for the presence of SARS-CoV-2 specific antibodies using the quantitative anti-spike IgG (SARS-CoV-2 spike RBD IgG, cut off ≥ 0.8 BAU/ml) according to manufacturer's recommendations. SARS-CoV-2 spike protein antibody titer (SP-AbT) were evaluated after at least 7 days after the 1 stand 2 ndvaccination, respectively. This study was performed between January 1 - July 15, 2021, at the University Medical Center Hamburg-Eppendorf, Germany, as part of the COVIDOUT trial (NCT04779346). All patients provided written informed consent. Aims of this study were to evaluate a possible correlation between SP-AbT and CD19+ B lymphocyte count, as well as to identify other factors impacting vaccination response. Results: 82 patients who received SARS-CoV-2 vaccines (including 67 patients with mRNA-, 8 with vector-based vaccines and 4 heterologous vaccinations) were included. 74 patients had diagnosis of MM, 4 of MGCS/smoldering MM and 4 of AL. Median age was 68 years (range 35-85) and 49 patients were male. In total, 37 patients (45.1%) received anti-CD38- and 2 (2.4%) anti-SLAMF7-targeting therapies at the time of vaccination, 52 (63.4%) patients received immunomodulatory drug (IMID)-based treatments and 13 patients (15.9%) were under active surveillance. 59% of patients had newly diagnosed and 41% refractory or relapsed disease. In total, 75.6% of all patients were in deep remissions (very good partial remission or better). Assessment of anti-SARS-CoV-2 antibody titers took place in median 23 days (range [r] 8-63 days) after the 1 stand 21 days (r: 6-53) after the 2 ndvaccination. A positive SARS-CoV-2 SP-AbT was detected in 31.9% of assessable patients with an overall median SP-AbT of 0 BAU/ml (r: 0-10328, mean 202.36) after the 1 stvaccination and increased up to 88.9% (median SP-AbT of 216.87 BAU/ml, r: 0-25720, mean 2139.29) after 2 ndvaccination. Of the patients not showing positive SP-AbT after the 1 stvaccination, 80.9% became positive after 2 ndvaccination, while 19.1 % remained negative. Median SP-AbT titer was significantly lower compared to patients who became positive already after 1 stvaccination (51.04 vs. 2191.87 BAU/ml, p<0.0001). Regarding immune status, a CD19+ B cell count of median 33.5/µl (r: 1-696/µl) was seen in the overall patient cohort;in patients with negative SP-AbT, median CD19+ B cell numbers were significantly lower compared to patients with positive titers (median CD19+ B cells: 2.0 vs. 52.5/µl, p=0.005). Overall, CD19+ B lymphocyte numbers correlate significantly with positive SP-AbT results and were identified as predictive factor in multivariate analysis. The previously suggested threshold of 30 CD19+ B cells/µl as being predictive for SP-AbT development could be validated. SP-AbT concentration was significantly lower with older age. Furthermore, median SP-AbT were significantly lower in patients with current anti-CD38 directed therapy (median SP-AbT: 1085.4 vs. 62.05 BAU/ml, p < 0.005). Conclusions: In spite of immunodeficiency and immunosuppressive therapy, most MM patients develop SP-AbT. However, about 11% of MM patients failed to develop SP-AbT after full vaccination, and thus remain on risk for COVID-19. Higher counts of CD19+ B lymphocytes, ith a threshold of 30 CD19+ B lymphocytes/µl, are predictive for SP-AbT formation and may further help to identify patients at higher risk of insufficient vaccination response in whom control of vaccination success and potential third vaccination are particularly important. Disclosures: Bokemeyer: GlaxoSmithKline: Research Funding;Inside: Research Funding;IO Biotech: Research Funding;Eisai: Research Funding;Daiichi Sankyo: Research Funding;Gilead Sciences: Research Funding;Blueprint Medicine: Research Funding;BerGenBio: Research Funding;Janssen-Cilag: Research Funding;Isofol Medical: Research Funding;AOK Health insurance: Consultancy;GSO: Consultancy;Bayer Schering Pharma: Consultancy;Gylcotope GmbH: Research Funding;ADC Therapeutics: Research Funding;Apellis Pharmaceuticals: Research Funding;Amgen: Research Funding;Alexion