Clinical trialPhase 3Multiple myeloma

Cilta-cel in lenalidomide-refractory multiple myeloma (CARTITUDE-4): an updated analysis including overall survival from an open-label, multicentre, randomised, phase 3 trial.

Lancet Oncol · 2026419 patients (208 cilta-cel, 211 standard care)

Einsele H, San-Miguel J, Dhakal B, et al. Lancet Oncol. 2026. 27:254-268

Study type: Clinical trial
Study name: CARTITUDE-4
Phase: Phase 3
Design: Open-label, multicentre randomised trial (1:1) (81 centres in the USA, Europe, Asia and Australia)
Sample size: 419 patients (208 cilta-cel, 211 standard care)
Source: Lancet Oncol · 2026
Trial registration: NCT04181827

In plain words

Cilta-cel is a type of CAR-T therapy: the patient's own immune cells are collected, trained in the laboratory to recognise myeloma cells and given back to the body once. In this study, people whose disease had come back after one to three lines of treatment and had become resistant to lenalidomide received either cilta-cel or one of the standard drug regimens. Over nearly three years of follow-up, cilta-cel kept the disease under control for much longer and lowered the risk of death by about 45%. This treatment has important side effects, such as a severe drop in white blood cells and a risk of infection, and should be given in experienced centres.

Key results

Not reached vs 11.8 months

Median progression-free survival

HR 0.29 (95% CI 0.22–0.39); median follow-up 33.6 months

Not reached vs not reached

Median overall survival

HR 0.55 (95% CI 0.39–0.79); p = 0.0009

24% vs 39%

Deaths in the safety population

50 vs 82 patients

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)

Apheresis, bridging therapy (at least one cycle of pomalidomide-bortezomib-dexamethasone or daratumumab-pomalidomide-dexamethasone), lymphodepleting chemotherapy (cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² IV daily for 3 days), then infusion of ciltacabtagene autoleucel at a dose of 0.75 × 10⁶ CAR-T cells per kg.

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

Pomalidomide-bortezomib-dexamethasone (PVd), 21-day cycles: pomalidomide 4 mg/day orally on days 1 to 14; bortezomib 1.3 mg/m² subcutaneously twice weekly for 2 weeks for eight cycles, then once weekly for 2 weeks in each cycle; dexamethasone 20 mg orally (or 10 mg in patients over 75 years) on days 1, 2, 4, 5, 8, 9, 11 and 12 for eight cycles, then on days 1, 2, 8 and 9 of each cycle.

Daratumumab-pomalidomide-dexamethasone (DPd), 28-day cycles: daratumumab 1800 mg subcutaneously weekly for 2 cycles, every 2 weeks for four cycles, then every 4 weeks; pomalidomide 4 mg/day orally on days 1 to 21; dexamethasone 40 mg per week (or 20 mg per week in patients over 75 years) orally or IV.

Source of the regimen details: Abstract of the paper in PubMed (cilta-cel dose and PVd/DPd regimens); lymphodepleting regimen from ClinicalTrials.gov NCT04181827 and the FDA label for CARVYKTI

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

Adults with lenalidomide-refractory multiple myeloma who had received one to three previous lines of therapy (including a proteasome inhibitor and an immunomodulatory drug), with ECOG performance status 0 or 1. The threshold for measurable disease was lowered on 2 July 2021 from 1.0 to 0.5 g/dL of serum monoclonal paraprotein.

Endpoints

Primary endpoint: progression-free survival (published previously).

In this report: the second prespecified interim analysis of overall survival and an updated analysis of progression-free survival in the intention-to-treat population; plus safety and patient-reported outcomes.

Safety and side effects

Maximum grade 3 adverse events: 30 of 208 patients (14%) in the cilta-cel group and 77 of 208 (37%) in the standard-care group; most commonly anaemia (72 patients [35%]) with cilta-cel and neutropenia (59 patients [28%]) with standard care. Maximum grade 4 adverse events: 156 patients (75%) with cilta-cel and 116 (56%) with standard care, mainly neutropenia (152 [73%] vs 112 [54%]). Serious adverse events occurred in 98 patients (47%) in each group. Deaths from treatment-related adverse events: six (3%; four from infection) with cilta-cel and five (2%; all from infection) with standard care.

Clinical significance and place in guidelines

This analysis shows that the benefit of cilta-cel in CARTITUDE-4 is not limited to progression-free survival but extends to a significant improvement in overall survival (HR 0.55) compared with PVd or DPd. According to the authors, these results support the use of cilta-cel from first relapse in lenalidomide-refractory myeloma.

Limitations

The trial was open-label. This report is an interim overall survival analysis, and median overall survival has not yet been reached in either group. Patients in the cilta-cel group needed bridging therapy before the infusion. Grade 4 adverse events (mainly neutropenia) and deaths from infection were notable.

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.