The Lancet JULY 24, 2021

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

Jesus G. Berdeja, Deepu Madduri, Saad Z. Usmani, Andrzej Jakubowiak, Mounzer Agha, Adam D. Cohen, A. Keith Stewart, Parameswaran Hari, Myo Htut, Alexander Lesokhin, Abhinav Deol, Nikhil C. Munshi, et al.

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Bottom Line

In this single-arm, phase 1b/2 study, a single infusion of the BCMA-targeting CAR-T therapy ciltacabtagene autoleucel (cilta-cel) demonstrated high, durable response rates and long-term efficacy in heavily pretreated patients with relapsed or refractory multiple myeloma.

Key Findings

1. The study demonstrated an overall response rate (ORR) of 98%, with 82.5% of patients achieving a stringent complete response.

2. At a median follow-up of 33.4 months, the median progression-free survival (PFS) was 34.9 months, with an estimated 47.5% of patients remaining progression-free at 36 months.

3. The median overall survival (OS) was not reached, with an estimated 62.9% of patients surviving at 36 months.

4. Achieving a complete response or sustained minimal residual disease (MRD) negativity was strongly associated with improved long-term progression-free survival outcomes.

Study Design

Design

Phase 1b/2, Single-arm Trial

Open-Label

Sample

Patients

Duration

33.4 mo

Median

Setting

Multicenter, US

Population Adults with relapsed or refractory multiple myeloma who had received ≥3 prior lines of therapy (including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody) and were refractory to the last line of therapy.

Intervention Single infusion of ciltacabtagene autoleucel (cilta-cel) at a target dose of 0.75 × 10^6 CAR-positive viable T cells/kg, administered following a 3-day lymphodepletion regimen of cyclophosphamide and fludarabine.

Comparator N/A (Single-arm trial)

Outcome Safety and the recommended phase 2 dose (Phase 1b); overall response rate (Phase 2).

Study Limitations

• The study was a single-arm trial without a randomized control group, limiting direct comparisons to standard-of-care therapies.

• The participant population was highly specific (heavily pretreated), which may limit the generalizability of these results to less refractory patient populations.

• The study identified notable safety concerns, including cytokine release syndrome and, in a subset of patients, unique neurotoxicity (including cases of parkinsonism), requiring careful patient selection and management strategies.

Clinical Significance

Cilta-cel provides a potent, high-efficacy therapeutic option for patients with multiple myeloma who have exhausted standard treatment options (triple-class refractory), shifting the treatment paradigm for relapsed/refractory disease by delivering durable, deep, and rapid responses.

Historical Context

The CARTITUDE-1 trial built upon the promising signals observed in the first-in-human LCAR-B38M study (LEGEND-2), confirming the efficacy of the BCMA-targeted CAR-T platform in a multicenter setting and establishing a foundational role for this modality in late-line treatment of refractory multiple myeloma.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the structural unique feature of ciltacabtagene autoleucel (cilta-cel) compared to other CAR-T therapies, and why is the B-cell maturation antigen (BCMA) targeted in multiple myeloma?

Key Response

Cilta-cel is a bivalent CAR-T cell therapy, meaning it features two single-domain antibodies that target two distinct epitopes on the BCMA molecule. BCMA is an ideal target because it is highly and selectively expressed on the surface of malignant plasma cells (and some healthy mature B cells) but is absent from other essential tissues and hematopoietic stem cells.

Resident

In the management of patients receiving cilta-cel as per the CARTITUDE-1 trial, what is the significance of 'delayed neurotoxicity' and how does its clinical presentation differ from classic ICANS?

Key Response

While Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) typically occurs early (within days) alongside CRS, cilta-cel is associated with delayed neurotoxicity (movement and neurocognitive treatment-emergent adverse events, or MNTs) occurring weeks to months post-infusion. This presents with symptoms like Parkinsonian-like tremors, handwriting changes, and cognitive slowing, requiring vigilant long-term monitoring beyond the initial 30-day window.

Fellow

The CARTITUDE-1 study reported a stringent complete response (sCR) rate of 67%. How should a clinician interpret the achievement of MRD negativity (10^-5) in these patients regarding the risk of late relapse, and what are the limitations of using MRD as a surrogate endpoint in RRMM?

