Updated results from a matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma

Abstract

Objective

This study used the latest available data cuts from the CARTITUDE-1 and KarMMa clinical trials to update previously published matching-adjusted indirect treatment comparisons (MAICs) assessing the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the FDA-approved idecabtagene vicleucel (ide-cel) dose range of 300 to 450 × 10⁶ CAR-positive T-cells in the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed).

Methods

MAICs were performed with the latest available individual patient data for cilta-cel (CARTITUDE-1) and published summary-level data for ide-cel (KarMMa). The analyses included treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was assessed for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

Results

Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p < .0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.65 [95% CI: 2.51, 12.69; p < .0001]; RR: 2.23), DoR (hazard ratio [HR]: 0.52 [95% CI: 0.30, 0.88; p = .0152]), PFS, (HR: 0.38 [95% CI: 0.24, 0.62; p < .0001]), and OS (HR: 0.43 [95% CI: 0.22, 0.88; p = .0200]) compared with ide-cel.

Conclusions

These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes over longer follow-up and highlight its therapeutic potential in triple-class exposed RRMM patients.

Keywords:

• relapsed or refractory multiple myeloma
• ciltacabtagene autoleucel
• CARTITUDE-1
• idecabtagene vicleucel
• KarMMa
• indirect treatment comparison

Introduction

Multiple myeloma (MM) is a highly heterogenous cancer characterized by an excess of monoclonal (M) proteins and rapid growth of malignant plasma cells¹. Despite many advancements in therapy with improved responses and survival, MM remains an incurable malignancy and most patients develop relapsed or refractory myeloma (RRMM). To address the need for new, efficacious treatment options, two novel chimeric antigen receptor T-cell (CAR-T) products have been introduced for the treatment of patients with RRMM.

Ciltacabtagene autoleucel (cilta-cel; JNJ-68284528) and idecabtagene vicleucel (ide-cel; bb2121) are two B-cell maturation antigen (BCMA)-targeted CAR-T therapies that have been approved by the Food and Drug Administration (FDA) and European Medicine Agency (EMA) in the treatment of RRMM^1–4. Ide-cel is a second-generation autologous CAR-T therapy with an extracellular anti-BCMA single-chain variable fragment, a 4-1BB costimulatory domain and CD3ζ signaling domain. Cilta-cel is unique in that it has two BMCA-specific single-binding domains, a 4-1BB costimulatory domain, and a CD3ζ signaling cytoplasmic domain. Both therapies have been evaluated in the treatment of patients who have previously received a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and a monoclonal antibody (MoAB) (i.e. triple-class exposed), with cilta-cel being evaluated in the CARTITUDE-1 trial⁵ and ide-cel being evaluated in the KarMMa trial⁶. However, these treatments have not been compared directly in any prospective clinical trial.

Previously, results of matching-adjusted indirect treatment comparisons (MAICs) assessing the comparative efficacy of cilta-cel versus ide-cel (FDA-approved dose range of 300 to 450 × 10⁶ CAR-positive T-cells) were published that demonstrated improved efficacy with cilta-cel versus ide-cel.⁷ However, new data cuts have since become available for both CARTITUDE-1 and KarMMa. Herein, we present updated MAIC results of cilta-cel versus ide-cel using longer-term follow-up data.

