Patterns of AKT, mTOR, ERK, and STAT3 pathway activation in MGUS, smoldering multiple myeloma, and multiple myeloma.

Abstract

8589 Background: Constitutive activation of key signaling pathways supports proliferation in multiple myeloma (MM). However, pathway activation in MGUS and smoldering multiple myeloma (SMM) compared to MM has not been characterized. We examined the levels of phosphorylated Akt, mTOR, ERK, and STAT3 expression by immunohistochemistry (IHC) in MGUS, SMM, and MM and assessed their impact on clinical outcomes. Methods: FFPE bone marrow biopsy samples were obtained during routine clinical care. Primary antibodies used were p-Akt (S473), p-mTOR(Ser2448), p-ERK1/2(Thr202/Tyr204), and p-STAT3 (Tyr705). Staining intensity was scored as: 0 (no staining), 1 ( < 50% of cells), 2 ( > 50%) and 3 (dark staining of all cells). Nominal variables were compared with Fisher's exact test and time to progression (TTP) was calculated with Kaplan Meier analysis. Results: Twenty-one MGUS, 20 SMM, and 18 MM patients were reviewed. Strong expression of p-Akt (2-3+ IHC score) was present in 15% of MGUS cases versus 62% of SMM and 61% of MM patients (p = 0.037). Strong p-mTOR expression was observed in SMM and MM patients compared to MGUS patients (100% and 94% versus 45%; p = 0.001). 61% of MM cases exhibited strong p-ERK expression versus 34% in SMM and 15% in MGUS (p = 0.042). There was non-significant trend toward higher p-STAT3 expression in MM versus SMM/MGUS (39% in MM versus 12% and 10% in SMM and MGUS; p = 0.15). Increased p-mTOR activity correlated with high expression of p-Akt(S473) in all patients (p = 0.023). TTP in SMM patients with high versus low p-ERK activity was significantly shorter (76 months vs 16 months; P = 0.046). No other signaling pathways demonstrated statistical differences in TTP or overall survival. Conclusions: Comprehensive IHC analysis across the spectrum from MGUS to SMM and MM demonstrated increased activity of multiple key signaling pathways as disease progression occurs. Expression of p-Akt(S473) and p-mTOR in SMM and MM is significantly higher than MGUS patients, suggesting an upregulation of these pathways is an early event in pathogenesis. Activation of p-ERK and p-STAT3 was more frequent in MM versus MGUS/SMM, suggesting they may be more active in advanced disease.