Background: Only a subset of MM patients benefit from treatment with IPI. In an effort to increase response and identify predictive immune biomarkers, we combined IPI with CP. We here report a significant correlation between overall survival (OS) and biomarkers of a pre-existing inflammatory state. Methods: 30 patients were treated with C (AUC = 6) and P (175mg/m²) every 3 weeks x 5 and IPI (3mg/kg) every 3 weeks x 4. Blood was collected throughout. OS Kaplan–Meier curves were compared by the log-rank test. Cutoff thresholds defining high or low levels of chemokines, B cell populations and PD-1⁺CD8⁺ T cell populations were established from the mean value of a given variable from all patients. Neutrophil to Lymphocyte Ratio (NLR) and Systemic Immune Inflammation Index defined as Platelet x Neutrophil to Lymphocyte Ratio (SII) were calculated at baseline and tested for association with OS. SII ≥ 1375 and NLR ≥ 5 were considered as high risk groups. Results: Median OS was 16.2 months, with a 3-year OS of 36.7% for all patients. High levels of CCL3 (HR = 2.79, p = 0.0159), CCL4 (HR = 8.36, p < 0.0001) and CXCL8 (HR = 3.52, p = 0.0037) were associated with worse OS. Advanced B cell differentiation before treatment was associated with worse patient outcomes. High levels of early differentiated Bm2 ( > 57%) were strongly associated with better OS: HR = 0.26 p = 0.004 whereas high eBm5+Bm5 ( > 14%) levels were strongly associated with worse OS: HR = 2.65, p = 0.029. Patients with higher proportions of PD-1⁺CD8⁺ T cells in circulation during treatment had poorer OS (HR = 3.84, p = 0.004) at week 10; (HR = 3.53, p = 0.005) at week 13 and (HR = 2.84, p = 0.040) at week 24. High risk SII (HR = 3.30, p = 0.0192) and NLR (HR = 2.367, p = 0.0486) were associated with worse OS. Conclusions: We have identified a significant correlation between pre-existing systemic inflammatory state and a poor response to IPI and CP. Specifically elevated CCL3, CCL4 and CXCL8, baseline B lymphocyte subset skewing, increased CD8⁺PD-1⁺ T lymphocytes, increased NLR and SII were all strongly associated to worse OS. Comprehensive immune monitoring provides evidence for new circulating biomarkers predicting outcome in MM patients treated with IPI and CP. Clinical trial information: NCT01676649