Cilta-Cel Improves PFS Vs SOC Regimen in Lenalidomide-Refractory Myeloma

“Cilta-cel has the potential to be a new standard of care for patients with lenalidomide-refractory myeloma after first relapse,” lead study author Binod Dhakal, MD, an associate professor at the Medical College of Wisconsin in Milwaukee, said in a presentation of the data.

Treatment with ciltacabtagene autoleucel (cilta-cel; Carvykti) produced significant improvements in progression-free survival (PFS) vs standard-of-care (SOC) pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) or daratumumab (Darzalex), pomalidomide, and dexamethasone (DPd) among those with lenalidomide (Revlimid)-refractory multiple myeloma, according to findings from the phase 3 CARTITUDE-4 study (NCT04181827).^1,2

Findings presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in The New England Journal of Medicine showed that at a median follow-up of 15.9 months (range 0.1-27), patients treated with cilta-cel (n = 208) experienced a median PFS that was not yet reached (NR; 95% CI, 22.8 months-not estimable [NE]) compared with 11.8 months (95% CI, 9.7-13.8) in those given SOC (n = 211; HR, 0.26; 95% CI, 0.18-0.38; P < .0001). The 12-month PFS rate was 76% in the cilta-cel arm and 49% in the SOC arm.

“Cilta-cel has the potential to be a new standard of care for patients with lenalidomide-refractory myeloma after first relapse,” lead study author Binod Dhakal, MD, an associate professor at the Medical College of Wisconsin in Milwaukee, said in a presentation of the data.

Cilta-cel was approved by the FDA in February 2022 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 drug (IMiD), and an anti-CD38 monoclonal antibody, based on data from the phase 1b/2 CARTITUDE-1 trial (NCT03548207).³

CARTITUDE-4 enrolled patients at least 18 years of age with multiple myeloma who had received 1 to 3 prior lines of therapy, including a PI and an IMiD, who were refractory to lenalidomide. Patients needed to have an ECOG performance status of 0 or 1. Prior CAR T-cell therapy or BCMA-targeted therapy was not allowed.

Patients were randomly assigned 1:1 to receive cilta-cel or SOC with physician’s choice of PVd or DPd. In the cilta-cel arm, patients received at least 1 cycle of bridging therapy with PVd or DPd following apheresis. Five to 7 days following lymphodepletion with 300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine per day for 3 days, patients in the experimental arm received cilta-cel at a target dose of 0.75 x 106 CAR+ T cells/kg.

Notably, patients in the cilta-cel arm received the same treatment as the SOC arm during the bridging phase prior to the infusion of the CAR T-cell therapy.

“During the time when both arms were [receiving] the same [SOC] treatment, there is an imbalance in early PFS events, with 22 in the cilta-cel arm and 8 in the SOC arm. By 3 months post-randomization, there were 31 PFS events in the cilta-cel arm and 27 in the SOC arm,” Dhakal explained.

Patients were stratified by choice of PVd/DPd, International Staging System (ISS) stage, and number of prior lines of therapy.

PFS served as the trial’s primary end point. Secondary end points included complete response (CR) or better rate, overall response rate (ORR), minimal residual disease (MRD) negativity, overall survival (OS), safety, and patient-reported outcomes.

Of the 419 patients who underwent randomization, 208 received cilta-cel and 211 received SOC; this comprised the intention-to-treat (ITT) population. The safety population consisted of 208 patients from both arms. Of the 208 patients in the cilta-cel arm who underwent apheresis and bridging therapy, 176 were infused with the CAR T-cell therapy. Thirty-two patients did not receive cilta-cel due to disease progression (n = 30) or death (n = 2) during bridging therapy. Notably, 20 of these patients received cilta-cel as a subsequent line of therapy.

Of the 176 patients to receive cilta-cel during CARTITUDE-4, 143 patients were ongoing in the post-treatment phase as of the data cutoff date of November 1, 2022. The median time from first apheresis to cilta-cel infusion was 79 days. Moreover, 208 of the 211 patients randomly assigned to the SOC arm received treatment. Seventy-seven patients were ongoing SOC treatment at the time of data cutoff.

