The Differential Effects of Bridging Therapy on Immune Microenvironment and Outcomes with Idecabtagene-Vicleucel in Multiple Myeloma

Introduction: T cell engaging immunotherapies have shown great promise in treating patients with relapsed/refractory multiple myeloma (RRMM). In this study, we investigated the role of bridging therapy on immune composition and immune-tumor microenvironment (iTME), and its subsequent impact on outcomes of patients with RRMM treated with commercial idecabtagene-vicleucel (ide-cel).

Methods: This study included 171 patients with RRMM patients (baseline characteristics similar to Afrough et.al., Blood Cancer Journal, 2024) treated with ide-cel from May 25, 2021, to November 2, 2023, at Moffitt Cancer Center. Differences in progression-free survival (PFS) were compared either by choice of bridging therapy or immune markers using Kaplan-Meier survival curves, log-rank tests, and Cox proportional hazard regression models. Absolute lymphocyte counts (ALC) were obtained for all patients at apheresis and pre-LD (lymphodepletion) to determine the role of bridging on ALC and the impact of ALC on outcomes to ide-cel. A representative sub-sampling of 39 MM patients’ iTME (CD138-negative selection from bone marrow mononuclear cells) post-apheresis/bridging but pre-LD were characterized by multi-parameter flow cytometry (MPF) using a 36-parameter lymphoid panel on Cytek Aurora from viably frozen samples and a 21-parameter myeloid panel on BD Symphony A5 within 24 hours of sample collection and analyzed using FlowJo V10 software.

Results: Ide-cel treated patients with RRMM were categorized into seven mutually exclusive groups by choice of bridging therapy, where BTZ (bortezomib) bridging (n=14) had significantly shorter PFS compared to no bridging (n = 64) group by log-rank test p = 0.03 and HR = 4.69 [1.39 – 15.84] (consistent with Afrough et.al.), while CFZ (carfilzomib)/SELI (n = 2, p = 0.62, HR = 2.81 [0.38 – 20.71]), BTZ/SELI (n = 8, p = 0.39, HR = 2.07 [0.61 – 6.99]), CFZ (n = 26, p = 0.33, HR = 1.65 [0.72 – 3.77]), SELI other (n = 5, p = 0.89, HR = 1.23 [0.26 – 5.93]), and other bridging (n = 52, p = 0.89, HR = 1.00 [0.55 – 1.81]; includes IMIDs, monoclonal antibodies, DCEP, venetoclax, etc.) groups showed non-significant differences in PFS when compared to no bridging.

ALC measurements were compared between apheresis and pre-LD, where patients receiving a BTZ-based regimen showed a significant decrease in ALC (paired t-test, p = 0.03), while patients receiving any other bridging therapy (p = 0.94) or no bridging (p = 0.83) showed no significant differences. A comparison of PFS between ALC high (top 30 percentile) and ALC low (bottom 30 percentile) pre-LD showed that the ALC low group had significantly lower PFS (log-rank test p = 0.03 and HR = 2.06 [1.11 – 3.80]), suggesting that the decrease in ALC associated with BTZ bridging may lead to shorter PFS.

Flow characterization of iTME post-bridging/pre-LD of 39 patients revealed that a lower CD4:CD8 ratio (bottom 10th percentile vs remaining) was associated with shorter PFS (log-rank test p = 0.06 and HR = 16.67 [1.79 – 155.56]). An unpaired t-test comparing the CD4:CD8 ratio between no bridging (median = 1.00) and BTZ (median = 0.38) groups showed a significant decrease (p = 0.005) in CD4:CD8 ratio, while no significant differences were observed in other groups; although BTZ/SELI (median = 0.59) and SELI other (median = 1.07) groups had improved CD4:CD8 ratios compared to BTZ bridging group.

Lastly, expression of T cell inhibitory markers 2B4 on CD4+ and CD160 on CD8+ T cells were significantly higher in BTZ (p = 0.007 and 0.01, respectively) bridging group compared to no bridging, while comparisons with other groups showed no significant differences. A comparison of PFS between the top 10 percentile and rest of the cohort by expression of 2B4 on CD4+ and CD160 on CD8+ showed an association with shorter PFS (p = 0.095 and HR = 10.61 [1.3 – 86.7], p=0.003 and HR = 52.9 [5.8 – 480.9], respectively).

Conclusion: BTZ bridging-associated shorter PFS following ide-cel treatment was attributed to therapy-induced changes to immune function, while other bridging therapies (SELI, CFZ, immunologics, etc.) showed non-significant changes. Intriguingly, SELI associated modulation of the T cell repertoire was able to rescue the negative effects of BTZ on ide-cel outcomes in SELI/BTZ group. The observed BTZ (but not CFZ) dependent impacts on iTME likely stem from differences in mechanisms of action and drug pharmacokinetics and need further investigation in a larger patient cohort.