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Osteolytic bone disease is a frequent complication of multiple myeloma, resulting in skeletal complications that are a significant cause of morbidity and mortality. It is the result of an increased activity of osteoclasts, which is not followed by reactive bone formation by osteoblasts. Recent studies have revealed novel molecules and pathways that are implicated in osteoclast activation and osteoblast inhibition. Among them, the most important include the receptor activator of nuclear factor-kappa B ligand/osteoprotegerin pathway, the macrophage inflammatory proteins and the activin-A that play a crucial role in osteoclast stimulation in myeloma, while the wingless-type (Wnt) signalling inhibitors (sclerostin and dickkopf-1) along with the growth factor independence-1 are considered the most important factors for the osteoblast dysfunction of myeloma patients. Finally, the role of osteocytes, which is the key cell for normal bone remodelling, has also revealed during the last years through their interaction with myeloma cells that leads to their apoptosis and the release of RANKL and sclerostin maintaining bone loss in these patients. This review focuses on the latest available data for the mechanisms of bone destruction in multiple myeloma. [ABSTRACT FROM AUTHOR]

The molecular pathways implicated in multiple myeloma (MM) development are rather unknown. We studied epigenetic and DNA damage response (DDR) signals at selected model loci (N-ras, p53, d-globin) in bone marrow plasma cells and peripheral blood mononuclear cells (PBMCs) from patients with monoclonal gammopathy of undetermined significance (MGUS; n=20), smoldering/asymptomatic MM (SMM; n=29) and MM (n=18), as well as in healthy control-derived PBMCs (n=20). In both tissues analyzed, a progressive, significant increase in the looseness of local chromatin structure, gene expression levels and DNA repair efficiency from MGUS to SMM and finally to MM was observed (all P<0.002). Following ex vivo treatment with melphalan, a gradual suppression of the apoptotic pathway occurred in samples collected at different stages of myelomagenesis, with the severity and duration of the inhibition of RNA synthesis, p53 phosphorylation at serine15 and induction of apoptosis being higher in MGUS than SMM and lowest in MM patients (all P<0.0103). Interestingly, for all endpoints analyzed, a strong correlation between plasma cells and corresponding PBMCs was observed (all P<0.0003). We conclude that progressive changes in chromatin structure, transcriptional activity and DDR pathways during myelomagenesis occur in malignant plasma cells and that these changes are also reflected in PBMCs. [ABSTRACT FROM AUTHOR]

The molecular pathways implicated in multiple myeloma (MM) development are rather unknown. We studied epigenetic and DNA damage response (DDR) signals at selected model loci (N-ras, p53, d-globin) in bone marrow plasma cells and peripheral blood mononuclear cells (PBMCs) from patients with monoclonal gammopathy of undetermined significance (MGUS; n=20), smoldering/asymptomatic MM (SMM; n=29) and MM (n=18), as well as in healthy control-derived PBMCs (n=20). In both tissues analyzed, a progressive, significant increase in the looseness of local chromatin structure, gene expression levels and DNA repair efficiency from MGUS to SMM and finally to MM was observed (all P<0.002). Following ex vivo treatment with melphalan, a gradual suppression of the apoptotic pathway occurred in samples collected at different stages of myelomagenesis, with the severity and duration of the inhibition of RNA synthesis, p53 phosphorylation at serine15 and induction of apoptosis being higher in MGUS than SMM and lowest in MM patients (all P<0.0103). Interestingly, for all endpoints analyzed, a strong correlation between plasma cells and corresponding PBMCs was observed (all P<0.0003). We conclude that progressive changes in chromatin structure, transcriptional activity and DDR pathways during myelomagenesis occur in malignant plasma cells and that these changes are also reflected in PBMCs. [ABSTRACT FROM AUTHOR]

