Abecma Continues to Improve Survival in Heavily Pretreated Patients With Multiple Myeloma

After long-term follow-up, the CAR-T cell therapy still boosted survival outcomes in patients with relapsed/refractory multiple myeloma, regardless of the number of prior lines of therapy received.

Abecma (idecabtagene vicleucel ; ide-cel; formerly bb2121), a chimeric antigen receptor (CAR)-T cell therapy, led to improved survival in patients with multiple myeloma who have been treated with many other lines of therapy, according to updated results from the KarMMa trial presented 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 relapse refractory multiple myeloma,” Dr. Larry D. Anderson, associate professor, UT Southwestern Medical Center, said during a presentation of the poster.

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

Overall response rate (ORR) – the percentage of patients who responded to the treatment – was 73% in the overall population, including a 33% complete response rate, where disease could not be detected (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 three prior lines of therapy (a total of 15 patients), the ORR was 73%, including a CRR of 53% and VGPR of 20%, compared with an ORR of 73% in those who received four or more (112 patients) lines of therapy, including a CRR of 30%, VGPR of 23%, and PR of 20%.

Average duration of response (DOR; the time patients’ disease was stable or in remission after being treated) was 10.9 months, 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 among those who experienced a CR; 10.4 months for those with VGPR; and 4.5 months in those with PRs.

Moreover, the rate of event-free 24-month DOR appeared to be similar in patients who received three or four or more lines of therapy. For those who received three lines of prior therapy, median DOR was eight months, compared with 10.9 months in those who received four or more lines of therapy.

Average progression-free survival (PFS) – meaning the length of time after treatment when the disease does not get worse – was 8.6 months 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, average PFS was similar among those who previously received three lines of therapy, compared with four or more prior lines of therapy (8.6 months vs 8.9 months, respectively).

On average, it took patients about one month to respond to therapy and about 2.8 months to experience a CR.

Median overall survival (OS) was 24.8 months, including a median OS of 22.0 months in those who received three lines of prior therapy and 25.2 months in those who received four 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), those with extramedullary disease (20.2 months), and those with triple refractory disease (21.7 months).

Regarding side effects, cytokine release syndrome (CRS; the effect of many inflammatory cytokine immune cells being release into the blood stream) and neurotoxicity (brain and/or nervous system damage) rates 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 Abecma 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 side effects 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 Abecma in the pivotal phase 2 KarMMa trial (NCT03361748)-including overall data and by prior line of therapy that patients had received (three compared to four or more), “since the FDA label is requiring at least four prior lines, and this study only required three,” he added.

In total, 140 patients who had received at least three 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 Abecma.

Patients were treated with Abecma across the target dose range of 150 (four patients), 300 (70 patients), and 450 (54 patients) 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 the start of the trial, the average patient age was 61 years (range, 33-78) and patients had a median of six 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% or more at screening (85%), ECOG performance status – which measures how functional a patient is on a range of 1 (fully functioning) to 5 (dead) – 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 six (range, 3-16) and 94% had previously undergone at least one autologous hematopoietic stem cell transplant (94%). Eighty-eight percent of patients required bridging therapy, a kind of pre-treatment before CAR-T cell thearpy. Eighty-nine percent of patients had double-refractory disease, 84% were triple-refractory and 26% were penta-refractory.

Patients who had received three prior lines of therapy had similar baseline characteristics, compared with those who received four 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 two- to four-month range, and overall survival less than nine 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.As a result, the FDA approved the agent for the treatment of adult patients with relapsed or refractory multiple myeloma after four 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.

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

  • KarMMa-2 (NCT03601078): a phase 2 trial of Abecma in triple-class-exposed patients and patients with high-risk multiple myeloma.
  • KarMMa-3 (NCT03651128): a phase 3 study of Abecma, 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 Abecma in patients with high-risk, newly diagnosed multiple myeloma.
  • KarMMa-7 (NCT04855136): an exploratory phase 1/2 study of Abecma combination therapies in patients with relapsed/refractory multiple myeloma.