Idecabtagene vicleucel versus ciltacabtagene autoleucel: a Sophie’s choice for patients with relapsed refractory multiple myeloma

KEYWORDS:

• Myeloma
• CAR T
• cilta-cel
• ida-cel
• BCMA

1. Introduction

Multiple myeloma (MM) is a plasma cell disorder characterized by malignant proliferation of clonal plasma cells in the bone marrow and accounts for about 10% of all hematologic malignancies [1–4]. Relapsed refractory (RR) MM with prior exposure to proteasome inhibitors (PI), immunomodulatory drugs (IMiD), and anti-CD38 monoclonal antibody (moAb), also known as triple-class exposed MM, is associated with poor prognosis with a median overall survival (OS) of less than 1 year [5,6]. Development of novel treatment modalities, including Chimeric Antigen Receptor (CAR) T-cell therapy, has led to a major breakthrough in the treatment armamentarium of RRMM.

1.1 Given exclusive and uniform expression on malignant plasma cells as well as established role in the differentiation and proliferation of plasma cells, B-cell maturation antigen (BCMA) has emerged as an ideal target for cellular therapies against RRMM [7]. BCMA targeting CAR T-cell therapy utilizes genetically modified autologous T-cells from a patient to target and destroy malignant plasma cells expressing the BCMA surface marker. Recently, efficacy and safety outcomes of two BCMA targeting CAR T-cell products, Idecabtagene Vicleucel (ide-cel; bb2121) and Ciltacabtagene Autoleucel (cilta-cel; JNJ-68284528), were published [8,9]. Here, we summarize the pertinent similarities and differences of these novel BCMA targeting CAR T-cell products as well as highlight the relevant aspects of their use in clinical practice. As it remains unclear whether one CAR T product with its superior safety and efficacy is preferable over the other, we discuss relevant patient-, disease-, and CAR T-related variables that may offer guidance to physicians facing something of a Sophie’s choice when treating patients with RRMM.

1.2 KarMMa-1 (NCT03361748) was an open-label, multicenter study, phase 2 trial investigating the safety and efficacy of ide-cel in patients with RRMM. After receiving three days of lymphodepleting chemotherapy (300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine), a total of 128 patients received a one-time infusion of 150–450 × 10⁶ per kilogram CAR-positive T-cells [8]. A total of 73% of the patients met the primary outcome of overall response rate (ORR) (95% CI 66–81; p < 0.001) with 33% obtaining a complete response (CR) or better. Median progression-free survival (PFS) and OS were 8.8 months (95% CI 5.6–11.6) and 19.4 months (95% CI 18.2-could not be estimated), respectively [8]. The most common grade ≥3 toxicities included neutropenia (89%), anemia (60%), thrombocytopenia (52%), and infections (22%). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 84% and 18% of patients, respectively, with grade ≥3 toxicities seen in less than 5% of the patients [8]. In March 2021, the US Food and Drug Administration (FDA) approved ide-cel for patients with RRMM with exposure to four prior lines of therapy including PI, IMiD, and anti-CD38 moAb.

1.3 CARTITUDE-1 (NCT03548207) was a multicenter, open-label, phase 1b/2 trial investigating dosing, safety, and efficacy of cilta-cel in 97 patients with RRMM. After receiving 3 days of lymphodepleting chemotherapy (300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine), a total of 97 patients received a one-time median infusion dose of 0.71 × 10⁶ (range 0.51–0.95 × 10⁶) per kilogram CAR-positive T-cells [9]. A total of 98% of the patients met the primary outcome of ORR (95% CI 91.2–99.4; p < 0.001) with 82% obtaining a stringent CR at 24 months and 93% of the 61 evaluable patients achieving minimal residual disease (MRD) negativity (10⁵). The 24-month PFS and OS were 60.5% and 74%, respectively, with median PFS and OS not reached [9]. The most common grade ≥3 toxicities were neutropenia (95%), anemia (68%), thrombocytopenia (60%), and infections (20%). CRS and ICANS occurred in 95% and 21% of patients, respectively. Grade ≥3 CRS and ICANS occurred in 4% and 9% of the patients, respectively [9]. About 10% of the patients experienced late onset neurotoxicity not described by ICANS diagnostic criteria. These events included parkinsonian-like movement disorders, cranial nerve paralysis, and neuropathy. About half of these patients did not recover from the neurotoxicity with one death occurring from neurotoxicity [9]. In March 2022, the FDA approved cilta-cel for patients with RRMM with exposure to four prior lines of therapy including PI, IMiD, and anti-CD38 moAb.

