Cilta-cel Induces Favorable MRD Negativity Rates in Heavily Pretreated Myeloma After Prior BCMA-Directed Therapy

Adam D. Cohen, MD

Ciltacabtagene autoleucel (cilta-cel; Carvykti) elicited high rates of minimal residual disease (MRD) negativity in patients with heavily pretreated multiple myeloma who received prior treatment with a BCMA-targeted therapy, according to data from cohort C of the phase 2 CARTITUDE-2 trial (NCT04133636).¹

Findings presented at the 19th International Myeloma Society Annual Meeting showed that at a median follow-up of 11.3 months, 7 of 10 evaluable patients who received cilta-cel achieved MRD negativity. In the 7 patients who received prior treatment with a BCMA-targeted antibody-drug conjugate (ADC), 5 were MRD negative. Two of 3 patients who received a prior BCMA-targeted bispecific antibody had MRD negativity at the 10^-5 threshold.

“These were small numbers [of patients], but they do show that cilta-cel can have efficacy after prior exposure to another BCMA-directed agent,” said Adam D. Cohen, MD, the director of Myeloma Immunotherapy and an associate professor of Medicine at the Hospital of the University of Pennsylvania, in an interview with OncLive^®. “Nonetheless, these response rates do seem lower than [the phase 1b/2] CARTITUDE-1 trial [NCT03548207)], which was a BCMA-naïve population.”

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, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, based on findings from the phase 1b/2 CARTITUDE-1 trial (NCT03548207).²

CARTITUDE-2 further explored cilta-cel, a CAR T-cell therapy expressing 2 BCMA-targeting, single-domain antibodies, in various patient populations with multiple myeloma. Although other BCMA-targeting therapies, such as ADCs and bispecific antibodies, are promising treatments for multiple myeloma, an unmet need remains for those who progress after these therapies.

Cohort C of CARTITUDE-2 enrolled patients with progressive multiple myeloma who received prior treatment with a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 monoclonal antibody, and a non-cellular BCMA-targeting therapy.

Enrolled patients underwent apheresis, and they were permitted to receive bridging therapy as needed. After the successful manufacturing of cilta-cel, patients underwent lymphodepletion with cyclophosphamide at 300 mg/m² and fludarabine at 30 mg/m² from day -5 to day -3. Cilta-cel was then administered at a target dose of 0.75 x 10⁶ CAR-positive viable T cells/kg (range, 0.5 x 10⁶-1.0 x 10⁶).

Post-infusion assessments occurred from day 1 to 100 following administration of cilta-cel, and posttreatment assessments occurred from day 101 until the end of the cohort.

The primary end point of the trial was MRD negativity assessed by next-generation sequencing or next-generation flow cytometry. Secondary end points comprised overall response rate (ORR); rates of stringent complete response (sCR), complete response (CR), and very good partial response (VGPR); duration of response (DOR); time to response; and incidence and severity of adverse effects (AEs). Progression-free survival (PFS) served as an exploratory end point.

A total of 24 patients were enrolled to cohort C; these patients were apheresed. Four of these patients discontinued, and 20 went on to receive conditioning treatment with cilta-cel; 13 of these patients received a prior ADC, and 7 received a prior bispecific antibody. The data cutoff was October 2021. The median follow-up for those who previously received an ADC was 11.8 months; for those who previously received a bispecific antibody, the median follow-up was 10.9 months.

Among the 13 patients who received a prior BCMA-targeted ADC, the median age was 66 years (range, 44-81), and 61.5% of patients were male. Moreover, 33.3% of patients had bone marrow plasma cells of at least 60%, 38.5% had extramedullary plasmacytomas, and 15.4% had a high-risk cytogenetic profile. The median prior lines of therapy received was 8 (range, 4-13), and 30.8% of patients received an anti-BCMA ADC as their last line of treatment. Additionally, 84.6% of patients were refractory to anti-BCMA therapy, 84.6% were triple-class refractory, and 53.8% were penta-drug refractory. All patients were refractory to their last line of therapy.

In the 7 patients who received a prior BCMA-targeted bispecific antibody, the median age was 60 (range, 49-71), and 57.3% were male. Notably, 28.6% of patients had bone marrow plasma cells of at least 60%, 14.3% of patients had high-risk cytogenetics, and no patients had extramedullary plasmacytomas. The median prior lines of therapy received in this subset was 8 (range, 6-12). Notably, 28.6% of patients had anti-BCMA therapy as their last line of treatment. All patients were triple-class refractory, 57.1% of patients were penta-drug refractory, and 85.7% of patients were refractory to their last line of treatment.

