Peripheral blood immune profiling in newly diagnosed multiple myeloma: Associations with MRD status and high-risk cytogenetics Free

Background:

Both cytogenetic risk and measurable residual disease (MRD) status are the most important clinically available prognostic markers in multiple myeloma (MM), yet immune correlates of these features remain incompletely defined. Peripheral blood (PB) immune profiling may offer insights into immune activation, exhaustion, and help predict treatment response in MM.

Objective:

To characterize differences in the PB immune profile by cytogenetic risk and MRD status, and to evaluate longitudinal changes following induction therapy.

Methods:

Univariate analysis was employed to compare the immune markers of high-risk versus non-high-risk FISH and those of MRD-positive versus MRD-negative. Reporting included the group sample size, median, interquartile range, and p-value of independent two-sample comparison of medians using the Wilcoxon rank-sum test (Wilcoxon Mann-Whitney U-test, or WMW test), normal approximation, two-sided probability. The false discovery rate (FDR) was controlled using the Benjamini-Hochberg procedure.

Results:

PB samples from newly diagnosed MM patients (N=57) were analyzed by flow cytometry at diagnosis, out of which 18 were also analyzed post-induction. The median age was 64.6 years, ranging from 58 years to 74 years. 25 patients were female and 32 patients were male. 33 patients were African American, and 24 patients were non-Hispanic White. Immune markers were compared between high-risk FISH (n=21) and non-high-risk FISH (n=36) groups, as well as between patients who were later MRD positive (n=17) or MRD negative (n=36). Longitudinal changes were assessed in subsets with paired samples: high-risk FISH (n=12), non-high-risk FISH (n=6), MRD positive (n=4), and MRD negative (n=15). At diagnosis, high-risk FISH patients had significantly higher ratios of CD4 effector memory to exhausted CD4 T cells, CD8 effector memory to CD8 central memory T cells, and absolute counts of CD8 T cells co-expressing TIM3 and PD1. They also had lower frequencies of non-class-switched memory B cells. Similarly, patients who did not achieve MRD negativity during their frontline treatment had higher frequencies of exhausted CD4 T cells (TIGIT+PD1+) and lower CD8 naïve T cells at baseline before treatment. However, none of these baseline differences remained significant after FDR correction.

Following induction therapy, immune shifts were observed, most prominently in B cell populations. In MRD-negative patients, there was a significant increase in the ratio of CD8 effector memory to exhausted CD8 T cells, and B cell subset changes remained significant after FDR adjustment. High-risk FISH patients also showed B-cell changes, but interpretation was limited by small sample sizes. In contrast, MRD-positive patients showed no significant immune changes over time.

Conclusion:

Baseline immune profiling suggests that patients with high-risk cytogenetics or eventual MRD positivity may have a more activated and exhausted PB immune landscape. Induction therapy appears to remodel the immune system more effectively in MRD-negative and high-risk FISH patients, particularly through shifts in B-cell and CD8+ memory subsets. These findings support further exploration of PB immune profiling as a prognostic tool and surrogate for early treatment response in MM.