Long-Term Follow-Up Continues to Support Ide-Cel Use in Heavily Pretreated Relapsed/Refractory Myeloma

Updated efficacy and safety results from the phase 2 KarMMa trial (NCT03361748) demonstrated continued deep and durable responses in patients with heavily pretreated relapsed/refractory multiple myeloma who were receiving idecabtagene vicleucel (ide-cel; Abecma) therapy, regardless of whether patients received 3 or at least 4 prior therapies, according to that were presented during the 18th International Myeloma Workshop.1

At a median follow-up of 24.8 months (range, 1.7-33.6), the overall response rate (ORR) was 73% in all patients treated with ide-cel (n = 128). Moreover, the complete response (CR) rate was 33%.

The median duration of response (DOR) was 10.9 months (95% CI, 9.0-11.4), the median progression-free survival (PFS) was 8.6 months (95% CI, 5.6-11.6), and the median overall survival (OS) was 24.8 months (95% CI, 19.9-31.2) with ide-cel.

Notably, the ORR, CR rate, and PFS were most prominent when ide-cel was given at the highest target dose of 450 x 106 CAR+ T cells at 81%, 39%, and 12.2 months, respectively. The median OS was 22 months (95% CI, 10.0-not evaluable [NE]) vs 25.2 months (19.9-NE) for patients who received 3 or 4 or more prior lines of therapy, respectively.

“The favorable benefit-risk profile of ide-cel [was observed] regardless of the number of prior lines of therapy supports its role as a treatment option of heavily pretreated relapsed/refractory multiple myeloma,” lead study author Larry D. Anderson, Jr, MD, PhD, associate professor in the Department of Internal Medicine of the Division of Hematology/Oncology at the Harold C. Simmons Comprehensive Cancer Center of UT Southwestern Medical Center, said in a virtual presentation of the data.

On March 26, 2021, the FDA approved ide-cel as the first cell-based gene therapy in multiple myeloma for the treatment of patients with relapsed/refractory multiple myeloma who had progressed on 4 or more prior lines of therapy, including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody.2

The regulatory decision was based on prior findings from the KarMMa trial, in which ide-cel induced an ORR of 72% with a favorable safety profile in this patient population.

Investigators on the study enrolled patients with relapsed/refractory disease who had received at least 3 prior regimens with at least 2 consecutive cycles each or best response of progressive disease. Patients had to have been previously exposed to an IMiD, a PI, and a CD38-directed monoclonal antibody and refractory to their last prior therapy per International Myeloma Working Group criteria.

The ide-cel manufacturing process, which holds a 99% success rate, started with leukapheresis, and was followed by bridging therapy at least 14 days before lymphodepletion, which consisted of 30 mg/m2 of fludarabine plus 300 mg/m2 of cyclophosphamide on days -5, -4, -3, and 0. Patients then received a single infusion of ide-cel.

ORR served as the primary end point of the study, with CR rate, safety, DOR, PFS, OS, pharmacokinetics, minimal residual disease, quality of life, and health economics and outcomes research as key secondary end points.

In the overall population, the median age was 61 years (range, 33-78) and 59% of patients were male. More than half of patients had an ECOG performance status of 1 (53%) and stage II disease (70%) per revised International Staging System criteria. Additionally, 35% of patients had high-risk cytogenetics, 51% had high tumor burden, 85% had tumor BCMA expression of at least 50%, and 39% had extramedullary disease.

The median time since initial diagnosis was 6 years (range, 1-18). Patients received a median of 6 (range, 3-16) prior anti-myeloma regimens. Nearly all patients (94%) underwent prior autologous stem cell transplant (ASCT); 34% underwent more than 1 ASCT, and 88% of patients received any bridging therapies for multiple myeloma.

Nearly all (94%) of patients were refractory to a CD38-directed monoclonal antibody, 84% were triple-class refractory, and 26% were penta-class refractory.

By number of prior treatments, the ORR was 73% in patients with 3 prior lines of therapy (n = 15) and 73% in patients with at least 4 prior lines of therapy (n = 113). The CR rates were 53% and 30%, respectively. In both groups, 20% of patients obtained a partial response (PR); 23% of patients with at least 4 prior therapies achieved a very good partial response (VGPR).