Methods

Data sources

Details of the CARTITUDE-1 and KarMMa clinical trials have been previously published in the original publication,⁷ however, the current MAICs used updated data cuts from both studies (Table 1). The treated population of CARTITUDE-1 consisted of 97 patients who received infusions of cilta-cel (median [range] dose: 0.71 × 10⁶ [0.51–0.95 × 10⁶] CAR-T cells/kg) after lymphodepletion⁸. The data cut-off for CARTITUDE-1 was January 2022 and the median follow-up duration was 27.7 months. The comparator population of interest for the present study consisted of 124 patients from KarMMa who underwent leukapheresis for the 300 × 10⁶ and 450 × 10⁶ CAR + T cells dose cohorts and received an initial infusion of ide-cel after lymphodepletion⁹. Although an additional four patients were treated in the 150 × 10⁶ CAR-T cells cohort⁹, this dose level has not been approved by the FDA and was therefore not included in the main analysis. The latest available data were used for the FDA-approved dose cohort (300 to 450 × 10⁶ CAR-T cells; N = 124) of KarMMa depending on the outcome (Table 1). For overall response rate (ORR) and complete response or better (≥CR) rate, the data cut-off was 21 December 2020 for which the median follow-up was 24.8 months^10–12. For duration of response (DoR) and progression-free survival (PFS), the data cut-off was 7 April 2020 with median follow-up duration of 15.4 months¹³. For overall survival (OS), the data cut-off was January 2020, with median follow-up of 13.3 months⁹. Given that DoR, PFS, and OS were not available for the FDA-approved doses from the latest published data cut for KarMMa^10–12, sensitivity analyses were performed for these outcomes using the latest available data (median follow-up 24.8 months) from the “all doses” cohort (150 to 450 × 10⁶ CAR-T cells; N = 128)^10–12.

Table 1. Availability of data from CARTITUDE-1 and KarMMa by outcome.

Data cut	Median follow-up	Outcome
		ORR	≥CR	DoR	PFS	OS
CARTITUDE-1 mITT
January 2022 data cut	27.7 months	✓	✓	✓	✓	✓
KarMMa FDA-approved dose cohort (300 to 450 × 10^6 CAR-T cells)
21 December 2020 data cut^10–12	24.8 months	✓	✓	X^a	X^a	X^a
7 April 2020 data cut^13	15.4 months	✓	✓	✓	✓	X
14 January 2020 data cut^9	13.3 months	✓	✓	✓	✓	✓

Abbreviations. CR, complete response; DoR, duration of response; FDA, Food and Drug Administration; mITT, modified intention-to-treat; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

^aResults were available for the “all doses” cohort (150 to 450 × 10⁶ CAR-T cells).

Outcomes

Five efficacy outcomes were assessed in this analysis: ORR, ≥CR rate, DoR, PFS, and OS. For detailed outcome definitions, please refer to the original publication⁷.

Statistical analyses

Matching-adjusted indirect comparison

For details on the MAIC methods please refer to the original publication⁷. In summary, individual patient data from CARTITUDE-1 and published summary-level data from KarMMa were used to estimate the relative effect of cilta-cel versus ide-cel^9–15. To adjust for imbalances in patient characteristics of prognostic significance, infused patients of CARTITUDE-1 who satisfied the eligibility criteria of KarMMa were reweighted to match the distribution of prognostic factors in KarMMa. To reflect the impact of weighting, the effective sample size (ESS) was calculated¹⁶.

Comparative efficacy for cilta-cel versus ide-cel was estimated for ORR and ≥ CR rate with odds ratios (ORs) and 95% confidence intervals (CIs) using weighted logistic regression. Relative risks (RRs) were also calculated as the ratio of response rates for cilta-cel versus ide-cel. For DoR, PFS, and OS, hazard ratios (HRs) and 95% CIs were estimated using a weighted Cox proportional hazards model¹⁷. All analyses were conducted based on the methods developed by Signorovitch et al¹⁸. and were in line with the National Institute of Health and Care Excellence (NICE) Evidence Synthesis Technical Support Document Series¹⁹.

Identification and rank ordering of prognostic factors

As in the original publication, the base case scenario adjusted for refractory status, cytogenetic profile, revised International Staging System (R-ISS) stage, and all plasmacytomas⁷. For details on the identification and ranking of prognostic factors, please refer to the original publication⁷.

Additional sensitivity analyses were performed, which adjusted for all commonly available rank-ordered variables (adding number of prior LOTs, time since MM diagnosis, age, prior stem cell transplant, ECOG status, and sex).

