Patients With Pretreated Myeloma Show Persistent Benefit of Ide-Cel at 2-Year Follow-Up

Positive efficacy results associated with chimeric antigen receptor (CAR) T-cell therapy from the phase 2 KarMMa trial (NCT03361748) of idecabtagene vicleucel (ide-cel; formerly bb2121; Abecma) in patients with heavily pretreated multiple myeloma at a 2-year follow-up were reported at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

“The favorable benefit-risk profile of ide-cel, regardless of the number of prior lines of therapy, supports its role as a treatment option for heavily pretreated, relapsed/refractory multiple myeloma,” Larry D. Anderson, MD, PhD, associate professor, UT Southwestern Medical Center, said during a presentation of the poster.

At the December 21, 2020, data cutoff, the median follow-up was 24.8 months (range, 1.7-33.6).

Overall response rate (ORR) was 73% in the overall population, including a 33% complete response rate (CRR; complete response [CR] or stringent complete response [sCR]), 20% with a very good partial response (VGPR), and 20% who had a partial response (PR). ORR rates were 50%, 69%, and 81%, respectively, across the 150, 300, and 450 million CAR T cell-dose arms, including CR/sCR rates of 25%, 29%, and 39%.

Of note, ORR did not vary by the number of prior lines of therapy received. For those who received 3 prior lines of therapy (n = 15), the ORR was 73%, including a CRR of 53% and VGPR of 20%, compared with an ORR of 73% in those who received ³4 (n = 112) lines of therapy, including a CRR of 30%, VGPR of 23%, and PR of 20%.

Median duration of response (DOR) was 10.9 months (95% CI, 9.0-11.4), including 9.9 months for the 300 million CAR T cells-dose arm and 11.3 months for the 450 million CAR T cells-dose arm -dose arm. Median DOR was 21.5 months in patients who experienced a CR or sCR. Median DOR by response were 21.5 months (95% CI, 12.5 to not estimable [NE]) among those who experienced a CR, 10.4 months (95% CI, 5.1-12.2) for those with VGPR, and 4.5 months (95% CI, 2.9-6.7) in those with PRs.

Moreover, the rate of event-free 24-month DOR appeared to be similar in patients who received 3 or 4 or more lines of therapy. For those who received 3 lines of prior therapy, median DOR was 8.0 months (95% CI, 3.3-11.4), compared with 10.9 months (95% CI, 9.2-13.5) in those who received 4 or more lines of therapy.

Median progression-free survival (PFS) was 8.6 months (95% CI, 5.6-11.6) across all target doses, including 5.8 months for the 300 million CAR T cells-dose arm and 12.2 months for the 450 million CAR T cells-dose arm -dose arm. Similarly, median PFS was similar among those who previously received 3 lines of therapy, compared with 4 or more prior lines of therapy (8.6 months (95% CI, 2.9-12.1) vs 8.9 months (95% CI, 5.4-11.6)]

The median time to first response was 1 month (range, 0.5-8.8), with a median time to CR of 2.8 months (range, 1.0-15.8).

Median overall survival (OS) was 24.8 months (95% CI, 19.9-31.2), including a median OS of 22.0 months (95% CI, 10.-NE) in those who received 3 lines of prior therapy and 25.2 months (95% CI, 19.9-NE) in those who received 4 or more lines of prior therapy. Moreover, OS was 20 months or longer across several key high-risk subgroups, including those aged 65 or older (21.7 months; 95% CI, 17.1-31.2), those with extramedullary disease (20.2 months; 95% CI, 15.5-28.3), and those with triple refractory disease (21.7 months; 95% CI, 18.2-NE).

In regard to safety, cytokine release syndrome (CRS) and neurotoxicity were similar, regardless of prior lines of therapy received, and were mostly low grade. In total, 85% and 18% of the overall population experienced at least 1 CRS or neurotoxicity event, respectively.

The safety profile of ide-cel was consistent with long-term follow-up, with similar rates of infections and secondary primary malignancies, and no unexpected gene therapy related toxicities were observed. The most common grade 3 to 4 adverse events (AEs) in the overall population were neutropenia (89%), anemia (61%), thrombocytopenia (52%), leukopenia (39%), lymphopenia (27%), and infections (27%).

