B-cell maturation antigen-targeting chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in relapsed/refractory multiple myeloma (RRMM). However, emerging non-immune effector cell-associated neurotoxicity syndrome (non-ICANS) neurologic events-including cranial nerve palsy (CNP) and immune effector cell (IEC)-parkinsonism (also called movement and neurocognitive toxicity)-warrant vigilance. This review summarizes clinical findings from the CARTITUDE trials, which evaluated ciltacabtagene autoleucel in > 300 patients with RRMM. CNP occurred in 6.3% of patients, with a lower incidence in more heavily pretreated patients (≥ 3 prior lines of treatment [pLOT]: 3% vs. 1-3 pLOT: 9%). Median CNP onset was day 22 postinfusion; most cases were low grade, and 90% recovered completely. IEC-parkinsonism involves motor, cognitive, and personality changes; lower incidence was observed in less heavily pretreated patients (1% vs. 6%). Median time to onset was 56 days postinfusion; however, with greater awareness, IEC-parkinsonism may be recognized earlier. Emerging data suggest that early, aggressive intervention may result in better outcomes. High CAR-T cell expansion is associated with increased risk of CNP and IEC-parkinsonism. In the early postinfusion period (days 10-28), absolute lymphocyte count (ALC) strongly correlates with circulating CAR-T cell levels and could help identify patients at increased risk of neurologic events. Prophylactic interventions, including a short course of steroids, triggered by elevated ALC before symptom onset, are under investigation. Education of patients, caregivers (including family), local oncologists, and neurologists seeing patients outside CAR-T infusion centers is essential to facilitate timely recognition, referral to the CAR-T center, and management.

7507 Background: CARTITUDE-1 evaluated cilta-cel in pts with heavily pretreated RRMM who historically have an expected median progression-free survival (PFS) of <6 months (mo) and median overall survival (OS) of ~1 year (y). At 33.4 mo median follow-up, median PFS was 34.9 mo, and median OS was not reached (36-mo OS rate, 62.9%; Lin et al, ASCO 2023). We report OS, ≥5 y progression-free outcomes, and safety with a median study follow-up of 60.3 mo. Methods: Pts in CARTITUDE-1 received a single cilta-cel infusion. Correlative analyses were performed utilizing drug product, baseline, and postinfusion samples. Pts are followed for progression, survival, and safety in a 15-y follow-up study, CARTinue (NCT05201781), with pt evaluations per local standard of care (reported annually at a minimum). Results: Of 97 pts treated, 32 (33.0%) remain alive and progression free for ≥5 y after cilta-cel, without further MM treatment. For these 32 pts, prior to enrollment in CARTITUDE-1, median time from start of last line of therapy (LOT) to progression was 4.0 mo (range, 0.7–48.6). Among the 32, median age was 60 y (range, 43–78), median number of prior LOT was 6.5 (range, 3–14), 23.3% had high risk cytogenetics, 12.5% had extramedullary disease (EMD), 90.6% were triple-class refractory, and 46.9% were penta-drug refractory. Baseline characteristics of pts who were progression free for ≥5 y, including those with high-risk cytogenetics and EMD, were comparable to pts with progressive disease (PD) within 5 y. Compared with pts who had PD within 5 y, biomarkers significantly associated with ≥5 y progression free status included a higher fraction of naïve T cells in the drug product, lower neutrophil to T cell ratio, higher hemoglobin and platelets at baseline, and higher effector-to-target ratio (Cmax to sBCMA at baseline). At Cmax, these pts also had significantly higher CD4 central memory CAR+ T cell subsets and CAR+ T cells that were positive for the activation markers CD38, CD25, and PD-1. Data were collected on a subset of pts from a single center where local serial MRD assessments were performed. All 12 pts at this center who were progression free for ≥5 y were MRD negative at 10 –6 and imaging negative by PET/CT yearly for 5 y. Overall, at 60.3 mo median follow-up in CARTITUDE-1 (N=97), median OS was 60.6 mo (95% CI, 41.9–NE). With continued follow-up, 3 additional pts reported a second primary malignancy (1 of which was acute myeloid leukemia; onset, 2.8 y after infusion). No new cases of movement and neurocognitive disorders were reported. Conclusions: The median OS for pts enrolled in CARTITUDE-1 was 5 y, and 33% of pts remain progression free for ≥5 y following a single cilta-cel infusion. These data provide the first evidence that cilta-cel is potentially curative in pts with RRMM. Clinical trial information: NCT03548207 , NCT05201781 .

