Monocyte subsets and serum inflammatory and bone-associated markers in monoclonal gammopathy of undetermined significance and multiple myeloma

Background. Monocyte/macrophages have been shown to be altered in monoclonal gam-mopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), with an impact on the disruption of the homeostasis of the normal bone marrow (BM) mi-croenvironment. Methods: We investigated the distribution of different subsets of monocytes (Mo) in blood and BM of newly‐diagnosed untreated MGUS (n = 23), SMM (n = 14) and MM (n = 99) patients vs. healthy donors (HD; n = 107), in parallel to a large panel of cytokines and bone‐associ-ated serum biomarkers. Results: Our results showed normal production of monocyte precursors and classical Mo (cMo) in MGUS, while decreased in SMM and MM (p ≤ 0.02), in association with lower blood counts of recently‐produced CD62L⁺ cMo in SMM (p = 0.004) and of all subsets of (CD62L⁺, CD62L⁻ and FcεRI⁺) cMo in MM (p ≤ 0.02). In contrast, intermediate and end‐stage non-classical Mo were increased in BM of MGUS (p ≤ 0.03), SMM (p ≤ 0.03) and MM (p ≤ 0.002), while normal (MGUS and SMM) or decreased (MM; p = 0.01) in blood. In parallel, increased serum levels of interleukin (IL)1β were observed in MGUS (p = 0.007) and SMM (p = 0.01), higher concentrations of serum IL8 were found in SMM (p = 0.01) and MM (p = 0.002), and higher serum IL6 (p = 0.002), RANKL (p = 0.01) and bone alkaline phosphatase (BALP) levels (p = 0.01) with decreased counts of FcεRI⁺ cMo, were restricted to MM presenting with osteolytic lesions. This translated into three dis-tinct immune/bone profiles: (1) normal (typical of HD and most MGUS cases); (2) senescent‐like (increased IL1β and/or IL8, found in a minority of MGUS, most SMM and few MM cases with no bone lesions); and (3) pro‐inflammatory‐high serum IL6, RANKL and BALP with significantly (p = 0.01) decreased blood counts of immunomodulatory FcεRI⁺ cMo‐, typical of MM presenting with bone lesions. Conclusions: These results provide new insight into the pathogenesis of plasma cell neoplasms and the potential role of FcεRI⁺ cMo in normal bone homeostasis.