Dhakal noted that baseline characteristics were well balanced between the 2 arms. The median age of patients in the cilta-cel arm was 61.5 years (range, 27-78) compared with 61.0 years (range, 35-80) in the SOC arm. Most patients in both arms were male (55.8% and 58.8%, respectively), White (75.5% and 74.4%), had an ECOG performance status of 1 or less (99.5% and 99.5%), and had ISS stage I disease (65.4% and 62.6%). Bone marrow plasma cells were at least 60% in 20.4% and 20.7% of patients in the cilta-cel and SOC groups, respectively. Additionally, 21.2% and 16.6% of patients had soft tissue plasmacytomas in the experimental and control arms, respectively.

The median time since diagnosis was 3 years (range, 0.3-18.1) in the cilta-cel arm and 3.4 years (range, 0.4-22.1) in the SOC arm. Patients had received a median of 2 (range, 1-3) prior lines of therapy in both arms. In the cilta-cel group, 32.7% of patients received 1 prior line of therapy, and 67.3% had received 2 or 3 prior lines of therapy; those rates were 32.2% and 67.8% in the SOC group, respectively.

In the cilta-cel arm, 59.4% of patients had high-risk cytogenetics, including 17p del (23.7%), t(14;16) (1.4%), t(4;14) (14.5%), and 1q gain/amplification (43.0%). Notably, 20.8% of patients had 2 more high-risk cytogenetic features. Among patients treated with SOC, 62.9% had high-risk cytogenetic features, including 17p del (20.5%), t(14;16) (3.3%), t(4;14) (14.3%), and 1q gain/amplification (51.0%). In this group, 23.3% of patients had 2 or more high-risk cytogenetic features.

Furthermore, 25.5% and 26.1% of patients were triple-class exposed in the cilta-cel and SOC arms, respectively. Penta-drug exposure was seen in 6.7% and 4.7% of patients, respectively. In patients treated with cilta-cel, 14.4% were triple-class refractory, 26.4% were bortezomib refractory, 3.8% were pomalidomide refractory, 23.1% were daratumumab refractory, and 49.5% were refractory to any PI. In the SOC arm, those rates were 15.6%, 22.7%, 4.3%, 21.3%, and 45.5%, respectively.

Additional data showed that the PFS benefit was observed across all prespecified subgroups, including patients who had 1 prior line of treatment (HR, 0.35; 95% CI, 0.19-0.66) and those who had 2 or 3 prior lines of therapy (HR, 0.24; 95% CI, 0.16-0.37).

Cilta-cel elicited an ORR of 84.6% compared with 67.3% with SOC (odds ratio, 3.0; 95% CI, 1.8-5.0; P < .0001). In the cilta-cel arm, 58.2% of patients achieved a stringent CR (sCR), 14.9% had a CR, 8.2% had a very good partial response (VGPR), and 3.4% had a PR. In the SOC arm, the sCR, CR, VGPR, and PR rates were 15.2%, 6.6%, 23.7%, and 21.8%, respectively.

The median duration of response (DOR) was NR in the cilta-cel group vs 16.6 months (95% CI, 12.9-NE) in the SOC group. The 12-month DOR rates were 84.7% (95% CI, 78.1%-89.4%) and 63.0% (95% CI, 54.2%-70.6%) for cilta-cel and SOC, respectively.

In the ITT population, 60.6% of patients treated with cilta-cel experienced MRD negativity at a 10-5 sensitivity compared with 15.6% of patients given SOC (odds ratio, 8.7; P < .0001). Among those evaluable for MRD in the cilta-cel arm (n = 144), 87.5% achieved MRD negativity vs 32.7% for those evaluable in the SOC arm (n = 101).

OS data were immature at the time of data cutoff (HR for cilta-cel vs SOC, 0.78; 95% CI, 0.5-1.2; P = .26).

Among the 176 patients who comprised the as-treated population, the ORR with cilta-cel was 99.4%, which included a sCR rate of 68.8%, a CR rate of 17.6%, a VGPR rate of 9.7%, and a PR rate of 3.4%. Seventy-two percent of these patients were MRD negative at a 10-5 sensitivity, and the 12-month PFS rate for this group was 90%.

In an informal comparison of data for cilta-cel from CARTITUDE-4 vs CARTITUDE-1, at a median follow-up of 18 months, the 12-month PFS rate from cilta-cel infusion was 85% in CARTITUDE-4 vs 76% in CARTITUDE-1. Eighty-six percent of patients treated with cilta-cel in CARTITUDE-4 had a CR or better, and 72% were MRD negative. Those rates were 80% and 58% in CARTITUDE-1, respectively.

