BACKGROUND:In CARTITUDE-4, a single infusion of ciltacabtagene autoleucel (cilta-cel) significantly prolonged progression-free survival in patients with lenalidomide-refractory multiple myeloma. We report updated overall survival and longer-term efficacy and safety outcomes. METHODS:CARTITUDE-4 is an open-label, multicentre, randomised, phase 3 trial at 81 hospital sites in the USA, Europe, Asia, and Australia. Eligible patients were adults (aged >18 years) with lenalidomide-refractory multiple myeloma, with one to three previous treatment lines, including a proteasome inhibitor and an immunomodulatory drug, and an Eastern Cooperative Oncology Group performance status of 0 or 1. After the trial started, the threshold defining measurable disease was lowered to 0·5 g/dL from 1·0 g/dL serum monoclonal paraprotein on July 2, 2021, to increase trial access. Patients were randomly assigned (1:1) via a computerised algorithm and balanced with permuted blocks, with stratification by physician's choice of pomalidomide-bortezomib-dexamethasone versus daratumumab-pomalidomide-dexamethasone, International Staging System stage, and number of previous treatment lines. Patients were assigned to cilta-cel (apheresis, bridging therapy [at least one pomalidomide-bortezomib-dexamethasone or daratumumab-pomalidomide-dexamethasone cycle], lymphodepletion, then cilta-cel infusion [0·75 × 106 CAR T cells per kg]) or standard of care (pomalidomide-bortezomib-dexamethasone [21-day cycles: 4 mg/day oral pomalidomide on days 1-14; 1·3 mg/m2 subcutaneous bortezomib twice a week for 2 weeks for eight cycles, then once a week for 2 weeks per cycle; 20 mg or, if aged >75 years, 10 mg oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 for eight cycles, then days 1, 2, 8, and 9 per cycle] or daratumumab-pomalidomide-dexamethasone [28-day cycles: 1800 mg subcutaneous daratumumab weekly for 2 cycles, every 2 weeks for four cycles, then every 4 weeks; 4 mg/day oral pomalidomide on days 1-21; 40 mg/week or, if aged >75 years, 20 mg/week oral or intravenous dexamethasone]). The primary endpoint was progression-free survival, previously published. In this Article, we report a prespecified second interim analysis of overall survival and an updated analysis of progression-free survival in the intention-to-treat population. This trial was registered at ClinicalTrials.gov (NCT04181827) and is ongoing. FINDINGS:Patients were randomly assigned between July 10, 2020, and Nov 17, 2021, to receive cilta-cel (n=208) or standard of care (n=211). At a median follow-up of 33·6 months (IQR 20·3-35·0), median progression-free survival was not reached (95% CI 34·5 months-not evaluable) in the cilta-cel group versus 11·8 months (9·7-14·0) in the standard-of-care group (HR 0·29 [95% CI 0·22-0·39]). Median overall survival was not reached (95% CI not evaluable) with cilta-cel versus not reached (37·7 months-not evaluable) with standard of care (HR 0·55 [95% CI 0·39-0·79]; p=0·0009). 30 (14%) of 208 patients in the cilta-cel group and 77 (37%) of 208 in the standard-of-care group had maximum grade 3 treatment-emergent adverse events, most commonly anaemia (72 [35%]) in the cilta-cel group and neutropenia (59 [28%]) in the standard-of-care group. Rates of maximum grade 4 treatment-emergent adverse events were 156 (75%) with cilta-cel and 116 (56%) with standard of care, most commonly neutropenia (152 [73%] with cilta-cel and 112 [54%] with standard of care). Serious treatment-emergent adverse events occurred in 98 (47%) patients in each group. Deaths in the safety population occurred in 50 (24%) in the cilta-cel group and 82 (39%) in the standard-of-care group, including due to treatment-related adverse events in six (3%; four due to infection) in the cilta-cel group and five (2%; all due to infection) in the standard-of-care group. INTERPRETATION:The significantly improved overall survival and patient-reported measures in CARTITUDE-4 reinforce the use of cilta-cel in treating relapsed or refractory multiple myeloma as early as after first relapse. FUNDING:Johnson & Johnson, Legend Biotech USA.