CARTITUDE-1 evaluated ciltacabtagene autoleucel (cilta-cel) in patients with heavily pretreated relapsed/refractory multiple myeloma (RRMM). We describe overall survival (OS), ≥5-year progression-free outcomes, associated biomarkers, and safety, with a median study follow-up of 61.3 months. For the 97 treated patients, median OS was 60.7 months (95% CI, 41.9 to not estimable). One third (32/97) of patients remain alive and progression-free for ≥5 years after a single cilta-cel infusion, without maintenance treatment. Twelve of these patients treated at a single center underwent serial minimal residual disease (MRD) and positron emission tomography-computed tomography assessments, and all (100%) were MRD-negative (at least 10 −5 threshold) and imaging-negative at year 5 or later after cilta-cel. Baseline characteristics, including the presence of high-risk cytogenetics and extramedullary disease, were generally comparable for the 32 patients who were progression-free for ≥5 years versus patients who had progressive disease by year 5. A trend of lower baseline tumor burden, higher fraction of naïve T-cells in the cilta-cel drug product, higher T cell-to-neutrophil ratio, higher hemoglobin and platelets at baseline, and higher effector-to-target ratio were associated with ≥5-year progression-free status. The safety profile of cilta-cel remained consistent with previous reports. To our knowledge, our data provide the first evidence that cilta-cel is potentially curative in patients with RRMM.

The treatment of multiple myeloma has changed dramatically in recent years, with huge strides forward made in the field. Chimeric antigen receptor T-cell therapy targeting the B cell maturation antigen (BCMA) is now widely approved in relapsed refractory patients and is moving into earlier treatment lines. In this review, we discuss the evidence underpinning current regulatory approvals and consider mechanisms through which CAR-T cell efficacy could be improved. These include tackling BCMA-loss, harnessing the immunosuppressive tumour microenvironment, manufacturing concerns including the potential role of other cellular sources, safety issues such as cytokine release syndrome and neurotoxicity, and optimal patient selection.

BackgroundCiltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor (CAR)-T cell therapy FDA approved for relapsed/refractory multiple myeloma (RRMM) after ≥4 lines of therapy (LOT). This report summarizes clinical response data from the study closeout of the Phase 1b/2 CARTITUDE-1 trial and respective correlative biomarker analyses.MethodsEligible patients (pts) received ≥3 prior LOT or were double refractory to proteasome inhibitor (PI) and immunomodulatory (IMiD) drugs; all received prior PI, IMiD, and anti-CD38 antibody therapy. Primary endpoint was overall response rate (ORR) and safety; secondary endpoints included progression free survival (PFS), overall survival (OS), duration of response (DOR), and minimal residual disease (MRD) negativity at 10−5. Pt and CAR-T drug product (DP) characteristics were evaluated to identify biomarkers of cilta-cel response.ResultsOf 97 pts, median follow-up was 33.4 mo (range, 1.5-45.2). Response rate was 97.9%; median duration of response (DOR) was 33.9 mo (95% confidence interval [CI], 25.5-not estimable [NE]). Median PFS was 34.9 mo (95% CI, 25.2-NE), with an estimated PFS rate of 47.5% at 36 mo. Median OS was not reached (NR), with an estimated OS rate of 62.9% at 36 mo. Of 49 pts evaluated for MRD, 26 had MRD negativity sustained for ≥12 mo; of these, 20 pts had sustained MRD-negative complete response or greater; median PFS was NR in these subgroups. No new safety signals were reported. CAR-T DP had a mixture of transduced (median [range], 16% [5%-32%]) and nontransduced T cells and a balanced distribution of CD4+ (median [range] frequency, 12% [2%-28%]) and CD8+ CAR+T cells (6% [2%-20%]). CAR+ T cell median peak expansion was at 730 cells/µL between 12 and 14 days post infusion, persisting a median (range) of 100 (20-912) days. Deep and durable responses (eg, best response, DOR) were achieved despite variable CAR-T cell expansion and lack of detectable CAR-T cell persistence over time. Some DP characteristics (eg, high CAR+CD8+ stem-like phenotype, low CAR+CD4+ Treg-like phenotype) were associated with longer DOR. Pt characteristics associated with baseline inflammatory markers correlated with shorter DOR. Pts with high-risk cytogenetics, tumor burden ≥60% bone marrow plasma cells, or baseline plasmacytomas demonstrated high ORR but numerically shorter PFS.ConclusionsA single infusion of cilta-cel was associated with a longer PFS than that previously reported for therapies approved for heavily pretreated RRMM. Correlative analyses could support identification of DP, pt, and tumor characteristics to help predict DOR to cilta-cel.

