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Objective/background: There are reports about the presence of paroxysmal nocturnal hemoglobinuria (PNH) clones in multiple myeloma (MM), but these have been demonstrated only in red blood cells (RBCs) and the previous reports utilized an obsolete diagnostic method. We carried out a study to identify the clones by flow cytometry (FC) and to understand their clinical significance., Methods: A prospective study on consecutive patients with newly diagnosed MM who were candidates for autologous stem cell transplantation (ASCT) from 2008 to 2012. We screened peripheral blood samples by FC for CD55- and/or CD59-deficient RBC, neutrophils, and monocytes. PNH testing was carried out at diagnosis, before ASCT and 3 months after ASCT, as well as sporadically during MM remission and at disease relapse., Results: A total of 31 patients were included in the study. PNH clones reaching a median size of 10.8% (range 4.0-18.7%) were found in 10 patients (32.3%). Clones were detected at diagnosis in nine patients and 3 months after ASCT in one patient. A correlation between the presence of the clones and subclinical hemolysis was observed. Nevertheless, the presence of the clones did not influence the overall management and prognosis of the patients., Conclusion: We confirmed findings of previous reports with current diagnostic guidelines and showed that although the size of the clones may be relatively large, their presence is probably not detrimental. The clinical significance of these clones and the possible mechanisms underlying their expansion in MM must be a subject of further investigation., (Copyright © 2015 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Following chemotherapy and/or the administration of growth factors, such as granulocyte-colony stimulated factor (G-CSF), hematopoietic stem cells (HSC) mobilize from bone marrow to peripheral blood. This review aims to systematically present the structure of the HSC "niche" and elucidate the mechanisms of their mobilization. However, this field is constantly evolving and new pathways and molecules have been shown to contribute to the mobilization process. Understanding the importance and the possible primary pathophysiologic role of each pathway is rather difficult, since they share various overlapping components. The primary initiating event for the mobilization of HSC is chemotherapy-induced endogenous G-CSF production or exogenous G-CSF administration. G-CSF induces proliferation and expansion of the myelomonocytic series, which leads to proteolytic enzyme activation. These enzymes result in disruption of various receptor-ligand bonds, which leads to the disanchorage of HSC from the bone marrow stroma. In everyday clinical practice, CXC chemokine receptor-4 (CXCR4) antagonists are now being used as mobilization agents in order to improve HSC collection. Furthermore, based on the proposed mechanisms of HSC mobilization, novel mobilizing agents have been developed and are currently evaluated in preclinical and clinical studies.

International Staging System (ISS), serum free light chain ratio (sFLCR) and lactate dehydrogenase (LDH) are well known, easily assessed independent prognostic indicators of outcome in multiple myeloma (MM). The purpose of the study was to re-examine the prognostic contribution of these variables in a multicenter setting with special attention to MM patients treated with autologous stem cell transplantation (ASCT) or novel agents (NA). Three hundred and five symptomatic newly diagnosed MM patients were retrospectively studied. Twenty-seven per cent, 32% and 41% were in ISS stages 1, 2, and 3, respectively. Fifty-six per cent of them presented kappa light chain monoclonality; median sFLCR was 27.04 (0.37-1.9 × 10(5) ) and 47.97 (0.26-2.3 × 10(7) ) for kappa patients and lambda patients, respectively; patients with sFLCR above median constituted the high sFLCR group. Thirty-one per cent of patients had increased LDH. As first line treatment, 55.7% received conventional treatment and 44.3% NA. After induction, 24% underwent ASCT, whereas 76% received NA at any line, either bortezomib (82.5%), thalidomide (48%) or lenalidomide (27%). When the 305 patients were analyzed together, staging, high sFLCR and abnormal LDH were predictive of survival. The same was true for patients that never received NA, whereas neither high sFLCR nor abnormal LDH constituted adverse factors in patients that received NA frontline. In the last group of patients, no difference was observed between ISS stages 2 and 3. The median 5-year survival of patients that never received NA versus those who did frontline was 29% vs 47%, 7% vs 52% and 24% vs 40% in patients with abnormal LDH, high sFLCR and ISS stage 3, respectively (p = 0.03, p < 0.00001 and p = 0.035). In conclusion, patients gaining the most from NA are those with an aggressive disease as reflected by advanced stage, abnormal LDH and high sFLCR. In addition, the adverse impact of these three variables is obscured by NA., (Copyright © 2012 John Wiley & Sons, Ltd.)

Neoangiogenesis is involved in the pathophysiology of multiple myeloma and angiopoietins possibly contribute to myeloma-induced neovascularization. Bortezomib's antineoplastic potential includes an anti-angiogenic effect. We determined serum levels of angiopoietin-1 and angiopoietin-2 with ELISA pre- and post-bortezomib administration in 35 patients with relapsed/refractory multiple myeloma. Pre-bortezomib, serum angiopoietin-1 levels did not differ in patients and in healthy individuals, while serum angiopoietin-2 levels were elevated. Corresponding serum angiopoietin-1/angiopoietin-2 ratio was reduced in patients compared with controls. After treatment, serum angiopoietin-1 levels increased, while serum angiopoietin-2 levels decreased, therefore the angiopoietin-1/angiopoietin-2 ratio increased and normalized. This increase was significant in patients who responded to treatment. In conclusion, angiopoietin-1/angiopoietin-2 ratio normalization reflected response to bortezomib.