Abstract Background The Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q) is a validated, disease-specific patient-reported outcome (PRO) instrument that measures symptoms and impacts experienced by patients with multiple myeloma (MM). We describe key measurement properties of the MySIm-Q instrument using CARTITUDE-4 data. Methodology The phase 3 CARTITUDE-4 (NCT04181827) trial compares ciltacabtagene autoleucel with standard-of-care regimens in patients with lenalidomide-refractory MM after 1–3 lines of therapy. Following US Food and Drug Administration guidance on the use of PRO measures in clinical trials, the reliability, as well as aspects of construct validity, convergent and discriminant validity of the MySIm-Q symptom and impact scores (2 separate concepts) were assessed. Results In total, 361 patients completed MySIm-Q assessments. Internal consistency results met the predefined threshold (McDonald’s ꞷ coefficient > 0.7; ꞷ=0.87 for total symptom scores, ꞷ=0.79 for total impact scores), while test-retest reliability was slightly below this threshold (intraclass correlation coefficient [ICC](2,1) > 0.70; ICC = 0.67 and 0.65, respectively). Known-groups validity of total symptom and total impact scores was established through multiple hypotheses. Factor scores estimated from the confirmatory factor analysis model were highly correlated with simple observed scores calculated in symptom and impact scores. Item-level convergent and discriminant validity was supported for all and nearly all items, respectively. Domain convergent and discriminant validity for total scores were largely met. Conclusions These results demonstrate that the MySIm-Q yields reliable and valid scores based on a number of evidentiary sources, supporting its use as a fit-for-purpose PRO instrument in clinical outcome assessments for patients with MM. Trial registration CARTITUDE-4: ClinicalTrials.gov ID: NCT04181827. Date of registration: 27 November 2019. URL: https://www.clinicaltrials.gov/study/NCT04181827 .

High-risk smoldering multiple myeloma (HR-SMM) carries an increased risk of progression to multiple myeloma, making it an ideal setting to test whether chimeric antigen receptor (CAR) T cell therapy can achieve curative outcomes. Here in this phase 2 study, patients with HR-SMM received ciltacabtagene autoleucel (cilta-cel) at 0.3-0.5 × 106 or >0.5 × 106 viable CAR+ T cells per kilogram without induction or bridging therapy. Patients with >40% marrow involvement were excluded. Primary endpoints were dose-limiting toxicities (DLTs) and treatment-emergent adverse events; secondary endpoints included response and minimal residual disease (MRD) negativity. As of 11 February 2026, 20 patients had been treated. The trial met the prespecified endpoints. No DLTs occurred. Adverse events included transient cytopenias (90% grade 3/4) and cytokine release syndrome (100% grade 1/2). Non-immune effector cell-associated neurotoxicity syndrome neurologic toxicities (NINTs) occurred in seven patients, with four comprising cranial nerve palsies that completely resolved. Three patients had persistent grade 1 symptoms. At a median follow-up of 15.3 months, all patients achieved MRD negativity 10-6 by 2 months and have remained MRD negative. Sixteen patients with follow-up >6 months achieved a complete response; no progression or deaths were observed. Cilta-cel produced rapid, deep, sustained MRD-negative responses in HR-SMM without induction therapy. Toxicities were consistent with the safety profile of cilta-cel. ClinicalTrials.gov: NCT05767359 .

ABSTRACT:In the primary analysis of ANDROMEDA, addition of subcutaneous daratumumab to VCd (bortezomib, cyclophosphamide, and dexamethasone; D-VCd) significantly improved hematologic complete response (CR) rate vs VCd, establishing D-VCd as the only approved therapy for light-chain (AL) amyloidosis. We present results from the preplanned final analysis. In this phase 3 trial, we randomly assigned 388 patients with newly diagnosed AL amyloidosis to 6 cycles of VCd alone (control group) or with subcutaneous daratumumab (D-VCd) followed by single-agent daratumumab every 4 weeks for up to 24 total cycles. The primary end point was hematologic CR. The updated hematologic CR rate was 59.5% for D-VCd vs 19.2% for VCd (odds ratio, 6.03; 95% confidence interval [CI], 3.80-9.58; P< .0001). Median time to hematologic CR was shorter with D-VCd (67.5 days [range, 8.0-879.0]) vs VCd (85.0 days [range, 14.0-617.0]). With a median follow-up of 61.4 months, significant improvement was observed with D-VCd vs VCd in major organ deterioration-progression-free survival (hazard ratio, 0.44; 95% CI, 0.31-0.63; P< .0001) and overall survival (hazard ratio, 0.62; 95% CI, 0.42-0.90; P = .0121). Cardiac and renal response rates were 2 to 3 times higher with D-VCd vs VCd. Achieving hematologic or cardiac CR was associated with improved major organ deterioration-progression-free survival and overall survival. Adverse events were consistent with the known safety profiles for VCd and daratumumab. Adding daratumumab to VCd resulted in deeper and more rapid hematologic responses and organ function recovery, translating to statistically significant improvement in both overall survival and major organ deterioration-progression-free survival in newly diagnosed AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT03201965.