We prospectively evaluated the effect of bortezomib, thalidomide and dexamethasone (VTD) consolidation on bone metabolism of 42 myeloma patients who underwent an autologous stem cell transplantation (ASCT). VTD started on day 100 post ASCT; patients received four cycles of VTD (first block), were followed without treatment for 100 days and then received another four VTD cycles (second block). During this 12-month period, bisphosphonates were not administered. Best response included stringent complete remission (sCR) in 15 (35.7%) patients, complete response (CR) in 13 (30.9%), vgPR in 7 (16.6%), PR in 4 (9.5%), while 3 (7.1%) patients developed a progressive disease (PD). Importantly, 33.3% and 47.6% of patients improved their status of response after the first and second VTD block, respectively. VTD consolidation resulted in a significant reduction of circulating C-terminal cross-linking telopeptide of collagen type I (CTX), soluble receptor activator of the nuclear factor-kappa B ligand (sRANKL) and osteocalcin (OC), whereas bone-specific alkaline phosphatase (bALP) remained stable compared with pre-VTD values. During the study period, only one patient with a PD developed a skeletal-related event (that is, radiation to bone). The median time to progression (TTP) after ASCT was 34 months and the median time of next treatment was 40 months. We conclude that VTD consolidation post ASCT reduces bone resorption and is associated with a very low incidence of skeletal-related events (SREs) despite the absence of bisphosphonates; the later do not appear to be necessary in this context. [ABSTRACT FROM AUTHOR]

Asymptomatic multiple myeloma (AMM) is characterized by a constant risk of progression to symptomatic myeloma. To evaluate previously recognized risk factors and to identify high-risk features we analyzed 96 patients with AMM and at least 18 months of follow-up. The progression rate at 1,2, and 3 years was 8%, 15% and 26%, respectively, and the projected 5-year progression rate was 38%. Extensive bone marrow (BM) infiltration, abnormal free light chain (FLC) ratio and serum monoclonal (M)-protein3 gr/dl were the most significant factors for progression, whereas the type of heavy (IgG vs IgA) or light chain or immunoparesis of the uninvolved immunoglobulins were not. Abnormal marrow signal of magnetic resonance imaging of the spine was associated with a significant risk of progression (median 15 months, P=0.001). Extensive BM infiltration 60% (hazard ratio, HR: 13.7, P<0.001) and FLC ratio100 (HR: 9, P=0.003) independently identified a 'very high-risk' group, which included 12.5% of patients with AMM and who progressed 18 months from initial diagnosis. Development of anemia and/or lytic bone lesions were the most common features of symptomatic progression. In conclusion, there is a subgroup of patients who have a substantial risk of progression to symptomatic disease that can be detected at diagnosis (either by extensive BM infiltration60% or FLC ratio100) and may be considered for immediate treatment. [ABSTRACT FROM AUTHOR]

Background Activin-A is a transforming growth factor -β superfamily member, which seems to be implicated in the biology of osteolytic disease in multiple myeloma. Design and methods Circulating activin-A was evaluated in 98 newly diagnosed myeloma patients (85 with symptomatic disease), in 40 patients with relapsed myeloma before and after four cycles of lenalidomide and dexamethasone (RD), in 27 healthy controls and in 10 monoclonal gammopathy of undetermined significance patients. Results Patients with newly diagnosed symptomatic myeloma had increased circulating activin-A compared with controls (P < 0.001), while patients with relapsed disease had elevated activin-A even compared with symptomatic patients at diagnosis (P < 0.001). High activin-A correlated with advanced International Staging System stage (P = 0.002), increased bone resorption (P < 0.001) and extensive bone disease (P = 0.03). Low levels of activin-A (<442 pg/ml) were associated with superior median overall survival: not reached versus 59 months (P = 0.04), while activin-A inversely correlated with survival as a continuous variable (P < 0.001). RD did not alter circulating activin-A after four cycles of treatment, even in responders. Conclusions High circulating activin-A correlates with advanced features of myeloma, supporting the rationale for the use of activin-A antagonists, such as sotatercept in myeloma. The inability of RD to reduce activin-A reveals RD as a good candidate for combination therapies with activin-A antagonists in myeloma. [ABSTRACT FROM AUTHOR]

