Prognostic or predictive value of circulating cytokines and angiogenic factors for initial treatment of multiple myeloma in the GIMEMA MM0305 randomized controlled trial

Ilaria Saltarella, Fortunato Morabito, Nicola Giuliani, Carolina Terragna, Paola Omedè, Antonio Palumbo, Sara Bringhen, Lorenzo De Paoli, Enrica Martino, Alessandra Larocca, Massimo Offidani, Francesca Patriarca, Chiara Nozzoli, Tommasina Guglielmelli, Giulia Benevolo, Vincenzo Callea, Luca Baldini, Mariella Grasso, Giovanna Leonardi, Manuela Rizzo, Antonietta Pia Falcone, Daniela Gottardi, Vittorio Montefusco, Pellegrino Musto, Maria Teresa Petrucci, Franco Dammacco, Mario Boccadoro, Angelo Vacca, Roberto Ria, Ilaria Saltarella, Fortunato Morabito, Nicola Giuliani, Carolina Terragna, Paola Omedè, Antonio Palumbo, Sara Bringhen, Lorenzo De Paoli, Enrica Martino, Alessandra Larocca, Massimo Offidani, Francesca Patriarca, Chiara Nozzoli, Tommasina Guglielmelli, Giulia Benevolo, Vincenzo Callea, Luca Baldini, Mariella Grasso, Giovanna Leonardi, Manuela Rizzo, Antonietta Pia Falcone, Daniela Gottardi, Vittorio Montefusco, Pellegrino Musto, Maria Teresa Petrucci, Franco Dammacco, Mario Boccadoro, Angelo Vacca, Roberto Ria

Abstract

Background: Several new drugs are approved for treatment of patients with multiple myeloma (MM), but no validated biomarkers are available for the prediction of a clinical outcome. We aimed to establish whether pretreatment blood and bone marrow plasma concentrations of major cytokines and angiogenic factors (CAFs) of patients from a phase 3 trial of a MM treatment could have a prognostic and predictive value in terms of response to therapy and progression-free and overall survival and whether these patients could be stratified for their prognosis.

Methods: Blood and bone marrow plasma levels of Ang-2, FGF-2, HGF, VEGF, PDGF-β, IL-8, TNF-α, TIMP-1, and TIMP-2 were determined at diagnosis in MM patients enrolled in the GIMEMA MM0305 randomized controlled trial by an enzyme-linked immunosorbent assay (ELISA). These levels were correlated both reciprocally and with the type of therapy and patients' characteristics and with a group of non-MM patients as controls.

Results: No significant differences were detected between the blood and bone marrow plasma levels of angiogenic cytokines. A cutoff for each CAF was established. The therapeutic response of patients with blood plasma levels of CAFs lower than the cutoff was better than the response of those with higher levels in terms of percentage of responding patients and quality of response.

Conclusion: FGF-2, HGF, VEGF, and PDGF-β plasma levels at diagnosis have predictive significance for response to treatment. The stratification of patients based on the levels of CAFs at diagnosis and their variations after therapy is useful to characterize different risk groups concerning outcome and response to therapy.

Trial registration: Clinical trial information can be found at the following link: NCT01063179.

Keywords: Angiogenic factors; Multiple myeloma; Overall survival; Progression-free survival; Response rate.

Conflict of interest statement

Ethics approval and consent to participate

The Local IRB approved this study and all patients gave their informed consent before the entry into the clinical trial in agreement with institutional guidelines.

Consent for publication

Not applicable.

Competing interests

Lorenzo De Paoli: honorary from Jansen, Abbvie, Celgene, Gilead, AMGEN, and Roche. Massimo Offidani: honorary and advisory from Janssen. Maria Teresa Petrucci: Honoraria and Advisory Board: Celgene, Janssen-Cilag, BMS, Takeda, Amgen. Roberto Ria: Honoraria and Advisory Board: Celgene, Janssen-Cilag, BMS, Italfarmaco, Amgen. The other authors declare no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Analysis of the CAF levels in blood and bone marrow plasma samples of MM patients. No differences are evident in their concentration between peripheral blood and bone marrow samples. Significantly higher levels of CAFs are detected in blood and bone marrow samples of MM patients as compared with control subjects (p < 0.0001 for all cytokines)
Fig. 2
Fig. 2
Response rate of MM patients based on CAF levels. The blood levels of CAFs significantly correlate with MM response to therapy. Lower levels of ANG-2 (p < 0.05), FGF-2 (p < 0.005), HGF (p < 0.05), IL-8 (p < 0.05), PDGF-BB (p < 0.005), TNF-α (p < 0.05), and VEGF (p < 0.005) are indicative of more profound response, VGPR or better, in all patients, with no evident differences between the two therapy regimens (VMPT-VT vs VMP: p = 0.1)
Fig. 3
Fig. 3
Progression-free and overall survival analysis in MM patients based on the peripheral blood plasma concentrations of FGF-2 and VEGF. The hierarchical clustering analysis of MM patients shows three distinct risk groups of patients based on the concentrations of FGF-2 and VEGF. High risk: patients who present both high FGF-2 and VEGF plasma levels showing a worse prognosis with significantly shorter PFS and OS; intermediate risk: patients who present high plasma levels in only one of the two cytokines; low risk: patients who show low blood levels in both angiogenic cytokines. Again, no evident differences between the two therapy regimens were detected

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