Clinical trialPhase 3Blood cancers (leukaemia, lymphoma and myeloma)Multiple myeloma

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma

N Engl J Med · 2023419 patients (208 cilta-cel, 211 standard care)

San-Miguel J, Dhakal B, Yong K, et al. N Engl J Med. 2023. 389:335-347

A newer report of this study has been published: Cilta-cel in lenalidomide-refractory multiple myeloma (CARTITUDE-4): an updated analysis including overall survival from an open-label, multicentre, randomised, phase 3 trial. (2026)

Study type: Clinical trial
Study name: CARTITUDE-4
Phase: Phase 3
Design: International, open-label randomised trial
Sample size: 419 patients (208 cilta-cel, 211 standard care)
Source: N Engl J Med · 2023
Trial registration: NCT04181827

In plain words

Cilta-cel is a type of CAR-T therapy that prepares the patient's own immune cells to attack a protein called BCMA on myeloma cells. This study showed that using it at an earlier stage (after 1 to 3 lines of treatment) lowers the risk of the disease getting worse by about 74%, and nearly three-quarters of patients reach a complete response. Side effects include fever and low blood pressure (usually mild) and, rarely, delayed nerve problems such as facial nerve palsy or movement problems, which need to be watched for in the months after treatment.

Key results

HR 0.26

Progression-free survival

95% CI 0.18–0.38; P<0.001; median not reached vs 11.8 months; median follow-up 15.9 months

75.9% vs 48.6%

12-month progression-free survival

73.1% vs 21.8%

Complete response or better

Overall response 84.6% vs 67.3%

60.6% vs 15.6%

MRD negative

Drugs in this study:Bortezomib (Velcade)Cyclophosphamide (Endoxan)Daratumumab (Darzalex)

Dose and schedule cards

Ciltacabtagene autoleucel (CAR-T; CARTITUDE-4)

Relapsed or refractory multiple myeloma after at least 1 line of therapy including a proteasome inhibitor and an immunomodulatory drug, refractory to lenalidomideCycle length: One-timeOn the page “Blood cancers (leukaemia, lymphoma and myeloma)” · Treatment regimens and dosing in multiple myeloma

Relapsed or refractory multiple myeloma after at least 1 line of therapy including a proteasome inhibitor and an immunomodulatory drug, refractory to lenalidomide

Drug	Dose	Route	Schedule
Lymphodepletion
Cyclophosphamide + fludarabine	Cyclophosphamide 300 mg/m² + fludarabine 30 mg/m² daily	IV	3 days
Single infusion
Ciltacabtagene autoleucel	0.5 to 1.0 × 10⁶ CAR-positive viable T cells/kg (maximum 1 × 10⁸)	IV	2 to 4 days after completion of lymphodepletion

Cycle length: One-time
Duration: One-time

Do not use a leukocyte-depleting filter.

On the page “Blood cancers (leukaemia, lymphoma and myeloma)” · Treatment regimens and dosing in multiple myeloma

Ciltacabtagene autoleucel (cilta-cel; CARTITUDE-4 trial)

Relapsed or refractory myeloma after at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory drug, and refractory to lenalidomideCycle length: Single doseOn the page “Multiple myeloma” · Relapsed myeloma: CAR T-cell therapy and bispecific antibodies

Relapsed or refractory myeloma after at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory drug, and refractory to lenalidomide

Drug	Dose	Route	Schedule
Lymphodepletion
Cyclophosphamide	300 mg/m² once daily	IV	3 days
Fludarabine	30 mg/m² once daily	IV	3 days
Ciltacabtagene autoleucel	0.5 to 1.0 × 10⁶ CAR-positive viable T cells per kg (maximum 1 × 10⁸)	IV	Once, 2–4 days after completion of lymphodepletion

Cycle length: Single dose
Duration: Single infusion (with bridging therapy if needed)

Dose and schedule from the FDA label for CARVYKTI: the patient should stay near the treatment centre for at least 2 weeks after the infusion and should not drive for 2 weeks. Cranial nerve palsy and peripheral neuropathy are distinctive toxicities of this product.

On the page “Multiple myeloma” · Relapsed myeloma: CAR T-cell therapy and bispecific antibodies

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Ciltacabtagene autoleucel (cilta-cel)

At least one cycle of bridging therapy (PVd or DPd), then conditioning chemotherapy with cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² IV daily for 3 days, and a single infusion of ciltacabtagene autoleucel at a target dose of 0.75 × 10⁶ CAR-positive viable T cells per kg.

2Standard care (physician's choice: PVd or DPd)

PVd (21-day cycles): pomalidomide 4 mg orally on days 1 to 14; bortezomib 1.3 mg/m² subcutaneously on days 1, 4, 8 and 11 (cycles 1 to 8) and days 1 and 8 (from cycle 9); dexamethasone 20 mg on the days of bortezomib and the day after.

DPd (28-day cycles): daratumumab 1800 mg subcutaneously weekly (cycles 1 and 2), every 2 weeks (cycles 3 to 6) and every 4 weeks (from cycle 7); pomalidomide 4 mg on days 1 to 21; dexamethasone 40 mg weekly (20 mg over 75 years). Until disease progression.

Source of the regimen details: ClinicalTrials.gov NCT04181827 (target dose 0.75 × 10⁶ viable CAR-T cells/kg, conditioning regimen and the PVd/DPd regimens)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with lenalidomide-refractory multiple myeloma who had received one to three previous lines of therapy (including a proteasome inhibitor and an immunomodulatory drug).

Endpoints

Primary endpoint: progression-free survival.

Secondary endpoints: complete response or better, overall response, MRD negativity and overall survival.

Safety and side effects

Most patients had grade 3 or 4 adverse events. Among 176 patients who received cilta-cel: cytokine release syndrome (CRS) 76.1% (grade 3 or 4: 1.1%; no grade 5); ICANS 4.5% (all grade 1 or 2); movement and neurocognitive symptoms (parkinsonism) in one patient (grade 1); cranial nerve palsy 9.1% (grade 2: 8.0%, grade 3: 1.1%); CAR-T-related peripheral neuropathy 2.8%.

Clinical significance and place in guidelines

Based on this study, in April 2024 the FDA approved cilta-cel (Carvykti) for patients with at least one prior line of therapy (including a proteasome inhibitor and an immunomodulatory drug) who are refractory to lenalidomide, and the EMA also approved it. Cilta-cel is now an important option from first relapse in lenalidomide-refractory patients; later analyses of this trial have also reported an overall survival benefit.

Limitations

The study was open-label. In the intention-to-treat analysis, a number of patients in the cilta-cel group never received the infusion because of disease progression during bridging therapy, and early deaths were more frequent in this group. Overall survival data were immature in this report. Availability, manufacturing time and cost of CAR-T are important practical limitations.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.