Abstract
Introduction
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.
Methods
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).
Results
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% versus EloPd, 49% versus IsaKd, 69% versus IsaPd, and 62% versus SVd. Similarly, cilta-cel patients had significant improvements in OS for all feasible comparisons: 52% versus EloPd, 58% versus IsaPd, and 60% versus SVd.
Conclusion
Cilta-cel patients demonstrated clinically meaningful benefits over EloPd, IsaKd, IsaPd, and SVd for response and survival outcomes, highlighting its superiority over alternative treatment options for patients with RRMM who have received at least one prior therapy and are refractory to lenalidomide.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12325-025-03205-8.
Keywords: Ciltacabtagene autoleucel, Matching-adjusted indirect comparison, Multiple myeloma
Key Summary Points
| Why carry out this study? |
| Comparative effectiveness data comparing treatments provides evidence to inform therapeutic decision-making and to contextualize the efficacy of CAR-T therapies for patients with relapsed/refractory multiple myeloma (RRMM) |
| Clinical trials providing head-to-head comparisons of ciltacabtagene autoleucel (cilta-cel) versus other approved and recommended therapies are not available |
| This matching-adjusted indirect comparison aimed to compare efficacy outcomes in patients with RRMM randomized to the cilta-cel arm of CARTITUDE-4 versus standard-of-care comparators that were not included in the CARTITUDE-4 trial including: elotuzumab + pomalidomide + dexamethasone (EloPd), isatuximab + carfilzomib + dexamethasone (IsaKd), isatuximab + pomalidomide + dexamethasone (IsaPd), and selinexor + bortezomib + dexamethasone (SVd) |
| What was learned from the study? |
| Patients with RRMM who received 1–3 prior lines of therapy, are refractory to lenalidomide and receive cilta-cel are significantly more likely to respond deeply to treatment and achieve a meaningful prolongation in progression-free survival and overall survival compared to EloPd, IsaKd, IsaPd, and SVd. |
| Cilta-cel is an effective treatment option for patients with RRMM who have received at least one other therapy and are lenalidomide-refractory |
Introduction
The approval of new treatment combinations, including immunomodulatory drugs (IMiD), proteasome inhibitors (PI), and monoclonal antibodies, has significantly improved outcomes for patients with multiple myeloma (MM) over the last decade [1]. However, many patients with MM will relapse, and thus will require treatment with multiple lines of therapy (LOT) and salvage regimens [2].
Patients with MM are considered to have relapsed/refractory disease (RRMM) if they are non-responsive to therapy or experience continued progression while on therapy or within 60 days of the end of last treatment [3]. The utilization of commonly used IMiDs, such as lenalidomide (LEN), as an early maintenance therapy is increasing, which limits subsequent treatment options once patients become refractory to these agents, with associated poor prognosis and outcomes overall [4–7]. The most common standard-of-care (SOC) combination treatments for patients who are refractory to LEN include daratumumab + pomalidomide + dexamethasone (DPd) and pomalidomide + bortezomib + dexamethasone (PVd) [8, 9]. Other SOC therapies vary by country, but broadly include doublet and triplet regimens based on daratumumab, pomalidomide, bortezomib, and carfilzomib. However, subsequent relapses may be increasingly difficult to treat as patients become multi-exposed and multi-refractory [8].
Novel therapies, such as chimeric antigen receptor T-cell (CAR-T), are needed to further improve survival for patients with RRMM in difficult-to-treat populations, including those who are LEN-refractory. Ciltacabtagene autoleucel (cilta-cel) is a novel B-cell maturation antigen-targeting CAR-T therapy that was recently approved in the United States for the treatment of adult patients with RRMM who have received ≥ 1 prior LOT, including a PI and an IMiD, and are refractory to LEN. This approval was based on the phase 3 CARTITUDE-4 trial (NCT04181827) which demonstrated the superior efficacy of a single cilta-cel infusion versus physician choice of DPd or PVd in terms of reduced risk of disease progression or death [10]. Recently, updated efficacy results from CARTITUDE-4 (median follow-up of 33.6 months), including overall survival (OS), were presented, with cilta-cel demonstrating significant OS benefit [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.39–0.79; P = 0.0009] and sustained PFS benefit (HR 0.29, 95% CI 0.22–0.39); P < 0.0001) over DPd or PVd [11].
