Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study

doi:10.1016/S0140-6736(21)00933-8

The Lancet

Volume 398, Issue 10297, 24–30 July 2021, Pages 314-324

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https://doi.org/10.1016/S0140-6736(21)00933-8 Get rights and content

Summary

Background

CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis.

Methods

This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 10⁶ CAR-positive viable T cells per kg) was administered 5–7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207.

Findings

Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 10⁶ CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6–15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2–99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9–1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9–not estimable), neither was progression-free survival (16·8–not estimable). The 12-month progression-free rate was 77% (95% CI 66·0–84·3) and overall survival rate was 89% (80·2–93·5). Haematological adverse events were common; grade 3–4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5–8) and median duration of 4·0 days (IQR 3–6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events.

Interpretation

A single cilta-cel infusion at the target dose of 0·75 × 10⁶ CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions.

Funding

Janssen Research & Development and Legend Biotech.

Introduction

Patients with multiple myeloma treated with immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies eventually relapse or become refractory to these therapies, leading to a poor prognosis.¹ A retrospective study of treatment outcomes in patients with multiple myeloma reported an overall response rate of 31% with a median overall survival of 9·3 months in refractory patients who were triple-class exposed.² Thus, there is an unmet need for novel and innovative therapies to improve long-term outcomes in this patient population.

Research in context

Evidence before this study

We searched PubMed on Dec 18, 2020, with no date restriction, using the keywords “relapsed or refractory”, “myeloma”, “B-cell maturation antigen”, “chimeric antigen receptor T (CAR T)”, and “clinical trial”. From the seven articles identified, one reported results with a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, idecabtagene vicleucel, which showed deep and durable responses in patients with relapsed or refractory multiple myeloma. Two studies reported results with LCAR-B38M, a novel CAR construct that consists of two BCMA single-domain antibodies designed to confer avidity. LEGEND-2 is an investigator-initiated, first-in-human phase 1 study in China that evaluated LCAR-B38M CAR T-cell therapy for relapsed or refractory multiple myeloma in patients previously treated with a proteasome inhibitor, immunomodulatory drug, or both. Following treatment with LCAR-B38M, patients had deep, durable responses with a manageable safety profile.

Added value of this study

In this phase 1b/2 study of citla-cel (using a CAR construct identical to LCAR-B38M, a single infusion of cilta-cel led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma, with a manageable safety profile at the recommended phase 2 dose. The overall response rate was 97%, with most patients achieving their first response within a month of infusion. Cilta-cel showed unprecedented clinical activity in this challenging-to-treat population compared with other novel anti-myeloma treatments.

Implications of all the available evidence

Cilta-cel might be a viable treatment option for patients with relapsed or refractory multiple myeloma, with the highest overall response rate achieved to date in this heavily pretreated population who received a previous proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody, including those who are triple-class refractory or penta-drug refractory. Cilta-cel is under further investigation in other populations of patients with multiple myeloma in earlier line settings.

Selinexor, a selective nuclear export inhibitor, and belantamab mafodotin, a B-cell maturation antigen (BCMA)-directed antibody and microtubule inhibitor conjugate, have been approved to treat patients with multiple myeloma who have received more than three previous therapies.3, 4 However, treatment with these agents has resulted in low overall response rates (<35%) and short progression-free survival (<5 months).3, 4 Ciltacabtagene autoleucel (also known as cilta-cel) is a chimeric antigen receptor T (CAR T)-cell therapy expressing two BCMA-targeting single-domain antibodies designed to confer avidity, and a CD3-ζ signalling domain with a 4-1BB costimulatory domain to optimise T-cell activation and proliferation.

In the phase 1, first-in-human LEGEND-2 study in China, LCAR-B38M CAR T cells yielded deep, durable responses with a manageable safety profile in patients with relapsed or refractory multiple myeloma who received previous proteasome inhibitors, immunomodulatory drugs, or both.5, 6 The overall response rate was 88%, with 42 (74%) of 57 patients achieving complete response or better, and the median duration of response was 22 months.⁶ The median progression-free survival for all-treated patients was 20 months (range 10–28) and 28 months (range 20–31) for those with minimal residual disease negativity.⁶

CARTITUDE-1 is a phase 1b/2 study of cilta-cel, using a CAR T cell construct identical to that used in LEGEND-2.⁵ Here, we report the initial safety and clinical activity results from the primary analysis of the combined phase 1b/2 CARTITUDE-1 study.

Section snippets

Study design and participants

CARTITUDE-1 is a single-arm, open-label, phase 1b/2 study done at 16 centres in the USA. An additional cohort in Japan is ongoing; these results will be reported separately. The study comprised a phase 1b and a phase 2, which occurred sequentially. The aims of phase 1b were to characterise cilta-cel safety and confirm the recommended phase 2 dose; the main aim of phase 2 was to evaluate cilta-cel clinical activity. Full study design details and eligibility criteria are summarised in the

Results

Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled and all underwent apheresis (figure 1). 16 (14%) did not receive cilta-cel infusion because of disease progression, death, or study withdrawal. No patient discontinued because of cilta-cel manufacturing failure.

97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 10⁶ CAR-positive viable T cells per kg (range 0·5 × 10⁶–1·0 × 10⁶).

Patient baseline characteristics

Discussion

A single infusion of cilta-cel led to early, deep, and durable responses in patients with relapsed or refractory multiple myeloma. A partial response or better was observed in 97% of treated patients, with 79% achieving their first response within 1 month of cilta-cel infusion. Most patients (67%) achieved stringent complete response; median duration of response and median progression-free survival were not reached at data cutoff. Notably, 62% of those who achieved complete response or better

Data sharing

The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available online. As noted on policy, requests for access to the study data can be submitted through Yale Open Data Access Project website.

Declaration of interests

JGB receives research funding from AbbVie, Amgen, Acetylon, Bluebird, Bristol Myers Squibb, Celgene, Cellularity, Constellation, CRISPR Therapeutics, CURIS, EMD Serono, Genentech, Glenmark, Janssen, Kesios, Lilly, Novartis, Poseida, Teva, Takeda Pharmaceuticals, and Vivolux, and is a consultant for Amgen, Bioclinica, Bristol Myers Squibb, Celgene, CRISPR Therapeutics, Janssen, Karyopharm, Kite Pharma, Legend, Prothena, Servier, Takeda Pharmaceuticals, and SecuraBio. DM is a consultant for and

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ArticlesCiltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Data sharing

Declaration of interests

Clin Lymphoma Myeloma Leuk

Lancet Oncol

Blood

Blood

Lancet Oncol

Blood Rev

Blood

Biol Blood Marrow Transplant

Blood

Lancet Oncol

Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy

Leukemia

oral selinexor-dexamethasone for triple-class refractory multiple myeloma

N Engl J Med

A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma

J Hematol Oncol

Clarification of the definition of complete response in multiple myeloma

Leukemia

Articles
Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study