Research ethics statement

The CARTITUDE-1 trial protocol was reviewed and approved by an independent ethics committee/institutional review board (IEC/IRB) at all participating sites. All patients participating in the trial provided written informed consent. Similarly, the KarMMa trial protocol was approved by local or independent IRBs or ethics committees at participating sites and all patients provided written informed consent.⁹ The current analyses were conducted in accordance with a protocol and statistical analysis plan developed prior to the start of data analysis.

Results

Population alignment

The baseline characteristics of the 97 treated patients in CARTITUDE-1 and the 124 patients in KarMMa who underwent infusion for both dose cohorts remained unchanged from the original publication⁷. For details of adjustment and the resulting ESS in each population, please refer to Supplementary Table A.1, adapted from the original publication⁷.

Overall response rate and ≥ complete response rate

For both the unadjusted and adjusted comparisons, the observed response rates, and the relative treatment effect estimates (RRs and ORs) are summarized in Table 2.

Table 2. Response rates and comparative efficacy for cilta-cel versus ide-cel.

	Unadjusted comparison			Base case adjusted^a comparison using FDA-approved doses cohort			All variables adjusted^b comparison using FDA-approved doses cohort (sensitivity)
	Observed response rate		OR^c (95% CI), p value	Adjusted response rate	OR^c (95% CI), p value	Relative risk^d	Adjusted response rate	OR^c (95% CI), p value	Relative risk^d
	Ide-cel	Cilta-cel	Cilta-cel vs ide-cel	Cilta-cel	Cilta-cel vs ide-cel	Cilta-cel vs ide-cel	Cilta-cel	Cilta-cel vs ide-cel	Cilta-cel vs ide-cel
Overall response rate	74.2%	97.9%	16.52 (3.85, 70.93), p = .0002	99.6%	94.93 (21.86, 412.25), p < .0001	1.34	99.5%	70.53 (12.23, 406.82), p < .0001	1.34
Complete response or better rate	33.1%	82.5%	9.53 (5.01, 18.13), p < .0001	73.6%	5.65 (2.51, 12.69), p < .0001	2.23	68.8%	4.47 (1.95, 10.26), p = .0004	2.08

Abbreviations. CI, confidence interval; ESS, effective sample size; FDA, Food and Drug Administration; OR, odds ratio.

^aPatients from CARTITUDE-1 who satisfied KarMMa’s eligibility criteria were adjusted for refractory status, cytogenetic profile, revised International Staging System stage, and all plasmacytomas in the base case analysis.

^bPatients from CARTITUDE-1 who satisfied KarMMa’s eligibility criteria were adjusted for refractory status, cytogenetic profile, revised International Staging System stage, all plasmacytomas, number of prior lines of therapy, years since multiple myeloma diagnosis, age, prior stem cell transplant, Eastern Cooperative Oncology Group status, and sex in the sensitivity analysis.

^cOdds ratios (ORs) >1 are in favor of cilta-cel versus ide-cel.

^dRelative risks are equal to the ratio of the adjusted response rates for cilta-cel versus the observed response rates for ide-cel.

Prior to adjustment, 98% of patients who received cilta-cel responded and 83% achieved ≥ CR (Figure 1). In comparison, 74% of patients treated with ide-cel responded and 33% achieved ≥ CR (Figure 1). After base case adjustment, patients treated with cilta-cel were 1.3-fold more likely to respond (OR: 94.93 [95% CI: 21.86, 412.25; p < .0001]; RR: 1.34) and 2.2-fold more likely to achieve ≥ CR (OR: 5.65 [95% CI: 2.51, 12.69; p < .0001]; RR: 2.23) compared to patients treated with ide-cel.

Figure 1. Overall response rates prior to adjustment for cilta-cel and ide-cel. Abbreviations. CR, complete response; PR, partial response; VGPR, very good partial response.

Duration of response

For both the unadjusted and adjusted comparisons, the relative treatment effect estimates (HRs) for DoR are summarized in Table 3.

Table 3. Estimated medians and comparative efficacy for cilta-cel versus ide-cel.