Background In CARTITUDE-4, ciltacabtagene autoleucel (cilta-cel) significantly improved progression-free survival (primary endpoint; previously reported) versus standard of care in patients with relapsed, lenalidomide-refractory multiple myeloma. We report here patient-reported outcomes. Methods In the ongoing, phase 3, open-label CARTITUDE-4 study, patients were recruited from 81 sites in the USA, Europe, Asia, and Australia, and were randomly assigned 1:1 to cilta-cel (target, 0 center dot 75 x 10(6) CAR-T cells/kg) or standard of care (daratumumab, pomalidomide, and dexamethasone; pomalidomide, bortezomib, and dexamethasone). Eligible patients had relapsed, lenalidomide-refractory multiple myeloma, received one to three previous treatment lines including a proteasome inhibitor and an immunomodulatory drug, and had an ECOG performance status of 0 or 1. Secondary endpoints reported here include time to sustained worsening of symptoms (Multiple Myeloma Symptom and Impact Questionnaire [MySIm-Q]; a key secondary endpoint) and change in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire Core C30 (intention-to-treat population) and EuroQol 5-Dimension 5-Level (EQ-5D-5L; intention-to-treat population). This study is registered with ClinicalTrials.gov number NCT04181827 and is ongoing. Findings Patients were enrolled from July 10, 2020, to Nov 17, 2021, and 419 of 516 screened patients were randomly assigned (cilta-cel, n=208; standard of care, n=211; median follow-up, 15 center dot 9 months [IQR 12 center dot 4 to 17 center dot 8]); median age was 61 years. 191 (92%) of 208 patients in the cilta-cel group and 190 (91%) of 209 evaluable patients in the standardof-care group completed baseline assessments. MySIm-Q compliance post-baseline was 70 to 81% (cilta-cel) and 79 to 89% (standard of care). MySIm-Q median time to sustained symptom worsening with cilta-cel versus standard of care was 23 center dot 7 versus 18 center dot 9 months (HR 0 center dot 42; 95% CI 0 center dot 26 to 0 center dot 68). 12-month mean changes for EORTC global health status (GHS) were +10 center dot 1 (95% CI 7 center dot 0 to 13 center dot 1) and -1 center dot 5 (95% CI -5 center dot 3 to 2 center dot 3) points and were +8 center dot 0 (95% CI 5 center dot 2 to 10 center dot 7) and +1 center dot 4 (95% CI -1 center dot 9 to 4 center dot 7) points for EQ-5D-5L visual analogue scale (VAS). Rates of clinically meaningful improvements in GHS and VAS were higher with cilta-cel than with standard of care. Interpretation Health-related QoL improvements and delayed symptom worsening support cilta-cel's clinical efficacy in lenalidomide-refractory disease. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Ciltacabtagene autoleucel (cilta-cel) is approved for relapsed or refractory multiple myeloma (RRMM). In the CARTITUDE-4 study (NCT04181827), cilta-cel demonstrated superior efficacy versus pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone in patients with RRMM after 1–3 prior lines of therapy (LOT). We conducted an indirect treatment comparison to understand the comparative efficacy of cilta-cel versus real-world (RW) physician’s choice of treatment for lenalidomide-refractory MM. De-identified data from the Flatiron Health MM cohort registry (January 2020 to May 2024) were compared with data from CARTITUDE-4 (data cutoff May 1, 2024). Key eligibility criteria for CARTITUDE-4 were used to match patients from the Flatiron database. Baseline covariates of prognostic significance were adjusted using inverse probability of treatment weighting. Outcomes for comparative effectiveness included progression-free survival (PFS), RW PFS, time to next treatment (TTNT), and overall survival (OS). Sensitivity analyses were conducted. The CARTITUDE-4 cohort included data from 208 patients who received cilta-cel; the median follow-up was 33.6 months. The real-world cohort included 932 patients (1445 eligible LOT) from the Flatiron database; the median follow-up was 23.6 months. In base case analyses, compared with the Flatiron cohort, patients treated with cilta-cel had improved PFS (hazard ratio [HR] 0.29 [95

