Car rates

Results of salvage therapies in post-CAR T MMRR relapses indicate an area of ​​unmet need

Patients with relapsed or refractory multiple myeloma who have relapsed after treatment with chimeric antigen receptor T-cell therapy directed by B-cell maturation antigen.

Survival outcomes were poor for patients with relapsed or refractory multiple myeloma (RRMM) who relapsed after treatment with T cell therapy directed by B cell maturation antigen (BCMA) and chimeric antigen receptor ( CAR), the results of a single-center retrospective analysis showed .1

After a relapse of CAR T-cell therapy, the median overall survival (OS) was 14.8 months (95% CI: 10.3-23.4). OS rate at 1 year was 57% (95% CI, 42.4%-75.3%) and 17% (95% CI, 6.7%-43.7%) at 2 years .

The median OS of patients who received salvage therapy with BCMA CAR T-cell therapy or bispecific therapy within 6 months of progression from initial BCMA CAR T-cell therapy was 18 months (95% CI, 11 .8 – not reached [NR]).

“Conventional treatments can elicit a response even with a history of refractory. However, the duration of the response appears to be limited,” said study lead author Kevin R. Reyes, a second-year medical student at the University of California, San Francisco School of Medicine, during the presentation of results at the International Myeloma Society 2022 Annual Meeting and Exposition.” Subsequent BCMA-led immunotherapies may be effective for these patients.”

So far, two BCMA-led CAR T-cell therapies have been approved by the FDA for the treatment of patients with MMRR: idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti ). Although these therapies have resulted in significant clinical responses, most patients eventually experience disease progression. The researchers sought to determine the outcomes of patients with MMRR who relapse after BCMA-led CAR T-cell therapy.

The analysis included all patients with MMRR who received BCMA-led CAR T-cell therapy, either as part of a clinical trial or with an approved therapy (n=78), between January 2017 and June 2022.

Efficacy results for analysis included progression-free survival (PFS) and OS for all patients, objective response rates (ORR) for specific salvage treatments, treatment duration per salvage line and OS from the time of disease progression.

The median age of all patients was 64.5 years (range, 33-77). Most patients were male (59%), had IgG disease (65%) and high-risk fluorescence in situ hybridization (FISH; 59%). Nineteen percent of patients had IgA disease, compared to 14% of patients with light chain disease only and only 1% of patients with IgD disease. Extramedullary disease was present in 26% of patients and the median plasma cell burden before CAR T cell infusion was 35% at baseline (range: 0% to 100%).

The median number of prior treatment lines was 7 (range, 1-14). All patients were previously exposed to lenalidomide (Revlimid), 91% to anti-CD38 therapies, 88% to bortezomib (Velcade), 86% to carfilzomib (Kyprolis) and cyclophosphamide and 85% to pomalidomide (Pomalyst).

The majority of patients were refractory to anti-CD38 treatment (85%), followed by lenalidomide (79%), pomalidomide (71%), carfilzomib (69%) and bortezomib (45%). Sixty-four percent of patients were triple refractory and 28% were penta refractory. Seventeen percent of patients were refractory to venetoclax (Venclexta), 12% to ixazomib (Ninlaro), 8% to elotuzumab (Empliciti) and 5% to panobinostat (Farydak).

Of all patients in the cohort, 57 received treatment in a clinical trial with a median dose of 308 x 106 CAR T cells (range, 0.2-600 x 106).

The best response to CAR T-cell therapy was rigorous complete response in 38%, complete response in 18%, very good partial response in 23%, partial response in 8%, stable disease in 11% and progressive disease in 3% of patients. . The median time to best response was 2.8 months (range: 0.2-17.7) and minimal residual disease negativity was achieved in 64% of patients.

After a median follow-up of 19 months, the median PFS to CAR T-cell therapy was 13 months (95% CI, 10.6-22.5) and the median OS was 31.4 months (CI at 95%, 26.5-NR).

In an analysis of patients with 1q copy number gain, patients with 3 or more 1q copies had worse OS than those with only 2 copies (24.8 months vs. NR). Among patients with high-risk FISH, as defined by the Revised International Staging System for Multiple Myeloma (R-ISS) criteria, median OS was NR compared to 31.4 months in those without high-risk disease according to FISH cytogenetics. However, Reyes noted that R-ISS does not currently classify 3 or more copies of 1q as high risk.

A total of 42 patients relapsed after CAR T-cell therapy and received a median of 3 salvage therapies after CAR T-cell therapy (range, 1-8). Salvage therapy with BCMA-directed CAR T-cell therapy (n=8) resulted in an ORR of 75% and a median treatment duration of 8.1 months, the highest of all salvage therapies.

With the salvage treatment a bispecific BCMA (n = 5), the ORR was 60% and the median treatment duration was 1.6 months. Anti-CD38 salvage therapy (n=19) resulted in an ORR of 52.6% and a median treatment duration of 3.0 months. Forty-one patients received salvage therapy with an alkylator, resulting in an ORR of 46.3% and a median treatment duration of 1.5 months.

In patients who were retreated with an agent to which they were previously exposed or refractory, the highest ORR was 73% in patients who received an alkylator (n=15) followed by 64% with anti-CD38 therapy (n=11), and 50% with an immunomodulatory agent (n=2).

Reyes suggested that possible limitations of the study included the small sample size, the fact that it was a single institution experiment, the heterogeneous use of salvage therapy, and the time to limited follow-up.

“New therapies and further clinical studies are badly needed for this patient population,” Reyes concluded.

Reference

Reyes KR, Liu YC, Huang CY, et al. Salvage treatments and clinical outcomes after BCMA CAR-T relapse in patients with relapsed/refractory multiple myeloma. Presented at: 2022 International Myeloma Society Annual Meeting and Exposition; September 25-27, 2022; Los Angeles, CA. Abstract OAB-051.