Introduction: CARTITUDE-2 (NCT04133636) is a phase 2 study evaluating cilta-cel, an anti-BCMA CAR-T therapy, in several MM patient populations. We present updated data with longer follow-up on cohort C patients with previous exposure to a non-cellular anti-BCMA immunotherapy. Methods: Cohort C patients with progressive MM after treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and non-cellular BCMA-targeting agent received a single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg) 5–7 days post lymphodepletion. Primary endpoint: minimal residual disease (MRD) negativity at 10-5. Secondary endpoints: overall response rate (ORR), duration of response (DOR), and adverse events (AEs). Results: As of June 1, 2022, 20 patients received cilta-cel (13 ADC exposed; 7 BsAb exposed). 6 patients (30%) received anti-BCMA treatment as last line of therapy (LOT; n=4 ADC, n=2 BsAb). During prior anti-BCMA treatment, best responses included very good partial response (ADC group: 2 patients, BsAb group: 1 patient), stringent complete response (ADC group: 1 patient), and complete response (BsAb group: 1 patient); the rest had best response of stable disease or PD (1 patient was not evaluable). At baseline (median age: 62.5 years, male: 60%), 3 (15%) patients had high-risk cytogenetics (all del17p), and 5 (25%) had baseline extramedullary disease. Patients had a median of 8 prior LOT; triple-class refractory (n=18 [90%]), penta-drug refractory (n=11 [55%]), refractory to non-cellular anti-BCMA treatment (n=16 [80%]) (Fig 1A). Median time from last anti-BCMA agent to cilta-cel infusion was 195 days. At a median follow-up of 18.0 months, 7/10 evaluable patients (70%) were MRD-negative at 10-5 (ADC group [n=5/7 evaluable, 71.4%]; BsAb group [n=2/3 evaluable, 66.7%]). ORR was 60% for the full cohort, 61.5% in the ADC group, and 57.1% in the BsAb group (Fig 1B). Median DOR was 12.8 months in the full cohort, 12.8 months in the ADC group, and 8.2 months in the BsAb group. Median PFS was 9.1 months in the full cohort, 9.5 months in the ADC group, and 5.3 months in the BsAb group. Cilta-cel responders had a shorter median duration of last anti-BCMA agent exposure (29.5 days) compared with non-responders (63.5 days). Responders also had a longer median time from last anti-BCMA treatment exposure to apheresis (161.0 days) than non-responders (56.5 days). Most common AEs were hematologic. CRS occurred in 12 (60%) patients (all grade 1/2); median time to onset was 7.5 days and median duration was 6.0 days. ICANS occurred in 4 (20%) patients (2 grade 3/4); median time to onset was 9.0 days and median duration was 7.0 days. ICANS was recovered or resolved in 3 patients. No patient had movement or neurocognitive treatment emergent AEs/parkinsonism. 12 deaths occurred: 8 due to PD, 2 due to COVID-19 pneumonia (not treatment related), 1 due to subarachnoid hemorrhage (not treatment related), and 1 due to C. difficile colitis (treatment related). Conclusions: Heavily pretreated patients with MM and previous exposure to a non-cellular anti-BCMA therapy showed favorable responses following cilta-cel treatment. However, depth and DOR appear lower than that seen in anti-BCMA-naive patients treated with cilta-cel (median DOR was not reached in heavily pretreated but anti-BCMA naive CARTITUDE-1 patients at 27.7 months). These data may help inform treatment plans, including sequencing and washout period between BCMA-targeting agents.

Cilta-cel, a BCMA-targeting chimeric antigen receptor T-cell therapy for multiple myeloma, was approved in USA on 28 February 2022, for patients with relapsed or refractory disease who have received ≥4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Approval in the EU followed for patients with ≥3 prior therapies. At median 28-month follow-up, the pivotal CARTITUDE-1 trial showed a 98% response rate (83% stringent complete response); median progression-free survival had not been reached, and adverse events could be managed with supportive therapy. Cilta-cel efficacy and safety in earlier lines of therapy, and its optimal sequencing in a complex treatment landscape are important areas of investigation.

(R,R′)-4′-Methoxy-1-naphthylfenoterol (MNF) promotes growth inhibition and apoptosis of human HepG2 hepatocarcinoma cells via cannabinoid receptor (CBR) activation. The synthetic CB1R inverse agonist, AM251, has been shown to block the anti-mitogenic effect of MNF in these cells; however, AM251 is also an agonist of the recently deorphanized, lipid-sensing receptor, GPR55, whose upregulation contributes to carcinogenesis. Here, we investigated the role of MNF in GPR55 signaling in human HepG2 and PANC-1 cancer cell lines in culture by focusing first on internalization of the fluorescent ligand Tocrifluor 1117 (T1117). Initial results indicated that cell pretreatment with GPR55 agonists, including the atypical cannabinoid O-1602 and l-α-lysophosphatidylinositol, dose-dependently reduced the rate of cellular T1117 uptake, a process that was sensitive to MNF inhibition. GPR55 internalization and signaling mediated by O-1602 was blocked by MNF in GPR55-expressing HEK293 cells. Pretreatment of HepG2 and PANC-1 cells with MNF significantly abrogated the induction of ERK1/2 phosphorylation in response to AM251 and O-1602. Moreover, MNF exerted a coordinated negative regulation of AM251 and O-1602 inducible processes, including changes in cellular morphology and cell migration using scratch wound healing assay. This study shows for the first time that MNF impairs GPR55-mediated signaling and, therefore, may have therapeutic potential in the management of cancer.

