Abstract
Idecabtagene vicleucel (ide‐cel) and ciltacabtagene autoleucel (cilta‐cel) have revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM), but direct comparisons are lacking. Leveraging an international multicenter RRMM cohort, we compared the outcome of ide‐cel (n = 162) versus cilta‐cel (n = 42). Co‐primary efficacy endpoints of the study were overall response rate (ORR) and progression‐free survival (PFS). Co‐primary safety endpoints were the incidence of cytokine release syndrome (CRS) and immune‐effector cell‐associated neurotoxicity syndrome (ICANS). Median turnaround time between apheresis and infusion was 47 days for ide‐cel versus 68 days for cilta‐cel (p < 0.001). Cilta‐cel showed significantly higher ORR (93% vs. 79%; p < 0.001), with complete response at Day 30 of 48% versus 26% (p < 0.001). The 10‐month PFS and overall survival (OS) was 82% and 90% for cilta‐cel versus 47% and 77% ide‐cel (p < 0.001 and p = 0.06), and improved outcome for cilta‐cel was confirmed after multivariable adjustment. Incidence of CRS and ICANS appeared similar (81% and 19% for cilta‐cel versus 85% and 19% for ide‐cel), while 10% and 7% in the cilta‐cel group versus 4% and 2% in the ide‐cel group showed severe CRS and ICANS grade 3–4, with CRS occurring significantly earlier for ide‐cel (median, 2 days vs. 4 days; p < 0.001). Nonrelapse mortality was 5% for cilta‐cel versus 3% for ide‐cel (p = 0.51). Cilta‐cel showed later peak of CAR‐T expansion at Day 14 versus Day 7 for ide‐cel, while cilta‐cel expansion was associated with ICANS. Our study provides real‐world evidence that cilta‐cel was associated with superior outcomes and distinct cellular dynamics versus ide‐cel in triple‐class exposed RRMM.
RESEARCH IN CONTEXT
Evidence before this study
Prior to this study, idecabtagene vicleucel (ide‐cel) and ciltacabtagene autoleucel (cilta‐cel) emerged as groundbreaking CAR‐T therapies for patients with relapsed/refractory multiple myeloma (RRMM). Both therapies demonstrated high overall response rates (ORR) and prolonged progression‐free survival (PFS) in their respective clinical trials (CARTITUDE‐1 and KarMMa‐1). However, direct comparative evidence is lacking, making it difficult for clinicians to determine the optimal choice for RRMM patients. Additionally, the safety profiles of these therapies, particularly concerning cytokine release syndrome (CRS), immune‐effector cell‐associated neurotoxicity syndrome (ICANS), and non‐relapse mortality needed further exploration in real‐world settings.
Added value of this study
This study, leveraging an international multicenter cohort of RRMM patients, provides the first direct real‐world comparison between ide‐cel and cilta‐cel, offering valuable insights into their relative efficacy and safety. The findings revealed that cilta‐cel demonstrated a significantly higher ORR (93% vs. 79%) and longer PFS, with a 10‐month PFS rate of 82% compared to 47% for ide‐cel. Although the incidence of CRS and ICANS was similar between the two therapies, cilta‐cel showed a slightly higher rate of severe CRS and ICANS, without increased risk for non‐relapse mortality. Furthermore, this study, for the first time, showed distinct cellular dynamics, revealing that cilta‐cel showed later peak expansion of CAR‐T cells at day 14 after infusion vs. day 7 for ide‐cel, while this expansion was associated with the development of ICANS only for cilta‐cel. Hence, this study not only highlights the superior clinical outcomes with cilta‐cel but also emphasizes the distinct cellular dynamics that might underlie these differences.
Implications of all the available evidence
The results of this study suggest that cilta‐cel may offer superior efficacy compared to ide‐cel for patients with triple‐class exposed RRMM, though at the cost of a potentially higher risk of severe CRS and ICANS, without the risk of increased non‐relapse mortality. These findings are critical for clinicians in making informed decisions about CAR‐T therapy selection, particularly in balancing the benefits of improved efficacy with the risks of adverse events. Moving forward, these insights could guide personalized treatment approaches and further research into optimizing CAR‐T therapy outcomes in RRMM. Additionally, the distinct cellular kinetics observed between ide‐cel and cilta‐cel warrant further investigation to better understand the mechanisms driving these differences and to potentially enhance the safety and efficacy of CAR‐T therapies in this challenging patient population.
INTRODUCTION
Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells in the bone marrow, leading to significant morbidity and mortality. 1 Despite astonishing advancements in treatment, 2 relapsed or refractory multiple myeloma (RRMM) remains a critical challenge (especially in triple‐class or penta‐refractory disease), necessitating innovative therapeutic approaches.
