Cilta-cel Elicits an ORR of 100% in Multiple Myeloma After Early Relapse on Initial Therapy

Niels W.C.J. van de Donk, MD

The CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel; Carvykti) generated a high response rate in patients with multiple myeloma who experienced early clinical relapse or failure to initial therapy, according to data from cohort B of the phase 2 CARTITUDE-2 trial (NCT04133636) presented during the 2022 EHA Congress.¹

At a median follow-up of 13.4 months (range, 5.2-21.7), cilta-cel produced an overall response rate (ORR) of 100% (95% CI, 82.4%-100%) in 19 patients; 90% of patients achieved a complete response (CR) or better and 95% had a very good partial response (VGPR) or better. The CAR T-cell therapy resulted in a partial response rate of 5%, and a stringent CR of 63%.

Notably, of the 15 patients with minimal residual disease (MRD)–evaluable samples, 93.3% (95% CI, 68.1%-99.8%) achieved negativity with treatment.

"These results are consistent with the responses that we [saw] in the phase 1b/2 CARTITUDE-1 trial [NCT03548207] and in [cohort A of] CARTITUDE-2,” Niels W.C.J. van de Donk, MD, study author and hematologist at the VU University Medical Center in Amsterdam, The Netherlands, said in a presentation of the data. “The efficacy and safety profile of cilta-cel in high-risk patients with multiple myeloma who experienced early clinical research or treatment failure support the continued exploration of cilta-cel in earlier lines of treatment.”

In February 2022, the FDA approved cilta-cel for the treatment of adult patients with relapsed/refractory multiple myeloma following 4 or more prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody, based on results from CARTITUDE-1.²

CARTITUDE-2 aimed to further evaluate cilta-cel in select patient populations with multiple myeloma. Prior data from cohort A of the trial demonstrated that patients who received 2 previous lines of therapy experienced an ORR of 95%, including 79% with a CR or better, and 90% with a VGPR or better.³

Efficacy and safety data from cohort B were presented during the 2022 EHA Congress.

Cohort B enrolled patients with multiple myeloma who experienced early relapse following initial treatment that included a PI and an IMiD. Patients were required to have disease progression per International Myeloma Working Group criteria within 12 months after treatment with autologous stem cell transplantation (ASCT) or from the start of anti-myeloma therapy for patients who did not have an ASCT.⁴

After screening, patients underwent apheresis followed by bridging therapy, as needed. Five days prior to infusion with cilta-cel, patients received 300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine for 3 days. On day 1 of the study, patients received a cilta-cel infusion with a target dose of 0.75 x 10⁶ CAR-positive viable T cells/kg. Post-infusion assessments were done from day 1 through 100, and posttreatment assessments were conducted from day 101 through the end of the cohort.

The primary end point of CARTITUDE-2 was MRD 10^-5 negativity, assessed by next-generation sequencing or next-generation flow. Secondary end points included ORR, duration of response (DOR), time to response, and safety.

Within cohort B, the median age was 58 years (range, 44-67). Most patients were male (73.7%), White (73.7%), had bone marrow plasma cells of less than 60% (78.9%), did not have extramedullary plasmacytomas (84.2%), and did not have a high-risk cytogenetic profile (84.2%). The median time since initial diagnosis was 1.15 years (range, 0.5-1.9), the median prior lines of therapy received was 1 (range, 1-1), and 78.9% of patients underwent prior ASCT. Notably, 21.1% of patients had a triple-class exposure status.

Moreover, 15.8% of patients were triple-class refractory, 78.9% were refractory to their last line of therapy, 78.9% were refractory to lenalidomide (Revlimid), 31.6% were refractory to bortezomib (Velcade), 15.8% were refractory to daratumumab (Darzalex), and 10.5% were refractory to thalidomide.

Additional data showed that the median DOR was not reached with CAR T-cell therapy. The median time to first response was 1.0 month (range, 0.9-9.7), and the median time to best response was 5.1 months (range, 0.9-11.8). The 12-month progression-free survival rate was 89.5% (95% CI, 64.1%-97.3%) with CAR T-cell therapy.

The peak expansion of CAR T cells occurred on day 13 (range, 9-210), and the median CAR T-cell persistence was 77 days (range, 41-222).

Levels of IL-6 and IFN-γ increased following infusion of cilta-cel, peaking at days 7 through 14 and returning to baseline levels within 2 to 3 months. Notably, the incidence of cytokine release syndrome (CRS) was associated with a higher peak of IL-6 and IFN-γ.

CRS was reported in 84% of patients; 1 patient had grade 3/4 CRS. The median time to onset of CRS was 8 days (range, 5-11), and the median duration was 3.5 days (range, 1-7). Additionally, 63% of patients received tocilizumab (Actemra) and 21% were given corticosteroids for CRS. This toxicity was resolved in all patients.

Neurotoxicity was reported in 26% of patients, and it had resolved in 3 of 5 patients. One patient experienced grade 1 immune effector cell–associated neurotoxicity syndrome, with a time to onset of 11 days and a duration of 4 days. Another patient experienced grade 3 movement and neurocognitive treatment-emergent adverse effects (MNTs)/parkinsonism that occurred at day 38. Notably, this patient had at least 2 risk factors for MNTs/parkinsonism, and they showed improvement at the time of data cutoff and achieved a CR.

“The incidence of MNT and parkinsonism decreased from 6% in CARTITUDE-1 to less than 0.5% after implementation of patient management strategies across the CARTITUDE program, and that includes to administer these patients effective bridging therapy to reduce tumor burden and to treat CRS or icons [early], if it occurs,” van de Donk said.

Regarding other safety data, hematologic adverse effects (AEs) of any grade included neutropenia (95%), anemia (58%), thrombocytopenia (58%), lymphopenia (32%), and leukopenia (26%).

Grade 3 or 4 hematologic AEs included neutropenia (90%), anemia (47%), thrombocytopenia (26%), lymphopenia (32%), and leukopenia (26%). Notably, the rate of grade 3/4 cytopenias that did to not improve to grade 2 or less by day 60 was 16% for thrombocytopenia, 11% for lymphopenia, and 11% for neutropenia.

One death occurred on the study, due to progressive disease on day 158. For the 1 patient treated in an outpatient setting, the safety profile of cilta-cel was found to be manageable.

References

1. Agha ME, van de Donk NWCJ, Cohen AD, et al. CARTITUDE-2, cohort B: Updated clinical data and biological correlative analyses of ciltacabtagene autoleucel, a BCMA-directed CAR-T cell therapy, in patients with multiple myeloma and early relapse after initial therapy. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S185.
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. Janssen. February 28, 2022. Accessed June 22, 2022. https://bit.ly/35yWwjv
3. Hillengass J, Cohen AD, Delforge M, et al. Updated results of the CARTITUDE-1: ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (CAR-T) therapy, in lenalidomide-refractory patients with progressive multiple myeloma (MM) after 1-3 lines prior lines of therapy. Presented at the 2022 Tandem Meeting; April 22-26, 2022; Salt Lake City, UT. Abstract 73.
4. A study of JNJ-68284528, a chimeric antigen receptor t cell (CAR-T) therapy directed against b-cell maturation antigen (BCMA) in participants with multiple myeloma (CARTITUDE-2). ClinicalTrials.gov. Updated June 21, 2022. Accessed June 22, 2022. https://clinicaltrials.gov/ct2/show/NCT04133636