Pharmaceuticals: Research Funding;Agile Therapeutics: Research Funding;Merck Serono: Consultancy, Other: Travel accomodation;Lilly/ImClone: Consultancy;Merck Sharp Dohme: Consultancy, Honoraria;AstraZeneca: Honoraria, Research Funding;BMS: Honoraria, Other: Travel accomodation, Research Funding;Bayer: Honoraria, Research Funding;Roche: Honoraria, Research Funding;Sanofi: Consultancy, Honoraria, Other: Travel accomodation;Merck KGaA: Honoraria;Abbvie: Research Funding;Boehringer Ingelheim: Research Funding;Celgene: Research Funding;Astellas: Research Funding;Karyopharm Therapeutics: Research Funding;Lilly: Research Funding;Millenium: Research Funding;MSD: Research Funding;Nektar: Research Funding;Rafael Pharmaceuticals: Research Funding;Springworks Therapeutics: Research Funding;Taiho Pharmaceutical: Research Funding;Pfizer: Other. Sinn: Incyte: Honoraria, Research Funding;Pfizer: Honoraria;Servier: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Research Funding;Astra Zenica: Consultancy, Research Funding;MSD: Consultancy, Research Funding;Sanofi: Consultancy;Bayer: Research Funding;BMS: Honoraria, Research Funding. Leypoldt: GSK: Consultancy, Other: Meeting attendance;Sanofi: Consultancy;Abbvie: Other: Meeting attendance. Weisel: Adaptiv Biotec: Consultancy;Abbvie: Consultancy;BMS: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding;GSK: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Research Funding;Karyopharm: Honoraria;Novartis: Honoraria;Oncopeptides: Consultancy, Honoraria;Pfizer: Honoraria;Roche: Honoraria;Takeda: Honoraria;Sanofi: Consultancy, Honoraria, Research Funding.
ABSTRACT
Background: Ciltacabtagene autoleucel (cilta-cel) is a CAR-T cell therapy expressing two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies. The multicohort, phase 2 CARTITUDE-2 study (NCT04133636) is evaluating the safety and efficacy of cilta-cel in various clinical settings for patients (pts) with multiple myeloma (MM) and exploring suitability of outpatient administration. Initial results from Cohort A are presented here. Methods: Pts from Cohort A had progressive MM after 1–3 prior lines of therapy (LOT), including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), were lenalidomide refractory, and had not received BCMA-targeting agents. A single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg) was given 5–7 days after start of lymphodepletion (daily cyclophosphamide [300 mg/m2] and fludarabine [30 mg/m2] for 3 days). Minimal residual disease (MRD) negativity at 10-5 was the primary objective, and response rates (per IMWG) and safety (per CTCAE;CRS and ICANS by ASTCT) were secondary outcomes. Results: At data cutoff (Feb 2021), the median follow-up was 5.8 months (2.5–9.8). Twenty pts (65% male;median age 60 years [38–75]) had received cilta-cel, with 1 pt treated in an outpatient setting. The median number of prior LOT was 2 (1–3): <3 prior LOT (n=12) and 3 prior LOT (n=8). All pts were exposed to PI, IMiD, and dexamethasone, 95% had received alkylating agents, and 65% had received daratumumab. 95% were refractory to the last LOT, and 40% were triple-class refractory. Overall response rate was 95% (95% CI: 75–100), 75% (95% CI: 51–91) achieved sCR/CR, and 85% (95% CI: 62–97) achieved ≥VGPR. Median time to first response was 1.0 month (0.7–3.3), and median time to best response was 1.9 months (0.9–5.1). Median duration of response was not reached. All 4 pts with MRD-evaluable samples at 10-5 at the time of data cutoff were MRD-negative. Hematologic adverse events (≥20%) were neutropenia (95%;grade [gr] 3/4: 90%), thrombocytopenia (80%;gr 3/4: 35%), anemia (65%;gr 3/4: 40%), lymphopenia (60%;gr 3/4: 55%), and leukopenia (55%;all gr 3/4). 85% of pts had CRS (gr 3/4: 10%). Median time to CRS onset was 7 days (5–9), with a median duration of 3.5 days (2–11). CAR-T cell neurotoxicity occurred in 20% of pts (all gr 1/2). ICANS was reported in 3 pts (1 gr 1 and 2 gr 2) with median time to onset of 8 days (7–11) and median duration of 2 days (1–2). One pt had gr 2 facial paralysis with onset at 29 days and duration of 51 days. One death from COVID-19 was assessed as treatment-related by investigator. For the pt treated in an outpatient setting, the safety profile was manageable. Conclusion: Early and deep responses with manageable safety were demonstrated after a single cilta-cel infusion at the recommended phase 2 dose. Updated findings will inform suitability of outpatient treatment for this study and for the CARTITUDE-2 and CARTITUDE-4 studies.