Comparative efficacy data on treatments can provide valuable evidence to inform therapeutic decision-making for healthcare providers, payers, and other stakeholders, and to contextualize the efficacy of CAR-T therapies in countries where SOC for patients with LEN-refractory RRMM may differ from DPd and PVd. While randomized controlled trials are considered the gold-standard study design for evaluating the relative efficacy of competing interventions, clinical studies providing head-to-head comparisons of cilta-cel versus other approved and recommended therapies for LEN-refractory patients are not available. This matching adjusted indirect comparison (MAIC) aimed to compare efficacy outcomes in patients with RRMM randomized to the cilta-cel arm of CARTITUDE-4 versus SOC comparators which were not included in the CARTITUDE-4 trial. Comparators selected for MAIC were those for which only published aggregate trial data were available and the trial populations had sufficient overlap with patients in the cilta-cel arm of CARTITUDE-4 trial including: elotuzumab + pomalidomide + dexamethasone (EloPd), isatuximab + carfilzomib + dexamethasone (IsaKd), isatuximab + pomalidomide + dexamethasone (IsaPd), and selinexor + bortezomib + dexamethasone (SVd). Given the lack of a common comparator between CARTITUDE-4 and the comparator trials, unanchored MAICs were performed using individual patient-level data (IPD) from the cilta-cel arm of CARTITUDE-4.
Methods
Feasibility Assessment
CARTITUDE-4 (NCT04181827) is a phase 3 randomized, open-label trial evaluating the efficacy and safety of cilta-cel versus physician’s choice of standard of care in patients with LEN-refractory disease previously treated with 1–3 prior LOT including a PI and an IMiD. The data cut-off for CARTITUDE-4 at the time of this analysis was May 2024 and the median duration of follow-up was 33.6 months.
A systematic literature review was conducted to identify clinical trials assessing comparator regimens of interest which included EloPd, IsaKd, IsaPd, and SVd, as well as other secondary comparator regimens which are used less frequently in patients with 1 prior LOT and are LEN-refractory (see Supplementary Materials). A total of 22 trials were included in the review and were assessed for feasibility of indirect treatment comparisons (ITC) for which various methods were recommended based on the availability of IPD, presence of a common comparator with CARTITUDE-4, and overlap in patient populations. Independent clinical experts were consulted regarding the feasibility of ITC analyses in particular regarding differences in prognostic factors and potential effect modifiers including but not limited to key demographic and disease characteristics, the number of prior LOT, LEN refractoriness, exclusion criteria around previous therapy exposure, i.e., prior IMiD and daratumumab exposure, and cytogenetic risk [12]. A summary of ITCs recommended across all relevant comparators is presented in Table S1. This publication presents the results of four ITCs that were recommended via MAIC for key non-CAR-T comparators of interest versus cilta-cel using data from CARTITUDE-4. The methods and results of other ITC methods and comparators are published elsewhere [13–15].
Given the lack of a common comparator between CARTITUDE-4 and the comparator trials, unanchored MAICs were performed using IPD from the cilta-cel arm of CARTITUDE-4. Published arm-level data for EloPd from ELOQUENT-3 (NCT02654132), LEN-refractory subgroup data for IsaKd from IKEMA (NCT03275285), IsaPd from ICARIA-MM (NCT02990338), and LEN-refractory subgroup data for SVd from BOSTON (NCT03110562) informed the comparator arms for each MAIC. ELOQUENT-3 is an open-label, randomized, phase 2 trial in patients with RRMM, including a population who were refractory to LEN and to a PI [16, 17]. IKEMA is an open-label, randomized phase 3 trial in patients with RRMM who received 1–3 prior LOT [18]. For our study, we utilized the results published for the subgroup of LEN-refractory patients [19]. ICARIA-MM is an open-label, randomized, phase 3 trial in patients with RRMM who had received ≥ 2 prior LOT, including LEN and a PI [20, 21]. BOSTON is a global, phase 3, randomized trial in patients with histologically confirmed MM and 1–3 prior anti-myeloma regimens [22]. For our study, we utilized the results published for the subgroup of LEN-refractory patients [23].
Matching-Adjusted Indirect Comparisons
Unanchored MAICs were performed consistent with guidelines issued by the NICE Decision Support Unit [24]. Prior to patient matching based on the average baseline characteristics, eligibility criteria from the comparator trials with regards to previous LOT were applied to the CARTITUDE-4 population to better align the CARTITUDE-4 population with the population from each comparator trial. With this approach, only cilta-cel patients from CARTITUDE-4 who satisfied the eligibility criteria from the comparator trials were included (Table 1). A sensitivity analysis was performed for comparisons to IsaKd, that further excluded cilta-cel patients in CARTITUDE-4 who had received prior carfilzomib (Table S2).
Table 1.
