Extended Data Fig. 4: Summary of Cytogenetic Risk Associated Immune Alterations in Multiple Myeloma.
(a) Survival based on CD8 Teff HLA+ cell abundance as a fraction of CD8+ T cells (p = 0.036, log-rank test). Cell abundances were batch-corrected using regression residuals. Cut-off was determined by maximally selected rank statistics at the 82% quantile (191 low, 39 high). (b) Progression-free survival analysis from regression of the above described CD8 Teff HLA+ metrics (p = 0.062, log-rank test) with cutoff set at the 89% quantile (205 low, 25 high). (c-d) Scaled expression of ‘dysfunctional’ T cell signature genes, including exhaustion and senescence markers (Supplementary Table 4). Dot plot (c) showing percent of cells expressing each gene with dot size and average expression with color (red = high, blue = low) and tile plot (d) showing average expression across cluster. Rows are clusters, and columns are genes, grouped by signature category. (e-f) Trajectory plots depict the predicted differentiation of CD8+ T cell subtypes from CD8+ naïve T cells. Arrows indicate directionality and dots represent trajectory clusters colored by batch-adjusted log-odds abundance and sized by cell count. Comparisons shown for patients with both t(4;14)[NSD2] and 1q21 gain (e) and TP53 complete loss (f) compared to those without them (orange = high, blue = low). (g) Per patient heatmap of overall IFN-I response signature scores. Red corresponds to high signature score, blue corresponds to a lower signature score. Signature scores are normalized within each cell lineage. Patients with no cells of a specific type will have a grey bar for their IFN-I signature score. Patient tumor cytogenetics are displayed in a title map to the left of the signature score plot. (h) Dot plots of differential cellular abundance analysis for patients with 1q21 gain in combination with other high-risk abnormalities. Each row corresponds to a comparison between 1q21 and other cytogenetic events. “HR_No1q” = high risk without 1q21 gain; “HR+1q21” = high risk with 1q21 gain. Colors indicate log-odds ratios, and shapes indicate two-sided p-values comparing cluster proportions from a linear model (circle = ns, diamond = p < 0.05, square = p < 0.01). (i) Dot plot of differential cellular abundance analysis for patients with partial or complete loss of TP53 via mutation or copy number loss. Partial loss is defined as either monoallelic loss of 17p13 or one non-synonymous mutation of TP53. Complete loss is defined as biallelic loss of 17p13 or monoallelic loss of 17p13 with mutation. (j) Dot plot summarizing differential cellular abundance analysis for patients with Chromothripsis or APOBEC events. (k-m) Box plots illustrating the relationship between bone marrow plasma percentages (>=20%, npatient = 74; <20%, npatient = 189), as estimated via flow cytometry before CD138 isolation (x-axis), and the abundance of CD8+ T effector memory cells (npatient=263) (k), BM-resident NK cells (l), and fibroblasts (m). Two-sided p-values for each comparison were computed using a linear model. In the box plots, bounds of the box represent the 25th and 75th percentile, with the center displaying the median. Whiskers extend to 1.5*IQR beyond the bounds of the box.
