Cilta-Cel Shows Real-World Feasibility and Efficacy With Acceptable Safety in R/R Myeloma

Surbhi Sidana, MD

Ciltacabtagene autoleucel (Carvykti; cilta-cel) produced deep responses in a real-world population of patients with relapsed/refractory multiple myeloma, and showcased a safety profile that proved to be consistent with clinical trial data, according to findings from retrospective analysis shared during the 2024 IMS Annual Meeting.¹

In a total of 236 patients who underwent apheresis with intent to manufacture standard-of-care (SOC) cilta-cel until December 31, 2022, the CAR T-cell therapy elicited an objective response rate (ORR) of 89%, which included a complete response (CR) rate of 70%. In a subgroup of patients who received product that conformed with FDA criteria (n = 192), the ORR and CR rates were numerically higher, at 94% and 74%, respectively. This was also true for the subgroup of patients who received conforming cilta-cel and a lymphodepletion regimen comprised of fludarabine and cyclophosphamide (n = 152), with an ORR of 95% and a CR rate of 76%. Although not a direct comparison, the ORR reported with cilta-cel in the phase 1/2 CARTITUDE-1 study (NCT03548207; n = 97) was 98%, with a CR rate of 83%.

With a median follow-up of 13 months from infusion with the CAR T-cell therapy, the estimated 12-month progression-free survival (PFS) rate in the total infused cohort was 68% (95% CI, 62%-74%). In the confirming and conforming plus lymphodepletion subgroups, these rates were 72% (95% CI, 66%-99%) and 73% (95% CI, 66%-81%), respectively. The 12-month PFS rate for those who had been enrolled in CARTITUDE-1 was 77%, and the median PFS was 34.9 months.
"Cilta-cel administration is feasible in a real-world population of patients with relapsed/refractory myeloma, despite over half of the patients not meeting eligibility criteria for the pivotal [CARTITUDE-1] trial,” Surbhi Sidana, MD, associate professor of medicine at Stanford University, in Stanford, California, said in a presentation of the data. “Cilta-cel results in deep response rates that are durable, and the toxicity profile was consistent with clinical trial data. I think it is very important to continue to monitor for second primary malignancies and deploy measures to manage delayed neurotoxicity and decrease non–relapse free mortality in the future.”

Cilta-cel, an autologous BCMA-targeted CAR T-cell therapy, was approved in February 2022 for use in adult patients with relapsed/refractory multiple myeloma after at least 4 lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody based on CARTITUDE-1 data.²

“In a trial, patients are very fit. You have to be near perfect to enroll in a trial—especially a CAR T trial, [so] a big question we all have is, how does this translate in the real world when our patients have more comorbidities and do not meet the perfect trial criteria?” Sidana underscored. To this end, Sidana and colleagues performed a retrospective analysis of patients who received treatment with cilta-cel at 16 US centers.

A total of 255 patients underwent leukapheresis for planned SOC cilta-cel between March 1, 2022, and December 31, 2022; 92.5% (n = 236) of these patients were infused with the CAR T-cell therapy. Nineteen patients did not proceed to infusion due to disease progression or death (n = 13), manufacturing failure (n = 3), myelodysplastic syndrome (n = 1), lung cancer (n = 1), or lost to follow-up (n = 1). The manufacturing failure rate at first attempt was 6% (n = 15) but the overall manufacturing failure rate was only 1%, Sidana noted. The median time from apheresis to cilta-cel infusion was 70 days (range, 36-275).

The retrospective analysis looked at three cohorts of patients: the total infused cohort (n = 236), the conforming cilta-cel cohort (n = 192), and the conforming cilta-cel with fludarabine/cyclophosphamide lymphodepletion cohort (n = 152). “Nineteen percent of patients had to receive alternate lymphodepletion because, as you all remember, in 2022, there was a critical fludarabine shortage in the United States,” Sidana said. “So, the last cohort resembles the trial treatment most closely.”

Sidana added that unsurprisingly, the real-world patients differ significantly from the trial patients. Specifically, 56% of the apheresed patients and 54% of the infused patients would not have met trial eligibility criteria, most commonly due to organ impairment, poor performance status, or low blood counts.

The median age of real-world patients who received infusion with cilta-cel (n = 236) was 64 years (range, 30-84); 26% of patients were at least 70 years old. Moreover, 11% of patients were Black and 8% were Hispanic. Most patients (89%) had an ECOG performance status of 0 or 1 and 19% had stage III disease by Revised Multiple Myeloma International Staging System criteria. The median prior lines of therapy received was 6 (range, 2-18); 85% of patients previously underwent autologous stem cell transplant, 69% were triple-class refractory, and 30% were penta-drug refractory. Fourteen percent of patients had prior exposure to a BCMA-targeted therapy.

“High-risk cytogenetics, defined similarly to CARTITUDE-1, were seen in 39% of patients—so numerically, more [than those in the trial, which was 13%],” Sidana noted. “Extramedullary disease [EMD], defined as [plasmacytomas] noncontiguous [from bone] lesions, so similar to CARTITUDE-1, were seen in 26% of patients, so numerically, more than [the 13% observed in] CARTITUDE-1. So, as you can see, [this was] a heavily pretreated population with high-risk features.”

The retrospective analysis also looked at the efficacy of cilta-cel in patients who previously received BCMA-directed therapy (n = 33). These patients previously received an antibody-drug conjugate (ADC) or a naked antibody (n = 16), a bispecific antibody (n = 8), CAR T-cell therapy (n = 6), an ADC and CAR T-cell therapy (n = 2), or an ADC and a bispecific antibody (n = 1).