Chimeric antigen receptor T‐cell (CAR‐T) therapy targeting BCMA has revolutionized treatment for advanced, heavily pretreated MM. Idecabtagene vicleucel (ide‐cel) and ciltacabtagene autoleucel (cilta‐cel) have both demonstrated impressive efficacy in clinical trials and real‐world studies. 3 , 4 , 5 , 6 Ide‐cel, the first approved CAR‐T cell for RRMM, showed significant response rates, while cilta‐cel, with its dual antigen‐binding domains, has also proven to be highly effective. Despite their success, direct comparisons between these therapies are lacking, and a head‐to‐head trial is unlikely. 7 This study aims to fill that gap by comparing the relative benefits and risks of ide‐cel and cilta‐cel in a real‐world setting.
We aimed to provide a comprehensive comparison of these two therapies in the context of RRMM, evaluating their clinical characteristics, efficacy, and safety profiles. Through this comprehensive comparison, we aim to provide valuable insights that can guide clinical decision‐making and optimize treatment strategies for patients with RRMM.
METHODS
Patients
In this multicenter retrospective observational study, we included only patients infused with BCMA‐directed CAR‐T for RRMM across international CAR‐T centers (seven from Germany, one from Switzerland, and one from Spain) starting from the approval of ide‐cel by the European Commission in August 2021. We included only patients with RRMM infused with either ide‐cel or cilta‐cel. Patients with less than three prior lines of therapy were excluded from the study. Lymphodepletion was done with fludarabine and cyclophosphamide, as per manufacturers' recommendations. Out‐of‐specification use was allowed to reflect real‐world applications. Data collection and analyses within the study were approved by local ethics committees of participating sites. This study is in accordance with the Declaration of Helsinki. The last data cut was performed in February 2024.
Endpoints and definitions
The primary objective of this study was the comparison of progression‐free survival (PFS) between ide‐cel and cilta‐cel. Secondary objectives include assessing overall response rates (ORR), overall survival (OS), and nonrelapse mortality (NRM) the safety profiles, incidence of cytokine release syndrome (CRS), and neurotoxicity associated with each therapy. Through this comprehensive comparison, we aimed to provide valuable insights that can guide clinical decision‐making and optimize treatment strategies for patients with RRMM. Cytokine release syndrome and ICANS were defined and graded in accordance with current recommendations. 8 Treatment response was assessed in line with current criteria from the International Myeloma Working Group Criteria. 9 Fulfillment of response criteria was as per investigator's discretion. PFS was defined as relapse/progression or death from the time of CAR‐T infusion. NRM was defined as death without relapse/progression (with relapse/progression as a competing event). OS was defined as the time from CAR‐T infusion to death of any cause or last follow‐up. High‐risk cytogenetics were defined by the presence of del(17p), t(4;14), t(14;16), and gain of 1q. 10 , 11 Plasma cell leukemia (PCL) was defined in accordance with the current consensus. 12 Extramedullary disease was defined as organ manifestation, assessed with CT scan, MRI, or PET/CT as per each center's policy, and sole paraskeletal involvement was excluded from that definition. Disease‐specific risk was categorized with the revised International Staging System (R‐ISS). CAR‐T‐specific risk in RRMM was categorized with the Myeloma CAR‐T Relapse model (MyCARe). 6
Statistical analysis
First, we described the characteristics and outcomes of both ide‐cel and cilta‐cel. Second, we compared the efficacy and safety of both products in an univariable fashion. Third, we aimed to identify whether either CAR‐T product was an independent predictor of outcome, adjusting for previously defined clinical variables of interest (age, sex, performance status at time of CAR‐T infusion, time between diagnosis and CAR‐T infusion, R‐ISS, extramedullary disease, cytogenetic risk, and triple‐class or penta‐refractory status). The distribution of patient and treatment characteristics was compared between both products, using Chi‐squared for categorical variables or the Mann–Whitney test for continuous variables. Survival estimates were calculated using the Kaplan–Meier method. Follow‐up of survivors from the time of CAR‐T infusion was calculated with the reverse Kaplan–Meier method. NRM was assessed using the cumulative incidence function. Regression modeling with respect to NRM was applied within a competing risks framework by using the Fine & Gray method, with relapse/progression as a competing event. Cox proportional hazards were used to examine the effects on survival outcomes. The proportional hazards assumption was checked using Schoenfeld residuals. Violations in categorical risk factors were resolved by stratifying the corresponding hazard ratios according to patient follow‐up. Multiple testing was corrected with the Benjamini‐Hochberg method. Risk ratios and 95% confidence intervals (CI) were used to calculate relative risks 10 months after CAR‐T infusion, for the treatment comparison ide‐cel versus cilta‐cel according to different subgroups. All analyses were conducted using R (Version 4.0.5).