Analysis sets for CARTITUDE-4 and comparator trials
| Comparator | Study | Patients | Exclusion criteria applied to CARTITUDE-4 |
Number of cilta-cel patients from CARTITUDE-4 remaining |
|---|---|---|---|---|
| EloPd | ELOQUENT-3 [16] | 60 | Patients with less than 2 prior LOT, not refractory to last LOT, or had prior pomalidomide excluded | 129 |
| IsaKd | IKEMA [19] | 57a | Patients refractory to anti-CD38b | 158 |
| IsaPd | ICARIA-MM [20] | 154 | Patients with less than 2 prior LOT, not refractory to last LOT, refractory to anti-CD38 or had prior pomalidomide excluded | 88 |
| SVd | BOSTON [23] | 53a | None | 208 |
EloPd elotuzumab, pomalidomide, dexamethasone, IsaKd isatuximab, carfilzomib, dexamethasone, IsaPd isatuximab, pomalidomide, dexamethasone, LOT line of therapy, SVd selinexor, bortezomib, dexamethasone
aSubgroup of patients refractory to lenalidomide
bA sensitivity analysis was conducted excluding patients refractory to anti-CD38 or prior carfilzomib resulting in 105 cilta-cel patients from CARTITUDE-4 remaining
The cilta-cel populations that satisfied the eligibility criteria of the comparator trials were adjusted to match the distribution of average baseline characteristics reported as aggregate data from each comparator trial [ELOQUENT-3 (n = 60), IKEMA (n = 57), ICARIA-MM (n = 154), and BOSTON (n = 53)]. Prognostic factors adjusted for in the analyses were identified a priori and ranked by importance, based on input from independent clinical experts; these varied by comparator based on the characteristics reported by comparator trials. To adjust for these factors, IPD from CARTITUDE-4 were reweighted such that the average baseline characteristics matched the summary level baseline characteristics reported in the publications for the comparator trials. For comparisons to EloPd and IsaPd, the following factors were available for matching in the base case: (1) refractory status to a PI, (2) high cytogenetic risk (as defined by each study based on the presence of cytogenetic abnormalities), and (3) International Staging System (ISS) for disease stage. For comparisons to IsaKd and SVd, the following factors were available for matching in the base case: (1) high cytogenetic risk, and (2) revised ISS disease stage. Sensitivity analyses were performed to expand the list of factors included for matching, which are presented in Table 2 with the population from cilta-cel presented after matching for the base case analyses.
Table 2.
Baseline characteristics observed by study and CARTITUDE-4 adjusted to comparator studies
| No. of patients | Cilta-cel (CARTITUDE-4) | EloPd (ELOQUENT-3) | Cilta-cel adjusted vs. EloPd | IsaKd (IKEMA)a | Cilta-cel adjusted vs. IsaKd | IsaPd (ICARIA-MM) | Cilta-cel adjusted vs. IsaPd | SVd (BOSTON)a | Cilta-cel adjusted vs. SVd | |
|---|---|---|---|---|---|---|---|---|---|---|
| 208 | 60 | 129 ESS: 86b |
57 | 158 ESS: 79b |
154 | 88 ESS: 26b |
53 | 208 ESS: 188b |
||
| Baseline characteristics matched in the base case scenario | ||||||||||
| Refractory status | Refractory to PI | 50% | 78% | 78% | – | – | 77% | 77% | – | – |
| Cytogenetic risk | High | 59% | 33% | 33% | 23% | 23% | 19% | 19% | 55% | 55% |
| ISS stage | I | 65% | 88% | 88% | 50% | 50% | 42% | 42% | – | – |
| II | 29% | 38% | 38% | 35% | 35% | – | – | |||
| III | 6% | 12% | 12% | 12% | 12% | 23% | 23% | – | – | |
| R-ISS stage | I | 21% | – | – | – | – | – | – | 31% | 31% |
| II | 75% | – | – | – | – | – | – | 61% | 61% | |
| III | 4% | – | – | – | – | – | – | 8% | 8% | |
| Baseline characteristics additionally matched in sensitivity analysesc | ||||||||||
| Prior lines | 1 previous treatment | 33% | – | – | 14 | 40 | – | – | 30% | 34% |
| 2 previous treatments | 40% | – | – | – | – | – | – | 40% | 39% | |
| Time from diagnosis | Median time from diagnosis to randomization (years) | 3 | 4.8 | 3.8 | – | – | 4.5 | 3.8 | 3.7 | 3.0 |
| Age | Age < 65 years | 61% | 37% | 49% | 53% | 62% | 35% | 48% | – | – |
| Age ≤ 65 and < 75 years | 37% | 42% | 49% | 38% | 34 | 44% | 50% | – | – | |
| Age ≥ 75 years | 3% | 21% | 2% | 9% | 4 | 21% | 2% | – | – | |
| Median age (years) | 62 | – | – | – | – | – | – | 65 | 62 | |
| LDH category | LDH < 300 U/L | 84% | 75% | 84% | – | – | – | – | – | – |
| LDH > ULN | 27% | –– | – | – | – | 31% | 22% | – | – | |
| Prior autologous HCT | Prior autologous stem-cell transplantation | 82% | 52% | 77% | – | – | 54% | 66% | 43% | 81% |
| ECOG PS | 0 | 55% | – | – | – | – | 36% | 60% | 43% | 55% |
| ≥ 1 | 45% | – | – | – | – | 64% | 40% | 57% | 45% | |
| Black | 3% | – | – | – | – | 1% | 3% | – | – | |
| Race | Otherd | 9% | – | – | – | – | 16% | 8% | – | – |
| White | 87% | – | – | – | – | 83% | 89% | – | – | |
| Sex | Male | 56% | 53% | 59% | – | – | 58% | 54% | 70% | 57% |
