Adjusted Comparison of Cilta-Cel Vs Standard Regimens Reveals Favorable Outcomes in Triple-Class Exposed Multiple Myeloma

Using data from the phase 1 CARTITUDE-1 trial (NCT03548207) and the real-world LocoMMotion (NCT04035226) study, investigators showed that treatment with the CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel; JNJ-68284528) was a better option for patients with triple-class exposed multiple myeloma vs standard options in this setting.1

For all response end points, rates were higher in CARTITUDE-1 than in LocoMMotion. Patients treated with cilta-cel reached an objective response rate (ORR) of 97.9%, with 82.5% of all patients having a complete response (CR) or better, compared with an ORR of only 31.4% with no CRs in the LocoMMotion cohort that was adjusted for baseline characteristics.

“CARTITUDE-1 results have shown the highest complete response rates and longest progression-free survival in heavily pretreated patients with relapsed/refractory multiple myeloma,” María-Victoria Mateos, MD, PhD, director of the myeloma unit at University Hospital of Salamanca in Spain, said during a presentation of the data at the 63rd American Society of Hematology Annual Meeting. “This indirect comparison using data from LocoMMotion demonstrates improved outcomes with cilta-cel compared with current clinical practice. These improvements were also associated with increased quality of life.”

LocoMMotion was undertaken as a prospective efficacy and safety study to evaluate real-world clinical regimens in relapsed or refectory multiple myeloma that is triple-class exposed. In the CARTITUDE-1 trial, the B-cell maturation antigen–targeting CAR T-cell therapy cilta-cel demonstrated efficacy and safety in patients with heavily pretreated multiple myeloma.2 As there was no standard-of-care comparator arm for CARTITUDE-1, an adjusted comparison of the 2 studies was performed to evaluate safety and efficacy of cilta-cel vs conventional therapy in context of current clinical practice.

Key inclusion criteria for LocoMMotion and CARTITUDE-1 were aligned, with both requiring patients to have progressive multiple myeloma per International Myeloma Working Group criteria; 3 or more prior lines of therapy or double-refractory disease; experience with prior proteasome inhibitors, immunomodulatory agents, and an anti-CD38 antibody; measurable disease; and an ECOG performance status of 0 or 1.

Patients in CARTITUDE-1 were screened and enrolled for apheresis (n = 113) and received bridging therapy as needed, followed by cyclophosphamide at 300 mg/m2 plus fludarabine at 30 mg/m2­ on days –5 through –3. Cilta-cel infusion was performed at a target of 0.75 × 106 CAR-positive viable T-cells/kg (range, 0.5-1.0 × 106). In total, 97 patients comprised the infused population.

“As cilta-cel is produced from patient’s cells for apheresis, there is a delay in patients receiving cilta-cel. This evaluation focused on infused patients,” Mateos said. “However, results from apheresed patients are also shown.”

In LocoMMotion, 248 patients were enrolled for whom 170 comprised the aligned population for comparison with CARTITUDE-1. Ninety-two unique regimens were use, including carfilzomib (Kyprolis) plus dexamethasone (12.9%); pomalidomide (Pomalyst), cyclophosphamide, and dexamethasone (10.9%); and pomalidomide and dexamethasone (9.7%). The high number of regimens used in this setting highlights the lack of standard-of-care options in this setting, said Mateos.

Observed rates of ORR, very good partial response (VGPR) or better, and CR or better were all significantly higher with cilta-cel, and patients were 3.12 times more likely to achieve ORR and 5.67 times more likely to achieve VGPR than those treated in LocoMMotion. With almost all patients having some response to cilta-cell therapy, the majority of patients had a CR or better, 12.4% had a VGPR, and 3.1% had a PR. In LocoMMotion, only 1 patient (0.6%) had a CR, 17.0% had a VGPR, and 25.3% had a PR. Adjusting for baseline characteristics to align with the CARTITUDE-1 trial reduced the response rate, with no patients having a CR, 16.7% having a VGPR, and 14.7% having a PR.

The median progression-free survival (PFS) in CARTITUDE-1 was not reached vs 4.3 months in LocoMMotion, with an 85% reduction in the risk of disease progression or death for the adjusted comparison (HR, 0.15; 95% CI, 0.08-0.29; P <.0001). The median overall survival (OS) was not reach in either set, but the adjusted comparison showed a statistically significant favorable outcome with cilta-cel vs standard of care (HR, 0.20; 95% CI, 0.09-0.41; P <.0001).

Additional analyses in all enrolled and infused/aligned patients demonstrated consistent findings, with cilta-cel treatment reliably leading to a statistically significant benefit in terms of both PFS and OS.

Health-related quality of life was also analyzed using the European Organisation for Research and Treatment of Cancer Quality of Life questionnaire QLQ-C30. Global health status improvement was significantly better with cilta-cel versus real-world data from LocoMMotion, with a 3.6% difference at day 28 (P = .22) and a 13.4% difference at day 352 (P <.01).

Although more patients in the cilta-cel group experienced adverse events (AEs), the toxicity profile was manageable. The most frequently reported AEs were hematologic in both groups, including neutropenia (95.9% vs 15.7%, respectively), anemia (81.4% vs 25.8%), thrombocytopenia (79.4% vs 23.0%), leukopenia (61.9% vs 7.3%), and lymphopenia (53.6% vs 6.5%).

Cytokine release syndrome (CRS) of any-grade occurred in most patients (94.8%) in the cilta-cel group, but only 4.1% had events that were grade 3 or 4 in severity. Similarly, neurotoxicity from cilta-cel occurred in 20.6% of patients, but only 9.3% were grade 3/4. No patients in LocoMMotion had CRS or neurotoxicity.

Notably, 6.2% of patients treated with cilta-cel experienced treatment-emergent AEs leading to death vs 7.7% in the real-world population.

Although criteria were aligned, differences in baseline characteristics were noted between the 2 datasets. As such, an inverse probability weighting was used to adjust for imbalances. Relative treatment effects between cilta-cel and real-world standard of care were weighted through logistic regression models for binary end points, such as those with risk and odds ratios, and weighted Cox proportional hazard models for time-to-event outcomes with a hazard ratio. Patient-reported outcomes were also analyzed as a change from baseline.

After weighting, baseline characteristics were well balanced. The majority of patients in CARTITUDE-1 and the post–inverse probability weighted (IPW) LocoMMotion trial had IgG-type myeloma (58.8% and 61.2%, respectively) and International Staging System stage I disease (62.9% and 65.4%). Most patients were either quadruple or penta-refractory in both CARTITUDE-1 (37.1% and 42.3%, respectively) and post-IPW LocoMMotion (32.0% and 51.1%).

“These data provide the highest quality real-world comparative evidence for cilta-cel and highlight its potential as a highly effective treatment option for triple-class exposed relapsed or refractory multiple myeloma.” Mateos concluded.

References

1. Mateos M-V, Weisel K, Martin T, et al. Ciltacabtagene autoleucel for triple-class exposed multiple myeloma: adjusted comparisons of cARTITUDE-1 patient outcomes versus therapies from real-world clinical practice from the LocoMMotion prospective study. Presented at: 63rd American Society of Hematology Annual Meeting; December 11-14, 2021; Atlanta, Georgia. Abstract 550. https://bit.ly/3GzH6IQ
2. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study Lancet. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8