Senior Associate Consultant Mayo Clinic, United States
Introduction: Immunomodulatory agents remain the cornerstone of multiple myeloma (MM) treatment. We previously published the phase 2 trial of lenalidomide and dexamethasone (Rd) as initial therapy for MM. From this cohort, we identified a subset of long-term responders (LTRs) after Rd was discontinued. We hypothesized that improved immunosurveillance induced by the immunomodulatory actions of lenalidomide was responsible for these exceptional responses. To that end, we performed single cell transcriptomics to characterize their immune microenvironment.
Methods: Between 2003 and 2011, 305 patients (pts) with newly diagnosed MM were treated with Rd induction. After exclusion of pts who were treated with stem cell transplantation or discontinued Rd for progression, there were 31 pts who discontinued Rd for reasons other than progression and were observed without treatment. These LTRs were defined as pts who were treated with Rd, with time to progression of 72 months or longer. Age matched controls were pts who received Rd induction but progressed within 72 months of Rd treatment. Single cell RNA sequencing was performed on CD138- sorted bone marrow (BM) at baseline and after 6 to 12 months of Rd. Gene set enrichment analyses using the reactome pathway were utilized to annotate differentially regulated biological processes using WebGestalt (https://www.webgestalt.org/).
Results: 12 BM samples were available from 10 LTR pts and 12 control pts at baseline and after induction. BM cells were clustered based on gene expression profile and annotated to various cellular lineages using canonical marker genes. The median age at diagnosis among the LTRs was 61.5 years and controls was 53.8 years. The median duration of Rd treatment among LTRs was 72 months (range 5-125) and 9 months (range 3-34) in controls. Within the memory CD4 T cell compartment there was significant enrichment of ribosomal proteins (RPs) (RPL10,12,13,18,27,29) among the LTRs compared to the controls at diagnosis and after treatment. RPs are required for effective mTOR-mediated, metabolic reprogramming of naïve to effector T cells. PPARγ which is implicated in mTOR mediated metabolic reprogramming of CD4 T cells, was upregulated in the memory CD4 T cell compartment in LTRs.
Conclusions: We demonstrate high expression of ribosomal proteins in the memory T cell CD4 compartment of LTRs at diagnosis and after treatment with Rd. Our study is limited by small numbers. However, our results show that the BM microenvironment in LTRs after lenalidomide therapy is characterized by a CD4 memory T cell pool with higher capacity for proliferation and differentiation. Our future goal is to compare the transcriptomic landscape of malignant cells between LTR and controls.
