Cilta-Cel Yields High MRD-Negativity Rates in Multiple Myeloma After Prior Anti-BCMA Treatment
Seven of 10 evaluable patients achieved minimal residual disease negativity after cilta-cel treatment.
This content originally appeared on our sister site, OncLive.
Patients with heavily pretreated multiple myeloma who received prior treatment with a BCMA-targeted therapy experienced high rates of minimal residual disease (MRD) negativity after being treated with ciltacabtagene autoleucel (cilta-cel; Carvykti).1
These findings from cohort C of the phase 2 CARTITUDE-2 trial (NCT04133636), were presented at the 19th International Myeloma Society Annual Meeting. Data 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,” Adam D. Cohen, MD, director, Myeloma Immunotherapy and associate professor of Medicine, Hospital of the University of Pennsylvania, said 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.”
Cilta-cel was approved for the treatment of relapsed/refractory multiple myeloma in February 2022 in adult patients after 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The approval was based on findings from the phase 1b/2 CARTITUDE-1 trial (NCT03548207).2
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CARTITUDE-2 further explored cilta-cel 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. Cilta-cel is a CAR T-cell therapy expressing 2 BCMA-targeting, single-domain antibodies,
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.”
