Lower Tumor Burden, Basal Inflammation Confer PFS With Ide-Cel in Myeloma

Peak granzyme B levels following infusion were increased in those who had longer PFS. According to the investigators, robust CAR T cell cytolytic function may correlate with more enduring responses.

Characteristics such as lower tumor burden and lower basal inflammation appear to correlate with improved progression-free survival (PFS) among patients with relapsed/refractory multiple myeloma who receive treatment with idecabtagene vicleucel (ide-cel; Abecma), according to correlative analysis findings from the phase 3 KarMMa-3 trial (NCT03651128) presented as a poster at the 2024 European Hematology Association Congress (EHA).¹

Those with a lower tumor burden based on reduced soluble B-cell maturation antigen (sBCMA) levels had a higher likelihood of experiencing a longer PFS (P <.00002). Lower concentrations of inflammatory factors such as tumor necrosis factor-alpha (TNF-α; P <.00001) and interleukin-10 (IL-10; P <.00001) also correlated with longer PFS.

Clinical parameters that conferred longer PFS included lower levels of beta-2 microglobulin (β2M; P = .00005), lactate dehydrogenase (LDH; P = .0001), ferritin (P = .002), and C-reactive protein (CRP; P = .02). At 6 months following infusion, 87% of patients with longer PFS, defined as more than 15.7 months, had minimal residual disease (MRD) negativity at a sensitivity of 10^–5 compared with 41% of those with a PFS of 15.7 months or shorter. The rates of MRD negativity in each respective group were 78% vs 14% after 6 months at a sensitivity of 10^–6 and 53% vs 6% after at least 8 months at a sensitivity of 10^–5.

In the multicenter, open-label KarMMa-3 trial, patients with relapsed/refractory multiple myeloma were assigned to receive ide-cel at a dose ranging from 150 to 450 x 10⁶ CAR-positive T cells following lymphodepletion or investigator’s choice of standard therapy.² Treatment options in the comparator arm included agents such as daratumumab (Darzalex), pomalidomide (Pomalyst), and dexamethasone, among others.

In these additional analyses of the KarMMa-3 trial, investigators centrally measured clinical chemistry, inflammation, immunology, and hematology parameters, with baseline visits taking place between bridging therapy and lymphodepletion. Additionally, ide-cel transgene levels were assessed in the peripheral blood via polymerase chain reaction (PCR)-based testing, and investigators evaluated sBCMA and 25 immune-related soluble factors.

Based on the median PFS of 15.7 months with ide-cel in the KarMMa-3 trial, investigators categorized patients as having a longer PFS of more than 15.7 months (n = 106) or a shorter PFS of no more than 15.7 months (n = 110).³ Additionally, P values were determined via the 2-sided Mann-Whitney-Wilcoxon test or the log-rank test as part of these exploratory analyses.

Peak granzyme B levels following infusion were increased in those who had longer PFS. According to the investigators, robust CAR T cell cytolytic function may correlate with more enduring responses. Decreased sBCMA levels following infusion also suggested robust pharmacodynamic responses to ide-cel and conferred prolonged PFS.

The overall response rate (ORR) was 97% among patients with longer PFS, which included a stringent complete response (sCR) or CR rate of 76%, a very good partial response (VGPR) rate of 18%, and a PR rate of 3%. The ORR for those with a shorter PFS was 65%, with reports of sCRs or CRs in 25%, VGPRs in 22%, and PRs in 19%.

Patients with longer PFS also tended to have higher cellular expansion, while PFS appeared to overlap between patients with and without detectable transgene levels. Additionally, 100% of patients with longer PFS had a completely cleared serum-free light chain compared with 54.5% of those who achieved a shorter PFS. Serum-free light chain clearance tended to last longer for patients with a longer PFS vs those with a shorter PFS (P = .00025).

References

1. Arnulf B, Thompson E, Piasecki J, et al. Association of patient factors and pharmacodynamic biomarkers with progression-free survival after idecabtagene vicleucel in patients from KarMMa-3. Presented at the 2024 European Hematology Association (EHA) Hybrid Congress; June 13-16, 2024; Madrid, Spain. Abstract P876.
2. Efficacy and safety study of bb2121 versus standard regimens in subjects with relapsed and refractory multiple myeloma (RRMM) (KarMMa-3). ClinicalTrials.gov. Accessed June 14, 2024. https://tinyurl.com/yck4n8w6
3. Otero PR, Aliawadhi S, Arnulf B, et al. Idecabtagene vicleucel (ide-cel) versus standard (std) regimens in patients (pts) with triple-class-exposed (TCE) relapsed and refractory multiple myeloma (RRMM): updated analysis from KarMMa-3. Blood. 2023;142(suppl 1):1028. doi:10.1182/blood-2023-178933