Characteristically, MM cells harbour to the BM compartment whereas extensive extramedullary growth is mainly observed in the terminal phase of the desease. The principal goal of this work was to study the interaction between MM cells and bone cells, i.e. osteoblasts and osteoclasts. Earlier our group showed that most MM cells produce HGF (198). Both osteoblasts and osteoclasts express the HFG receptor c-met (182), and effects of HGF on activity, survival, adhesion, migration, or the production of other factors from these cell types may be of importance. The second aim of this study was to identify other MM cell-derived factors with effects on bone cells or the ECM in bone. Finally, MM cells do not only influence the BM but the MM cells themselves are highly affected by this environment, for instance by stromal IL-6 production. Therefore, we were interested in local factors produced by the osteoblasts or osteoclasts that could affect MM cells, either in a stimulatory manner in analogy to paracrine IL-6 production, or in an inhibitory manner.
Until recently, only retrospective studies had been published on salvage high-dose melphalan (HDM) with autologous stem cell 'transplantation' (ASCT). In a prospective, nonrandomized phase-2 study, we treated 53 bortezomib-naïve patients with bortezomib–dexamethasone as induction and bortezomib included in the conditioning regimen along with the HDM. Median progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS) after start of reinduction therapy were 21.6, 22.8 and 46.6 months, respectively. For 49 patients who completed salvage bortezomib–HDM(II) with ASCT, there was no significant difference of PFS and TNT after HDM (II) compared with after the initial HDM(I), and thus patients were their own controls (PFS (I: 20.1 vs II: 19.3 months (P=0.8)) or TNT (I: 24.4 vs II: 20.7 months (P=0.8)). No significant differences in the response rates after salvage ASCT compared with the initial ASCT. Bortezomib–HDM conditioning combo was feasible, and toxicity was as expected for patients treated with bortezomib and ASCT. In conclusion, in bortezomib-naïve patients treated at first relapse with salvage ASCT including bortezomib, PSF and TNT did not differ significantly from initial ASCT and median OS was almost 5.5 years with acceptable toxicity. A recent prospective randomized study confirms salvage ASCT to be an effective treatment.
Abstract Objectives In contrast to secondary primary malignancies (SPM) following multiple myeloma (MM), less is known about previous malignancies. We therefore conducted a population‐based study to assess the patterns of previous malignancies in MM patients as well as the risk for SPM. Methods Using data from the Cancer Registry of Norway, we included 9574 MM patients and 37 810 matched control subjects. The association between previous malignancies and a subsequent diagnosis of MM was analysed by a logistic regression model and the risk for SPM by a Cox model. Results A previous diagnosis of myeloproliferative neoplasia (MPN) (OR 3.57; 95% CI:1.45‐8.80) and Hodgkin lymphoma (HL) (OR 3.66; 95% CI: 1.40‐9.55) was associated with the subsequent development of MM. For MPN, the association with MM was explained by an excess of primary myelofibrosis (PMF) in the MM group. The overall incidence of a previous malignancy was not different between MM patients and the control subjects (OR 0.93; 95% CI: 0.87‐1.00). MM patients had an increased risk for secondary acute myelogenous leukaemia/myelodysplastic syndromes (HR 6.1, 95% CI: 3.9‐9.5). Conclusions A previous diagnosis of HL and PMF was associated with a subsequent diagnosis of MM, whereas the overall incidence of previous cancers was not increased for MM patients.
Osteopontin (OPN) is a non-collagenous matrix protein produced by various cells including osteoblasts, osteoclasts and several types of tumor cells. It is involved in a number of physiologic and pathologic events including adhesion, angiogenesis, apoptosis, inflammation, wound healing and tumor metastasis. We wanted to investigate the potential role of OPN in multiple myeloma.Myeloma cells and stromal cells from myeloma patients were investigated as potential OPN-producers. Furthermore, OPN was tested in proliferation, migration and adhesion assays with myeloma cells. Serum and plasma OPN in myeloma patients were measured by enzyme-linked immunosorbent assay (ELISA). OPN levels were correlated to disease variables at diagnosis and to disease outcome.Myeloma cells produce OPN, and stromal cells from myeloma patients express higher levels of OPN than stromal cells from healthy controls. The myeloma cell lines ANBL-6 and INA-6 adhered to OPN. NOD/SCID mice inoculated with OPN-producing ANBL-6 cells had elevated levels of murine OPN in serum, whereas human OPN was not detectable. Plasma and serum levels of OPN were significantly higher in myeloma patients than in healthy individuals. Interpretation and Conclusions. Myeloma cell lines adhere to OPN, indicating that elevated stromal expression of OPN may be one of the factors responsible for the retention of myeloma cells in the bone marrow. The elevated plasma OPN levels in myeloma patients could be due to both production of OPN by the tumor cells and tumor-induced production of OPN by non-tumor cells.
Binding of urokinase (uPA) to its receptor (uPAR; CD87) focuses proteolytic activity on the cell surface and this system is of importance in malignant matrix degradation and tumour invasion. By immunocytochemistry and flow cytometry, we found that primary myeloma cells and myeloma cell lines expressed uPA and uPAR. Soluble uPA was present in cell line supernatants and lysates in low concentrations. In cell lines, uPA and uPAR were located both on the cell surface and intracellularly, but the expression of both proteins was low. Higher levels of uPAR was detected on the cell surface of primary myeloma cells. When primary myeloma cells were gated by CD45 expression, stronger expression was found on immature CD45 + cells than on mature CD45 −/dim cells. Finally, both myeloma cell lines and primary cells were able to cleave a uPA‐specific substrate showing that the uPA system is functionally active. We conclude that myeloma cells are able to produce uPA and uPAR. This opens up a possible role of the uPA system in myeloma cell invasion and in the proteolytic digestion of bone matrix.
