Association of patient (pt) factors and pharmacodynamic biomarkers with progression-free survival (PFS) after idecabtagene vicleucel (ide-cel) in pts from KarMMa-3.
Authors: Thompson Ethan G. , Piasecki Julia , Rodríguez-Otero Paula , Mateos Maria-Victoria , Arnulf Bertrand , Desai Keyur , Wu Fan , Courtney Carolyn , Cook Mark , Martin Nathan 
Published: June 2024

7527

Background: Ide-cel, a B-cell maturation antigen (BCMA) CAR T cell therapy (tx), significantly improved PFS vs standard regimens in pts with triple-class–exposed relapsed or refractory MM (13.8 vs 4.4 mo, P<0.001) in KarMMa-3. Median PFS in the ide-cel treated population (pop; n=225) was 15.7 (95% CI, 12.5–18.9) mo (Rodríguez-Otero ASH 2023). PFS benefit of ide-cel was consistent across high-risk pt subgroups. Previous analyses indicated that lower levels of baseline soluble BCMA (sBCMA; measure of tumor burden) and lower basal inflammatory markers were positively associated with response to ide-cel. This analysis identified pre- and post-tx pt factors and pharmacodynamic biomarkers associated with longer PFS with ide-cel in the treated pop. Methods: Median PFS (15.7 mo) of the treated KarMMa-3 pop was used to divide pts into 2 groups: longer PFS (>15.7 mo; n=106) or shorter PFS (≤15.7 mo; n=110). Censored pts (n=9) who had a PFS <15.7 mo were excluded. Pre- and post-tx values for laboratory parameters, MM assessments, sBCMA, inflammatory cytokines, ide-cel transgene persistence, and minimal residual disease (MRD; 10−5 sensitivity) were evaluated. Serum free light chains (sFLCs) were evaluated as biomarkers of plasma cell clearance; clearance was defined as level below limit of detection of both involved and heterotypic sFLC. Analyses were post hoc and exploratory; statistical tests were used to identify relationships of interest. Results: In total,94% of pts with longer PFS achieved a best overall response of ≥very good partial response and had lower levels of β-2 microglobulin ( P<0.01), lactate dehydrogenase ( P<0.01), and sBCMA ( P<0.01) at baseline. Inflammatory markers (eg, tumor necrosis factor, ferritin, C-reactive protein) were significantly higher ( P<0.05) in pts with shorter vs longer PFS at baseline. All pts with longer PFS (100%) achieved sFLC clearance after ide-cel infusion. Among pts who achieved initial clearance, pts with longer PFS had a longer duration of sFLC clearance than shorter PFS ( P<0.001), suggesting more durable engraftment of ide-cel and tumor control. Within MRD-evaluable pts, those with longer PFS achieved higher MRD negativity vs shorter PFS (87% vs 41%) at 6 mo post infusion with sustained MRD negativity (53% vs 4%) lasting 8–12+ mo. No apparent relationship was observed between PFS and ide-cel persistence at 6-, 9- and 12-mo post-infusion. Conclusions: Pts with longer PFS after ide-cel infusion had relatively lower tumor burden and lower levels of peripheral inflammatory markers before tx, highlighting the importance of managing baseline tumor burden before CAR T cell infusion to achieve optimal response. Complete and sustained clearance of sFLCs within the first few mo post infusion was associated with longer PFS. MRD negativity at 6 mo and sustained MRD negativity were enriched in pts with longer PFS. Clinical trial information: NCT03651128 .