RESULTS
The total cohort comprised 204 patients, of whom 162 received ide‐cel and 42 received cilta‐cel. Median age at the time of CAR‐T infusion was 61 years (range, 28–82 years) for ide‐cel and 61 years (range, 24–84 years) for cilta‐cel (p = 0.32). Median time between diagnosis and CAR‐T infusion was 7.4 years for ide‐cel versus 6.9 years for cilta‐cel (p = 0.53). Time between apheresis and CAR‐T infusion was significantly different between both treatment groups (p < 0.001). The median turnaround time was 47 days (range, 28–190 days) for ide‐cel and 68 days (range, 33–139 days) for cilta‐cel.
More than half of the patients in each treatment group had an ECOG performance status of 1 at the time of CAR‐T infusion. Extramedullary disease was present at the time of CAR‐T infusion in 29% in the ide‐cel group and 48% in the cilta‐cel group, while PCL was present in 4% in the ide‐cel group and none in the cilta‐cel group.
Median number of prior lines of therapy was 6 for both groups. Refractory status was triple‐class for 64% in the ide‐cel group and 67% in the cilta‐cel group, and 36% in the ide‐cel group and 24% in the cilta‐cel group were penta‐refractory at the time of CAR‐T infusion. Eleven percent in the ide‐cel group and 10% in the cilta‐cel group had a history of prior exposure to BCMA‐directed therapy.
Most patients in both treatment groups were exposed to autologous stem cell transplantation before CAR‐T infusion. Most patient characteristics were generally well‐balanced between both treatment groups (Table 1).
Table 1.
Patient characteristics.
| Characteristic | Ide‐cel (n = 162) | Cilta‐cel (n = 42) | p |
|---|---|---|---|
| Age, median (range) | 61 (28–83) | 61 (24–84) | 0.32 |
| Sex, no. (%) | 0.08 | ||
| Male | 106 (65) | 21 (50) | |
| Female | 56 (35) | 21 (50) | |
| Race/Ethnicity, no. (%) | 0.35 | ||
| Non‐Hispanic White | 150 (93) | 42 (100) | |
| Non‐Hispanic Black | 4 (2) | 0 | |
| Hispanic | 5 (3) | 0 | |
| Other | 3 (2) | 0 | |
| ECOG, no. (%) | 0.11 | ||
| 0 | 52 (32) | 6 (14) | |
| 1 | 90 (56) | 70 (71) | |
| 2 | 18 (11) | 6 (14) | |
| 3 | 2 (1) | 0 | |
| R‐ISS, no. (%) | 0.35 | ||
| I | 33 (22) | 5 (12) | |
| II | 84 (55) | 27 (64) | |
| III | 35 (23) | 10 (24) | |
| Unknown | 10 | 4 | |
| Extramedullary disease, no. (%) | 47 (29) | 20 (48) | 0.03 |
| Plasma cell leukemia, no. (%) | 7 (4) | 0 | 0.19 |
| High‐risk cytogenetics, no. (%) | 76 (52) | 16 (52) | 0.94 |
| Unknown | 17 | 11 | |
| Prior transplantation, no. (%) | 0.03 | ||
| Autologous | 145 (90) | 42 (100) | |
| Allogeneic | 11 (7) | 0 | |
| Prior lines of therapy, no. (%) | 6 (3–14) | 6 (4–10) | 0.41 |
| Refractory status, no. (%) | |||
| Triple‐class | 104 (64) | 29 (67) | 0.77 |
| Penta | 58 (36) | 10 (24) | 0.20 |
| Prior anti‐BCMA exposure, no. (%) | 18 (11) | 4 (10) | 0.77 |
| Time between diagnosis and infusion in years, median (range) | 7.4 (0.2–27.6) | 6.9 (0.2–23.9) | 0.53 |
| Time between apheresis and infusion in days, median (range) | 47 (28–190) | 68 (33–139) | <0.001 |
| Follow‐up in months, median (95% CI) | 12.5 (11.7–13.3) | 8.9 (6.6–11.3) | <0.001 |
In terms of safety outcomes (Table 2), the incidence of CRS was similar between both treatment groups (p = 0.51), with 81% in the cilta‐cel group versus 85% in the ide‐cel group showing CRS of any grade after CAR‐T infusion. Half of the patients in both groups had grade 1 CRS, while 10% in the cilta‐cel groups versus 4% in the ide‐cel group showed CRS grade 3–4. The onset of CRS appeared to be significantly earlier in the ide‐cel group (median, 2 days) versus the cilta‐cel group (median, 4 days; p < 0.001).
Table 2.