| Female | 44% | 47% | 41% | – | – | 42% | 46% | 30% | 43% | |
| Immunoglobulin subtype | Myeloma subtype IgA | 18% | – | – | – | – | 22% | 14% | – | – |
| Myeloma subtype IgG | 54% | – | – | – | – | 66% | 61% | – | – | |
| Myeloma subtype light–chain | 23% | – | – | – | – | 10% | 14% | – | – | |
| Myeloma subtype other | 5% | – | – | – | – | 2% | 12% | – | – | |
| Creatinine clearance | ≥ 60 mL/min | 87% | 76% | 84% | – | – | 61% | 84% | – | – |
| > 60 mL/min | 87% | – | – | – | – | – | – | 74% | 87% | |
EloPd elotuzumab, pomalidomide, dexamethasone, ESS effective sample size, ECOG Eastern Cooperative Oncology Group, HCT hematopoietic cell transplantation, IsaKd isatuximab, carfilzomib, dexamethasone, IsaPd isatuximab, pomalidomide, dexamethasone, ISS International Staging System, LDH lactate dehydrogenase, PI proteasome inhibitor, PS performance status, R-ISS Revised International Staging System, SCT stem-cell transplantation, SVd selinexor, bortezomib, dexamethasone, ULN upper limit of normal
aLenalidomide-refractory population
bFor base case only
cReported baseline characteristics reflect values after matching for the base case. The sensitivity analysis versus IsaKd excluded additional cilta-cel patients from CARTITUDE-4; characteristics for matching for this scenario are presented in Supplementary Table 2. All characteristics matched for sensitivity analyses (except those in italics) were perfectly matched to the comparator trial population. Italics represent characteristics that could not be matched due to impact on the effective sample size (< 20)
dData not captured for specific races encompassed in this category
Outcomes of interest for the MAIC included overall response rate (ORR), very good partial response or better (≥ VGPR) rate, and complete response or better (≥ CR) rate, as well as progression-free survival (PFS) and overall survival (OS) when reported. Reconstructed IPD were derived from reported results for the comparators by replicating an individual-level dataset for response outcomes and by simulating PFS and OS data from digitally scanned, published Kaplan–Meier curves using a published, validated method [25]. For the MAIC of cilta-cel versus IsaKd, the IKEMA trial only reported PFS for the lenalidomide refractory subgroup as rates at 6, 12, and 18 months. These data were used to simulate a complete survival curve by fitting an exponential model through these reported estimates and assuming a constant risk between subsequent timepoints for which PFS estimates were reported. An MAIC of cilta-cel versus IsaKd was not feasible for OS, as IKEMA did not report OS results for the subgroup of LEN-refractory patients. For comparisons to EloPd, only investigator-assessed response and PFS Kaplan–Meier curves were available, and therefore the MAIC of cilta-cel versus EloPd were based on investigator-assessed outcomes. For all other MAICs, independent review committee-assessed response and PFS were used for analysis.
Comparative efficacy was estimated for response outcomes using a weighted logistic regression analysis which produced results in terms of odds ratios (OR) and corresponding 95% CI. For ease of interpretation, corresponding response rate ratios (RR) were also derived from the model for response outcomes. PFS and OS were analyzed using a weighted Cox proportional hazards model, reflecting the relative benefit for cilta-cel versus comparators in terms of HR and corresponding 95% CI.
Ethics/Ethical Approval
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. This analysis utilized de-identified data from published clinical trial data and therefore ethics committee approval was not required. Each individual trial included in this analysis was approved by independent ethics committees or institutional review boards at each study site and all patients provided written informed consent before enrolling in each clinical trial. Study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.
Results
Population Adjustment
The models for the base case analyses were based on the ability to match factors ranked most important by clinical experts while maintaining a sufficient sample size. Table 2 presents baseline characteristics that were matched in the MAIC models for each comparison and the effective sample size (ESS) for cilta-cel for each base case comparison. The baseline characteristics and ESS for the sensitivity analysis performed for cilta-cel versus IsaKd that expanded the exclusion criteria to exclude patients refractory to anti-CD38 or prior carfilzomib are presented in Table S2. Sensitivity analyses were also performed for all comparators by matching on additional prognostic factors ranked based on clinical importance, while maintaining ESS ≥ 20 (Table S3).