BACKGROUND:Early continuous lenalidomide use for multiple myeloma (MM) treatment has led to more patients with lenalidomide-refractory disease at earlier lines of therapy (LOTs). Real-world treatment practices and outcomes in elderly patients with comorbidities are not well characterized. MATERIALS AND METHODS:Using the Surveillance, Epidemiology, and End Results-Medicare database, we analyzed data from patients who were diagnosed with MM between 2014 and 2019, had 1 to 3 prior LOTs, including a proteasome inhibitor and an immunomodulatory drug, and were lenalidomide refractory. Patients were followed from index (initiation of first subsequent LOT after meeting eligibility criteria and after January 1, 2016) until death, end of continuous Medicare enrollment, or December 31, 2020. RESULTS:This analysis included 1297 patients (median age, 75 years). The mean National Cancer Institute Comorbidity Index score was 0.87 and 81% had at least 1 comorbidity. Singlet, doublet, and triplet therapies each accounted for ∼30% of index regimens. The most common regimens, ± corticosteroid, were daratumumab-pomalidomide (15%), pomalidomide (13%), and daratumumab (12%). Median overall survival and time to next treatment (TTNT) were 29.3 and 8.5 months, respectively. TTNT decreased with successive LOTs (1 prior LOT, 11.0 months; 3 prior LOTs, 6.1 months). CONCLUSION:Elderly patients with comorbidities and lenalidomide-refractory disease after 1 to 3 LOTs receive suboptimal regimens, have poor outcomes, and move rapidly through treatments, highlighting the need for new effective treatments for this difficult-to-treat population.

Introduction Ciltacabtagene autoleucel (Cilta-cel) is a multiple myeloma (MM) specific CAR-T cell therapy targeting BCMA. Teclistamab (Tec), and talquetamab (Tal) are MM directed T cell bispecifics (BsAbs) targeting BCMA and GPRC5D, respectively. All three therapies are designed to harness the anti-tumor activity of T cells. Yet, little is known about their use in concert and/or their preferred sequencing to ensure maximal therapeutic benefit. Likewise, little data exist exploring the impact of daratumumab (Dara), a monoclonal antibody targeting CD38, on the efficacy of Cilta-cel. Our reverse translation work aims to characterize the underlying mechanistic interactions between these therapies to potentially inform on their optimal clinical utilization and help accelerate the development of regimens with curative intent in MM. Results Using an in vitro model in which healthy donor T cells were exposed to MM tumor cells and either Tec or Tal, we showed that exposure to BsAbs induced downregulation of CD28 on T cells and up-regulation of markers associated with T cell exhaustion. Downstream assays using these BsAb pre-exposed T cells revealed diminished expansion and reduced transduction efficiency during the generation of research grade Cilta-cel, and a reduced capacity of the derived CAR-T products to kill MM cells in a serial cytotoxicity assay. Tec and Tal produced similar results, suggesting this effect is BMCA and GPRC5D target agnostic. These data may have revealed an underlying mechanism to previously published studies in which MM patients who had been administered BCMA BsAbs prior to apheresis exhibited a lower response rate and a shorter duration of response to BCMA CAR-T as compared to patients who had not been administered BsAbs prior to apheresis. Interestingly, when BsAbs were concurrently added with research-grade Cilta-cel to MM cells, enhanced cytotoxicity was observed in a synergistic manner. These observations were associated with increased levels of activation and proliferation of the CAR negative T cells present in the co-culture along with increased expression of FAS and ICAM-1 on the tumor cells. Such characteristics are also aligned with CAR-T mediated increases in bystander killing, which in turn could help lower the threshold for response to BsAbs. The effect was most striking in models containing suboptimal CAR-T effector cells to tumor cells (E:T) ratio, which may be more representative of compromised T cell fitness and/or high tumor burden. Additionally, even a small percentage of CAR-T cells synergized with BsAbs, suggesting that introduction of BsAbs away from CAR-T peak expansion may still enhance clinical benefit. Finally, the addition of Dara, with or without BsAbs, also synergistically enhanced the in vitro cytotoxicity of research-grade Cilta-cel against MM cells. In contrast to BsAbs, Dara was shown to limit the overall expansion of research grade Cilta-cel. However, immunophenotyping data showed that the remaining CAR-T cells exhibited a reduction in the frequency of exhausted T cells and CD38+ Tregs, potentially indicating improved T cell fitness. Conclusion These preliminary data support careful consideration of the timing of apheresis with respect to treatment with BsAbs, to preserve T cell fitness. They also suggest that Tec, Tal and Dara, alone or in combination, may have an important role in bridging and maintenance strategies to enhance the cytotoxic activity of Cilta-cel, if labeling indications permit. Furthermore, these agents may potentially optimize reduced Cilta-cel cytotoxicity resulting from BsAb exposure prior to apheresis. Ultimately, mechanisms unraveled by this study may help guide trial designs and the development of novel therapeutic regimens, although more investigation will be required.