Safety.
| Outcome | Ide‐cel (n = 335) | Cilta‐cel (n = 178) | p |
|---|---|---|---|
| CRS, no. (%) | 0.51 | ||
| None | 24 (15) | 8 (19) | |
| Grade 1 | 91 (56) | 20 (48) | |
| Grade 2 | 40 (25) | 10 (24) | |
| Grade 3 | 6 (4) | 2 (5) | |
| Grade 4 | 1 (<1) | 2 (5) | |
| Onset of CRS in days, median (range) | 1 (0–18) | 3 (0–15) | <0.001 |
| ICANS, no. (%) | 0.28 | ||
| None | 76 (81) | 34 (81) | |
| Grade 1 | 15 (16) | 5 (12) | |
| Grade 2 | 1 (1) | 0 (0) | |
| Grade 3 | 0 (0) | 2 (5) | |
| Grade 4 | 2 (2) | 1 (2) | |
| Onset of ICANS in days, median (range) | 3 (0–24) | 6 (1–22) | <0.001 |
The incidence of ICANS was similar, with ICANS of any grade occurring in 19% in both the cilta‐cel group and the ide‐cel group, respectively. However, severe ICANS grade 3–4 was seen in 7% of the cilta‐cel group versus 2% of the ide‐cel group. No grade 5 event was observed. Median onset of ICANS occurred significantly earlier in the ide‐cel group (median, 3 days) versus the cilta‐cel group (median, 6 days). Delayed neurotoxicity was observed in four patients (2%) with ide‐cel, occurring 105, 55, 39, and 29 days after CAR‐T infusion, respectively. In the cilta‐cel group, two patients (5%) experienced delayed neurotoxicity, occurring 70 days and 51 days after CAR‐T infusion, respectively. All six events were completely resolved with the use of corticosteroids. No parkinsonism was observed.
Next, we evaluated possible differences in resource utilization between both treatment groups. The median length of the hospital stay was 14 days (range, 6–63 days) in the ide‐cel group versus 17 days (range, 7–69 days) in the cilta‐cel group (p = 0.002). The use of tocilizumab was similar between both groups (p = 0.34), being used in 67% in the ide‐cel group versus 65% in the cilta‐cel group. Use of corticosteroids appeared to be more likely in the cilta‐cel group (p = 0.04), being used in 26% in the ide‐cel group versus 35% in the cilta‐cel group.
The cilta‐cel group showed a deep and significantly higher ORR of 93% versus 79% for the ide‐cel group (p < 0.001). Early response appeared to be deeper for cilta‐cel, showing complete response at Day 30 after CAR‐T infusion of 48% in the cilta‐cel group versus 26% in the ide‐cel group (p < 0.001). Responses appeared to deepen and increase significantly over time in the cilta‐cel group, while ORR in the ide‐cel group appeared to be stable (Figure 1A).
Figure 1.
Efficacy of ide‐cel and cilta‐cel. (A) Response, CR, complete response; PR, partial response; VGPR, very good partial remission. (B) Progression‐free survival, PFS. (C) Overall survival, OS.
After a median follow‐up for survivors of 9.7 months in the cilta‐cel group versus 12.1 months in the ide‐cel group (p = 0.02), the 10‐month PFS was 82% (95% confidence interval [CI]: 70%–94%) in the cilta‐cel group versus 47% (95% CI: 39%–55%) in the ide‐cel (p < 0.001). The 10‐month OS was 90% (95% CI: 81%–99%) in the cilta‐cel group versus 77% (95% CI: 70%–84%) in the ide‐cel group (p = 0.06).
Next, we evaluated the outcome in NRM and aimed to dissect the causes of death and potential differences between both treatment groups. The 10‐month NRM was 3% (95% CI: 0%–5%) in the ide‐cel group versus 5% (3%–12%) in the cilta‐cel group (p = 0.51; Figure 2A). The 1‐month NRM was 2% (95% CI: 1%–4%) in the ide‐cel group versus 0% in the cilta‐cel group.
Figure 2.
Nonrelapse mortality and causes of death. (A) Nonrelapse mortality, NRM. (B) Causes of death, HLH, hemophagocytic lymphohistiocytosis.
Of a total of 47 deaths, 43 occurred in the ide‐cel group and four deaths occurred in the cilta‐cel group. Causes of death were distributed significantly differently between the treatment groups (p = 0.004; Figure 2B). Of all deaths in the respective treatment group, relapse or progression was the main cause of death in 74% in the ide‐cel group versus 25% in the cilta‐cel group. Furthermore, infection or (septic) shock was the cause of death in 26% in the ide‐cel group and 50% in the cilta‐cel group. Hemophagocytic lymphohistiocytosis (HLH) was the cause of death in one patient (25%) in the cilta‐cel group (5 months after CAR‐T infusion), while no event of HLH occurred in the ide‐cel group. Early NRM within the first 1 month after CAR‐T infusion was driven by infection, in line with recent reports. 13
First, we aimed to test the MyCARe model in the two treatment groups. 6 Distribution according to MyCARe risk (including the following risk factors: presence of EMD or PCL, high‐risk cytogenetics, lenalidomide‐refractoriness, ferritin levels at the time of CAR‐T infusion) was as follows: 25% in the ide‐cel group and 19% in the cilta‐cel group showed low risk, 53% and 38% were intermediate risk, and 22% and 43% were high risk (p = 0.03). The MyCARe model was prognostic for PFS in both ide‐cel and cilta‐cel (p < 0.001, respectively), while cilta‐cel showed significantly improved outcomes for each risk group by pairwise comparison. Pairwise comparison for 10‐months PFS according to risk group between ide‐cel and cilta‐cel was 60% and 100% for low risk (p = 0.05), 47% and 83% (p = 0.006) for intermediate risk, and 31% and 72% for high risk (p = 0.002).