Key Response

Cilta-cel achieved high rates of MRD negativity (92% of evaluable patients), which strongly correlates with prolonged progression-free survival. However, late relapses still occur, possibly due to extramedullary disease not captured by bone marrow MRD or BCMA antigen escape (loss or downregulation). As a surrogate, MRD is highly sensitive for local marrow response but may not fully represent the total body tumor burden in complex RRMM.

Attending

Given the 'one-and-done' nature of cilta-cel demonstrated in CARTITUDE-1 versus the continuous therapy model of bispecific antibodies (e.g., teclistamab), how does the safety-to-efficacy profile of cilta-cel influence the sequencing of therapy for a triple-class refractory patient with a slow-growing versus rapidly progressive relapse?

Key Response

Cilta-cel offers a treatment-free interval and deeper responses, making it highly desirable for patients seeking quality of life. However, the manufacturing lead time (apheresis to infusion) makes it risky for rapidly progressive 'explosive' disease where the patient may not survive the wait. In contrast, off-the-shelf bispecifics may be preferred for urgent debulking, even if they require ongoing administration.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The CARTITUDE-1 trial utilized a single-arm design. Evaluate the statistical validity of comparing its results to the LocoMMotion or MAMMOTH cohorts, and discuss how 'selection bias' inherent in CAR-T manufacturing impacts the generalizability of the reported 97% overall response rate.

Key Response

Single-arm trials for CAR-T often suffer from 'immortal time bias' and 'selection bias,' as patients must survive the screening and manufacturing period (median 29 days in this study) to be included in the modified ITT analysis. Comparisons to real-world cohorts like LocoMMotion must use matching-adjusted indirect comparisons (MAIC) to account for differences in baseline fitness, as patients who fail to make it to CAR-T infusion are often those with the most aggressive biology.

Journal Editor

The CARTITUDE-1 results show exceptional efficacy, but the patient population had a median of 6 prior lines of therapy. As a reviewer, what concerns would you raise regarding the attrition rate between the 113 patients enrolled and the 97 patients actually dosed, and how does this affect the 'Real-World' applicability of the study?

Key Response

Editors look for the gap between the Enrolled (ITT) and Dosed (mITT) populations. In this study, 16 patients (14%) did not receive the drug due to death, disease progression, or withdrawal. A high attrition rate suggests that the drug, while effective for those who get it, may not be reachable for a significant portion of the intended heavily pretreated population, potentially overstating the drug's effectiveness in a clinical setting.

Guideline Committee

Based on the durability of response in CARTITUDE-1, should cilta-cel be prioritized over standard-of-care combinations (e.g., pomalidomide-dexamethasone-based triplets) in patients who have failed 1-3 lines of therapy, and what evidence is required to update current NCCN guidelines to reflect this?

Key Response

Current guidelines (NCCN) originally placed cilta-cel in the 4th-line+ setting. To move into earlier lines (1-3), guideline committees require Phase 3 randomized controlled trials (like CARTITUDE-4) comparing CAR-T directly to standard-of-care triplets. CARTITUDE-1 provided the proof-of-concept for high-depth response, but the risk of secondary malignancies (T-cell lymphomas) and long-term neurotoxicity requires a superior risk-benefit ratio compared to established, less toxic early-line agents.

Clinical Landscape

Noteworthy Related Trials

2021

KarMMa Trial

n = 140 · NEJM

Tested

Idecabtagene vicleucel (ide-cel)

Population

Relapsed or refractory multiple myeloma

Comparator

None (single-arm)

Endpoint

Overall response rate

Key result: Idecabtagene vicleucel demonstrated significant clinical efficacy in patients with heavily pretreated multiple myeloma.

2022

CARTITUDE-2 Trial

n = 100 · Lancet Oncol

Tested

Ciltacabtagene autoleucel

Population

Multiple myeloma with different clinical presentations

Comparator

None (single-arm)

Endpoint

Minimal residual disease-negative rate

Key result: Cilta-cel showed high response rates and a manageable safety profile in earlier lines of treatment and diverse patient cohorts.

2022

MajesTEC-1 Trial

n = 165 · NEJM

Tested

Teclistamab

Population

Relapsed or refractory multiple myeloma

Comparator

None (single-arm)

Endpoint

Overall response rate

Key result: The BCMA-directed bispecific antibody teclistamab provided durable clinical responses in patients who had received extensive prior therapy.

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