ABSTRACT
Background: Ciltacabtagene autoleucel (Cilta-cel) is a chimeric antigen receptor T (CAR-T) cell therapy expressing two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies designed to confer avidity. CARTITUDE-2 (NCT04133636) is a multicohort, phase 2 study evaluating cilta-cel safety and efficacy in various clinical settings for patients with multiple myeloma (MM) and exploring suitability of outpatient administration. Aims: We report initial results from Cohort A of CARTITUDE-2. Methods: All patients provided informed consent. Patients from Cohort A had progressive MM after 1-3 prior lines of therapy (LOT), including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), were lenalidomide refractory, and had no prior exposure to BCMA-targeting agents. A single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg) was given 5-7 days after initiating lymphodepletion (cyclophosphamide [300 mg/m2] and fludarabine [30 mg/m2] daily for 3 days). The primary objective was minimal residual disease (MRD) 10-5 negativity. Secondary outcomes were response rates per International Myeloma Working Group criteria and safety (adverse events [AEs] were graded per Common Terminology Criteria for Adverse Events;cytokine release syndrome [CRS] and immune effector cell?associated neurotoxicity syndrome [ICANS] were graded per American Society for Transplantation and Cellular Therapy). Results: At the data cutoff of Feb 2021 (median follow-up of 5.8 months;range: 2.5-9.8), 20 patients (65% male;median age 60 years [range: 38-75]) had received cilta-cel;one patient was treated in an outpatient setting. Patients received a median of 2 prior LOT (range: 1-3);12 patients received <3 prior LOT and 8 received 3 prior LOT. All patients were exposed to PI, IMiD, and dexamethasone, 95% to alkylating agents, and 65% to daratumumab. The majority (95%) were refractory to their last LOT, and 40% were triple refractory. The overall response rate was 95% (95% CI: 75-100) with 75% (95% CI: 51-91) achieving ≥complete response, and 85% (95% CI: 62-97) achieving ≥very good partial response. Median time to first response was 1.0 month (range: 0.7-3.3), and median time to best response was 1.9 months (range: 0.9-5.1). The median duration of response was not reached. All patients (n=4) with MRD-evaluable samples at 10-5 at the time of data cutoff were MRDnegative. Hematologic AEs (in ≥20% of patients) were neutropenia (95%;grade 3/4: 90%), thrombocytopenia (80%;grade 3/4: 35%), anemia (65%;grade 3/4: 40%), lymphopenia (60%;grade 3/4: 55%), and leukopenia (55%;all grade 3/4). CRS occurred in 85% of patients;10% were grade 3/4. The median time to CRS onset was 7 days (range: 5-9), with a median duration of 3.5 days (range: 2-11). CAR-T cell neurotoxicity occurred in 20% of patients (all grade 1/2). Three patients had ICANS (1 was grade 1;2 were grade 2) with median time to onset of 8 days (range: 7-11) and median duration of 2 days (range: 1-2). One patient had grade 2 facial paralysis with time to onset of 29 days and duration of 51 days. One death occurred due to COVID-19, which was assessed as treatment-related by investigator. The safety profile was manageable in the patient treated in an outpatient setting. Summary/Conclusion: A single cilta-cel infusion at the recommended phase 2 dose led to early and deep responses with manageable safety in patients with MM who had received 1-3 prior LOT. Updated efficacy and safety findings will inform suitability of outpatient treatment in this and other cohorts of CARTITUDE-2 as well as the CARTITUDE-4 study.