Supplementary Figures and Tables

Introduction: Cilta-cel is a dual-binding, BCMA-targeting CAR-T cell therapy that has shown high rates of deep and durable response in patients (pts) with relapsed/refractory multiple myeloma (RRMM), and significantly prolonged PFS vs SOC in pts with lenalidomide-refractory MM after 1-3 prior lines of therapy (LOT; HR, 0.26) in the phase 3 CARTITUDE-4 trial. CAR-T therapies are associated with AEs related to immune activation, including neurologic toxicities (Gonzalez Castro. Neuro-Oncol Pract. 2020). Here, we describe the clinical experience with presentation and management of cranial neuropathy (CNP) in pts treated with cilta-cel in the CARTITUDE-1, CARTITUDE-2 Cohorts A, B, and C, and CARTITUDE-4 studies. Methods: CARTITUDE-1 and CARTITUDE-2 Cohort C pts had ≥3 prior LOT, incl PIs, IMiDs, and anti-CD38 mAbs, or were double-refractory to PI and IMiD; CARTITUDE-2 Cohort C pts also had non-cellular anti-BCMA therapy. CARTITUDE-2 Cohort B pts relapsed within 12 months of initial therapy. CARTITUDE-2 Cohort A and CARTITUDE-4 pts had 1-3 prior LOT, incl PI and IMiD, and were lenalidomide-refractory. After apheresis, pts received bridging therapy, then 1 cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) 5-7 days (d) after lymphodepletion. Pts presenting with signs/symptoms of cranial nerve impairment commonly underwent a diagnostic workup that included CSF analysis and brain MRI at investigator discretion. Correlative data were available for pts in CARTITUDE-4: cilta-cel levels and T cell memory phenotypes in peripheral blood were assessed by flow cytometry, and serum cytokines were measured using multiplex sandwich immunoassays on the Meso Scale Discovery platform. Results: Of the 332 pts infused with cilta-cel as study treatment in CARTITUDE-1, CARTITUDE-2 (Cohorts A, B, and C), and CARTITUDE-4, 21 (6.3%) developed CNP (TABLE); most cases were grade (gr) 2 (n=3 gr 3). 6 pts had CNP that affected both sides; most unilateral impairments were left-sided. Median time to onset was 22 d (range 17-101; 81% had onset on d 22 +/- 5). Cranial nerve (CN) VII was involved in all pts; 2 pts had additional CNs involved (1 CN III [gr 3], 2 CN V [gr 3]). Twelve pts had concurrent neurologic symptoms/neurotoxicities (headache, n=7; n=1 each for dysgeusia, parosmia, restlessness, peripheral sensory neuropathy, polyneuropathy, amnesia, aphasia, agitation, depressed level of consciousness). Clinical characteristics of pts with or without CNP were comparable. In the 21 pts with CNP, median age was 64 years; 81% were male; at baseline, 1 pt had high disease burden (BM 95% plasma cells), 4 had plasmacytomas (1 bone-based); 1 pt had ISS stage III. Most pts responded to bridging therapy. Six pts had an infection after cilta-cel infusion and prior to CNP onset (bacterial, n=5; CMV, n=2; both, n=1). CRS rate was comparable between pts with vs without CNP. 90% of pts with CNP had preceding CRS (all gr 1/2; median onset, d 7; median duration, 3 d); 13 received tocilizumab for CRS. One pt had preceding gr 2 ICANS; no pts had movement/neurocognitive TEAEs (MNT) at any time. CSF analysis and brain MRI were performed in 14 and 17 pts, respectively. No evidence of infectious or malignant etiology was identified in any of these cases; MRI showed facial nerve enhancement in 7 pts, in whom there were no other significant findings. Most CNP cases were treated with corticosteroids for median 13 d. CNP resolved in 19/21 pts within median 66 d, including the 3 pts with gr 3 CNP. In CARTITUDE-4, pts with CNP had significantly higher levels of CAR+ T cell expansion (C max) and greater exposure to CAR+ T cells (AUC 0-CNP onset) than those without CNP (FIGURE). Pts with CNP had a trend toward higher peak concentration and exposure level (AUC 0-CNP onset) of IL-6, IL-10, and IL-2Rα, but not in IFNγ. The differentiation pattern of memory T cells from apheresis to the time of peak CAR+ T expansion (T max) was comparable in pts with vs without CNP; CAR+ T cells at T max were dominant with central memory T cells in both groups. Conclusions:Ptstreated with CAR-T cells, including cilta-cel, may experience CNP.The pathogenesis of the events in these 3 studies was unknown/idiopathic, but it is important to rule out etiology of infection or MM progression. Most cases were low-grade and resolved with a limited course of corticosteroids. CNP in CARTITUDE-4 was associated with higher exposure to CAR-T cells before onset, but no predictive clinical factors have been established.

Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel), an anti-BCMA chimeric antigen receptor (CAR)-T cell therapy, in various populations of patients with multiple myeloma (MM). We previously reported 17-month median follow-up results from cohort A (1-3 prior lines of therapy [LOT] and lenalidomide [len]-refractory) and 18-month median follow-up results from cohort B (early relapse: ≤12 months after either autologous stem cell transplant [ASCT] or start of initial anti-myeloma treatment, if not transplanted). Cilta-cel is also under evaluation in patients with len-refractory MM after 1-3 LOT in the phase 3 CARTITUDE-4 study, which showed cilta-cel significantly prolonged progression-free survival (PFS) vs standard of care (HR, 0.26) at a median follow-up of 16 months. Here, we present updated efficacy and safety data from CARTITUDE-2 cohorts A and B, both with a median follow-up of ~29 months. Methods: Patients in cohorts A and B, all naive to CAR-T and/or anti-BCMA therapies, received a single cilta-cel infusion (target dose 0.75×10 6 CAR+ viable T cells/kg) 5-7 days after lymphodepletion. In both cohorts, the primary endpoint was minimal residual disease (MRD)-negativity (10 -5 threshold, by next-generation sequencing or next-generation flow cytometry). Management strategies were implemented after the phase 1b/2 CARTITUDE-1 study to reduce risk of movement and neurocognitive treatment-emergent adverse events (MNTs). Results: As of April 2023, 20 patients in cohort A had received cilta-cel (median follow-up, 29.9 months; 35% with high-risk cytogenetics; median 2 prior LOT; 95% refractory to last LOT; 40% triple-class refractory; 85% with prior ASCT). At the same data cut-off, 19 patients in cohort B hadreceived cilta-cel (median follow-up, 27.9 months; 16% with high-risk cytogenetics; 79% refractory to last LOT; 16% triple-class refractory; 79% with prior ASCT). All (100%) 17 MRD-evaluable patients in cohort A and 14 (93%) of 15 MRD-evaluable patients in cohort B achieved MRD negativity (10 -5 threshold). Eight (40%) of 20 patients in cohort A and 10 (53%) of 19 patients in cohort B sustained MRD negativity at 10 -5 for ≥6 months (Table 1). In the 20 patients in cohort A and 19 in cohort B, cilta-cel led to overall response rates of 95% (complete response or better [≥CR], 90%) and 100% (≥CR, 90%), respectively. Median PFS was not reached in either cohort, and 24-month PFS rates were 75% in cohort A and 73% in cohort B; respective 24-month overall survival rates were 75% and 84%. In cohort A, hematologic treatment-emergent adverse events (TEAEs) occurring between 17.1- and 29.9-month median follow-up included maximum grade (gr) 3/4 leukopenia in 1 patient (all gr,12 total; 60%), maximum gr 3/4 lymphopenia in 2 patients (all gr,16 total; 80%), and maximum gr 3/4 thrombocytopenia in 1 patient (all gr,16 total; 80%). In cohort B, no new patients reported hematologic TEAEs between 18.0- and 27.9-month median follow-up (Table 2). In cohort A, no new patients had CAR-T cell neurotoxicity, and no patients had a second primary malignancy (SPM). In cohort B, no new patients had MNTs, but other neurotoxicity (gr 2 sensory loss) occurred in 1 additional patient (all gr, 5 total; 26%) and resolved; and SPM (gr 4 choroid melanoma) occurred in 1 additional patient (all gr, 2 total; 11%). One new death (total 5) occurred in cohort A on day 666 due to progressive disease, and 1 new death (total 4) occurred in cohort B on day 749 due to cardiac arrest (not treatment related). Conclusions: These longer-term follow-up data show that patients treated with cilta-cel in earlier LOT, both those with len-refractory MM after 1-3 LOT (cohort A) and those with early relapse (cohort B), experienced deep and durable responses. No new CAR-T-related safety signals, except for 1 additional CAR-T cell neurotoxicity in cohort B, were reported. Cohort A provides insight into potential longer-term survival outcomes that may be expected in the phase 3 CARTITUDE-4 trial, which enrolled the same patient population but has shorter follow-up thus far. The long-term cohort B data highlight the durable efficacy of cilta-cel in patients who had early relapse; this is a functionally high-risk population for whom standard risk factors, including a high-risk cytogenetic profile, may not predict risk of relapse and for whom there is significant unmet need.