	Unadjusted comparison			Base case adjusted^a comparison using FDA-approved doses cohort		Base case adjusted^a comparison using “all doses” cohort (sensitivity)		All variables adjusted^b comparison using FDA-approved doses cohort (sensitivity)
	Median, months (95% CI)		HR^c (95% CI), p value	Median, months (95% CI)	HR^c (95% CI), p value	Median, months (95% CI)	HR^c (95% CI), p value	Median, months (95% CI)	HR^c (95% CI), p value
	Ide-cel	Cilta-cel	Cilta-cel vs ide-cel	Cilta-cel	Cilta-cel vs ide-cel	Cilta-cel	Cilta-cel vs ide-cel	Cilta-cel	Cilta-cel vs ide-cel
Duration of response^d	10.7 (8.1, 11.4)	NR (23.3, NR)^e	0.35 (0.23, 0.54), p < .0001	23.3 (12.0, NR)^e	0.52 (0.30, 0.88), p = .0152	23.3 (12.5, NR)	0.51 (0.32, 0.83), p = .0063	20.2 (9.0, NR)^e	0.59 (0.34, 1.02), p = .0610
Progression-free survival	8.9 (5.7, 11.6)	NR (24.5, NR)^e	0.27 (0.18, 0.41), p < .0001	25.2 (13.4, NR)^e	0.38 (0.24, 0.62), p < .0001	25.2 (13.7, NR)	0.38 (0.25, 0.60), p < .0001	22.8 (10.3, NR)^e	0.43 (0.26, 0.71), p = .0010
Overall survival^f	19.5 (18.9, NR)	NR (NR, NR)	0.31 (0.18, 0.52), p < .0001	NR (30.1, NR)	0.43 (0.22, 0.88), p = .0200	NR (26.1, NR)	0.58 (0.34, 1.00), p = .0490	NR (30.1, NR)	0.49 (0.23, 1.04), p = .0638

Abbreviations. CI, confidence interval; FDA, Food and Drug Administration; HR, hazard ratio; NR, not reached.

^aPatients from CARTITUDE-1 who satisfied KarMMa’s eligibility criteria were adjusted for refractory status, cytogenetic profile, revised International Staging System stage, and all plasmacytomas in the base case analysis.

^bPatients from CARTITUDE-1 who satisfied KarMMa’s eligibility criteria were adjusted for refractory status, cytogenetic profile, revised International Staging System stage, all plasmacytomas, number of prior lines of therapy, years since multiple myeloma diagnosis, age, prior stem cell transplant, Eastern Cooperative Oncology Group status, and sex in the sensitivity analysis.

^cHazard ratios (HRs) <1 are in favor of cilta-cel.

^dFor KarMMa, estimates were calculated using the number of responders (N = 92).

^eMedians should be interpreted with caution, as reached when few patients were still at risk and may be an underestimate.

^fFor KarMMa, estimates were calculated using publicly available data, which excluded one patient who received a non-conforming product that did not meet product release specifications for ide-cel (N = 123).

The unadjusted HR for DoR for cilta-cel versus ide-cel was 0.35 (95% CI: 0.23, 0.54; p < .0001) (Figure 2). After base case adjustment, DoR was significantly longer for cilta-cel compared to ide-cel (HR: 0.52 [95% CI: 0.30, 0.88); p = .0152]).

Figure 2. Observed (unadjusted) and adjusted (base case) Kaplan–Meier plots of duration of response. Base case results adjusted for refractory status, cytogenetic profile, revised International Staging System stage, and all plasmacytomas. Abbreviations. CI, confidence interval; ESS, effective sample size; HR, hazard ratio.

The Grambsch-Therneau test²⁰ for violation of the proportional hazards assumption was non-significant for the base case adjusted analysis (p = .69), indicating that the proportional hazards assumption was not violated.

Progression-free survival and overall survival

For both the unadjusted and adjusted comparisons, the relative treatment effect estimates (HRs) for PFS and OS are summarized in Table 3. PFS data were available for all 124 patients in KarMMa who underwent infusion for the 300 × 10⁶ and 450 × 10⁶ CAR + T cells dose cohorts, whereas OS data were only available in the public domain for 123 of these patients (the available data removed one patient who received a non-conforming product that did not meet the product release specifications for ide-cel)¹⁴.