ABSTRACT
Introduction: The randomized, open-label, multicenter, phase 3 CANDOR study compared carfilzomib, dexamethasone, and daratumumab (KdD) to carfilzomib and dexamethasone (Kd) in patients with multiple myeloma who have relapsed after 1-3 prior lines of therapy (ClinicalTrials.gov, NCT03158688). In the previously reported primary analysis (Dimopoulos et al, Lancet 2020), a significant progression-free survival (PFS) benefit was demonstrated in patients treated with KdD vs patients treated with Kd (hazard ratio [HR], 0.63 [95% CI, 0.46-0.85];two-sided P=0.0027). However, after a median follow-up of 16.9 months, median PFS was not reached in the KdD arm. Here, we report updated efficacy and safety outcomes from the CANDOR study. Methods: Adult patients with relapsed or refractory multiple myeloma (RRMM) received 28-day cycles of KdD or Kd (randomized 2:1). In the primary analysis, PFS was the primary endpoint and overall survival (OS) a key secondary endpoint. In this prespecified interim OS analysis, statistical testing was based on the actual number of OS events observed by the data cutoff (approximately 36 months after enrollment of the first patient);PFS was summarized descriptively. Disease progression was determined locally by investigators in an unblinded manner and centrally by the sponsor using a validated computer algorithm (Onyx Response Computer Algorithm [ORCA]) in a blinded manner. PFS and OS were compared between the KdD and Kd arms using a stratified log-rank test, and HRs were estimated by a stratified Cox proportional-hazards model. Results: Patients were randomized to KdD (n = 312) and Kd (n = 154). Of all randomized patients, median age was approximately 64 years;42% received previous lenalidomide, and 33% were lenalidomide refractory;90% received previous bortezomib, and 29% were bortezomib refractory. At the data cutoff date of June 15, 2020, 199 (63.8%) patients in the KdD arm and 88 (57.1%) in the Kd arm remained on study. Among patients treated with KdD and Kd, 140 (44.9%) and 85 (55.2%) had PFS events, respectively;median follow-up was 27.8 months (KdD) and 27.0 months (Kd). Median PFS by ORCA was 28.6 months for the KdD arm versus 15.2 months for the Kd arm (HR, 0.59 [95% CI, 0.45-0.78];Figure). OS data were not mature and will be updated at a future prespecified analysis. Median treatment duration was 79.3 weeks with KdD versus 40.3 weeks with Kd. Grade ≥3 adverse events (AEs) occurred in 87.0% and 75.8% of patients in the KdD and Kd arms, respectively, and fatal AEs occurred in 8.8% and 4.6%;one fatal AE in the KdD arm (due to arrhythmia) and one fatal AE in the Kd arm (due to COVID-19 pneumonia) had occurred since the primary analysis. Carfilzomib treatment discontinuation rates due to AEs were 26.0% with KdD and 22.2% with Kd. Exposure-adjusted AE rates per 100 patient years were: 171.2 and 151.9 for grade ≥3 AEs and 6.9 and 5.6 for fatal AEs in the KdD and Kd arms, respectively. Updated data by key subgroups will be presented. Conclusion: With approximately 11 months of additional follow-up, a 13.4-month improvement in median PFS was observed in patients treated with KdD (28.6 months) versus patients treated with Kd (15.2 months;HR, 0.59 [95% CI, 0.45-0.78]). Safety was consistent with previously reported results. KdD continues to show a favorable benefit-risk profile and represents an efficacious treatment option for patients with RRMM. [Formula presented] Disclosures: Dimopoulos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau;BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau;Celgene: Consultancy, Ho oraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau. Quach: GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Consultancy;Amgen, Celgene, karyopharm, GSK, Janssen Cilag, Sanofi.: Membership on an entity's Board of Directors or advisory committees;Amgen, sanofi, celgene, Karyopharm, GSK: Research Funding;GlaxoSmithKline, Karyopharm, Amgen, Celgene, Janssen Cilag: Honoraria. Mateos: EDOMundipharma: Consultancy;Adaptive: Consultancy;Pharmamar: Consultancy;GlaxoSmithKline: Consultancy;AbbVie: Consultancy;Takeda: Consultancy;Amgen: Consultancy;Celgene: Consultancy;Janssen: Consultancy. Landgren: Pfizer: Consultancy, Honoraria;Merck: Other;Cellectis: Consultancy, Honoraria;Juno: Consultancy, Honoraria;Glenmark: Consultancy, Honoraria, Research Funding;BMS: Consultancy, Honoraria;Binding Site: Consultancy, Honoraria;Celgene: Consultancy, Honoraria, Research Funding;Pfizer: Consultancy, Honoraria;Karyopharma: Research Funding;Merck: Other;Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding;Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding;Glenmark: Consultancy, Honoraria, Research Funding;Juno: Consultancy, Honoraria;Seattle Genetics: Research Funding;Cellectis: Consultancy, Honoraria;Seattle Genetics: Research Funding;Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding;BMS: Consultancy, Honoraria;Adaptive: Consultancy, Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Binding Site: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding;Karyopharma: Research Funding. Leleu: Incyte: Honoraria;Merck: Honoraria;Novartis: Honoraria;Amgen: Honoraria;GSK: Honoraria;Sanofi: Honoraria;BMS-celgene: Honoraria;Janssen: Honoraria;Oncopeptide: Honoraria;AbbVie: Honoraria;Carsgen: Honoraria;Karyopharm: Honoraria. Siegel: Janssen: Consultancy, Honoraria, Speakers Bureau;Merck: Consultancy, Honoraria, Speakers Bureau;Amgen: Consultancy, Honoraria, Speakers Bureau;Celulatiry: Consultancy;Karyopharma: Consultancy, Honoraria;Takeda: Consultancy, Honoraria, Speakers Bureau;BMS: Consultancy, Honoraria, Speakers Bureau. Weisel: Takeda: Consultancy, Honoraria;Amgen: Consultancy, Honoraria, Research Funding;Karyopharm: Consultancy, Honoraria;Adaptive: Consultancy, Honoraria;Bristol-Myers Squibb: Consultancy, Honoraria;GlaxoSmithKline: Honoraria;Sanofi: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding;Celgene: Consultancy, Honoraria, Research Funding;Abbvie: Consultancy, Honoraria;Roche: Consultancy, Honoraria. Gavriatopoulou: Takeda: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;Genesis Pharma: Consultancy, Honoraria;Karyopharm: Consultancy, Honoraria;Amgen: Consultancy, Honoraria. Oriol: Janssen: Consultancy;Celgene: Consultancy, Speakers Bureau;Amgen: Consultancy, Speakers Bureau. Rabin: Janssen, BMS/Celgene, Takeda, Karyopharm, Amgen: Consultancy;Janssen, BMS/Celgene, Takeda: Other: Travel;Jansse, BMS/Celgene, Takeda: Speakers Bureau. Nooka: GlaxoSmithKline: Consultancy, Honoraria, Other: Personal Fees: Travel/accomodations/expenses, Research Funding;Karyopharm Therapeutics, Adaptive technologies: Consultancy, Honoraria, Research Funding;Spectrum Pharmaceuticals: Consultancy;Celgene: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding;Oncopeptides: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Research Funding;Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding;Sanofi: Consultancy, Honoraria;Adaptive Technologies: Consultancy, Honoraria;Takeda: Consultancy, Honoraria, Research Funding. Ding: Amgen: Current Employment. Zahlten-Kumeli: Amgen: Current Employment, Current equity holder in publicly-traded compan . Usmani: Celgene: Other;GSK: Consultancy, Research Funding;Pharmacyclics: Research Funding;Array Biopharma: Research Funding;Seattle Genetics: Consultancy, Research Funding;Merck: Consultancy, Research Funding;Incyte: Research Funding;SkylineDX: Consultancy, Research Funding;Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding;Sanofi: Consultancy, Honoraria, Research Funding;Abbvie: Consultancy;BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding;Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding;Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding.
