Cytomegalovirus immunoglobulin serology prevalence in patients with newly diagnosed multiple myeloma treated within the GMMG-MM5 phase III trial.

OBJECTIVES: The seroprevalence of antibodies against Cytomegalovirus (CMV) is an established poor prognostic factor for patients receiving an allogeneic stem cell transplantation. However, the impact of CMV serology on outcome after autologous stem cell transplantation remains unknown. METHODS: Here, we analyzed the CMV immunoglobulin (Ig) serology of 446 newly-diagnosed multiple myeloma (MM) patients of the GMMG-MM5 phase III trial with a median follow-up of 58 months. RESULTS: CMV IgG and IgM positivity was seen in 51% and 6% of the patients, respectively. In multivariate analysis CMV IgG and CMV IgM serology show an age-depending effect for PFS. We identified positive CMV IgG/positive CMV IgM serology as an age-depending beneficial factor on PFS. DISCUSSION: Younger patients with a positive CMV IgG/positive CMV IgM serology experienced a favorable effect on PFS, whereas a positive CMV IgG/positive CMV IgM serology at older age has a disadvantageous effect on PFS.

Serum cytokines predict efficacy and toxicity, but are not useful for disease monitoring in lung cancer treated with PD-(L)1 inhibitors.

Introduction: PD-(L)1 inhibitors (IO) have improved the prognosis of non-small-cell lung cancer (NSCLC), but more reliable predictors of efficacy and immune-related adverse events (irAE) are urgently needed. Cytokines are important effector molecules of the immune system, whose potential clinical utility as biomarkers remains unclear. Methods: Serum samples from patients with advanced NSCLC receiving IO either alone in the first (1L, n=46) and subsequent lines (n=50), or combined with chemotherapy (ICT, n=108) were analyzed along with age-matched healthy controls (n=15) at baseline, after 1 and 4 therapy cycles, and at disease progression (PD). Patients were stratified in rapid progressors (RP, progression-free survival [PFS] <120 days), and long-term responders (LR, PFS >200 days). Cytometric bead arrays were used for high-throughput quantification of 20 cytokines and other promising serum markers based on extensive search of the current literature. Results: Untreated NSCLC patients had increased levels of various cytokines and chemokines, like IL-6, IL-8, IL-10, CCL5, G-CSF, ICAM-1, TNF-RI and VEGF (fold change [FC]=1.4-261, p=0.026-9x10-7) compared to age-matched controls, many of which fell under ICT (FC=0.2-0.6, p=0.014-0.002), but not under IO monotherapy. Lower baseline levels of TNF-RI were associated with longer PFS (hazard ratio [HR]= 0.42-0.54; p=0.014-0.009) and overall survival (HR=0.28-0.34, p=0.004-0.001) after both ICT and IO monotherapy. Development of irAE was associated with higher baseline levels of several cytokines, in particular of IL-1ß and angiogenin (FC=7-9, p=0.009-0.0002). In contrast, changes under treatment were very subtle, there were no serum correlates of radiologic PD, and no association between dynamic changes in cytokine concentrations and clinical outcome. No relationship was noted between the patients' serologic CMV status and serum cytokine levels. Conclusions: Untreated NSCLC is characterized by increased blood levels of several pro-inflammatory and angiogenic effectors, which decrease under ICT. Baseline serum cytokine levels could be exploited for improved prediction of subsequent IO benefit (in particular TNF-RI) and development of irAE (e.g. IL-1ß or angiogenin), but they are not suitable for longitudinal disease monitoring. The potential utility of IL-1/IL-1ß inhibitors in the management and/or prevention of irAE in NSCLC warrants investigation.