Response
Observed response rates including ORR, ≥ VGPR, and ≥ CR were higher for cilta-cel patients versus all comparators (Table 2. Baseline characteristics observed by study and CARTITUDE-4 adjusted to comparator studies Table 3). After population adjustment, cilta-cel patients were significantly more likely to achieve an overall response than patients treated with EloPd, IsaPd, and SVd (1.5, 1.4, and 1.2 times the rate of responders, respectively, P < 0.01). Superior response outcomes for cilta-cel were even more pronounced for deeper level of response after matching, with cilta-cel patients being 4.0, 1.3, 2.5 and 2.3 times more likely to achieve ≥ VGPR, and 9.3, 2.1, 17.4 and 8.1 times more likely to achieve ≥ CR, compared to patients treated with EloPd, IsaKd, IsaPd, and SVd, respectively (all P < 0.0001, except ≥ VGPR vs. IsaKd [P = 0.091]).
Table 3.
Observed and MAIC-adjusted responses by treatment comparison
| Observed response | Adjusted comparisons | ||||
|---|---|---|---|---|---|
| Cilta-cel adjusteda response | OR (95% CI)b | RR (95% CI)c | P valued | ||
| ORR | |||||
| Cilta-cel | 84.6% | – | 1.00 | – | – |
| EloPde | 53.3% | 81.8% | 3.93 (1.87–8.26) | 1.53 (1.18–1.99) | 0.0003 |
| IsaKd | 82.5% | 88.0% | 1.56 (0.61–3.97) | 1.07 (0.93–1.23) | 0.3497 |
| IsaPd | 60.4% | 84.0% | 3.44 (1.39–8.54) | 1.39 (1.15–1.68) | 0.0077 |
| SVd | 67.9% | 84.2% | 2.51 (1.24–5.07) | 1.24 (1.02–1.51) | 0.0102 |
| ≥ VGPR | |||||
| Cilta-cel | 81.3% | – | 1.00 | – | – |
| EloPde | 20.0% | 79.6% | 15.59 (6.86–35.43) | 3.98 (2.36–6.72) | < 0.0001 |
| IsaKd | 66.7% | 83.8% | 2.58 (1.17–5.69) | 1.26 (1.02–1.55) | 0.0191 |
| IsaPd | 31.8% | 80.1% | 8.63 (3.65–20.40) | 2.52 (1.90–3.34) | < 0.0001 |
| SVd | 35.8% | 80.9% | 7.60 (3.88–14.89) | 2.26 (1.56–3.27) | < 0.0001 |
| ≥ CR | |||||
| Cilta-cel | 76.9% | – | 1.00 | – | – |
| EloPde | 8.3% | 77.1% | 37.06 (13.11–104.82) | 9.25 (3.93–21.80) | < 0.0001 |
| IsaKd | 38.6% | 80.7% | 6.67 (3.16–14.09) | 2.09 (1.48–2.95) | < 0.0001 |
| IsaPd | 4.5% | 78.9% | 78.62 (26.62–232.15) | 17.36 (8.23–36.61) | < 0.0001 |
| SVd | 9.4% | 76.4% | 31.10 (11.64–83.07) | 8.10 (3.47–18.91) | < 0.0001 |
CI confidence interval, CR complete response, EloPd elotuzumab, pomalidomide, dexamethasone, IsaKd isatuximab, carfilzomib, dexamethasone, IsaPd isatuximab, pomalidomide, dexamethasone, OR odds ratio, ORR objective response rate, RR relative response ratio, SVd selinexor, bortezomib, dexamethasone, VGPR very good partial response
aCilta-cel adjusted is the estimated ORR for cilta-cel, after matching population to the comparator
bOR for cilta-cel versus comparators, based on logistic regression
cRR is equal to the ratio of the adjusted response rates for cilta-cel versus comparators
dP values for response outcomes were computed based on the estimated ORs. All hypothesis tests were conducted at the 5% significant level
eResults for EloPd are based on investigator (INV) assessment; Observed cilta-cel responses for INV-assessed responses: ORR = 83.7%, ≥ VGPR = 79.8%, ≥ CR = 72.1%
PFS
While median PFS was not reached for cilta-cel patients, observed medians for the comparators ranged between 10.2 months (for both EloPd and SVd) and 19.4 months (IsaKd). After population adjustment, patients treated with cilta-cel had a significantly lower risk of disease progression or death compared to all four comparator treatments. Adjusted HRs were 0.36 (95% CI 0.21–0.62) versus EloPd, 0.51 (95% CI 0.29–0.90) for IsaKd, 0.31 (95% CI 0.14–0.68) versus IsaPd, and 0.38 (95% CI 0.24–0.59) versus SVd, corresponding to a reduction in the risk of disease progression or death of 64% versus EloPd, 49% versus IsaKd, 69% versus IsaPd, and 62% versus SVd. Figure 1 presents the observed and adjusted Kaplan–Meier curves of PFS for all treatments.
Fig. 1.