Ciltacabtagene autoleucel (cilta-cel) is a CAR-T cell therapy that has shown efficacy in patients with relapsed/refractory multiple myeloma, as well as improvements in health-related quality of life. Here, we capture patient perspectives on treatment with cilta-cel to provide additional context to previously reported clinical outcomes. Qualitative interviews from 36 patients showed cilta-cel met or exceeded treatment expectations. Introduction: Ciltacabtagene autoleucel (cilta-cel), a novel chimeric antigen receptor T (CAR-T) cell therapy, has demonstrated early, deep, and durable clinical responses in heavily pretreated patients with relapsed/refractory multi-ple myeloma (RRMM), and improvements in health-related quality of life (HRQoL) in CARTITUDE-1 (NCT03548207). Patient perspectives on treatment provide context to efficacy outcomes and are an important aspect of therapeutic evaluation. Methods: Qualitative interviews were conducted in a subset of CARTITUDE-1 patients (n = 36) at screen-ing, Day 100, and Day 184 post cilta-cel on living with MM, therapy expectations, and treatment exper iences dur ing the study. Results: Patients most wanted to see change in symptoms with the greatest impact on HRQoL: pain (85.2%) and fatigue (74.1%). The primary treatment expectation was achieving remission (40.7%), followed by extended life expectancy (14.8%). Patients most often defined meaningful change as improvement in symptoms (70.4%) and return to normalcy (40.7%). The percentage of patients reporting symptoms (pain, fatigue, bone fracture, gastrointestinal, neuropathy, and weakness) decreased from 85.2% to 22.2% across symptom types at baseline to 29.2% to 0% on Day 184 after cilta-cel. Improved symptoms and positive sentiments corresponded with improved perception of overall health status and reduced pain level, respectively. Most patients reported that their expectations of cilta-cel treatment had been met (70.8%) or exceeded (20.8%) at Day 184, and 70.8% of patients considered cilta-cel therapy better than their previous treatments. Conclusion: Overall HRQoL improvements and qualitative interviews showed cilta-cel met patient expectations of treatment and suggest the long treatment-free period also contributed to positive sentiments.