Next, we evaluated the distribution and outcomes according to the patient's race/ethnicity. All patients in the cilta‐cel group were of Non‐Hispanic White origin versus 93% in the ide‐cel group (Table 1). Non‐Hispanic Black was the background of 3% in the ide‐cel group, another 3% were of Hispanic origin, and 2% showed other background. PFS was not significantly different according to race/ethnicity in the ide‐cel group (p = 0.79), with 10‐month estimates of 48% for Non‐Hispanic White and 41% for all other backgrounds combined.
We investigated outcomes for the comparison of ide‐cel and cilta‐cel within prespecified key clinical subgroups (including age, sex, performance status at the time of CAR‐T infusion, R‐ISS, extramedullary disease, cytogenetic risk, and triple‐class or penta‐refractory status, as well as prior exposure to BCMA‐directed therapy). We first calculated relative risks 10 months after CAR‐T infusion for PFS to depict crude long‐term comparisons.
The comparison of cilta‐cel versus ide‐cel within and across key subgroups indicated a significantly reduced risk for relapse/progression or death with cilta‐cel by 68%, with a risk ratio of 0.32 (95% CI: 0.25–0.42; Figure 3). The suggested effect was maintained for almost all subgroups, except for ECOG performance status of 2 to 3 showing a risk ratio of 0.22 (95% CI: 0.04–1.35), age of 65 years or older at time of CAR‐T infusion showing a risk ratio of 0.87 (95% CI: 0.43–1.73), R‐ISS stages I and III showing risk ratios of 0.17 (0.01–2.49) and 0.46 (95% CI: 0.17–1.21), and prior exposure to BCMA‐directed therapy showing a risk ratio of 0.14 (95% CI: 0.01–1.96). However, notably, both effects for R‐ISS stage I and exposure to BCMA‐directed therapy may be influenced by absolute patient numbers in the cilta‐cel arm, showing no events of relapse/progression or death in five and four patients, respectively.
Figure 3.
Forest plot for progression‐free survival. BCMA, B‐cell maturation antigen; EMD, extramedullary disease; R‐ISS, Revised International Staging System.
Then, we developed a Cox regression for both PFS and OS, adjusting the main comparison of cilta‐cel and ide‐cel for the following variables: age, turnaround time, time from diagnosis to CAR‐T infusion, presence of EMD, high‐risk cytogenetics, penta‐refractory status, and exposure to BCMA‐directed therapy before CAR‐T infusion (Table 3). As a result, the hazards ratio comparing cilta‐cel and ide‐cel in terms of PFS and OS were 0.21 (95% CI: 0.09–0.50; p < 0.001) and 0.24 (95% CI: 0.07–0.81; p = 0.02), both in favor of cilta‐cel.
Table 3.
Cox regression on progression‐free and overall survival.
| Variable | Hazard ratio | 95% CI | p |
|---|---|---|---|
| Progression‐free survival | |||
| Treatment | |||
| Ide‐cel | Reference | ||
| Cilta‐cel | 0.21 | 0.09–0.50 | <0.001 |
| Extramedullary disease | 1.68 | 1.11–2.54 | 0.01 |
| High‐risk cytogenetics | 1.92 | 1.25–2.93 | 0.003 |
| Age, continuous | 1.02 | 0.99–1.04 | 0.21 |
| R‐ISS, continuous | 1.05 | 0.76–1.44 | 0.78 |
| Penta‐refractory | 1.07 | 0.97–1.17 | 0.18 |
| Prior anti‐BCMA exposure | 1.21 | 0.62–2.35 | 0.58 |
| Turnaround time, continuous | 1.00 | 0.99–1.01 | 0.91 |
| Time from diagnosis to infusion, continuous | 0.97 | 0.92–1.02 | 0.25 |
| Overall survival | |||
| Treatment | |||
| Ide‐cel | Reference | ||
| Cilta‐cel | 0.24 | 0.07–0.81 | 0.02 |
| Extramedullary disease | 1.72 | 0.88–3.36 | 0.11 |
| High‐risk cytogenetics | 1.50 | 0.74–3.02 | 0.26 |
| Age, continuous | 0.97 | 0.96–1.01 | 0.19 |
| R‐ISS, continuous | 1.35 | 0.82–2.23 | 0.23 |
| Penta‐refractory | 1.05 | 0.90–1.21 | 0.56 |
| Prior anti‐BCMA exposure | 1.12 | 0.42–3.02 | 0.82 |
| Turnaround time, continuous | 1.01 | 0.99–1.02 | 0.48 |
| Time from diagnosis to infusion, continuous | 0.82 | 0.74–0.92 | <0.001 |
Other variables retained significant for PFS were presence of EMD (p = 0.01) and high‐risk cytogenetics (p = 0.003). Importantly, turnaround time between apheresis and CAR‐T infusion did not appear to be associated with PFS (p = 0.91). In terms of OS, the only other variable associated with outcome was the time between diagnosis and CAR‐T infusion, with a hazard ratio of 0.82 (p < 0.001).