“Long-term results from the KarMMA trial continue to demonstrate frequent, deep, and durable responses in heavily pretreated patients with [relapsed/refractory multiple myeloma],” the study authors write in the poster. “ORR, CRR, DOR, and PFS were consistent with previous reports and patients received similar benefit regardless of the number of prior lines of therapy.”

In his presentation, Anderson presented data on long-term efficacy and safety following treatment with ide-cel in the pivotal trial-including overall data and by prior line of therapy that patients had received (3 vs ≥4), “since the FDA label is requiring at least 4 prior lines, and this study only required 3,” he added.

In total, 140 patients who had received at least 3 prior lines of therapy for multiple myeloma including an IMiD, a PI, and an anti-CD38 antibody and were refractory to their last treatment regimen, were enrolled in the study. However, only 128 patients received infusion with ide-cel.

Patients were treated with ide-cel across the target dose range of 150 (n = 4), 300 (n = 70), and 450 (n = 54) million CAR T cells.

ORR served as the primary end point of the study. Secondary end points included CRR, safety, DOR, PFS, OS, pharmacokinetics, minimal residual disease, quality of life, and health economics and outcomes research.

At baseline, the median patient age was 61 years (range, 33-78) and patients had a median of 6 years (range, 1-18) since their diagnosis. A majority of the patients were male (59%), had high tumor burden (51%), B-cell maturation antigen (BCMA) expression ≥50% at screening (85%), ECOG performance status of 1 (53%), and Revised International Staging System disease stage of II (70%). Thirty-five percent of patients had high-risk features.²

The median number of prior therapies was 6 (range, 3-16) and 94% had previously undergone at least 1 autologous hematopoietic stem cell transplant (94%). Eighty-eight percent of patients required bridging therapy. Eighty-nine percent of patients had double-refractory disease, 84% were triple-refractory, and 26% were penta-refractory.

Patients who had received 3 prior lines of therapy had similar baseline characteristics, compared with those who received 4 or more prior lines, including differences in extramedullary disease, high-risk cytogenetics, prior refractoriness, and time since the initial diagnosis to screening.

“Patients with relapsed/refractory multiple myeloma previously exposed to immunomodulatory agents, protease inhibitors, and anti-CD38 antibodies have poor outcomes with subsequent therapy using previously approved regimens, with expected response rates in the 26% to 31% range, PFS in the 2- to 4-month range, and overall survival less than 9 months,” Anderson explained.

However, the BCMA-directed CAR T-cell therapy previously demonstrated favorable tolerability with deep, durable responses in patients who were heavily pretreated with relapsed/refractory multiple myeloma.² As a result, the FDA approved the agent for the treatment of adult patients with relapsed or refractory multiple myeloma after 4 or more prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody, representing the first BCMA–directed CAR T-cell therapy approved.³

The study authors noted that ide-cel is being explored in ongoing clinical trials, including the following:

• KarMMa-2 (NCT03601078): a phase 2 trial of ide-cel in triple-class-exposed patients and patients with high-risk multiple myeloma.
• KarMMa-3 (NCT03651128): a phase 3 study of ide-cel, compared with standard regimens in triple-class-exposed patients with 2 to 4 lines of prior therapy.
• KarMMa-4 (NCT04196491): a phase 1 trial of ide-cel in patients with high-risk, newly diagnosed multiple myeloma.
• KarMMa-7 (NCT04855136): an exploratory phase 1/2 study of ide-cel combination therapies in patients with relalpsed/refractory multiple myeloma.

References

1. Anderson LD, Munshi NC, Shah N, et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in relapsed and refractory multiple myeloma: Updated KarMMa results. J Clin Oncol. 2021; 39 (suppl 15):8016. doi:10.1200/JCO.2021.39.15_suppl.8016.

2. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850.

3. U.S. Food and Drug Administration Approves Bristol Myers Squibb’s and bluebird bio’s Abecma (idecabtagene vicleucel), the First Anti-BCMA CAR T Cell Therapy for Relapsed or Refractory Multiple Myeloma. News release. Bristol Myers Squibb. March 26, 2021. Accessed June 4, 2021. https://bit.ly/3m0V915.