The phase 2 CARTITUDE study showed encouraging response in the heavily-pretreated multiple myeloma population. Now, the phase 3 CARTITUDE-4 trial is underway.
According to to updated data from cohort A of the phase 2 CARTITUDE study (NCT04133636), encouraging response were induced with ciltacabtagene autoleucel (cilta-cel; Carvykti) in patients with multiple myeloma who had received 1 to 3 prior lines of therapy and were refractory to lenalidomide (Revlimid).1
Findings were presented at the 19th International Myeloma Society (IMS) Annual Meeting.
At a median follow-up of 17.1 months (range, 3.3-23.1), a single infusion of the CAR T-cell therapy induced an objective response rate (ORR) of 95% (95% CI, 75.1%-99.9%) among 20 evaluable patients. Ninety percent of patients achieved complete response (CR) or better and 95% experienced very good partial response (VGPR) or better. The stringent CR rate was 85%, the CR rate was 5%, and the VGPR rate was 5%. Notably, responses to cilta-cel were found to deepen over time.
The median time to first response was 1.0 month (range, 0.7-3.3) and the median time to best response was 2.6 months (range, 0.9-13.6). The median duration of response (DOR) in these patients was not reached and an estimated 90% of responders continued to respond to cilta-cel for 12 months.
Moreover, the 15-month progression-free survival (PFS) rate with the CAR T-cell therapy was 70% (95% CI, 45.1%-85.3%). All patients evaluable for minimal residual disease (MRD) at the 10-5 threshold (n = 16) were negative (95% CI, 79.4-100.0).
“At a longer median follow-up of 17.1 months, a single infusion of cilta-cel led to deepening and durable responses in patients with multiple myeloma who received 1 to 3 lines of therapy and were lenalidomide refractory,” lead study author Adam D. Cohen, MD, director of Myeloma Immunotherapy and associate professor of medicine at the Hospital of the University of Pennsylvania, said in a presentation of the data. “The safety profile was manageable and predictable, including in the patient treated in an outpatient setting.”
Patients with multiple myeloma who experience progression following 1 to 3 lines of treatment and who are refractory to lenalidomide and/or proteasome inhibitors (PIs) have limited therapeutic options available to them.
In February 2022, the FDA approved cilta-cel for the treatment of adult patients with relapsed or refractory multiple myeloma following 4 or more previous lines of therapy, including a PI, an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody.2 The decision was based on data from the phase 1b/2 CARTITUDE-1 trial (NCT03548207), in which the therapy elicited an ORR of 98% (95% CI, 92.7%-99.7%) in this population.3 In May 2022, the European Commission granted conditional approval to cilta-cel for those with relapsed or refractory multiple myeloma who have received at least 3 prior therapies, including a PI, IMiD, and an anti-CD38 antibody.4
Patients with progressive multiple myeloma following 1 to 3 previous lines of therapy and who were lenalidomide refractory were enrolled to cohort A. Participants underwent screening, apheresis, and then bridging therapy, as needed. Patients received cyclophosphamide at 300 mg/m2 plus fludarabine at 30 mg/m2 on day -5 to day -3. On day 1, cilta-cel was given at a target dose of 0.75 x 106 (0.5-1.0 x 106) CAR-positive viable T cells/kg.
The primary end point of the trial was MRD 10-5 negativity as assessed by next-generation sequencing or next-generation flow. Key secondary end points included ORR per International Myeloma Working Group response criteria, DOR, and time to response, as well as incidence and severity of adverse effects (AEs).
A prior analysis of cohort A showed that at a median follow-up of 14.3 months, cilta-cel elicited an ORR of 95%. Eighty-five percent of patients experienced CR or better and 90% of had VGPR or better.
As of January 2022, 20 patients had a median follow-up of 17.1 months; 1 of these patients had received treatment in the outpatient setting. Among these patients, the median age was 60 years (range, 38-75). Sixty-five percent of patients were male, 90% were White, 15% had at least 1 extramedullary plasmacytoma, and 15% had 60% or more of bone marrow plasma cells. Thirty-five percent of patients had high-risk cytogenetics; 15% had del17p and 25% had t(14;16).