Observed and adjusted Kaplan–Meier plots of PFS for cilta-cel versus EloPd (a), IsaKd (b), IsaPd (c), and SVd (d). Dark green denotes values for cilta-cel observed, light green cilta-cel adjusted, and blue each comparator. CI confidence interval, EloPd elotuzumab, pomalidomide, dexamethasone, ESS effective sample size, HR hazard ratio, IsaKd isatuximab, carfilzomib, dexamethasone, IsaPd isatuximab, pomalidomide, dexamethasone, LOT line of therapy, NA not assessed, SVd selinexor, bortezomib, dexamethasone
OS
While median OS was not reached for cilta-cel patients at the time of analysis, observed medians for the comparators ranged between 24.5 months (IsaPd) and 29.9 months (EloPd). After population adjustment, patients treated with cilta-cel had a significantly lower risk of death compared to all three comparator treatments; no OS data were available for the LEN-refractory subgroup of patients from IKEMA. Adjusted HRs were 0.48 (95% CI 0.29–0.80) versus EloPd, 0.42 (95% CI 0.21–0.81) versus IsaPd, and 0.40 (95% CI 0.25–0.67) versus SVd, corresponding to a reduction in the risk of death of 52% versus EloPd, 58% versus IsaPd, and 60% versus SVd. Figure 2 presents the observed and adjusted Kaplan–Meier curves of OS for all treatments with available data.
Fig. 2.
Observed and adjusted Kaplan–Meier plots of OS for cilta-cel versus EloPd (a), IsaPd (b), and SVd (c). Dark green denotes values for cilta-cel observed, light green cilta-cel adjusted, and blue each comparator. CI confidence interval, EloPd elotuzumab, pomalidomide, dexamethasone, ESS effective sample size, HR hazard ratio, IsaPd isatuximab, pomalidomide, dexamethasone, LOT line of therapy, NA not assessed, SVd selinexor, bortezomib, dexamethasone
Sensitivity Analyses
The results of the sensitivity analysis for cilta-cel versus IsaKd that expanded the criteria excluding patients’ refractory to anti-CD38 or prior carfilzomib were consistent with the base case. Cilta-cel patients were significantly more likely to achieve ≥ VGPR and ≥ CR compared to patients treated with IsaKd [adjusted relative risk ratio 95% CI) 1.27 (1.02–1.58), P = 0.0354; 2.14 (1.51–3.05), P < 0.0001, respectively]. Cilta-cel patients also had a significantly lower risk of disease progression or death compared to IsaKd [adjusted HR (95% CI) 0.45 (0.22–0.94), P = 0.0338].
The results of the sensitivity analyses that matched on additional prognostic factors were generally consistent with the base case estimates for all comparisons and outcomes but with wider 95% CI given lower ESS (Table S3).
Discussion
RRMM remains particularly challenging to treat, and emerging CAR-T treatments are showing therapeutic potential for patients across LOT. While multiple combination options have recently become available for use in patients with RRMM, guideline recommendations for newer therapies are often broad, while optimal sequencing has not yet been established [26]. Evaluating comparative efficacy, particularly in the absence of head-to-head trials and given the number of interventions available, is therefore important to inform clinical practice.
The MAICs performed adjusted for differences in the distribution of mean baseline characteristics thereby allowing for interventions assessed in separate trials without a common comparator arm to be compared. Our findings demonstrate that patients with RRMM who received 1–3 prior LOT and receive cilta-cel are significantly more likely to respond deeply to treatment, achieve a meaningful increase in PFS, and experience prolonged OS versus EloPd, IsaKd, IsaPd, and SVd. These findings complement the comparative evidence from the CARTITUDE-4 trial wherein cilta-cel demonstrated significant improvements in response, PFS, and OS compared to DPd/PVd [11]. Considering the totality of evidence regarding the efficacy of cilta-cel in earlier LOT, it is expected that this therapy will have a substantial impact on response to treatment, disease progression, and survival compared to current SOC regimens. Our MAICs provide valuable information to contextualize the efficacy of cilta-cel for settings where SOC for these patients may be different from DPd/PVd.
The results of the present analysis also complement findings of other recently published ITCs evaluating cilta-cel versus other comparators. The results of a network meta-analysis by Mina et al., which included data from CARTITUDE-4, show that cilta-cel confers a statistically significant PFS benefit relative to pomalidomide + dexamethasone, IsaPd, and EloPd, and a numeric trend in favor of cilta-cel versus all comparator regimens except EloPd in terms of OS, when analyses were performed based on the ITT populations including patients with 1–3 prior LOT [15]. The results of a sensitivity analysis using subgroup data for patients who received 2–3 prior LOT found cilta-cel to be statistically significant in OS compared to EloPd, consistent with the findings of this MAIC [15]. Alsdorf et al. performed inverse probability treatment weighting using cilta-cel data from CARTITUDE-4 and compared it to data from three clinical trials assessing daratumumab combinations and their comparators (CASTOR, CANDOR, and APOLLO) [13]. In this analysis, cilta-cel showed a statistically significant benefit in PFS, ≥ VGPR, and ≥ CR versus all comparators (DVd, DKd, Vd, Kd, Pd) [13]. In an unanchored MAIC of cilta-cel utilizing data from CARTITUDE-1 and CARTITUDE-4 compared to ide-cel from KarMMA-3, cilta-cel showed statistically significant improvements in PFS, ORR, ≥ VGPR, and ≥ CR in patients with 2–4 prior LOT [14].
