Simple SummaryWe investigated the distribution of different subsets of monocytes (Mo) in blood and bone marrow (BM) of newly-diagnosed untreated monoclonal gammopathy of undetermined significance ... Show moreSimple SummaryWe investigated the distribution of different subsets of monocytes (Mo) in blood and bone marrow (BM) of newly-diagnosed untreated monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM) and active multiple myeloma (MM), and its relationship with immune/bone serum-marker profiles. Our results showed decreased production of BM Mo with decreased counts of classical Mo (cMo) in BM and blood of SMM and MM, but not MGUS. Conversely, intermediate and non-classical Mo were significantly increased in MGUS, SMM and MM BM. In parallel, increased levels of interleukin (IL)1 beta were observed in a fraction of MGUS and SMM, while increased serum IL8 was characteristic of SMM and MM, and higher serum IL6, RANKL and bone alkaline phosphatase concentrations, together with decreased counts of Fc epsilon RI(+)cMo, were restricted to MM presenting with bone lesions. These results provide new insights in the pathogenesis of plasma cell neoplasms and the potential role of Fc epsilon RI(+)cMo in normal bone homeostasis.Background. Monocyte/macrophages have been shown to be altered in monoclonal gammopathy 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) microenvironment. 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-associated 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 Fc epsilon RI+) 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)1 beta 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 Fc epsilon RI+ cMo, were restricted to MM presenting with osteolytic lesions. This translated into three distinct immune/bone profiles: (1) normal (typical of HD and most MGUS cases); (2) senescent-like (increased IL1 beta 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 Fc epsilon RI+ 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 Fc epsilon RI+ cMo in normal bone homeostasis. Show less
Monoclonal proteinaemia (M-proteinemia) is associated with multiple myeloma (MM) or other hematological malignancies. In the absence of these diseases the term MGUS (Monoclonal Gammopathy of... Show moreMonoclonal proteinaemia (M-proteinemia) is associated with multiple myeloma (MM) or other hematological malignancies. In the absence of these diseases the term MGUS (Monoclonal Gammopathy of Undetermined Significance) is used. During 1991-1993 1464 patients with newly diagnosed M-proteinemia in the mid-western of The Netherlands (1.6 million inhabitants) were registered in a database and followed annually. Information on characte_ristics, laboratory and bone marrow test results, skeletal-X-rays as well as M-protein related diagnosis were obtained. At diagnosis potential discriminatory serum markers like interleukin-6 and syndecan-1 proved to be of no informative value. The reported correlation between solid tumors and M-proteinemia was rather based on a diagnostic selection bias than on a causal role. Long-term follow-up (median 9.0 years for those alive) showed that survival of MGUS patients is reduced compared to an age-matched cohort of the Dutch population. Age, gender and serum albumen were important factors for survival; the annual 0.4% risk for malignant transformation was influenced by M-protein level and IgA-isotype. In MM early response to melphalan-prednisone chemotherapy as measured by the rate of serum M-protein decrement was of prognostic value. Interferon maintenance therapy in MM-patients prolonged progression free survival, but not overall survival without affecting quality of life. Show less
