Real-World Cilta-Cel Outcomes Extend Beyond Trial Populations in R/R Myeloma

A large registry-based retrospective study has found that ciltacabtagene autoleucel (cilta-cel; Carvykti), a B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T-cell therapy, produced deep and durable responses in patients with relapsed/refractory multiple myeloma (R/R MM) treated in routine clinical practice, a population more comorbid and more heavily pretreated than those enrolled in pivotal trials, according to results published in Blood Cancer Journal.¹

The analysis, which utilized the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, enrolled 595 patients who received standard-of-care cilta-cel between March 2022 and December 2023 and had at least a 100-day post–CAR T evaluation. Results showed a best overall response rate (ORR) of 87%, a very good partial response (VGPR) or better rate of 75%, and 12-month rates of progression-free survival (PFS) and overall survival (OS) of 73% (95% CI, 68%-77%) and 85% (95% CI, 81%-88%), respectively, in a population where 70% had at least 1 clinically significant comorbidity.

“This study provides important reassurance that the efficacy of cilta-cel extends beyond the highly selected patient populations enrolled in clinical trials. Despite substantial comorbidity burden, outcomes remained favorable in routine clinical practice,” lead investigator Doris K. Hansen, MD, associate professor at Moffitt Cancer Center in Tampa, Florida, said in an interview with Targeted Oncology. “Studies like this that tell us how all of the patients will do, regardless of trial eligibility, are very important to inform everyday clinical practice.”

A Comorbid, Heavily Pretreated Population

The enrolled cohort reflected the realities of everyday practice in ways that clinical trial populations typically do not, Hansen emphasized. The median age was 64 years (range, 34-84), and 70% of patients carried at least 1 clinically significant comorbidity prior to infusion, including moderate to severe cardiac disease (26%), pulmonary disease (24%), and renal impairment (5%).

The median number of prior lines of therapy was 7 (range, 4-24), with 85% of patients triple-class exposed and 55% penta-drug exposed. High-risk cytogenetics were present in 27%, extramedullary disease in 13%, and at least 50% high bone marrow plasma cell burden in 14%. Notably, 8% had received prior BCMA-directed therapy, most commonly the antibody-drug conjugate belantamab mafodotin (Blenrep), and 57% received bridging therapy before infusion.

Hansen underscored why examining this population matters. “Clinical trials often enroll highly selected patients with fewer comorbidities and better performance status. Real-world studies such as this are important because they help us understand how these therapies perform in the broader population of patients we treat every day,” she said.

Compared with the pivotal phase 1b/2 CARTITUDE-1 trial (NCT03548207), which reported an ORR of 98%, a complete response (CR) or better rate of 83%, and 12-month PFS and OS rates of 77% and 89%, respectively, the real-world outcomes were modestly lower, a finding investigators attributed to the higher comorbidity burden and broader prior-therapy exposure in the registry population.^1,2

“Although longer-term follow-up is needed, the study demonstrates favorable clinical activity of cilta-cel in a real-world patient population of older, heavily pretreated patients, the majority of whom had at least 1 significant comorbidity,” said Hansen.

Subgroup Outcomes and Predictors of Survival

Multivariable analyses identified several factors independently associated with inferior PFS, including male sex, high-risk cytogenetics, prior BCMA-directed therapy, high bone marrow plasma cell burden, ECOG performance status of 2 or worse, elevated baseline lactate dehydrogenase, and elevated baseline ferritin of at least 150 ng/mL. Adverse prognostic factors for OS overlapped substantially, with the addition of platelet count of less than 50,000/µL before infusion.

Patients with prior BCMA-directed therapy had a 12-month PFS of 51% vs 74% in those without prior BCMA exposure (P <.001), a finding consistent with published data in both cilta-cel and idecabtagene vicleucel (ide-cel; Abecma) real-world settings, the investigators stated.¹ Among those who received bendamustine lymphodepletion during a national fludarabine shortage, CR rates were independently lower compared with patients who received standard fludarabine and cyclophosphamide (OR, 0.50; 95% CI, 0.32-0.78; P =.0025), though differences in PFS and OS did not reach statistical significance.

Manageable Toxicity, With Attention to Delayed Neurotoxicity

Hansen stressed that although CAR T-cell therapy is highly efficacious, it is necessary to be mindful of its safety profile. She said that the tolerability was similar to clinical trials of cilta-cel; cytokine release syndrome (CRS) occurred in 80% of patients, with grade 3 or higher events in 4%. Immune effector cell–associated neurotoxicity syndrome (ICANS) was observed in 22%, with grade 3 or higher in 4%.