Study Limitations
Across MAIC analyses, IPD from CARTITUDE-4 were adjusted to match the mean baseline characteristics, as reported in the publications for the comparator trials. Cilta-cel patients from CARTITUDE-4 were also excluded prior to matching to better align the population with each comparator trial in terms of key inclusion/exclusion criteria. The exclusion of cilta-cel patients and reweighting of cilta-cel IPD to match the distribution of prognostic factors observed in the comparator trials resulted in a loss in precision. Furthermore, MAIC results may also not be generalizable to all patient populations, as the analysis is based on the specific patient populations included in the matched comparator trials.
While the choice of variables included in the base case were based on a ranking exercise by clinical experts, this process is subjective and could potentially influence results. Sensitivity analyses included nearly all available characteristics to mitigate this risk; however, there may still be risk of residual bias due to unmeasured or unknown confounding factors. The degree of overlap between trial populations had an impact on the number of factors that could be matched. For comparisons of cilta-cel versus IsaPd (ICARIA-MM), a number of prognostic factors deemed important by clinical experts (i.e., lactate dehydrogenase, prior autologous hematopoietic cell transplantation, race, and immunoglobulin subtype), could not be included in the set of matched variables, as doing so resulted in significant reductions in ESS (< 20). Despite this limitation, results from sensitivity analyses matched on an expanded number of factors consistent with the base case and consistent with another published ITC analysis [15].
While data for LEN-refractory patients were available from BOSTON and IKEMA to support comparisons to SVd and IsaKd, LEN-refractory status could not be adjusted for in the MAICs versus IsaPd and EloPd (refractoriness only to PI). While all patients from the cilta-cel cohort were refractory to LEN, only 94% of the IsaPd patients from ICARIA-MM and 90% of the EloPd patients from ELOQUENT-3 were refractory to LEN. Since refractoriness to LEN is associated with poorer prognosis, reported results of the MAIC may rather underestimate the relative efficacy of cilta-cel versus IsaPd and EloPd.
Finally, despite the fact that only limited data on IsaKd were available for LEN-refractory patients from IKEMA, reported PFS estimates allowed for the estimation of a simulated Kaplan–Meier curve, and in turn for MAIC analyses to be performed for this outcome.
Conclusion
Cilta-cel demonstrated clinically meaningful benefits over EloPd, IsaKd, IsaPd, and SVd across response and survival outcomes, highlighting its superiority over alternative treatment options for patients with RRMM who have received at least one prior therapy and who are refractory to LEN. These comparisons provide valuable information regarding the comparative efficacy of cilta-cel versus comparators that were not assessed in the CARTITUDE-4 trial and can be used to help inform both clinical and health-policy decisions.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgments
Medical Writing, Editorial, and Other Assistance
The authors thank Brooke Middlebrook, CMPP, of PPD, a Thermo Fisher company, for medical writing and editorial support. This support was funded by Janssen and provided in accordance with Good Publication Practice 2022 guidelines.
Author Contributions
Noemi Puig, Joris Diels, Suzy van Sanden, João Mendes, Heather Burnett, Allie Cichewicz, Seina Lee, Teresa Hernando, Jordan M. Schecter, Nikoletta Lendvai, Nitin Patel, José María Sanchez-Pina, Serena Rocchi, Roberto Mina, Paolo Corradini, Michele Cavo, Jesús San Miguel, Leyla Shune, Abdullah M. Khan, Surbhi Sidana, Xavier Leleu, Salomon Manier, Brea Lipe, Katja Weisel, and Joaquin Martinez-Lopez contributed to the study conception and design. Material preparation and data collection were performed by Heather Burnett, Allie Cichewicz, Joris Diels, and Suzy van Sanden. Analyses were performed by Joris Diels and Suzy van Sanden. All authors read and approved the final manuscript.
Funding
Funding for this study and the Rapid Service Fee for publishing this article were provided by J&J Innovative Medicine, 1000 US Highway 202, Raritan, NJ, 08869, USA.
Data Availability
The data sharing policy of Janssen Pharmaceutical Companies is available at https://www.janssen.com/clinical-trials/transparency. For the comparator trials, ELOQUENT-3 [16, 17], IKEMA [18], ICARIA-MM [20, 21], and BOSTON [22] data sharing statements are available within the full text publications.