“The censoring of data beyond 16 months [in CARTITUDE-4] warrants caution regarding any long-term interpretation [between CARTITUDE-1 and CARTITUDE-4].” Dhakal said.

Regarding safety, all patients in both arms of CARTITUDE-4 experienced at least 1 any-grade adverse effect (AE). The rates of grade 3/4 AEs were 96.6% for cilta-cel and 94.2% for SOC. Serious AEs of any grade occurred in 44.2% of patients in the cilta-cel arm and 38.9% of those in the SOC arm. Rates of grade 3/4 serious AEs were 32.2% and 33.7%, respectively.

The most common any-grade hematologic AEs included neutropenia (89.9% for cilta-cel and 85.1% for SOC), anemia (54.3% and 26.0%), thrombocytopenia (54.3% and 31.3%), and lymphopenia (22.1% and 13.9%). Grade 3/4 hematologic AEs consisted of neutropenia (89.9% for cilta-cel and 82.2% for SOC), anemia (35.6% and 14.4%), thrombocytopenia (41.3% and 18.8%), and lymphopenia (20.7% and 12.0%). Dhakal noted that most high-grade cytopenias resolved to grade 2 or lower by day 30.

Any-grade infections were reported in 62.0% of patients treated with cilta-cel and 71.2% of patients given SOC. Rates of grade 3/4 infections were 26.9% and 24.5%, respectively. The most common any-grade infections included upper respiratory tract (18.8% for cilta-cel and 26.0% for SOC), lower respiratory tract (9.1% and 17.3%), and COVID-19 (13.9% and 26.4%). Grade 3/4 infections consisted of upper respiratory tract (1.9% for cilta-cel and 1.9% for SOC), lower respiratory tract (4.3% and 3.8%), and COVID-19 (2.9% and 5.8%).

Notably, 10 patients in the cilta-cel arm died due to treatment-emergent AEs (TEAEs), which included 7 due to COVID-19. Five patients in the SOC arm died due to TEAEs, which included 1 due to COVID-19.

“Three of the patients who died [due to COVID-19] in the cilta-cel arm were unvaccinated,” Dhakal said. “The COVID-19 deaths highlight the need for strict prevention measures and aggressive treatment of COVID-19 in patients receiving CAR T-cell therapies. No COVID-19 deaths occurred in the cilta-cel arm after safety measures consistent with international guidelines were introduced.”

Additionally, 76.1% of patients treated with cilta-cel experienced any-grade cytokine release syndrome (CRS), including 1.1% of patients who had grade 3/4 CRS. The median time to CRS onset was 8 days, and the median duration was 3 days. All cases of CRS resolved. Immune effector cell–associated neurotoxicity syndrome (ICANS) was reported in 4.5% of patients, and no grade 3/4 events occurred. The median time to ICANS onset was 10 days, the median duration was 2 days, and it was resolved in all patients.

Other CAR T-cell–related neurotoxicity of any grade was observed in 17.0% of patients, with grade 3/4 events observed in 2.3% of patients. AEs of note included cranial nerve palsy (any-grade, 9.1%; grade 3/4, 1.1%), peripheral neuropathy (2.8%; 0.6%), and movement and neurocognitive (MNT) TEAEs (0.6%; 0%). The median time to onset of cranial nerve palsy was 21 days, the median duration was 77 days, and this resolved in 14 of 16 patients. Peripheral neuropathy had a median onset of 63 days and a median duration of 201 days; it resolved in 3 of 5 patients. MNT occurred in 1 patient at 85 days, and it did not resolve by the time of data cutoff.

"Use of cilta-cel in earlier lines may lead to improved tolerability. Overall, cilta-cel has the potential to be a new standard of care for patients with lenalidomide-refractory myeloma after first relapse,” Dhakal concluded.

References

1. Dhakal B, Yong K, Harrison SJ, et al. First phase 3 results from CARTITUDE-4: Cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma. J Clin Oncol. 2023;41(suppl 17):LBA106. doi:10.1200/JCO.2023.41.17_suppl.LBA106
2. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. Published online June 5, 2023. doi:10.1056/NEJMoa2303379
3. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. News release. FDA. February 28, 2022. Accessed June 5, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/