2. Despite significant breakthroughs in the treatment landscape over the last 10 years, MM remains an incurable disease. With modest efficacy (ORR 26–34%, median PFS <5 months) seen with several recently approved agents including selinexor, belantamab mafodotin, and melphalan flufenamide, treatment of triple-class exposed RRMM remains a challenge [10–12]. In comparison, commercially approved CAR T-cell therapy clearly has superior efficacy with an ORR of 75–98% and a median duration of response of 9–22 months [8,9]. These responses are seen early (time to first response <1 month; time to best response <3 months) and may persist for long periods of time, allowing patients not only a durable treatment-free remission but also an overall improved quality of life. Although these two BCMA-directed CAR T products target the same antigen with a similar mechanism of action and have been studied in heavily pretreated RRMM patients, there are several important differences including CAR T construct, cell doses, and the patient populations studied in the two pivotal clinical trials. These characteristics (highlighted in Table 1) may explain the differences seen in efficacy and safety profile of the two products. In the absence of a randomized controlled trial and head-to-head comparison, it is difficult to state that whether one CAR T product is superior to the other.

Table 1. Comparison of available BCMA CAR T-cell therapies

	Idecabtagene vicleucel (n = 124)	Ciltacabtagene autoleucel (n = 97)
Baseline Characteristics
Target CAR T dose	450 million	0.75 million/kilogram
Median age (range)	61 years (33–78)	61 years (56–68) 61 years (43 to 78 years)
Median prior lines (range)	6 (3–16)	6 (4–8) 6 (3–18)
Bridging therapy	87%	75%
R-ISS stage II/ III	86%	66%
Triple-refractory disease^a	84%	88%
Penta-refractory disease^b	26%	42%
High-risk cytogenetics^c	35%	24%
Extramedullary disease^d	40%	13%
Toxicity
CRS (all; grades 3–4)	85% (6%)	95% (5%)
Median onset of CRS, duration	1 day, 5 days	7 days, 4 days
ICANS (all; grades 3–4)	19% (3%)	17% (2%)
Median onset of ICANS, duration	2 days, 3 days	8 days, 4 days
Infections (all; grade 3–4)	69% (22%)	59% (23%)
Grades 3–4 neutropenia > 1 month	40%	30%
Grades 3–4 thrombocytopenia > 1 month	48%	41%
Delayed neurotoxicity	–	12%
Efficacy
ORR	73%	97%
sCR or CR	33%	sCR 78%
MRD negativity rate (10^-5)	33/119 (28%)	53/97 (58%)
Median PFS	9.2 months (95% CI, 6.0 to 12.1)	24 mo PFS: 60.5% (95% CI, 48.5 to 70.4)
Median OS	19.5 months (95% CI, 18.9 to NR)	24 mo OS: 74% (95% CI, 61.9 to 82.7)
Median time to best response (range)	2.8 months (1.0 to 11.8)	2.6 month (1.0 to 6.1)
Median duration of response	11.1 months (95% CI, 9.1 to 11.3)	21.8 months (95% CI, 21.8 – NR)

Key; CRS: cytokine release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; ORR: overall response rate; sCR: stringent complete response; CR: complete response; MRD: minimum residual disease; PFS: progression-free survival; OS: overall survival; NR: not reached

a: triple-refractory disease was refractory to one or more proteasome inhibitors, one or more immunomodulatory drugs, and one anti-CD38 antibody; b: penta-refractory disease was refractory to two or more proteasome inhibitors, two or more immunomodulatory drugs, and one anti-CD38 antibody; c: high-risk cytogenetic abnormalities included the following: del(17p), t(4;14), t(14;16); d: extramedullary disease was defined as paraskeletal soft-tissue masses or soft-tissue masses spreading outside of the bone marrow