Background In CARTITUDE-4, ciltacabtagene autoleucel (cilta-cel) significantly improved progression-free survival (primary endpoint; previously reported) versus standard of care in patients with relapsed, lenalidomide-refractory multiple myeloma. We report here patient-reported outcomes. Methods In the ongoing, phase 3, open-label CARTITUDE-4 study, patients were recruited from 81 sites in the USA, Europe, Asia, and Australia, and were randomly assigned 1:1 to cilta-cel (target, 0·75 × 106 CAR-T cells/kg) or standard of care (daratumumab, pomalidomide, and dexamethasone; pomalidomide, bortezomib, and dexamethasone). Eligible patients had relapsed, lenalidomide-refractory multiple myeloma, received one to three previous treatment lines including a proteasome inhibitor and an immunomodulatory drug, and had an ECOG performance status of 0 or 1. Secondary endpoints reported here include time to sustained worsening of symptoms (Multiple Myeloma Symptom and Impact Questionnaire [MySIm-Q]; a key secondary endpoint) and change in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire Core C30 (intention-to-treat population) and EuroQol 5-Dimension 5-Level (EQ-5D-5L; intention-to-treat population). This study is registered with ClinicalTrials.gov number NCT04181827 and is ongoing. Findings Patients were enrolled from July 10, 2020, to Nov 17, 2021, and 419 of 516 screened patients were randomly assigned (cilta-cel, n=208; standard of care, n=211; median follow-up, 15·9 months [IQR 12·4 to 17·8]); median age was 61 years. 191 (92%) of 208 patients in the cilta-cel group and 190 (91%) of 209 evaluable patients in the standard- of-care group completed baseline assessments. MySIm-Q compliance post-baseline was 70 to 81% (cilta-cel) and 79 to 89% (standard of care). MySIm-Q median time to sustained symptom worsening with cilta-cel versus standard of care was 23·7 versus 18·9 months (HR 0·42; 95% CI 0·26 to 0·68). 12-month mean changes for EORTC global health status (GHS) were +10·1 (95% CI 7·0 to 13·1) and –1·5 (95% CI –5·3 to 2·3) points and were +8·0 (95% CI 5·2 to 10·7) and +1·4 (95% CI –1·9 to 4·7) points for EQ-5D-5L visual analogue scale (VAS). Rates of clinically meaningful improvements in GHS and VAS were higher with cilta-cel than with standard of care. Interpretation Health-related QoL improvements and delayed symptom worsening support cilta-cel's clinical efficacy in lenalidomide-refractory disease. Funding Janssen Research & Development, Legend Biotech USA.

The phase 3 CARTITUDE-4 trial demonstrated superiority of ciltacabtagene autoleucel (cilta-cel) over daratumumab, pomalidomide and dexamethasone, or pomalidomide, bortezomib and dexamethasone, in lenalidomide-refractory patients with relapsed/refractory multiple myeloma (RRMM) who received 1–3 prior lines of therapy. The comparative efficacy of cilta-cel was previously evaluated against other common regimens. Here, we present an updated comparative efficacy assessment, including OS, between cilta-cel (CARTITUDE-4 34-month median follow-up) and common regimens. Individual patient data were available from CARTITUDE-4 (cilta-cel), CASTOR (daratumumab, bortezomib and dexamethasone [DVd]), CANDOR (daratumumab, carfilzomib and dexamethasone [DKd] and carfilzomib and dexamethasone [Kd]) and APOLLO (pomalidomide and dexamethasone [Pd]). Inverse probability of treatment weighting (IPTW) was used to adjust for key baseline patient characteristic imbalances. Relative efficacies were estimated with response rate ratios and 95

Matching adjusted indirect comparisons (MAICs) were performed to compare the efficacy of cilta-cel versus elotuzumab + pomalidomide + dexamethasone (EloPd), isatuximab + carfilzomib + dexamethasone (IsaKd), isatuximab + pomalidomide + dexamethasone (IsaPd), and selinexor + bortezomib + dexamethasone (SVd) in patients with relapsed or refractory multiple myeloma (RRMM) who have received at least one prior therapy and are lenalidomide-refractory. Unanchored MAICs were performed using individual patient-level data (IPD) for all apheresed patients randomized to the cilta-cel arm of CARTITUDE-4 (n = 208) and published arm-level data for EloPd from ELOQUENT-3 (n = 60), IsaKd from IKEMA (lenalidomide-refractory subgroup, n = 57), IsaPd from ICARIA-MM (n = 154), and SVd from BOSTON (lenalidomide-refractory subgroup, n = 53). Eligibility criteria from each comparator trial were applied to the cilta-cel arm IPD, and further imbalances in patient characteristics were adjusted by weighting the cilta-cel patient data to match the reported baseline characteristics of the comparator trials. Comparative efficacy was estimated for overall response rate, very good partial response or better (≥ VGPR) rate, complete response or better (≥ CR) rate, progression-free survival (PFS), and overall survival (OS). After adjustment, cilta-cel patients were significantly more likely to achieve an overall response versus EloPd, IsaPd, and SVd, and were significantly more likely to achieve ≥ VGPR and ≥ CR versus all comparators. Cilta-cel patients also had significant reductions in the risk of disease progression or death (PFS) versus all comparators: 64