Last, we evaluated CAR‐T dynamics, finding that ide‐cel was associated with significantly earlier expansion (p < 0.001), peaking at Day 7 after infusion. In contrast, cilta‐cel expansion peaked at Day 14 (Figure 4).
Figure 4.
CAR‐T dynamics between ide‐cel and cilta‐cel after infusion.
In terms of efficacy, CAR‐T dynamics showed significant differences between patients achieving more than partial response and partial response or less (Figure 5A). In the ide‐cel group, no difference in expansion was found at Day 7 while patients with more than partial response showed peak expansion at Day 14, which was significantly higher than those with partial response or less (p = 0.003). This difference was maintained at Day 28 after CAR‐T infusion (p = 0.006). In the cilta‐cel group, CAR‐T expansion peaked at Day 14 for both patients with more than partial response and those with partial response or less. However, significant differences in expansion were found, with higher CAR‐T levels for patients with deeper responses (p = 0.05).
Figure 5.
Association of CAR‐T expansion with efficacy (A) and safety (B) for ide‐cel and cilta‐cel. CRS, cytokines release syndrome; ICANS, immune‐effector cell‐associated neurotoxicity syndrome; PR, partial response.
In terms of safety (Figure 5B), in the ide‐cel group, patients who developed CRS showed higher CAR‐T expansion at Day 7 (p = 0.05). In the cilta‐cel group, patients with CRS showed significantly higher CAR‐T expansion at Days 7 and 14 after CAR‐T infusion. Evaluating expansion profiles for patients with or without ICANS, no significant differences were found in the ide‐cel group, while patients who received cilta‐cel and developed ICANS showed significantly higher CAR‐T expansion at Days 14 and 28.
DISCUSSION
The introduction of ide‐cel and cilta‐cel has transformed the treatment landscape for patients with triple‐class exposed RRMM. While direct comparisons between these therapies are challenging due to differences in trial designs, many physicians view cilta‐cel as potentially more promising based on results from the CARTITUDE‐1 and KarMMa‐1 trials. 3 , 4 , 7 Since a prospective head‐to‐head clinical trial is unlikely, real‐world data analysis is crucial for providing insights that reflect everyday clinical practice. 14 To address this, we conducted an international cohort study with a well‐balanced patient population, offering a valuable comparison of these two groundbreaking treatments.
Our study demonstrated that cilta‐cel was associated with deeper and more durable remissions and subsequently improved PFS compared to ide‐cel across various risk categories, including patients with EMD, high‐risk cytogenetics, triple‐class or penta‐refractory disease, as well as prior anti‐BCMA exposure.
The enthusiasm about the excellent results achieved with ide‐cel (and even more so with cilta‐cel) in triple‐class exposed RRMM was tempered by a recent meta‐analysis that raised concerns regarding NRM, primarily based on data from clinical trials with a limited number of real‐world cilta‐cel patients. 15 However, our study, which included patients treated outside clinical trials, found a lower incidence of nonrelapse mortality compared to the respective meta‐analysis (3% and 5% vs. 6% and 15% for ide‐cel and cilta‐cel, respectively) and no significant differences between cilta‐cel and ide‐cel. These results are in line with previous real‐world reports, suggesting that real‐world data may provide a more accurate representation of NRM risks associated with these therapies. 5 , 6 , 16 Our findings might appear counterintuitive at first since clinical trial populations usually represent a more selective and less frail patient cohort. Nevertheless, these results might reflect the steep learning curve in managing CAR‐T therapies and that centers have become adept at handling known side effects, such as CRS and ICANS. More crucially, these centers are proficient in managing infectious complications based on recently published guidelines. 17
Deaths due to progressive disease were more frequent in ide‐cel patients. This might be influenced by an immortal time bias in the cilta‐cel group, leading to a potentially higher NRM due to infections instead of progressive disease compared to ide‐cel. Nevertheless, our study highlights the necessity of close follow‐up, antibacterial prophylaxis during the initial months, management of prolonged cytopenia, immunoglobulin substitution, and vaccinations to mitigate infectious risks post‐CAR‐T therapy. 17
Our data also indicated a higher incidence of HLH and severe as well as delayed neurotoxicity with cilta‐cel, while no parkinsonism was observed. Several cases of late‐onset motor neuron disease or parkinsonism have been reported after cilta‐cel. 18 , 19 The pathomechanisms, reversibility, and optimal management of these conditions are still under investigation, making close monitoring and screening essential in future treatments.
