Single Infusion Cilta-cel Produces Strong Response Rate in Heavily Pretreated Myeloma Refractory to Lenalidomide

A single infusion of ciltacabtagene autoleucel (cilta-cel) for patients with multiple myeloma who were lenalidomide (Revlimid) refractory and underwent a median of 2 previous lines of therapy produced a strong overall response rate (ORR) of 95%, according to results from cohort A of the phase 2 CARTITUDE-2 trial (NCT04133636) presented at the 2021 American Society of Hematology Annual Meeting & Exposition.¹

At a median follow-up of 14.3 months (range, 3.3-19.0), the CAR T-cell therapy elicited responses in 19 of 20 patients (95% CI, 75.1%-99.9%). Of those who responded to treatment, 85% (95% CI, 62.1%-96.8%) achieved a complete response (CR) or better, and 90% (95% CI, 68.3%-98.8%) experienced a very good partial response (VGPR) or better. The median duration of response (DOR) to the treatment had not yet been reached.

Moreover, of the 13 patients who had samples that were evaluable for minimal residual disease (MRD) at 10^-5 threshold, 92% (95% CI, 64.0%-99.8%) had negative status following treatment.

“At a longer median follow-up, a single infusion of cilta-cel led to early and deep responses in patients with multiple myeloma who received 1 to 3 lines of therapy and were lenalidomide refractory,” lead study author Yael C. Cohen, MD, of Tel-Aviv Sourasky (Ichilov) Medical Center and Sackler School of Medicine, Tel Aviv University, stated in a poster presentation on the data. “The safety profile was manageable with no incidence of movement and neurocognitive treatment-emergent adverse effects [MNTs], including the patient treated in the outpatient setting.”

Limited therapeutic options are available to patients with progressive multiple myeloma who have previously received 1 to 3 lines of therapy and who are refractory to lenalidomide and/or proteasome inhibitors (PIs) such as bortezomib (Velcade) and carfilzomib (Kyprolis). To address this need, several CAR T-cell therapies are under exploration for potential use in this population.

One such product is cilta-cel, which is a therapy that expresses 2 BCMA-targeting, single-domain antibodies that were developed to confer avidity. Results from the phase 1b/2 CARTITUDE-1 trial (NCT03548207) demonstrated that a single cilta-cel infusion was able to produce deep, durable responses in patients with multiple myeloma who had previously received a median of 6 lines of therapy.²

At a median follow-up of 12.4 months (interquartile range [IQR], 10.6-15.2), 97 patients received the CAR T-cell product. Cilta-cel elicited an ORR of 97% (95% CI, 91.2%-99.4%), with 67% of patients experiencing a stringent CR to treatment. These responses were noted to deepen over time, and the median DOR had not yet been reached (95% CI, 15.9–not estimable [NE]) at a data cutoff of September 1, 2020. At this time, the median progression-free survival (PFS) had also not been reached (95% CI, 16.8–NE).

For the multicohort CARTITUDE-2 trial, investigators set out to examine the CAR T-cell product in earlier-line settings for patients with multiple myeloma. They are also evaluating whether the product can feasibly be delivered in the outpatient setting.

Cohort A of the trial enrolled patients who had progressive disease following 1 to 3 previous lines of treatment, which included a PI and an immunomodulatory drug. Patients were refractory to lenalidomide and were not previously exposed to a BCMA-targeted agent.³

Study participants underwent a screening period that ranged from 1 to 28 days, followed by apheresis, and then received bridging therapy, if needed. From day -5 to -3, patients were given a lymphodepletion regimen comprised of cytarabine at 300 mg/m² plus fludarabine at 30 mg/m². Five to 7 days after lymphodepletion was started, patients were then given a single cilta-cel infusion, with a target dose of 0.75 x 10⁶ (range, 0.5 x 10⁶ to 1.0 x 10⁶) CAR-positive viable T cells/kg.

The primary end point of the trial was MRD 10^-5 negativity, as evaluated by next-generation sequencing. Key secondary end points included ORR, per International Myeloma Working Group response criteria, DOR, time and duration of MRD negativity, as well as incidence and severity of toxicities.

Among the 20 patients enrolled to the cohort, the median age was 60 years (range, 38-75), and 65.0% were male. Additionally, 15% had extramedullary disease, 15% had bone marrow plasma cells that were 60% or higher, and 35% had a high-risk cytogenetic profile. Fifteen percent of patients had del17p and 25% had t(14;16). Patients received a median of 2 lines of prior therapy (range, 1-3) and 85% previously underwent autologous stem cell transplantation.