The prognostic value of baseline serum free light chain ratio (sFLCR) was investigated in 94 multiple myeloma (MM) patients. sFLCR was calculated as kappa/lambda or lambda/kappa, depending on the patients' dominating monoclonal light chain. Median baseline sFLCR was 3.57 in kappa-MM patients, 45.09 in lambda-MM. 'High' sFLCR (> or = the observed median value for kappa- and lambda-MM respectively) correlated with elevated serum creatinine and lactate dehydrogenase, extensive marrow infiltration and light chain type MM. The 5-year disease-specific survival was 82% and 30% in patients with sFLCR lower than and equal or greater than the median, respectively (P = 0.0001). sFLCR was an independent prognostic factor.

Unlabelled: Neovascularisation and bone resorption are related to myeloma disease activity., Objectives: To investigate the possible prognostic importance of serum syndecan-1, basic fibroblast growth factor (bFGF) and osteoprotegerin (OPG) levels, the relationship between them, with parameters of disease activity and the effect of treatment on their levels., Patients and Methods: Twenty-seven patients were studied from diagnosis and an additional five from remission, for a median follow-up of 40 months. Twenty-three patients received chemotherapy plus bisphosphonates and nine only bisphosphonates. Sera from 11 healthy individuals (HI) were used as controls. Cytokines were determined by commercially available enzyme-linked immunosorbent assays (ELISA) kits., Results: In HI, median syndecan-1 was 40 ng/mL (28-75), bFGF 8 pg/mL (7-30), OPG 35 pg/mL (4-100). Pretreatment median serum syndecan-1 was 177.5 ng/mL (34-3500), bFGF 11.5 pg/mL (8-65) and OPG 100 pg/mL (4-1000). Pretreatment syndecan-1, bFGF and OPG serum levels were increased in patients compared with HI (P = 0.001, 0.03 and 0.01, respectively). Syndecan-1 and bFGF levels were correlated with stage (P = 0.004 and 0.03, respectively). Both syndecan-1 and OPG levels were correlated with beta2M (P = 0.04 and 0.01, respectively). Patients with elevated syndecan-1 and bFGF serum levels had shorter survival than patients with normal levels (P = 0.01 and 0.05, respectively). After chemotherapy syndecan-1 and OPG levels were found to be decreased in responders and syndecan-1 level was reduced in patients receiving bisphosphonates alone., Conclusions: Pretreatment syndecan-1, bFGF and OPG levels were found to be increased at diagnosis. Syndecan-1 and OPG fluctuated according to MM activity. Elevated serum syndecan-1 and bFGF levels predicted short survival.

Hematopoietic stem cell (HSC) mobilization involves cleavage of ligands between HSC and niche components. However, there are scarce data regarding the role of bone cells in human HSC mobilization. We studied biochemical markers of bone metabolism and angiogenic cytokines during HSC mobilization in 46 patients' sera with lymphoma and multiple myeloma, by ELISA. Significant changes between pre-mobilization and collection samples were found: (1) Bone alkaline phosphatase (BALP) increased, indicating augmentation of bone formation; (2) Receptor activator of Nf-κB ligand/osteoprotegerin ratio (RANKL/OPG) increased, showing osteoclastic differentiation and survival; however, there was no evidence of increased osteoclastic activity; and (3) Angiopoietin-1/Angiopoietin-2 ratio (ANGP-1/ANGP-2) decreased, consistent with vessel destabilization. Poor mobilizers had significantly higher carboxy-terminal telopeptide of collagen type I (CTX) and lower ANGP-1 at pre-mobilization samples, compared to good ones. CTX, amino-terminal telopeptide of collagen type I (NTX) and ANGP-1 pre-mobilization levels correlated significantly with circulating CD34+ peak cell counts. Our results indicate that bone formation and vessel destabilization are the two major events during human HSC mobilization. Osteoblasts seem to be the orchestrating cells, while osteoclasts are stimulated but not fully active. Moreover, ANGP-1, CTX and NTX may serve as predictors of poor mobilization. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: As the interaction between hematopoietic stem cells (HSCs) and endosteal and endothelial niches in HSCs homing is essential, we aimed to study bone turnover and angiogenesis in 29 patients with lymphoma/multiple myeloma undergoing hematopoietic stem cell transplantation (HSCT). Methods: Serum samples were collected before high‐dose chemotherapy (HDT), at the end of HDT, after HSC infusion, at the nadir of myelotoxicity, and at engraftment. Bone metabolism (CTX, TRACP‐5b, bALP, OC, DKK1, RANKL, OPG), and angiogenesis (Ang1, Ang2) markers were measured. These markers were also measured in 21 control patients before and after conventional chemotherapy. Results and Conclusions: Bone resorption declined during HSCT (decrease in TRACP‐5b [P < .001] and CTX [P = .006]). Bone formation declined as well (decrease in bALP and OC [P < .001 for both]). RANKL/OPG ratio, an indicator of osteoclastic activation, did not change significantly (P = .5). Ang1/Ang2 ratio, a vessel equilibrium marker, decreased significantly (P < .001) suggesting endothelial destabilization. The changes observed in the control group were similar except of bALP and RANKL/OPG ratio. Moreover, Ang1/Ang2 ratio on the day after HSC infusion strongly correlated with time to neutrophil and platelet engraftment (P < .001 for both). Conclusively, bone turnover and vessel destabilization represent important events during HSCT probably reflecting the effect of chemotherapy. [ABSTRACT FROM AUTHOR]