We describe two patients in whom malignant monoclonal T-cell lymphoproliferation developed after administration of chimeric antigen receptor (CAR) T-cell therapy with ciltacabtagene autoleucel (cilta-cel) in the phase 3 CARTITUDE-4 trial. Monoclonal T cells from both patients had detectable CAR transgene expression and integration. The clinicogenomic features of these CAR transgenic T-cell lymphoproliferative neoplasms suggest that multiple potential intrinsic or extrinsic factors (or both) contributed to their pathogenesis, such as transduction of preexisting TET2-mutated T cells, followed by acquisition of further oncogenic genomic variants. Other potential contributors include germline genomic variation, viral infections, and previous treatment for myeloma. In the absence of direct evidence, the contribution of insertional mutagenesis to the development of T-cell lymphoma is currently unclear. (Funded by Johnson & Johnson and Legend Biotech USA; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).

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.

ABSTRACT Background Early (often continuous) treatment of multiple myeloma (MM) with lenalidomide has become common practice, leading to an increase in lenalidomide‐refractory disease. Methods We report real‐world treatment patterns, health care resource utilization (HCRU), and outcomes for patients with lenalidomide‐refractory MM using data from Optum US Claims and Optum electronic health record (EHR) databases with index date from January 2016 to March 2022 (Claims) or December 2021 (EHR). Eligible patients had received 1–3 prior lines of therapy (LOT), including a proteasome inhibitor. Results A total of 1383 and 1597 patients with lenalidomide‐refractory disease were included from the Claims and EHR databases, respectively, with median ages of 72 and 68 years and mean Charlson Comorbidity Index scores of 4.0 and 3.1. The most common treatment combinations were daratumumab–pomalidomide–dexamethasone, daratumumab–bortezomib–dexamethasone, and pomalidomide–dexamethasone (~5% each). From LOT 2 to LOT 6, treatment attrition (patients who died or received no further treatment) was 95.2% to 95.9%. Median time to next treatment was 5.4 (Claims) and 5.9 months (EHR). Median OS was 35.2 (Claims) and 41.2 months (EHR). HCRU was consistent across LOT. Conclusions Patients with lenalidomide‐refractory MM who received 1–3 prior LOT had poor outcomes and moved quickly through available therapies, demonstrating an unmet need to improve outcomes in this difficult‐to‐treat patient population.

PURPOSENewly approved drugs and combinations treating multiple myeloma (MM) have resulted in substantial improvements in patients' survival. To deliver rapid access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to evaluate the minimal residual disease-negative complete response (MRD-CR) as an intermediate end point for progression-free survival (PFS) and overall survival (OS) in newly diagnosed (ND) transplant-eligible (NDTE) patients, ND transplant-ineligible (NDTinE) patients, and patients with relapsed/refractory (RR) MM.PATIENTS AND METHODSIndividual patient data from 20 randomized multicenter trials were collected. Eleven studies (4,773 patients) with sufficient data were analyzed to evaluate whether 9- or 12-month MRD-CR classified at a 10-5 threshold could be reasonably likely to predict the clinical benefit of new agents regarding PFS and OS. Global odds ratio (OR) was estimated using the bivariate Plackett Copula model. Supportive evaluation included correlations of the treatment effects on MRD-CR end points and PFS/OS, evaluated by both linear regression (R2weighted least squared) and Copula (R2Copula) models.RESULTSThe analysis demonstrated that both 9- and 12-month MRD-CR strongly correlated with PFS at patient level in NDTE patients, NDTinE patients, and patients with RRMM. Global ORs ranged from 3.06 to 16.24, all with 95% CIs excluding 1.0. Encouraging trial-level correlations (R2, 0.61-0.70) were observed by pooling three populations and were stronger (R2, 0.67-0.78) in the ND population. Similar results were observed for OS.CONCLUSIONOur findings provided the support for use of MRD-CR classified at a 10-5 threshold at either 9 or 12 months after starting of the treatment, as an intermediate end point to support accelerated approvals, in future trials in NDTE patients, NDTinE patients, and patients with RRMM.