There are several other differences between cilta‐cel and ide‐cel that we identified in our current analysis that impact clinical management. The longer turnaround time with cilta‐cel could impact bridging strategies. Patients may require additional therapies to control disease progression during the waiting period for cilta‐cel manufacturing and preparation. Importantly, for the comparison of ide‐cel and cilta‐cel, turnaround time did not impact the outcome after multivariable adjustment.
In line with results from CARTITUDE‐1 and KarMMa‐1, the onset of CRS occurred later with cilta‐cel compared to ide‐cel. Therefore, patients treated with cilta‐cel may necessitate longer follow‐up and the delayed onset might have consequences for the possible application of CAR‐T in the ambulatory setting. 20 , 21
Furthermore, cilta‐cel was associated with longer hospitalization periods compared to ide‐cel. Cilta‐cel treatment often necessitated higher steroid use to manage CRS or other inflammatory side effects. Increased steroid use can suppress the immune system, leading to a higher risk of infectious complications. This is similar to what has been observed with bispecific antibodies, where steroid use has been linked to increased susceptibility to infections. 22 , 23 , 24 Therefore, clinicians must balance the need for steroids with the risk of infection and consider prophylactic measures to protect patients.
Next, we analyzed, the comparative cellular dynamics of both products, finding that CAR‐T expansion was different between both groups, associated with efficacy and safety. Ide‐cel showed peak expansion at Day 7, which was driven by patients who showed subsequent partial response or less. While both products' expansion was associated with CRS, only cilta‐cel expansion showed association with ICANS, with higher expansion for patients who developed ICANS. These results provide the first evidence of the role of peripheral blood CAR T‐cell monitoring as a biomarker with prognostic utility for distinct CAR‐T‐specific toxicities as well as efficacy, with the potential to design product‐specific preemptive or therapeutic measures, as currently discussed for other CAR‐T indications such as lymphoma. 25
We acknowledge several limitations, mainly due to the retrospective nature of our study. Although both treatment groups were relatively well balanced for key clinical characteristics, the sample size for cilta‐cel was smaller and follow‐up was still significantly longer for ide‐cel, limiting the generalizability for long‐term prediction of differences, especially in overall survival identified in the present analysis. As the choice of treatment was as per center's discretion, we cannot rule out selection bias, although we applied standard methods to account for differences. In addition, to maximize comparability and further ensure sufficient follow‐up, we only included patients with triple‐class exposed RRMM, limiting the translation of results for recently approved earlier lines. We compared two commercially available CAR‐T products that are not accessible in multiple countries and (socioeconomic) environments worldwide (and probably never will be) due to complexity and costs. Importantly, and in line with recent findings, 26 we found no differences in distribution and outcome according to race/ethnicity. However, only a small number of non‐white individuals were included in this study, limiting its value to study ethnic disparities. Last, the field of academic CAR‐T products is rapidly evolving, 27 , 28 with the aim to increase access to this promising therapy, with comparable safety and efficacy after crude comparisons with commercial CAR‐T. 6 In the future, benchmarking and collaboration are needed to ensure comparability without ignoring onset differences in manufacturing, access, and design in each setting. 29
In summary, our study provides real‐world evidence that cilta‐cel treatment leads to superior outcomes compared to ide‐cel in triple‐class exposed RRMM patients, exhibiting distinct cellular dynamics requiring product‐specific monitoring and follow‐up. Despite comparable and low non‐relapse mortality in both treatment groups, the different toxicity profiles of cilta‐cel must be taken into account in routine clinical practice.
AUTHOR CONTRIBUTIONS
Maximilian Merz and Nico Gagelmann designed the study, collected and analyzed data, and wrote the first draft of the manuscript. Friedrich Stölzel, Bastian von Tresckow, Kristin Rathje, Roland Fenk, Tobias Holderried, Fabian Müller, Natalia Tovar, Aina Oliver‐Cáldes, Vladan Vucinic, Soraya Kharboutli, Ben‐Niklas Bärmann, Francis Ayuk, Uwe Platzbecker, Anca‐Maria Albici, Nathalie Schub, Friederike Schmitz, Cyrus Khandanpour, Marcel Teichert, Barbara Jeker, Michele Hoffmann, Nicolaus Kröger, Carlos Fernández de Larrea, and Thomas Pabst collected and interpreted data, and wrote the manuscript.