The unadjusted HR for cilta-cel versus ide-cel was 0.27 (95% CI: 0.18, 0.41; p < .0001) for PFS (Figure 3) and 0.31 (95% CI: 0.18, 0.52; p < .0001) for OS (Figure 4). After base case adjustment, cilta-cel was statistically significantly longer compared to ide-cel for PFS (HR: 0.38 [95% CI: 0.24, 0.62; p < .0001]) and for OS (HR: 0.43 [95% CI: 0.22, 0.88; p = .0200]).

Figure 3. Observed (unadjusted) and adjusted (base case) Kaplan–Meier plots of progression-free survival. Base case results adjusted for refractory status, cytogenetic profile, revised International Staging System stage, and all plasmacytomas. Abbreviations. CI, confidence interval; ESS, effective sample size; HR, hazard ratio.

Figure 4. Observed (unadjusted) and adjusted (base case) Kaplan–Meier plots of overall survival. Base case results adjusted for refractory status, cytogenetic profile, revised International Staging System stage, and all plasmacytomas. Abbreviations. CI, confidence interval; ESS, effective sample size; HR, hazard ratio.

The Grambsch-Therneau test²⁰ for violation of the proportional hazards assumption was non-significant for both outcomes in the base case adjusted analysis (PFS: p = .63; OS: p = .07), indicating that the proportional hazard assumption was not violated.

Sensitivity analyses

The sensitivity analyses of the time-to-event outcomes using the “all doses” cohort from the latest data cut for KarMMa showed superior outcomes for cilta-cel versus ide-cel over longer follow-up and were consistent with the base case comparative estimates presented in Table 3 for the FDA-approved doses. Comparative efficacy estimates for the “all doses” comparison were as follows: DoR: HR = 0.51 (95% CI: 0.32, 0.83; p = .0063); PFS: HR = 0.38 (95% CI: 0.25, 0.60; p < .0001); OS: HR = 0.58 (95% CI: 0.34, 1.00; p = .049).

The sensitivity analyses that incrementally adjusted for additional baseline characteristics (for details, please refer to the original publication⁷) showed superior outcomes for cilta-cel versus ide-cel. Comparative efficacy estimates for the all variables adjusted comparison were as follows: ORR: OR = 70.53 (95% CI: 12.23, 406.82; p < .0001); RR = 1.34; ≥CR rate: OR = 4.47 (95% CI: 1.95, 10.26; p = .0004); RR = 2.08; DoR: HR= 0.59 (95% CI: 0.34, 1.02; p = .0610); PFS: HR = 0.43 (95% CI: 0.26, 0.71; p = .0010); and OS: HR = 0.49 (95% CI: 0.23, 1.04; p = .0638).

Discussion

Despite an ever-changing treatment landscape, with several new drugs being approved in the past decade^2,21–25, MM remains a difficult to treat and incurable disease. Patients who relapse after receiving IMiDs, PIs, and anti-CD38 MoABs (i.e. triple-class exposed patients) have a particularly high unmet need for new safe and effective treatments. Given that head-to-head clinical trials evaluating the efficacy and safety of cilta-cel and ide-cel have not been conducted, MAICs are a valid alternative to estimate the relative treatment effect. Previous analyses have been published and showed improved efficacy with cilta-cel compared with ide-cel; however, follow-up data were limited to 18 months for cilta-cel and 13.3 months for ide-cel⁷. Since the publication of previous MAIC, longer-term follow-up data >2 years from CARTITUDE-1 and KarMMa became available, allowing an updated assessment of the comparative efficacy of cilta-cel and ide-cel to better inform healthcare decisions for physicians, patients, and policy makers.