The median DOR was 8.0 months (95% CI, 3.3-11.4) in patients with 3 prior lines of therapy and 10.9 months (95% CI, 9.2-13.5) in patients with at least 4 prior lines of therapy. The 24-month event-free DOR rate was 18.2% vs 21.3%, respectively. When measuring DOR by response, the median DOR was 21.5 months (95% CI, 12.5-NE), 10.4 months (95% CI, 5.1-12.2), and 4.5 months (95% CI, 2.9-6.7) in those who achieved a greater than CR, VGPR, and PR, respectively.

The median PFS was 8.6 months (95% CI, 2.9-12.1) vs 8.9 months (95% CI, 5.4-11.6), for those who received 3 and 4 or more lines of prior treatment, respectively.

Overall, the 1, 1.5, and 2-year OS rates were 78%, 65%, and 51%, respectively. The median OS exceeded 20 months across several key high-risk patient subgroups, Anderson explained.

The median OS was 21.7 months (95% CI, 17.1-31.2) months in patients under the age of 65 years vs 28.3 months (95% CI, 20.2-NE) in those aged at least 65 years. In patients without high-risk cytogenetics, the median OS was 31 months (95% CI, 20.2-NE) vs 19.9 months (95% CI, 12.8-NE) in those with high-risk cytogenetics.

Additionally, the median OS was NE (95% CI, 21.3-NE) in patients without extramedullary disease vs 20.2 months (95% CI, 15.5-28.3) in those with extramedullary disease. For patients without triple-refractory disease, the median OS was 31.2 months (95% CI, 19.9-NE) compared with 21.7 months (95% CI, 18.2-NE) in those with triple-class refractory disease.

Regarding safety in the overall population, 84% of patients reported at least 1 cytokine release syndrome (CRS) event; 78% of these were grade 1 or 2, 4% were grade 3, and less than 1% were grade 4 or grade 5. The median time to onset of CRS was 1 day (range, 1-12) and the median duration of CRS was 5 days (range, 1-63).

At least 1 neurotoxicity event occurred in 18% of patients treated with ide-cel; 9% of these were grade 1, 5% were grade 2, and 4% were grade 3. The median time to onset of neurotoxicity was 2 days (range, 1-10) and the median duration of neurotoxicity was 3 days (range, 1-26).

The incidences of CRS and neurotoxicity were similar in patients who received 3 or at least 4 prior lines of therapy and consisted of mostly low-grade events.

Regarding adverse effects (AEs) of special interest, similar rates of infections and secondary primary malignancies were observed with the longer follow-up. Additionally, no unexpected gene therapy–related toxicities were reported with ide-cel.

Similar rates of hematologic and nonhematologic AEs of interest were observed in patients with both 3 and at least 4 prior lines of therapy.

Any-grade hematologic AEs of interest in the overall population included neutropenia (91%), anemia (70%), thrombocytopenia (64%), leukopenia (42%), and lymphopenia (28%). Of these, 89%, 61%, 52%, 39%, and 27% of events were grade 3 or 4, respectively. All-grade nonhematologic AEs of interest included infections (70%), secondary primary malignancies (7%) and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (3%). Of these, 27%, 2%, and 2% were grade 3 or 4, respectively.

The median time to recovery of grade 3 or higher neutropenia and thrombocytopenia was 2 months.

Ide-cel is being further evaluated in ongoing phase 1, 2, and 3 clinical trials of multiple myeloma, including the phase 2 KarMMa-2 (NCT03601078), the phase 3 KarMMa-3 (NCT03651128), the phase 1 KarMMa-4 (NCT04196491), and the phase 1/2 KarMMa-7 trials (NCT04855136).

References

1. Anderson LD, Shah N, Jagannath S, et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, for the treatment of patients with relapsed and refractory multiple myeloma: updated results from KarMMa. Presented at: 18th International Myeloma Workshop; September 8-11, 2021; Vienna, Austria. Abstract OAB27.
2. FDA approves idecabtagene vicleucel for multiple myeloma. News release. FDA. March 26, 2021. Accessed September 10, 2021. https://bit.ly/3hjpUxz