Additional data showed that in 13 evaluable patients who received prior treatment with an ADC, cilta-cel produced an ORR of 61.5% (95% CI, 31.6%-86.1%), which included a sCR rate of 8%, a CR rate of 31%, and a VGPR rate of 23%. The median time to first response was 1 month (range, 0.9-5.1), and the median time to best response was 2.6 months (range, 0.9-9.9). In the 8 responders, the median DOR was 11.5 months (95% CI, 7.9–not estimable [NE]), and 6 responders were ongoing in follow-up. The median PFS in this subgroup was 9.5 months (95% CI, 1.0-NE).

Notably, only 1 of 4 patients who received an anti-BCMA ADC as their last line of treatment experienced a clinical response to cilta-cel, compared with 7 of 9 patients who had at least 1 other prior line of therapy in between an ADC and cilta-cel. Additionally, 7 of 8 responders did not respond to prior treatment with a BCMA-targeted ADC. The 8 responders also had a shorter median treatment duration of their last anti-BCMA ADC, and the median time between their last anti-BCMA ADC and apheresis/cilta-cel was longer.

Among 7 patients who had prior treatment with a bispecific antibody, the ORR was 57% (95% CI, 18.4%-90.1%), which comprised a CR rate of 14%, a VGPR rate of 29%, and a partial response rate of 14%. Notably, 2 patients died before a confirmed response. The median time to first response was 0.9 months (range, 0.9-6.0), and the median time to best response was 1.4 months (range, 0.9-7.0). In the 4 responders, the median DOR was 8.2 months (95% CI, 4.4-NE), and 3 responders were ongoing in follow-up. The median PFS was 5.3 months (95% CI, 0.6-NE).

Both patients who received an anti-BCMA bispecific antibody as their last line of treatment prior to cilta-cel achieved a clinical response, and 2 of 5 patients who had at least 1 line of therapy between the bispecific antibody and cilta-cel achieved a response. Three of 4 patients who responded to cilta-cel did not respond to their last anti-BCMA bispecific antibody. Like the ADC subgroup, responders had a shorter median treatment duration of their last anti-BCMA ADC, and the median time between their last anti-BCMA ADC and apheresis/cilta-cel was longer.

A biomarker analysis showed that prior to cilta-cel treatment, the mean serum BCMA baseline levels were 211 ug/L (range, 0.4-943) and 203 ug/L (range, 1.3-541) in the ADC and bispecific antibody groups, respectively. Pharmacokinetic data indicated that CAR T-cell expansion was lower in the ADC group vs the bispecific antibody group and patients in CARTITUDE-1.

Regarding safety, the most common any-grade hematologic AEs experienced in the ADC and bispecific subgroups, respectively, included neutropenia (92% vs 71%), anemia (77% vs 57%), thrombocytopenia (69% vs 100%), leukopenia (54% vs 57%), and lymphopenia (31% vs 29%). Grade 3/4 hematologic AEs included neutropenia (92% vs 71%), anemia (54% vs 57%), thrombocytopenia (62% vs 86%), leukopenia (54% vs 57%), and lymphopenia (31% vs 29%).

By day 60, 69% of the cases of thrombocytopenia, 77% of lymphopenia cases, and 85% of neutropenia cases had resolved to grade 2 or less in the ADC group. Those rates were 83%, 100%, and 100%, respectively, in the bispecific antibody group.

Six patients in each cohort experienced grade 1/2 cytokine release syndrome (CRS), although no instances of grade 3 or higher were reported. Among all patients who had CRS, the median time to onset was 7.5 days (range, 2-10), and the median duration was 7.0 days (range, 2-9). All patients received at least 1 treatment for CRS.

Additionally, 2 patients in each group had immune effector cell–associated neurotoxicity syndrome (ICANS); this effect was grade 3/4 in severity for 1 patient in each subgroup. The median time to ICANS onset was 9.0 days (range, 4-13), and the median duration was 7.0 days (range, 4-20). ICANS resolved in 3 patients.

Notably, no movement and neurocognitive treatment-emergent AEs or parkinsonism were observed with cilta-cel.

Four deaths occurred in the ADC group, including 3 due to progressive disease and 1 due to COVID-19 pneumonia. Three deaths were reported in the bispecific antibody group, due to C difficile colitis, COVID-19 pneumonia, and subarachnoid hemorrhage.

“You certainly can give cilta-cel after a prior BCMA-directed therapy. The response rate appears to be around 60% in this small cohort. It is a good option,” Cohen concluded. “The question remains whether this is the optimal time to use cilta-cel, given the much higher response rates that were seen in a BCMA-naïve population. We’re going to need larger datasets and perhaps real-world data to try to answer these questions about how to best sequence these different BCMA-directed treatments.”

References

1. Cohen AD, Mateos M-V, Cohen YC, et al. Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents. Presented at: 19th International Myeloma Society Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-044
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 August 28, 2022. https://bit.ly/35yWwjv