The median number of prior lines of therapy received was 2 (range, 1-3). Eighty-five percent of patients underwent prior autologous stem cell transplantation. The majority (65%) of patients were triple-class exposed and 20% were penta-drug exposed.
Regarding refractory status, 40% of patients were triple-class refractory and 5% were penta-drug refractory. Moreover, 40%, 10%, 35%, and 60% of patients were refractory to bortezomib (Velcade), carfilzomib (Kyprolis), pomalidomide (Pomalyst), and daratumumab (Darzalex), respectively. Ninety-five percent of patients were refractory to the last line of therapy received.
Peak expansion of CAR T cells occurred on day 11 (range, 8.7-42.9), and the median CAR T-cell persistence was 153 days (range, 57.1-336.8). Moreover, levels of interleukin (IL)-6, interferon (IFN)-γ, IL-2Rα, and IL-10 increased following infusion with cilta-cel, peaked at days 7 to 14, and returned to baseline levels within 2 to 3 months following post infusion.
Cilta-cel was found to have a manageable toxicity profile. Investigators observed cytokine release syndrome (CRS) in 95% of patients; 10% of patients experienced grade 3/4 CRS. The median time to onset was 7 days (range, 5-9) and the median duration was 3 days (range, 2-12). This toxicity was found to resolve within 7 days in 90% of patients at the time of data cutoff. Investigators treated this effect with tocilizumab (Actemra) in 70% of patients and/or corticosteroids in 30% of patients.
Severity of CRS was linked with higher peak of IL-6, IFN-γ, IL-2Rα, and IL-10.
Additionally, 3 patients experienced immune effector cell–associated neurotoxicity syndrome (ICANS) with the CAR T-cell therapy; this effect was grade 1 in 2 patients and grade 2 in 1 patient. The median time to onset of ICANS was 8 days (range, 7-10), and the median duration was 3 days (range, 1-3).
Hematologic adverse effects experienced with cilta-cel included neutropenia (any grade, 95%; grade 3/4, 95%), thrombocytopenia (any grade, 80%; grade 3/4, 35%), anemia (any grade, 75%; grade 3/4, 45%), lymphopenia (any grade, 70%; grade 3/4, 70%), and leukopenia (any grade, 55%; grade 3/4, 55%).
Most initial grade 3 or 4 cytopenias recovered to grade 2 or less by day 60. This was also true for 80% of patients with neutropenia, 85% of patients with thrombocytopenia, and 95% for those with lymphopenia.
Four deaths occurred following infusion of cilta-cel; 1 was due to treatment-related COVID-19 and occurred on day 100, 1 was due to non–treatment-related sepsis which happened on day 394. Two deaths at days 426 and 550 were attributed to disease progression.
In the phase 3 CARTITUDE-4 trial (NCT04181827), investigators will compare the safety and efficacy of cilta-cel with pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone.
1. Cohen AD, Einsele H, Delforge M, et al. Updated clinical data and biological correlative analyses of ciltacabtagene autoleucel (cilta-cel) in lenalidomide-refractory multiple myeloma after 1-3 prior lines of therapy: CARTITUDE-2 cohort A. Presented at: 19th International Myeloma Society Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-045
2. US FDA approves Carvytki (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. Janssen. February 28, 2022. Accessed August 28, 2022. https://bit.ly/35yWwjv
3. Carvykti (ciltacabtagene autoleucel) suspension for intravenous infusion. Prescribing information. Janssen Biotech and Legend Biotech Corporation; 2022. Accessed August 28, 2022.
4. Carvykti (ciltacabtagene autoleucel) granted conditional approval by the European Commission for the treatment of patients with relapsed and refractory multiple myeloma. News release. Legend Biotech Corporation. May 26, 2022. Accessed August 28, 2022. https://bwnews.pr/3Q3HkN2