Introduction: Cilta-cel is a BCMA-targeting CAR T-cell therapy that was recently approved by the US FDA for the treatment of adult patients (pts) with relapsed/refractory multiple myeloma (RRMM) after ≥4 prior lines of therapy (LOT) including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 monoclonal antibody. In the phase 1b/2 CARTITUDE-1 study, cilta-cel demonstrated deep and durable responses in heavily pretreated pts with RRMM. The ORR was 97.9%, and at a median follow-up of 28 months (mo) the DOR was not reached. Of the 97 pts, 61 were evaluable for minimal residual disease (MRD) negativity (clonoSEQ v2.0, Adaptive Biotechnologies), with 56 (91.8%) of these 61 pts achieving MRD negativity (10-5) at any point. We sought to characterize the baseline and disease characteristics of pts with sustained MRD negativity (pts who continued to remain MRD negative ≥6 mo and ≥12 mo). Methods: Eligible pts had MM and received ≥3 prior therapies or were refractory to a PI, and IMiD, and had received a PI, IMiD, and an anti-CD38 antibody. Pts received a single cilta-cel infusion (target dose 0.75x106 CAR+ viable T cells/kg) 5-7 days post lymphodepletion. MRD negativity was a secondary objective of the phase 2 part of CARTITUDE-1 and was assessed on bone marrow samples at baseline; day 28; and 6, 12, 18, and 24 mo using next-generation sequencing, regardless of disease status. An additional sample was collected and assessed at the time of suspected complete response and every 12 mo until progressive disease (PD) for pts who remained on the study. Evaluable samples passed calibration and quality control and included sufficient cells for evaluation at 10-5 testing threshold. Characteristics were analyzed in pts who had MRD negativity <6 mo, or sustained ≥6 mo and ≥12 mo. Pts who did not achieve MRD negativity at any time point were considered to be MRD positive. Landmark analyses were conducted at 6 and 12 mo to address immortal time bias. Results: Of the 56 pts who achieved MRD negativity in CARTITUDE-1, 50 had at least 6 mo follow up without progression after initial MRD-negativity and 44 had at least 12 mo follow up without progression after initial MRD-negativity. MRD negativity was sustained for ≥6 mo in 68% (34 of 50 with at least 6 mo follow-up without progression after initial MRD-negativity) and ≥12 mo in 55% (24 of 44 with at least 12 mo follow-up without progression after initial MRD-negativity; all 6 pts evaluable for sustained MRD at ≥6 mo but not ≥12 mo had PD). Pts with sustained MRD negativity (≥6 mo, and ≥12 mo) had longer progression free survival (PFS; Figure 1A) compared with pts who did not (MRD negative <6 mo; consistent with results from landmark analyses). Key pt and disease characteristics in these different groups (Figure 1B), and potential associations with sustained MRD negativity were analyzed descriptively. Baseline extramedullary plasmacytomas were less common in pts with MRD sustained for ≥6 mo (8.8%, n=3/34) and ≥12 mo (4.2%, n=1/24) compared with pts who had MRD negativity <6 mo (18.2%, n=4/22). Pts with sustained MRD negativity also had trends toward longer median time since diagnosis (5.9 y and 7.0 y for pts with MRD negativity sustained ≥6 and ≥12 mo, respectively versus 4.8 y for those with MRD negativity <6 mo). Other baseline characteristics, including presence of high-risk cytogenetics, ECOG performance status, ISS stage, number of prior LOT, penta-drug refractoriness, and refractoriness to last LOT did not differ across MRD subgroups, and were similar to the overall CARTITUDE-1 population. Conclusions: Based on our descriptive analysis, pts receiving cilta-cel achieved MRD negativity irrespective of their high-risk cytogenetics and ISS status, number of prior LOT and penta-drug refractoriness. While MRD negativity alone (<6 mo group) did not appear to provide PFS benefit when compared to MRD positive pts, the small number of pts in the MRD positive group prevents comparisons with those who achieved MRD negativity. Presence of extramedullary plasmacytoma at baseline, and time since diagnosis might be factors that impact achievement of sustained MRD negativity. These data suggest that while cilta-cel is effective for a broad range of pts, specific pt and disease characteristics may be associated with sustained MRD negativity and better long-term outcomes. Figure 1: (A) Progression Free Survival (B) Pt Demographics and Disease Characteristics Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Introduction: Cohort B of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study is evaluating cilta-cel in patients with multiple myeloma (MM) and early relapse (≤12 months after autologous stem cell transplant [ASCT] or ≤12 months after start of initial treatment with anti-myeloma therapy). This patient population has functionally high-risk disease and represents an unmet medical need, as progression within 1 year of starting initial therapy is a poor prognostic factor, with overall survival <2 years in these patients. Here we present updated clinical results and cytokine analyses. Methods: Patients with MM, 1 prior line of therapy (proteasome inhibitor and immunomodulatory drug required), early disease progression (≤12 months after ASCT or ≤12 months after start of anti-myeloma therapy for patients who did not undergo ASCT), and treatment-naive to CAR-T/anti-B-cell maturation antigen (BCMA) therapies were eligible. Bridging therapy was permitted between apheresis and CAR-T cell infusion. A single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) was administered post lymphodepletion. Safety and efficacy were evaluated. Primary endpoint was minimal residual disease (MRD) negativity by next generation sequencing at 10-5. Management strategies were used to reduce risk of movement/neurocognitive treatment-emergent adverse events (MNTs)/parkinsonism. Pharmacokinetics, CAR-T cell phenotype, and cytokine profiles are also being evaluated. Results: As of June 1, 2022, 19 patients received cilta-cel (median age 58 years [range 44–67]; 74% male; 16% high-risk cytogenetics, 63.2% standard risk, 21.1% unknown) and 16 remained on study. Median follow-up was 17.8 months (range 5.2–26.3). 79% of patients had prior ASCT. Overall response rate was 100% (100% very good partial response or better; 90% complete response or better) (Figure). Median time to first response was 0.95 months (range 0.9–9.7); median time to best response was 5.1 months (range 0.9–11.8). Of 15 MRD-evaluable patients, 14 (93%) achieved MRD 10-5 negativity during the study. Median duration of response was not reached. 12-month event-free rate was 84%; 12-month progression-free survival (PFS) rate was 90%. Most common treatment-emergent AEs (TEAEs) were hematologic (grade 3/4: neutropenia, 90%; lymphopenia, 42%; thrombocytopenia, 26%; leukopenia, 26%). Cytokine release syndrome (CRS) occurred in 16 (84.2%) patients (grade 4, n=1). Median time from cilta-cel infusion to onset of CRS was 8 days (range 5–11); CRS resolved in all patients. Immune effector cell-associated neurotoxicity syndrome (grade 1) occurred in 1 patient. Movement and neurocognitive TEAEs/parkinsonism (grade 3) occurred in 1 patient (previously reported). 3 patients died post cilta-cel at days 158, 417, and 451 due to progressive disease. Interleukin (IL)-6, interferon gamma, IL-2Rα, and IL-10 levels increased after infusion, peaking at days 7–14 and coincident with the timing of CRS, and returning to baseline levels within 2–3 months after infusion. Conclusions: In this functionally high-risk patient population (all of whom relapsed within a year of receiving standard of care upfront therapy, including ASCT [79%]), 90% remained progression-free at 1 year after cilta-cel treatment. At this longer follow-up of 18 months, results show durability and deepening of response to cilta-cel and maintenance of PFS rate, representing a potentially significant advancement in a population with high unmet need.