2.1 While ida-cel contains a murine scFv single binding domain for the BCMA antigen, cilta-cel has two camelid VH binding domains conferring higher activity and less immunogenicity. Whether this is truly related to the better depth and duration of remission seen with cilta-cel remains unknown, especially considering a majority of CAR T-cells are no longer detectable at 6- and 12-month post-infusion [8]. While both trials enrolled patients that had heavily pretreated RRMM, refractory to the last line of therapy, more patients in the KarMMa-1 trial had high-risk cytogenetic abnormalities (deletion 17p, t(4;14), t(14;16)), advanced R-ISS stage, and extra medullary disease when compared to CARTITUDE-1 trial. Perhaps this explains some of the differences seen in depth and duration of response between the two products.

2.2 Although the vast majority of patients (84–95%) developed CRS in the two trials, most of the events were grade 1 or 2 in severity and were managed with supportive care and tocilizumab. The median CAR T-cell dose in CARTITUDE-1 trial was much lower (0.71 × 10⁶ per kilogram) which may explain late onset of CRS (median onset at 7 days). The relatively late onset of CRS with cilta-cel raises the possibility of not only administering the product but also managing these patients in the outpatient setting, perhaps allowing for better reimbursement for the cost of CAR T-cell therapy. About 10% of the patients in the CARTITUDE-1 trial developed late onset neurotoxicity features that lasted more than 3 months and were not reversible for some of the patients. While the more recent clinical trials with cilta-cel have avoided this late neurotoxicity with interventions including bridging chemotherapy, early use of corticosteroids, and frequent handwriting monitoring, late onset neurotoxicity remains of concern in patients with underlying neurological disorders. Persistent/prolonged grades 3–4 neutropenia and thrombocytopenia were seen more commonly in patients receiving ida-cel as compared to cilta-cel, raising the concern for greater utilization of supportive measures including anti-infective prophylaxis, transfusions, and growth factors. However, the incidence of all grade and grade 3+ infections were similar between the two products. The listed price for ida-cel is $419,000 versus $465,000 for cilta-cel. Although both products are expensive, CAR T-cell therapy appears to be a reasonably cost-effective treatment for heavily pretreated RRMM, given that the patients do not need any maintenance post-treatment. As already seen with lymphomas, real-world analyses using consortium and registry data will answer more questions about the safety and efficacy of CAR T-cell therapy for RRMM. Such analyses are likely to provide insight into the role of CAR T-cell therapy in patients that have been historically excluded from clinical trials due to performance status, comorbidities, and more aggressive disease biology.

2.3 While cilta-cel appears to be more favorable for outpatient administration, ida-cel may be a better option for patients with underlying neurological conditions or central nervous system disease. Given high demand and manufacturing limitations, access to a CAR T product in a timely manner will be a critical and perhaps more important factor than safety, efficacy, or cost differences, influencing physicians’ choice between the two products. Availability of two CAR T products may address some of the access issues, but whether it will comprehensively address the manufacturing limitations remains to be seen. Until then, without a head-to-head comparison, any cross-trial or matched-adjusted indirect comparisons are unlikely to establish the superiority of one CAR T product over another.

3. Conclusion

The availability of two commercially approved CAR T-cell therapy products is a milestone in the treatment landscape of RRMM. Both products appear highly effective with tolerable safety profiles. In the absence of a randomized controlled trial, choice of CAR T-cell product will be individualized, depending on a careful review of the safety and efficacy of the product for each patient and perhaps more importantly, access to treatment in a timely manner.

Declaration of Interest

H Hashmi declares that they are on the advisory board for Janssen, Bristol-Myers Squibb, and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A peer reviewer on this manuscript has received advisory board and honoraria from Celgene/BMS and Janssen. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Funding

This paper was not funded.