Background: The introduction of proteasome inhibitors (PIs) and lenalidomide as treatment for newly diagnosed multiple myeloma (MM) has led to an increased population of lenalidomide-refractory patients. Limited data are available characterizing current treatments and outcomes in this difficult-to-treat population. Methods: Individual patient-level data were analyzed from the treatment arms of multiple daratumumab studies, including APOLLO, CASTOR, CANDOR, EQUULEUS, ALCYONE, MAIA, GRIFFIN, POLLUX, and CASSIOPEIA. Included patients were PI exposed and lenalidomide refractory, received 1-3 prior lines of therapy (LOT), and had an Eastern Cooperative Oncology Group performance status < 2. Treatments and outcomes were analyzed by number of prior LOT in the lenalidomide-refractory population. Time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Findings: Out of 4764 patients, 915 patients (prior LOT, one [n = 114]; two [n = 462]; three [n = 339]) met inclusion criteria. Median follow-up was 29.7 months (range 28.0-31.7). The overall response rate was 55.4 %. Estimated median TTNT was 9.7 months, median PFS was 10.0 months, and median OS was 27.5 months. Response rates and PFS decreased as number of prior LOT increased. Prognostic factors for response, TTNT, PFS, and OS included International Staging System stage, baseline plasmacytoma status, baseline hemoglobin, antiCD38-refractory status, and cytogenetic risk status. Interpretation: Lenalidomide-refractory patients treated with 1-3 prior LOT have poor PFS and OS, which generally worsen with each additional LOT, highlighting the need for new and effective treatments for this population.

Introduction: CARTITUDE-4 is a phase 3 randomized controlled trial (RCT) assessing the efficacy and safety of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in patients with relapsed and refractory multiple myeloma (RRMM) who have received one to three prior line(s) of therapy that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI), and who are refractory to lenalidomide. CARTITUDE-4 demonstrated superiority of cilta-cel over PVd and DPd on progression-free survival (PFS) and response rates (overall response rate [ORR], very good partial response [VGPR] or better, and complete response [CR] or better [CR or stringent CR]). Other available therapies for the treatment of this patient population where individual patient data was available for analysis include: daratumumab in combination with bortezomib and dexamethasone (DVd), bortezomib in combination with dexamethasone (Vd), carfilzomib in combination with daratumumab and dexamethasone (DKd) or dexamethasone alone (Kd), and pomalidomide in combination with dexamethasone (Pd). This analysis aims to compare efficacy outcomes in patients randomized to the cilta-cel arm (i.e., patients apheresed or infused with cilta-cel) in CARTITUDE-4 vs each of these regimens in the same target population. Methods: Individual patient data were collected from the CARTITUDE-4 (cilta-cel), CASTOR (DVd and Vd), CANDOR (DKd and Kd), and APOLLO (Pd) RCTs. Patients who met CARTITUDE-4 eligibility criteria were identified from the above mentioned RCTs. As no patients in the comparative trials had prior treatment with anti-CD38, patients with prior exposure to anti-CD38 therapies in the cilta-cel cohort were excluded. Key prognostic baseline covariates including refractory status, ISS stage, presence of extramedullary disease, and time to progression on prior line, were adjusted for using inverse probability of treatment weighting (IPTW), with average treatment effect in the treated weights. Differences in baseline characteristics were assessed using standardized mean differences. PFS, ORR, VGPR or better, and CR or better were compared between patients in the cilta-cel arm and the comparator regimens. Relative efficacy of cilta-cel vs comparator regimens were estimated with hazard ratios (HRs) and 95% confidence intervals (CIs) from weighted Cox proportional hazards models for PFS, and response rate ratios (RRs) and 95% CIs from weighted logistic regression models for ORR, VGPR or better, and CR or better. Sensitivity analyses using alternative statistical approaches and including additional covariates were explored. Results: After the exclusion of 53 patients with prior exposure to an anti-CD38 therapy, 155 patients in the cilta-cel arm remained. Across the comparative trials, 44 patients treated with DVd, 46 patients treated with Vd, 98 patients treated with DKd, 46 patients treated with Kd, and 92 patients treated with Pd met the inclusion criteria of CARTITUDE-4. Baseline covariates were similar across the cohorts after IPTW. Patients randomized to the cilta-cel arm showed significant improvements in PFS (adjusted HRs from 0.11 vs Vd to 0.51 vs DKd), VGPR or better (adjusted RRs from 1.51 vs DKd to 5.13 vs Vd), and CR or better rate (adjusted RRs from 2.90 vs DKd to 35.24 vs Pd) (Table). Improvements in ORR were also observed against all comparator regimens (adjusted RRs from 1.22 vs DKd to 1.90 vs Pd), though were marginally not statistically significant vs DVd and Kd. Treatment with DKd consistently yielded the best results out of all comparator regimens, but results were still in favor of cilta-cel. Results of cilta-cel benefit were consistent across sensitivity analyses, yielding adjusted HRs below 1.00 and RRs above 1.00 in all cases against other comparator regimens. Conclusions: Data from CARTITUDE-4 and these analyses demonstrate the benefit of cilta-cel over additional regimens commonly used in clinical practice, highlighting its potential to become a new standard of care option for patients with RRMM, who have received one to three prior lines(s) of therapy, including an IMiD and a PI, and who are refractory to lenalidomide. These comparisons provide valuable information to contextualize the efficacy of CARVYKTI in countries where standard of care may be different from DPd/PVd.