Notably, 65% of patients were triple-class exposed, 40% were triple-class refractory, 20% were penta-drug exposed, and 5% were penta-drug refractory. All participants were refractory to lenalidomide, and 40%, 10%, 35%, and 60% were refractory to bortezomib, carfilzomib, pomalidomide (Pomalyst), and daratumumab (Darzalex), respectively. Ninety-five percent of participants were refractory to the last line of therapy they had received.

Data from the initial analysis of this cohort showed that at a median follow-up of 5.8 months (range, 2.5-9.8), cilta-cel was found to elicit an ORR of 95% (95% CI, 75%-100%), with 75% (95% CI, 51%-91%) of patients having achieved a stringent CR or CR. Moreover, 85% (95% CI, 62%-97%) of patients achieved a VGPR or better to the therapy.

At the 2021 ASH Annual Meeting, Cohen presented updated data from cohort A. Additional data indicated that the median time to first response with cilta-cel was 1.0 months (range, 0.7-3.3), and the median time to best response was 2.6 months (range, 0.9-7.9).

Moreover, the PFS rate at 6 months was 95% (95% CI, 69.5%-99.3%) with the CAR T-cell product; at 12 months, this rate was 84% (95% CI, 59.1%-94.7%).

Regarding safety, the adverse effects (AEs) experienced by 20% or more of the 20 patients included neutropenia (any grade, 95%; grade 3 or 4, 95%), thrombocytopenia (80%; 35%), anemia (75%; 45%), lymphopenia (65%; 65%), and leukopenia (55%; 55%).

The incidence of initial grade 3 or 4 toxicities that did not recover to at least grade 2 severity by day 60, was 20% for neutropenia, 15% for thrombocytopenia, and 5% for lymphopenia.

Additionally, 95% of patients experienced cytokine release syndrome (CRS); 2 of these patients had grade 3 or 4 CRS. The median time to CRS onset in these patients was 7 days (range, 5-9) and the median duration was 4 days (range, 2-11). Ninety percent of patients had this toxicity resolve at the time of data cutoff. Seventy percent of patients received tocilizumab (Actemra).

Moreover, 3 patients experienced immune effector cell–associated neurotoxicity syndrome; this was grade 1 in 2 patients and grade 2 in 1 patient. In these patients, the median time to onset was 8 days (range, 7-10), and the median duration of the effect was 3 days (range, 1-3).

With the implementation of patient management approaches across the CARTITUDE program, the incidence of MNTs was found to decrease, and no MNT cases were reported in this cohort.

Following infusion with the CAR T-cell therapy, 4 patients have died; 2 were due to disease progression. One patient died of COVID-19, and this was determined to be related to treatment, and the other patient died because of sepsis that was not determined to be related to cilta-cel.

Follow-up for this cohort is ongoing. In the phase 3 CARTITUDE-4 trial (NCT04181827), investigators are comparing the use of cilta-cel with the combination of pomalidomide, bortezomib, and dexamethasone, and the combination of daratumumab, pomalidomide and dexamethasone, in patients with relapsed and lenalidomide-refractory multiple myeloma.⁴

References

1. Cohen YC, Cohen AD, Delforge M, et al. Efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy, in lenalidomide-refractory patients with progressive multiple myeloma after 1-3 prior lines of therapy: updated results from CARTITUDE-2. Presented at: 2021 ASH Annual Meeting; December 11-13, 2021; Atlanta, GA. Poster 3866.
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 ore refractory multiple myeloma (CARTITUDE-1): a phase 1/2 open-label study. Lancet. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8
3. Agha ME, Cohen AD, Madduri D, et al. CARTITUDE-2: efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, in patients with progressive multiple myeloma (MM) after one to three prior lines of therapy. J Clin Oncol. 2021;39(suppl 15):8013. doi:10.1200/JCO.2021.39.15_suppl.8013
4. A study comparing JNJ-68284528, a CAR-T therapy directed against B-cell maturation antigen (BCMA), versus pomalidomide, bortezomib, and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in participants with relapsed and lenalidomide-refractory multiple myeloma (CARTITUDE 4). ClinicalTrials.gov. Updated December 3, 2021. Accessed December 14, 2021. https://clinicaltrials.gov/ct2/show/NCT04181827