Hansen described delayed non-ICANS neurotoxicity (NINTs), particularly parkinsonism and related movement disorders, as “one of the greatest safety concerns” as CAR T moves into earlier lines of treatment. NINTs including the movement and neurocognitive toxicities of greatest clinical concern occurred in 5% of patients, comprising parkinsonism in 2.7% and cranial nerve palsies in 2.5%, with cranial nerve VII palsies predominating.

Treatment-related mortality was 5%, with infection representing the most common cause of death. Encouragingly, this rate was comparable to clinical trials and lower than that reported in some prior real-world studies, Hansen noted. Moving forward, continued efforts to better predict, identify, and mitigate NINTs will be critical as CAR T-cell therapies are used more broadly and in earlier lines of treatment.

The analysis identified high bone marrow plasma cell burden as independently associated with both grade 2 or higher CRS and any-grade ICANS.¹ Patient age of 70 years or older, hemoglobin lower than 8 g/dL, and a hematopoietic cell transplantation–specific comorbidity index of at least 2 were each additionally associated with ICANS risk, findings that may help clinicians risk-stratify patients for inpatient vs outpatient infusion.

Bridging Strategies and NINT Mitigation

Hansen pointed to disease control before CAR T infusion as one of the most important modifiable determinants of outcomes, particularly with respect to NINT risk. Citing a concurrent analysis presented at the American Society of Hematology Annual Meeting by co-investigator Surbhi Sidana, MD, Hansen noted that patients who achieved a response to bridging therapy were approximately 10 times less likely to develop parkinsonism than those who did not respond.³

“…Achieving disease control before CAR T infusion may be one of the most important modifiable risk factors for reducing the risk of NINT,” Hansen said. She added that bispecific antibodies targeting alternative antigens, such as talquetamab (Talvey), which targets GPRC5D, have emerged as promising bridging strategies that can reduce disease burden while avoiding additional BCMA-directed therapy before cilta-cel infusion. She also said that emerging biomarkers, including peak absolute lymphocyte count, may also help identify patients at increased risk for delayed NINT and inform future risk-adapted mitigation strategies.^3,4

Looking Ahead

Real-world studies help us better understand which patients can benefit from CAR T-cell therapy outside of the strict eligibility criteria used in clinical trials. Patients with comorbidities, including renal impairment, should not be excluded from referral solely on that basis. These data also provide important insights into expected outcomes and toxicities, allowing clinicians to better tailor supportive care and monitoring strategies for individual patients.

Although this study represents the largest real-world analyses of cilta-cel to date, longer follow-up will be important to better characterize long-term outcomes, second primary malignancies, and delayed neurologic toxicities. As with many registry-based studies, certain disease-specific variables and biomarker data were not uniformly available, which may limit more detailed risk stratification analyses.¹

For Hansen, the 5-year outcomes from CARTITUDE-1, where approximately one-third of patients remained in remission and off treatment, set the benchmark for what longer real-world follow-up should aim to demonstrate.² “What I would like to see with longer follow-up is a good proportion of patients remaining in remission and off therapy for many years. One of the major benefits of CAR T-cell therapy is the potential to provide meaningful treatment-free intervals, which can have a tremendous impact on patients' quality of life.”

REFERENCES

1. Hansen DK, Dima D, Mian H, et al. Safety and efficacy of ciltacabtagene autoleucel for relapsed/refractory multiple myeloma: a CIBMTR study. Blood Cancer J. 2026. doi:10.1038/s41408-026-01496-w

2. Jagannath S, Martin TG, Lin Y, et al. Long-term (≥5-year) remission and survival after treatment with ciltacabtagene autoleucel in CARTITUDE-1 patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2025;43(25):2766–2771.

3. Sidana S, Reid B, Dima D, et al. Enhancing the safety of ciltacabtagene autoleucel in relapsed multiple myeloma (MM): Identification of potentially modifiable risk-factors associated with delayed neurotoxicity and non-relapse mortality. Blood. 2025;146(suppl 1):1034. doi:10.1182/blood-2025-1034

4. Hosoya H, Velayati A, Dima D, et al. Rapid peak CAR-T expansion is associated with delayed neurotoxicity following ciltacabtagene autoleucel in multiple myeloma. Blood. 146(suppl 1):96. doi: 10.1182/blood-2025-96