Introduction: CARTITUDE-4 is a phase 3 randomized controlled trial (RCT) assessing the efficacy and safety of citacabtagene autoleucel (cilta-cel) versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in patients with relapsed and refractory multiple myeloma (RRMM) with 1-3 prior line(s) of therapy (LOT) that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI), and who are refractory to lenalidomide. This updated analysis compares the relative efficacy of cilta-cel from the CARTITUDE-4 study with Real-World Physician's Choice (RWPC) using an external control arm from the Flatiron Health MM cohort registry. Methods: Data from Jan 2020 until May 2024 were extracted from the Flatiron Health US MM cohort registry of deidentified patient-level electronic health records for patients who matched key eligibility criteria for CARTITUDE-4 (1-3 prior LOT, Eastern Cooperative Oncology Group performance status [ECOG PS] of 0-1, lenalidomide refractory, PI and IMiD exposed, eGFR ≥40 mL/min/1.73 m2, and hemoglobin ≥8 g/dL). The clinical cut-off for the updated prespecified analysis of CARTITUDE-4 was 1 May 2024, and the index date of Flatiron was restricted to trial enrollment period 2020-2021. As the base case, inverse probability of treatment weighting (IPTW) was used to adjust for unbalanced baseline covariates: PI-refractory status, anti-CD38-refractory status, cytogenetic profile, International Staging System (ISS) stage, time to progression on last regimen, number of prior LOT, years since diagnosis, age, and hemoglobin level; additionally, prior transplant, ECOG PS, race, sex, and MM type were added in the fully adjusted sensitivity analyses. Comparative effectiveness was estimated for progression-free survival (PFS), overall survival (OS) and time to next treatment (TTNT). Sensitivity analyses conducted were multivariate regression, doubly robust method, and first observation vs all observations. Results: The CARTITUDE-4 cohort consisted of 208 patients in the cilta-cel arm (median follow-up of 34 months) and the Flatiron cohort consisted of 423 patients, corresponding to 667 eligible LOTs (external control arm; median follow-up, 37.6 months). Baseline characteristics were similar between the two cohorts after adjustment. According to National Comprehensive Cancer Network guidelines (NCCN) categorization, the most commonly used regimens in RWPC were NCCN recommended for 1-3 PL len-refractory (42.7%), NCCN 1-3 PL other (10.3%) and NCCN 1-3 PL useful in certain circumstances (19.5%). There is a significant number of regimens used that are not recommended by NCCN (25.6%). Among NCCN recommended for 1-3 PL len-refractory category (N=285), daratumumab, pomalidomide ± dexamethasane (41.1%), daratumumab, bortezomib ± dexamethasone (16.8%) and daratumumab, carfilzomib ± dexamethasone (12.6 %) are the most common regimens. In this updated analysis, cilta-cel demonstrated significant OS benefit, the adjusted HR (95% CI) for cilta-cel vs RWPC was 0.52 (0.36, 0.75); median (95% CI) OS for cilta-cel and RWPC was not reached and 44.81 (33.91, NE) months, respectively. Cilta-cel also improved PFS (adjusted hazard ratio [HR], 0.28 (0.22, 0.36)) vs RWPC; median (95% CI) PFS for cilta-cel was not reached (NR; 34.5−NE) vs 7.43 (6.37, 9.40) months for RWPC. The adjusted HR (95% CI) for cilta-cel vs RWPC was 0.32 (0.25, 0.42) for TTNT; median (95% CI) TTNT for cilta-cel and RWPC was NR (33.7−NE) and 9.33 (6.83, 11.07) months, respectively. Cilta-cel treatment benefit was robust and consistent across all sensitivity analyses including full models. Conclusions: These results consistently demonstrate a superior clinical benefit for cilta-cel vs RWPC on all measured outcomes. Cilta-cel reduced the risk of progression or death by 72% vs RWPC and reduced the risk of death or moving to the next treatment by 68%. In this update, cilta-cel further demonstrates superior overall survival benefit vs. RWPC, with a reduction of the risk of death by 48%. Results of the full model and sensitivity analyses were consistent with the base case. This data highlight the value of cilta-cel as an effective therapy in PI-exposed, len-refractory MM as early as first relapse. References: Touzeau C, et.al, EHA Library. Touzeau C. 06/13/2024; 421031; P967