Declarations
Conflict of Interest
Noemi Puig: Amgen: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; The Binding Site: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Joris Diels, Suzy van Sanden, João Mendes, Seina Lee, Teresa Hernando, Jordan M. Schecter, and Nikoletta Lendvai: Employees of Janssen and shareholders of Johnson & Johnson. Nitin Patel: Employee and shareholder of Legend Biotech USA Inc., has divested equity with BMS (via spouse). Heather Burnett and Allie Cichewicz: Employees of Evidera, a Thermo Fisher Company which provides consulting and other research services to life science companies. In their salaried positions, they work with a variety of companies and is precluded from receiving payment or honoraria directly from these organizations for services rendered. Evidera received payment from Johnson & Johnson for the conduct of this study. José María Sanchez-Pina: Consultancy and Speakers Bureau Johnson and Johnson, Gilead, Amgen, SanofiSerena Rocchi: Nothing to disclose. Roberto Mina: Received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, GSK, Janssen, Sanofi, Takeda, Menarini Stemline and Pfizer; participated in advisory boards for Amgen, Bristol Myers Squibb, GSK, Janssen, Sanofi and Pfizer. Paolo Corradini: Honoraria and travel received from: Abbvie, Amgen, BeiGene, BMS, Eli Lilly, Gilead/Kite, GSK, Incyte, Janssen, Jazz Pharma, Novartis, Pfizer, Roche, Sanofi, SOBI, Takeda. Michele Cavo: Served as a consultant and received travel grants from Janssen. Jesus San Miguel: declares participation on advisory boards and consulting services, on behalf of my Institution, for Abbvie, Amgen, BMS, Celgene, GSK, Haemalogix, Janssen-Cilag, Karyopharm, MSD, Novartis, Pfizer, Takeda, Regeneron, Roche, Sanofi, SecuraBio and Gilead-Kite. Leyla Shune: serves as on J&J advisory boards. Abdullah M. Khan: Received research funding from BMS and Sanofi; member of the Speakers Bureau for Amgen, BMS, and Sanofi. Surbhi Sidana: Has received Research Funding: Magenta Therapeutics, BMS, Allogene, Janssen, Novartis and serves as a consultant for: Magenta Therapeutics, BMS, Janssen, Sanofi, Takeda, Regeneron, Abbvie, Pfizer, BiolineRx, Legend, Genentech, Arcellx, Kite. Xavier Leleu: Kite, A Gilead Company: Consultancy, Honoraria. Salomon Manier: Research funding Janssen, Celgene/BMS; Consultant for Abbvie, Adaptive Biotechnology, Amgen, Celgene/BMS, GlaxoSmithKline, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda; Travel funding: Abbvie, Adaptive Biotechnology, Amgen, Celgene/BMS, GlaxoSmithKline, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi. Brea Lipe: Consulting: Janssen, Sanofi, Karyopharm, BMS, Pfizer, GSK and Research: Amgen, Karyopharm. Katja Weisel: Research Grant: Abbvie, Amgen, BMS/Celgene, GSK, Janssen, Sanofi (to the Institution). Honoraria: Abbvie, Amgen, Adaptive Biotech, Astra Zeneca, Beigene, BMS, Celgene, Janssen, GSK, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, Takeda; Adisory Board: Abbvie, Amgen, Adaptive Biotech, Beigene, BMS, Celgene, Janssen, GSK, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, Takeda. Joaquin Martinez-Lopez: has stock ownership in altum, statb therapeutics; has received honorarium from Johnson and Johnson, BMS, Pfizer, Incity, Roche, Sanofi, Novartis; has served as a consultant for Johnson and Johnson, BMS, Pfizer, Incity, Roche, Sanofi, Novartis; has served on Speaker’s Bureau for Johnson and Johnson, BMS, Pfizer, Incity, Roche, Sanofi, Novartis, Amgen; has research funding from BMS, J&J, Incity, Pfizer, Amgen and travel funds from Johnson and Johnson, BMS, Pfizer, Incity, Roche, Sanofi, Novartis.
Ethical Approval
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. This analysis utilized de-identified data from published clinical trial data and therefore ethics committee approval was not required. Each individual trial included in this analysis was approved by independent ethics committees or institutional review boards at each study site and all patients provided written informed consent before enrolling in each clinical trial. Study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.
Footnotes
Prior Presentation: This manuscript is based on work that was presented at the 65th American Society of Hematology Annual Meeting (December 9–12, 2023, San Diego, CA, USA).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data sharing policy of Janssen Pharmaceutical Companies is available at https://www.janssen.com/clinical-trials/transparency. For the comparator trials, ELOQUENT-3 [16, 17], IKEMA [18], ICARIA-MM [20, 21], and BOSTON [22] data sharing statements are available within the full text publications.