In patients with lenalidomide-refractory multiple myeloma after one to three previous lines of treatment, a single ciltacabtagene autoleucel infusion resulted in a lower risk of disease progression or death than highly effective standard of care treatments (physician’s choice of pomalidomide-bortezomib-dexamethasone or daratumumab-pomalidomide-dexamethasone) at a median follow-up of 15.9 months. At 12 months, the rate of progression-free survival (PFS) was 75.9% as compared with 48.6% with standard of care. Similar effects were seen in all subgroups that were evaluated, including patients with high-risk cytogenetic abnormalities, soft-tissue plasmacytomas, triple class-refractory disease, stage III status according to the International Staging System, and other high-risk features.
Moreover, ciltacabtagene autoleucel had higher response rates, deeper and more durable responses, and a higher frequency of minimal residual disease (MRD) negativity than standard of care; the time until patient-reported worsening of symptoms was complementary to clinical outcomes. The results from the phase III CARTITUDE-4 study were reported at 2023 ASCO Annual Meeting on 5 June in Chicago, IL, US by Dr. Binod Dhakal of the Medical College of Wisconsin in Milwaukee, WI, US along with a simultaneous publication in The New England Journal of Medicine by Dr. Jesús San-Miguel of the Clínica Universidad de Navarra in Navarra, Spain, and study colleagues. Drs. San-Miguel and Dhakal contributed equally to this article.
Most patients with multiple myeloma have a relapse after standard treatment, and outcomes worsen with each subsequent line of treatment. Lenalidomide is an immunomodulator that is recommended for newly diagnosed and relapsed or refractory multiple myeloma. The frequency of lenalidomide resistance is increasing, which has led to a growing need for new, effective treatments for lenalidomide-refractory disease. High treatment attrition also highlights the need to use effective treatments early.
The authors wrote in the background that in early phase studies, ciltacabtagene autoleucel, a chimeric antigen receptor T-cell (CAR-T) therapy directed against B-cell maturation antigen, led to early, deep, and durable responses in patients with relapsed or refractory multiple myeloma. In the phase Ib–II CARTITUDE-1 study involving patients who had received at least three lines of treatment, the median PFS was 34.9 months. The phase II CARTITUDE-2 study showed the efficacy of ciltacabtagene autoleucel in small groups (cohorts A and B) at earlier disease stages, with response rates of 95-100% and an estimated duration of response of at least 12 months in 79-89% of patients who had a response. After approximately 1.5 years of follow-up, 75- 90% of patients remained progression-free.
In a phase III study of another CAR-T therapy, idecabtagene vicleucel, involving patients who had received two to four lines of treatment for multiple myeloma, investigators found a median PFS of 13.3 months (hazard ratio [HR] 0.49 as compared with standard treatments).
The phase III, randomised, open-label CARTITUDE-4 study compared ciltacabtagene autoleucel with the physician’s choice of either of two highly effective standard of care treatments in patients with lenalidomide-refractory multiple myeloma after one to three lines of treatment. The authors reported the efficacy and safety results from the interim analysis. The primary outcome was PFS.
A total of 419 patients underwent randomisation: 208 to receive ciltacabtagene autoleucel and 211 to receive standard of care. At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median PFS was not reached in the ciltacabtagene autoleucel group and was 11.8 months in the standard of care group (HR 0.26, 95% confidence interval [CI] 0.18 to 0.38; p < 0.001). PFS at 12 months was 75.9% (95% CI 69.4 to 81.1) in the ciltacabtagene autoleucel group and 48.6% (95% CI 41.5 to 55.3) in the standard of care group.
More patients in the ciltacabtagene autoleucel group than in the standard of care group had an overall response (84.6% versus 67.3%), a complete response or better (73.1% versus 21.8%), and an absence of MRD (60.6% versus 15.6%). Death from any cause was reported in 39 and 46 patients (HR 0.78, 95% CI 0.5 to 1.2).
Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received ciltacabtagene autoleucel in the as-treated population, 134 patients (76.1%) had cytokine release syndrome (CRS) of which 1.1% were grade 3 or 4 and there was no grade 5, 8 patients (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 patient had movement and neurocognitive symptoms (grade 1), 16 patients (9.1%) had cranial nerve palsy (8% grade 2; 1.1% grade 3), and 5 patients (2.8%) had CAR-T-related peripheral neuropathy (2.3% grade 1 or 2; 0.6% grade 3).
CAR-T-specific adverse events were manageable with appropriate supportive care. Lower rates of cytopenias, CRS, and CAR-T-related neurotoxicity were seen in CARTITUDE-4 than in CARTITUDE-1, which suggests that ciltacabtagene autoleucel may have a better side-effect profile when used earlier in treatment. Effective bridging therapy enables better control of tumour burden before CAR-T infusion. The incidence of movement and neurocognitive adverse events was also lower in CARTITUDE-4 (0.6%) than in CARTITUDE-1 (6.0%), a difference that may be related to management strategies that were implemented to mitigate this risk. Cranial nerve palsies are a recognised side effect of CAR-T therapies, and such events that were observed in CARTITUDE-4 study were mild to moderate; most cases had resolved by the data-cut-off date. No clear risk factors for cranial nerve palsies have been identified, and the mechanism is not understood.
The authors concluded that they found a favourable risk-benefit profile for a single infusion of ciltacabtagene autoleucel as compared with standard of care. As with other myeloma treatments, real-world translation of clinical studies results will be influenced by a variety of factors, including patient selection and fitness, patient heterogeneity, treatment accessibility and setting, and patient or physician preference. The strong PFS benefit and rapid and deep response with ciltacabtagene autoleucel highlight the potential for ciltacabtagene autoleucel to become a treatment option for patients with myeloma after the first relapse.
They commented that a potential limitation of the study design was that two highly efficacious triplet regimens (daratumumab-carfilzomib-dexamethasone and isatuximab-carfilzomib-dexamethasone) were not approved at the time of study initiation and could not be included as standard of care options. These two regimens have since entered clinical practice as treatment options. However, the populations in these studies differed from CARTITUDE-4 study population, and lenalidomide resistance was not a criterion for inclusion. Understanding the mechanisms of drug resistance is an area of interest that will ultimately assist in the sequencing of myeloma treatments.
The study was supported by Janssen Research and Development and Legend Biotech USA.
References
- San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. NEJM; Published online 5 June 2023. DOI: 10.1056/NEJMoa2303379
- Dhakal B, Yong K, Harrison SJ, et al. First phase 3 results from CARTITUDE-4: Cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma. J Clin Oncol 41, 2023 (suppl 17; abstr LBA106).