The results from this updated analysis using longer-term follow-up data showed that cilta-cel continues to provide superior efficacy compared with ide-cel beyond the follow-up period included in the original MAIC publication. While the updated estimates were consistent with those in the original publication, the use of more mature data resulted in more precise confidence intervals around these estimates. A summary of the base case results from both the original publication and the present analyses is presented in Supplementary Table B.1. The base case analyses adjusting for the most clinically important factors (i.e. refractory status, cytogenetic profile, R-ISS stage, and all plasmacytomas) showed statistically significant results in favor of cilta-cel compared with ide-cel for all outcomes (ORR, ≥CR rate, DoR, PFS, and OS).

Patients treated with cilta-cel were 1.3-fold more likely to respond (ORR) and 2.2-fold more likely to achieve a ≥ CR than patients treated with ide-cel. The observed ≥ CR rate for CARTITUDE-1 in the present analysis (82.5%), notably exceeded the observed rate for patients in the 300 × 10⁶ and 450 × 10⁶ CAR + T cells dose cohorts in KarMMa (33.1%). These results were consistent with those published previously, with cilta-cel demonstrating an increased likelihood of a deeper response compared with ide-cel.

Furthermore, cilta-cel reduced the risk of disease progression or death by 48% in responders (DoR) and 62% in all patients (PFS) compared with ide-cel. These findings were consistent with the sensitivity analyses and the previously published MAIC.⁷ After a median follow-up duration of 27.7 months, base case adjusted median DoR and median PFS for cilta-cel were 23.3 months and 25.2 months. These estimates exceed the median DoR of 10.7 months and the median PFS of 8.9 months observed for patients in the FDA-approved dose (300 × 10⁶ and 450 × 10⁶ CAR + T cells) cohorts in KarMMa. It should be noted that at the time of the present analyses, no DoR or PFS data were available for the FDA-approved dose cohorts from the latest published data cut for KarMMa (data cut-off was 21 December 2020 with median duration of follow-up of 24.8 months). Therefore, sensitivity analyses using the latest published data for KarMMa in the “all doses” cohort were performed and results were consistently in favor of cilta-cel. However, it should be noted that the median DoR and PFS for the “all doses” cohort of KarMMa from the latest published data cut (DoR: 11.0 [95% CI: 8.1, 12.3]; PFS: 8.8 [95% CI: 5.7, 11.6] months) are unlikely to differ significantly from those of the FDA-approved dose cohorts as only 4 of the 128 patients fall outside the FDA-approved dose range.

In the evaluation of OS, the current analysis found that cilta-cel significantly reduced the risk of death by 57% (p = .0200) compared with ide-cel. These results were consistent with those published previously, however the use of longer follow-up data provided a statistically significant result in favor of cilta-cel. It should be noted that at the time of the present analyses, no new OS data were available for the FDA-approved dose cohorts from KarMMa. In the absence of new data for the FDA-approved doses, sensitivity analyses using the latest published data for KarMMa (data cut-off was 21 December 2020 with median duration of follow-up of 24.8 months) in the “all doses” cohort were performed and results were consistent in favor of cilta-cel. However, it should be noted that the median OS for the “all doses” cohort of KarMMa from the latest published data cut (24.3 [95% CI: 19.9, 31.4] months) is unlikely to differ significantly from that of the FDA-approved dose cohorts as only 4 of the 128 patients fall outside the FDA-approved dose range.

Notable strengths of these analyses have been discussed previously⁷ and remain applicable herein. However, an additional strength of these updated analyses is the use of the most contemporary data cut available for each outcome from both CARTITUDE-1 and KarMMa. The use of the most mature data available for the comparators lends additional credibility to the findings. Furthermore, although IPD was not available for KarMMa, reliable reconstruction of the observed IPD was possible through the simulation of IPD from published Kaplan–Meier plots for DoR, PFS, and OS using the validated Guyot method^26–28. The Kaplan–Meier curves developed from simulated IPD were nearly identical to the published Kaplan–Meier curves, with potential slight discrepancies in the exact timings of censoring, which are expected to have only a minimal impact on the estimated HRs.

