(OA-73) Longitudinal Multi-Omic Profiling Uncovers Immune Escape and Predictors of Response in Multiple Myeloma

Multiple myeloma (MM) is an incurable malignancy of clonally expanded plasma cells. Advances in MM-targeted therapies, autologous stem cell transplantation (ASCT), and immunotherapy have improved outcomes. Several features contribute to MM’s response to therapy including cytogenetics, tumoral heterogeneity, and composition of the immune microenvironment (IME).  However, the dynamics of the IME through treatment and interplay between MM and the IME during disease progression remains incompletely understood.

Methods:

To this end, we longitudinally evaluated MM and the IME at disease onset, response after therapy, and disease progression in patients from the MM Research Foundation CoMMpass study (NCT01454297). To facilitate a comprehensive characterization of the disease course, we generated single-cell profiles of 243 CD138^neg bone marrow biopsies collected across the disease course from 102 patients. Combining the IME analysis with bulk RNA and whole-genome sequencing data from the malignant CD138^pos compartment enabled characterization of mechanisms by which MM escapes surveillance and leads to disease progression.

Results:

Single-cell RNA sequencing of 243 CD138^neg bone marrow samples from 102 patients generated profiles of 631,226 high-quality cells after quality control and doublet filtering. Longitudinal analyses from baseline to first response after induction and ASCT revealed that CD8⁺ T effector cells were significantly increased (Log₂ Fold Proportion, L₂FP = 1.35, adj.p = 2.4e^-5), while limiting the proportion of CD8⁺ T effector memory cells (L₂FP = -0.94, adj.p = 8.0e^-3), potentially impairing immune surveillance. These shifts appear to be influenced by interferon gamma signaling (adj.p = 1.5e^-3). Stratifying patients by duration of response after ASCT revealed that patients with sustained response had greater naïve B cell proliferation (L₂FP = 1.96, adj.p = 8.6e^-4) which supported robust humoral reconstitution and correlated with improved progression-free survival (HR = 0.48, p = 2.3e^-4). At disease progression, MM cells upregulated cancer-testis antigens (CTAg; p = 4.9e^-5) and immune effector genes (p = 5.7e^-10). This was accompanied by impairment of the IME, including depletion of B cell subclusters (adj.p’s < 0.05), enrichment of myeloid-derived suppressor cell genes in monocytes (adj.p’s < 0.05), and T cell exhaustion (adj.p’s < 0.05)—highlighting a distinct transcriptional program that may promote immune evasion and disease acceleration.

Conclusions:

Our longitudinal analysis of one of the largest cohorts of CD138^neg scRNAseq and CD138^pos bulk sequencing adds to the valuable insights produced by the CoMMpass study. Naïve B repopulation and diverse Ig production post-ASCT are promising biomarkers to enhance post-ASCT risk stratification. CTAg enrichment at disease progression appears to promote multi-faceted IME escape mechanisms. Ongoing studies will build on these findings to provide critical insights for design of targeted therapeutics to enhance response to therapy.