CONFLICT OF INTEREST STATEMENT
Nico Gagelmann: Consulting or Advisory Role: Stemline Therapeutics, MorphoSys Travel, Accommodations, Expenses: Bristol Myers Squibb/Celgene, Janssen. Maximilian Merz: Honoraria: Janssen, BMS GmbH & Co KG, Amgen, AbbVie, Stemline Therapeutics, Takeda, Sanofi, Pfizer Consulting or Advisory Role: Janssen, BMS GmbH & Co KG, Pfizer, Sanofi Research Funding: Janssen, SpringWorks Therapeutics, Roche/Genentech Travel, Accommodations, Expenses: Janssen, Stemline Therapeutics, Pfizer. Aina Oliver‐Caldés: Travel, Accommodations, Expenses: Janssen. Friedrich Stölzel: Honoraria: Medac, Jazz Pharmaceuticals, Consulting or Advisory Role: Glycostem, Travel, Accommodations, Expenses: SERVIER. Anca‐Maria Albici: Honoraria: AbbVie, Travel, Accommodations, Expenses: SERVIER. Natalie Schub: Honoraria: Janssen Oncology, Consulting or Advisory Role: BMS, Travel, Accommodations, Expenses: Kite/Gilead. Soraya Kharboutli: Honoraria: Bristol Myers Squibb GmbH, Travel, Accommodations, Expenses: Janssen, Bristol Myers Squibb, Sobi, Novartis. Fabian Müller: Honoraria: AstraZeneca, Bristol Myers Squibb/Pfizer, Kite/Gilead, Consulting or Advisory Role: Bristol Myers Squibb/Pfizer, Janssen, Kite/Gilead, Kite/Gilead, Novartis, Miltenyi Biomedicine, Research Funding: Kite/Gilead, Travel, Accommodations, Expenses: SOBI, Janssen. Vladan Vucinic: Honoraria: Janssen, BMS GmbH & Co KG, Gilead Sciences, Amgen, Consulting or Advisory Role: Gilead Sciences, Janssen, BMS GmbH & Co KG, Amgen, Travel, Accommodations, Expenses: Sobi, Janssen, Gilead Sciences, Amgen. Uwe Platzbecker: Honoraria: Celgene/Jazz, AbbVie, Curis, Geron, Janssen, Consulting or Advisory Role: Celgene/Jazz, Novartis, BMS GmbH & Co KG, Research Funding: Amgen (Inst), Janssen (Inst), Novartis (Inst), BerGenBio (Inst), Celgene (Inst), Curis (Inst), Patents, Royalties, Other Intellectual Property: Part of a patent for a TFR‐2 antibody (Rauner et al. Nature Metabolics 2019), Travel, Accommodations, Expenses: Celgene. Francis Ayuk: Honoraria: Bristol Myers Squibb/Celgene, Kite/Gilead, Janssen, Miltenyi Biomedicine, Novartis, Takeda, Mallinckrodt/Therakos, medac pharma, Consulting or Advisory Role: Bristol Myers Squibb/Celgene Research Funding: Mallinckrodt/Therakos. Nicolaus Kröger: Honoraria: Novartis, Celgene (Inst), Sanofi, Jazz Pharmaceuticals (Inst), Kite/Gilead, RIEMSER (Inst), AOP Orphan Pharmaceuticals, BMS GmbH & Co KG, Neovii, Alexion Pharmaceuticals, Takeda, Pierre Fabre Consulting or Advisory Role: Neovii, Sanofi, Jazz Pharmaceuticals, Novartis, Celgene, RIEMSER, Gilead Sciences, Speakers' Bureau: AOP Orphan Pharmaceuticals, Research Funding: Neovii (Inst), Novartis (Inst), Celgene (Inst), Riemser (Inst), Travel, Accommodations, Expenses: Neovii, Novartis, Gilead Sciences, Jazz Pharmaceuticals, Sanofi, Celgene. Carlos Fernández de Larrea: Honoraria: Janssen, BeiGene, Bristol Myers Squibb/Celgene, Pfizer, Amgen, GlaxoSmithKline Consulting or Advisory Role: Janssen, Bristol Myers Squibb/Celgene, Amgen, Pfizer, Sanofi, BeiGene Research Funding: Janssen (Inst), Bristol Myers Squibb/Celgene (Inst), Amgen (Inst), GlaxoSmithKline (Inst) Travel, Accommodations, Expenses: Janssen, Amgen, GlaxoSmithKline, Bristol Myers Squibb/Celgene, BeiGene, Pfizer. No other potential conflicts of interest were reported.
FUNDING
No funding was received.
ACKNOWLEDGMENTS
Open Access funding enabled and organized by Projekt DEAL.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.