Key Clinical Summary

• Pre-apheresis lenalidomide (LEN) in newly diagnosed multiple myeloma (NDMM) improved T-cell fitness and drug product phenotype compared to patients with only autologous stem cell Transplant (ASCT).
• Cohort 3 showed more favorable immune signatures, superior soluble B-cell maturation antigen (BCMA) clearance (93.3% vs 77.4%), and enhanced pharmacodynamic activity.
• Findings derive from a cross-cohort analysis of KarMMa-2, highlighting LEN’s potential to optimize idecabtagene vicleucel (ide-cel) outcomes post-ASCT.

A new cross-cohort analysis from the phase 2 KarMMa-2 trial suggests that lenalidomide given before apheresis may improve T-cell fitness and downstream ide-cel performance in newly diagnosed multiple myeloma. The analysis compares immune characteristics and pharmacodynamic outcomes between patients receiving ASCT alone and those receiving an added LEN cycle before CAR T-cell collection.

Study Findings

The analysis focused on cohort 2c (C2c), consisting of NDMM patients with < Very Good Partial Response (VGPR) after ASCT, and cohort 3 (C3), enrolling NDMM patients with < complete response (CR) who received a cycle of LEN prior to apheresis. Median time from ASCT to enrollment was 5.8 months in C2c and 4.2 months in C3.

Baseline soluble BCMA (sBCMA) levels—an indicator of tumor burden—were lower in NDMM overall compared with relapsed/refractory multiple myeloma (RRMM), but C3 showed a lower median sBCMA (14.5 ng/mL) than C2c (27 ng/mL). Immune profiling via CyTOF demonstrated more favorable T-cell attributes in C3, including higher CD8 Tem and lower CD8 Temra frequencies, accompanied by reduced expression of exhaustion markers (CD57, PD1, CD38) on both CD4 and CD8 subsets. CD4 cells in C3 also expressed lower Ki67 and CTLA4 and higher CD27 within central and effector memory compartments, suggesting a less differentiated profile.

C3 patients exhibited elevated IL-2, IL-7, and perforin levels—features associated with enhanced CAR T cytolytic capacity—while reduced IFNγ signaled a more permissive immune environment. Baseline proteomics identified >200 analytes differentially expressed between cohorts, with enrichment of myelocytomatosis oncogene (MYC) target pathways.

Drug product analysis showed trends toward greater potency and lower CD57 expression among C3-derived CAR T products. After infusion, C3 demonstrated higher early abundance of effector memory CAR T cells and maintained lower PD1 and CD38 expression on both endogenous and CAR T populations.

Pharmacodynamic activity also favored C3: sBCMA clearance occurred in 93.3% (28/30) of C3 patients versus 77.4% (24/31) in C2c. CAR T expansion and cellular kinetics were similar between cohorts and consistent with patterns observed in KarMMa-3.

Clinical Implications

These findings suggest that a single LEN cycle before apheresis may meaningfully enhance the biological quality of T cells collected for CAR T manufacturing in NDMM. For oncology leaders and pathway decision-makers, the data point to a potentially modifiable factor in optimizing ide-cel efficacy post-ASCT, particularly for patients with suboptimal initial response.

By improving T-cell differentiation status, reducing exhaustion markers, and enhancing cytokine support, LEN may help counteract ASCT-induced T-cell dysfunction. The improved sBCMA clearance in C3 further signals greater pharmacodynamic impact, which could translate into deeper or more durable responses if validated in larger cohorts.

Conclusion

The KarMMa-2 cross-cohort analysis provides early evidence that pre-apheresis lenalidomide may strengthen T-cell quality and pharmacodynamic effects of ide-cel in NDMM. Future studies are needed to confirm whether these biologic improvements translate into superior long-term clinical outcomes.

Reference

Tang H, Thompson E, Descalzi-Montoya D, et al. Impact of lenalidomide pre-apheresis on markers of T cell fitness and pharmacodynamic biomarkers in newly diagnosed multiple myeloma patients with suboptimal response to autologous stem cell transplantation. Presented at: ASH 2025; December 6-9; Orlando, FL.