ABSTRACT
Background: Cilta-cel is a CAR T-cell therapy expressing two BCMA-targeting, single-domain antibodies designed to confer avidity. The multicohort, phase 2 CARTITUDE-2 study (NCT04133636) is evaluating cilta-cel safety and efficacy in various clinical settings for patients (pts) with MM and exploring suitability of outpatient administration. Here, we present initial results from Cohort A. Methods: Cohort A pts had progressive MM after 1-3 prior lines of therapy (LOT), including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), were lenalidomide refractory, and had no prior exposure to BCMA-targeting agents. A single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg) was given 5-7 days (d) after start of lymphodepletion (daily cyclophosphamide [300 mg/m2 ] and fludarabine [30 mg/m2 ] for 3 d). The primary objective was minimal residual disease (MRD) 10 negativity. Secondary outcomes were response rates (IMWG) and safety (per CTCAE;CRS and ICANS by ASTCT). Results: As of Feb 2021 data cutoff (median follow-up: 5.8 months [mo];range: 2.5-9.8 mos), 20 pts (65% male;median age 60 years [38-75]) received cilta-cel;1 pt was treated in an outpatient setting. Pts received a median of 2 prior LOT (1-3);12 pts received < 3 prior lines and 8 received 3 prior LOT. All pts were exposed to PI, IMiD, and dexamethasone, 95% to alkylating agents, and 65% to daratumumab. The majority (95%) were refractory to the last LOT;40% were triple refractory. Overall response rate was 95% (95% CI: 75-100), 75% (95% CI: 51-91) achieved stringent CR/CR, and 85% (95% CI: 62-97) achieved ≥VGPR. Median time to first response was 1.0 mo (0.7-3.3);median time to best response was 1.9 mo (0.9-5.1). Median duration of response was not reached. All pts (n = 4) with MRD-evaluable samples at 10 at data cutoff were MRD-negative. Hematologic AEs ≥20% were neutropenia (95%;gr 3/4: 90%), thrombocytopenia (80%;gr 3/4: 35%), anemia (65%;gr 3/4: 40%), lymphopenia (60%;gr 3/4: 55%), and leukopenia (55%;all gr 3/4). CRS occurred in 85% of pts;10% were gr 3/4. Median time to CRS onset was 7 d (5-9), with a median duration of 3.5 d (2-11). CAR T-cell neurotoxicity occurred in 20% of pts (all gr 1/2). Three pts had ICANS (1 gr 1;2 gr 2);median time to onset was 8 d (7-11) and median duration was 2 d (1-2). One pt had gr 2 facial paralysis;time to onset was 29 d with a duration of 51 d. One death occurred due to COVID-19 (assessed as treatment (tx)-related by investigator). Safety profile was manageable in the pt treated in an outpatient setting. Conclusions: A single cilta-cel infusion at the recommended phase 2 dose led to early and deep responses with a manageable safety profile in pts with MM who had 1-3 prior LOT. Updated efficacy and safety findings will inform suitability of outpatient tx in this and other cohorts of CARTITUDE-2 as well as the CARTITUDE-4 study.