As in any comparison using non-randomized data, the potential for residual confounding cannot be disregarded. Furthermore, some clinically relevant prognostic factors were not collected in CARTITUDE-1 (e.g. 1q abnormalities) or reported in KarMMa (for details, please refer to the discussion in the original publication⁷) however, the most important factors, as identified in close consultation with multiple independent clinical experts, were accounted for. It should also be noted that while 45.2% of 73 patients who received bridging therapy in CARTITUDE-1 had a transient decrease in tumor burden (defined as change in serum M-protein, urine M-protein, or difference between involved and uninvolved free light chain) prior to cilta-cel infusion, a decrease in tumor burden does not equate to being a responder per IMWG criteria. No subjects in CARTITUDE-1 achieved CR while on bridging therapy⁸. In the KarMMa study, the 4% of patients who received bridging therapy and had a confirmed partial or very good partial response as per investigator assessment also did not achieve a CR⁹. Therefore, there is no indication that patients in CARTITUDE-1 had a different disease biology than those in KarMMa. Furthermore, as per trial protocol, bridging therapy must have been previously received in a prior line of therapy and therefore all patients who received bridging therapy had either progressed or been non-responsive to those same agents prior to enrollment in CARTITUDE-1.

Since the focus of the present study was to update previously published comparative efficacy analyses using the latest published data with longer follow-up from both studies, safety outcomes were not assessed⁷. Future studies may be conducted including real-world data to address this data gap.

These updated analyses using the latest published data with longer follow-up from both studies were consistent with previously published comparative efficacy analyses in favor of cilta-cel compared with ide-cel in the treatment of triple-class exposed patients with RRMM, specifically in terms of response rates and survival outcomes. Future studies using real-world data may be used to fill this evidence gap and validate the findings from the current analyses.

Conclusion

The results of this updated MAIC analysis using longer follow-up data showed that the superior efficacy of cilta-cel compared with ide-cel was maintained for all outcomes studied (ORR, ≥CR rate, DoR, PFS, and OS). Overall, the results indicate that cilta-cel offers substantial clinical benefits for patients with triple-class exposed RRMM, greater than those provided by ide-cel.

Transparency

Declaration of funding

This work was supported by Janssen Pharmaceuticals and Legend Biotech.

Declaration of financial/other relationships

TM is a consultant for GlaxoSmithKline and receives research funding from Janssen, Amgen, and Sanofi. SZU receives grant support from Pharmacyclics, receives grant support and consulting fees from Amgen, Bristol-Myers Squibb, Celgene, Sanofi, Seattle Genetics, Janssen, Takeda, SkylineDx, Merck, and GlaxoSmithKline, and consulting fees from AbbVie, Karyopharm, and Mundipharma. JMS, TR, WD, TY, AB, SVS, JD, and SV are employed by Janssen and have restricted stock units and/or stock options. CCJ is employed by Janssen and is a consultant physician at the Memorial Sloan Kettering Cancer Center. LP and AG are employed by Legend Biotech, Piscataway, NJ, USA. MB and IAS are employed by EVERSANA, Burlington, ON, Canada, and AH is employed by EVERSANA, Chicago, IL, USA, which was contracted by Janssen to work on this project. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors were responsible for study conception and design. JD, SVS were responsible for acquisition and analysis. All authors were responsible for drafting or reviewing the manuscript and approving the final version. All authors were responsible for interpretation of data and revising it critically.

Acknowledgements

The CARTITUDE-1 study and these analyses were funded by Janssen Research & Development, LLC, and Legend Biotech, Inc. Medical writing support was provided by EVERSANA and funded by Janssen Global Services, LLC. The authors acknowledge the contribution of Eloquent Scientific Solutions for the editorial support.

Data availability statement 

Requests for access to the CARTITUDE-1 trial study data may be submitted through the Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. The data sharing policy of Janssen Pharmaceutical Companies is available at https://www.janssen.com/clinical-trials/transparency. For KarMMa study, a data sharing statement is available with the full text of the primary publication at NEJM.org.¹²