Supplementary Figures and Tables

Plasmablastic lymphoma (PBL) is a rare subtype of aggressive large B-cell lymphoma, with a dismal prognosis despite aggressive therapies. New approaches are needed for those with refractory disease. PBL expresses antigens similar to multiple myeloma (MM), including B-cell maturation antigen (BCMA). Chimeric antigen receptor T-cell (CAR-T) therapy directed against BCMA has shown efficacy for the treatment of heavily pretreated MM with low rates of grades 3 and 4 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in a phase Ib/II trial (A Study of JNJ-68284528, a CAR-T Directed Against BCMA in Participants With Relapsed or Refractory Multiple Myeloma (CARTITUDE-1), NCT03548207). However, data for the use of BCMA CAR-T for treating PBL are lacking.We report a challenging case of multiple refractory PBL that emerged from B-cell acute lymphoblastic leukemia in an adolescent who failed to respond to an allogeneic hematopoietic cell transplant. The patient developed rapidly advancing disease despite withdrawal of immunosuppression, treatment with etoposide, ibrutinib, and daratumumab, prompting consideration of BCMA CAR-T (under emergency investigational new drug (eIND)). The patient achieved a complete remission (CR), without recurrent acute graft versus host disease (GVHD), CRS or ICANS after BCMA CAR-T therapy. BCMA CAR-T expansion was detected in vivo, peaking on day 15. The patient remains in CR for more than a year post CAR-T therapy, supporting consideration of immunotherapy for future patients with refractory PBL, a disease with few treatment options.

Background: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant eligible, daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) is recommended by the National Comprehensive Cancer Network guidelines as induction therapy followed by autologous stem cell transplant (ASCT), consolidation, and maintenance therapy. Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor (CAR)-T cell therapy with 2 B-cell maturation antigen (BCMA)-targeting single-domain antibodies. In the phase 1b/2 CARTITUDE-1 study, a single infusion of cilta-cel resulted in deep and durable responses with a manageable safety profile in heavily pretreated patients with relapsed/refractory MM. At a median follow-up of 27.7 months, the overall response rate (ORR) was 98%, 83% of patients achieved stringent complete response (CR), and median duration of response was not reached. The randomized, open-label, global, multicenter, phase 3 EMagine/CARTITUDE-6 study (EMN28/68284528MMY3005; NCT05257083) aims to compare the efficacy of DVRd followed by cilta-cel and lenalidomide versus DVRd followed by ASCT, DVRd, and lenalidomide. Study Design and Methods: Eligible patients are aged ≥18 years with NDMM per International Myeloma Working Group diagnostic criteria, have measurable disease at screening, and have high-dose therapy and ASCT as part of their intended initial treatment plan. Exclusion criteria are patients who have received any prior therapy for MM or smoldering myeloma (except a short course of corticosteroids). After giving informed consent, patients are randomized 1:1 into 2 treatment arms (target recruitment: N=750). In the cilta-cel arm, patients will undergo apheresis before receiving 6 cycles of DVRd induction. After induction, patients will receive lymphodepletion (intravenous cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily for 3 days), followed by a single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) 5-7 days later. After the cilta-cel infusion, patients will receive lenalidomide post CAR-T therapy for 2 years (or longer, at investigator discretion). In the control arm, patients will receive 4 cycles of DVRd induction, followed by ASCT and 2 cycles of DVRd consolidation. Patients will then receive lenalidomide maintenance for 2 years (or longer at investigator discretion). The dual primary endpoints are progression-free survival (PFS) and minimal residual disease (MRD)-negative CR sustained for ≥12 months, with MRD status determined by next-generation sequencing at a sensitivity of at least 10-5. Secondary endpoints include ORR, ≥CR rate, overall MRD-negative CR rate, time to subsequent therapy, PFS on next-line therapy, overall survival, adverse events, pharmacokinetic/pharmacodynamic markers, and changes in health-related quality of life. Exploratory correlative biomarker analyses will also be performed. Enrollment opens in September 2022, with anticipated primary completion in June 2026. This study will investigate the efficacy and safety of a cellular therapy approach with cilta-cel versus standard of care ASCT in patients with NDMM who are transplant eligible. Figure: EMagine/CARTITUDE-6 Study Design Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cachexia is associated with increased morbidity and mortality in cancer. The White adipose tissue (WAT) synthesizes and releases several pro-inflammatory cytokines that play a role in cancer cachexia-related systemic inflammation. IFN-γ is a pleiotropic cytokine that regulates several immune and metabolic functions. To assess whether IFN-γ signalling in different WAT pads is modified along cancer-cachexia progression, we evaluated IFN-γ receptors expression (IFNGR1 and IFNGR2) and IFN-γ protein expression in a rodent model of cachexia (7, 10, and 14 days after tumour implantation). IFN-γ protein expression was heterogeneously modulated in WAT, with increases in the mesenteric pad and decreased levels in the retroperitoneal depot along cachexia progression. Ifngr1 was up-regulated 7 days after tumour cell injection in mesenteric and epididymal WAT, but the retroperitoneal depot showed reduced Ifngr1 gene expression. Ifngr2 gene expression was increased 7 and 14 days after tumour inoculation in mesenteric WAT. The results provide evidence that changes in IFN-γ expression and signalling may be perceived at stages preceding refractory cachexia, and therefore, might be employed as a means to assess the early stage of the syndrome.