“Not surprisingly, we found that the response rates were lower in patients who had received prior BCMA-directed therapy, and the PFS was also lower, although we did not observe a difference based on the type of prior BCMA therapy,” Sidana said. In this cohort, the ORR was 70% with cilta-cel, which included a CR rate of 42%. The median PFS was 13.6 months in this group.

“I think what we saw was that timing of BCMA therapy, the last exposure, may play a critical role in future impact of next BCMA therapy,” Sidana said. “Half of our patients in this cohort, so 45% of them, had received the last BCMA exposure within 6 months of cilta-cel infusion and we observed that these patients had lower response rates and numerically lower PFS.”

Those who had their last BCMA exposure within 6 months vs 6 months or longer experienced ORRs of 54% and 94%, respectively (P = .03); respective CR rates were 31% and 56%, respectively (P = .2). The median PFS in these respective subgroups was 6.2 months vs 16.8 months (P = .29).

“When we look at subgroups of interest, it’s not a surprise that patients with high-risk cytogenetics [P < .001] and EMD [P < .001] had inferior PFS,” Sidana noted. “Those who were not eligible for CARTITUDE-1 [P = .004] also had inferior PFS. We did not see any differences based on age, 70 years or greater [P = .31], or based on the type of lymphodepletion therapy [P = .42] that the patients received.”

Overall survival (OS) data were not mature. However, the estimated 12-month OS rate in the infused cohort was 82% (95% CI, 77%-87%); in the conforming and conforming plus fludarabine/cyclophosphamide lymphodepletion cohorts, these respective rates were 86% (95% CI, 81-91%) and 86% (95% CI, 80%-92%). In earlier reports of the CARTITUDE-1 cohort, the 12-month OS rate was 89%.

Investigators also examined factors that could independently predict which patients would experience inferior PFS with cilta-cel. “We saw a signal for prior BCMA-directed therapy, but this was not statistically significant, with a Pvalue of 0.08. But three other factors showed that they were statistically significant for both PFS and OS—and high-risk cytogenetics [PFS, P = .006; OS, P = .005] and EMD [PFS, P = .009; OS, P = .04] being there doesn’t surprise anyone. But increasingly, we are seeing data that patients who go on [to receive] CAR T, whether it’s cilta-cel or even with other CAR T[-cell products], who have high baseline ferritin at the time of lymphodepletion [≥400 ng/mL; PFS, P < .001; OS, P < .001], have adverse prognosis for both PFS and OS, and the biology of that is not well understood at this moment.”

The safety data observed in the real-world population with cilta-cel were consistent with what was reported on the clinical trial, according to Sidana.

The non–relapse mortality rate was 10% and the major causes included infections (n = 12), cytokine release syndrome (CRS; n = 3), delayed neurotoxicity (n = 3), IEC-HS (n = 2), CRS and infection (n = 1), immune effector cell–associated neurotoxicity syndrome (ICANS; n = 1), and second primary malignancy (n = 1). Second primary malignancies were reported in 8.5% of patients; when excluding non-melanoma skin cancer, this rate was 5.5% and 1.3% of malignancies were myeloid neoplasms or acute leukemia. One patient developed T-cell lymphoma. “This is tracking with data that were seen with 1 year of follow-up with CARTITUDE-1,” Sidana said.

In the real-world cohort, any-grade CRS was reported in 75% of patients; this was grade 3 or higher in 5% of patients. The median time to onset of CRS was 7 days (range, 0-14). Any-grade ICANS occurred in 14% of patients and it was grade 3 or higher in 4% of patients. Ten percent of patients experienced delayed neurotoxicity in the form of cranial nerve palsy (5%), Parkinsonism (2%), or other (n = 8). Severe infections were experienced by 21% of patients.

Data from a multivariable analysis revealed that poor performance status and high ferritin at baseline increased risk of grade 2 or higher CRS. Moreover, poor performance status and penta-refractory status was linked with increased risk of ICANS.

Disclosures: Dr Sidana disclosed receipt of research funding from Magenta Therapeutics, BMS, Allogene, Janssen, and Novartis. She also serves in a consulting or advisory board role for BMS, Janssen, Sanofi, Oncopeptides, Takeda, Regeneron, Abbvie, Pfizer, BiolineRx, Legend, and Kite/Arcellx.

References

1. Sidana S, Patel KK, Peres LC, et al. Safety and efficacy of standard of care ciltacabtagene autoleucel for relapsed/refractory multiple myeloma (RRMM): real world experience. Presented at: 2024 IMS Annual Meeting; Rio de Janeiro, Brazil; September 25-28, 2024. Accessed September 30, 2024. Presentation OA-11.
2. US FDA approves CARVYKTI (ciltacabtagene autoleucel), Janssen’s first cell therapy, a BCMA-directed CAR-T immunotherapy for the treatment of patients with relapsed or refractory multiple myeloma. News release. Johnson & Johnson. February 28, 2022. Accessed September 30, 2024. https://www.jnj.com/media-center/press-releases/u-s-fda-approves-carvykti-ciltacabtagene-autoleucel-janssens-first-cell-therapy-a-bcma-directed-car-t-immunotherapy-for-the-treatment-of-patients-with-relapsed-or-refractory-multiple-myeloma