Lytic bone disease is a frequent complication of multiple myeloma (MM). Lytic lesions rarely heal and X-rays are of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone resorption (amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX and CTX, respectively) or CTX generated by matrix metalloproteinases (ICTP)) and bone formation provide information on bone dynamics and reflect disease activity in bone. These markers have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity and response to anti-resorptive treatment in MM. Urinary NTX, serum CTX and serum ICTP are elevated in myeloma patients with osteolytic lesions and correlate with advanced disease stage. Furthermore, urinary NTX and serum ICTP correlate with risk for skeletal complications, disease progression and overall survival. Bone markers have also been used for the early diagnosis of bone lesions. This International Myeloma Working Group report summarizes the existing data for the role of bone markers in assessing the extent of MM bone disease and in monitoring bone turnover during anti-myeloma therapies and provides information on novel markers that may be of particular interest in the near future. [ABSTRACT FROM AUTHOR]

Skeletal-related events (SREs) are common in patients with osteolytic lesions from multiple myeloma (MM), and result in substantial morbidity. We report herein a comprehensive, retrospective, multivariate analysis of prognostic factors for survival and first on-study SRE in MM patients using data from the phase III, randomized study comparing zoledronic acid with pamidronate in MM or breast cancer. Cox regression analyses were used to assess 22 variables for prognostic significance (defined as associations with P<0.05) in patients with bone metabolism marker assessments and complete baseline variable data. Of 510 evaluable MM patients, 282 had complete covariate information and were included in models. Reduced Cox multivariate models identified five significant prognostic factors for first SRE (weight, race, high N-terminal cross-linked telopeptide of type I collagen (NTX), high pain score, and need for narcotic analgesics) and seven for survival (age, SRE history, myeloma subtype, anemia, high lactate dehydrogenase, high NTX, and low albumin levels). High NTX was the only variable associated with elevated risks of both first SRE and death (P0.02 for each). These analyses identified prognostic factors for SREs and survival in patients with MM. Taken together with current staging systems, these factors could further facilitate decision making for optimal treatment of myeloma bone disease, although further prospective assessments are needed. [ABSTRACT FROM AUTHOR]

Several imaging technologies are used for the diagnosis and management of patients with multiple myeloma (MM). Conventional radiography, computed tomography (CT), magnetic resonance imaging (MRI) and nuclear medicine imaging are all used in an attempt to better clarify the extent of bone disease and soft tissue disease in MM. This review summarizes all available data in the literature and provides recommendations for the use of each of the technologies. Conventional radiography still remains the ‘gold standard’ of the staging procedure of newly diagnosed and relapsed myeloma patients. MRI gives information complementary to skeletal survey and is recommended in MM patients with normal conventional radiography and in all patients with an apparently solitary plasmacytoma of bone. Urgent MRI or CT (if MRI is not available) is the diagnostic procedure of choice to assess suspected cord compression. Bone scintigraphy has no place in the routine staging of myeloma, whereas sequential dual-energy X-ray absorptiometry scans are not recommended. Positron emission tomography/CT or MIBI imaging are also not recommended for routine use in the management of myeloma patients, although both techniques may be useful in selected cases that warrant clarification of previous imaging findings, but such an approach should ideally be made within the context of a clinical trial. [ABSTRACT FROM AUTHOR]

This phase 2 study aimed to determine the efficacy and safety of the combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide (VMDT) and its effect on bone remodeling and angiogenesis in relapsed/refractory myeloma. Bortezomib (1.0 mg/m2) was given on days 1, 4, 8, 11, oral melphalan (0.15 mg/kg) on days 1–4, whereas thalidomide (100 mg per day) and dexamethasone (12 mg/m2) were administered on days 1–4 and 17–20 of a 28-day cycle, for four cycles. Patients without disease progression continued for up to eight cycles. VMDT effect on bone remodeling was evaluated by measuring osteoclast regulators (soluble receptor activator of nuclear factor-κ B ligand/osteoprotegerin ratio, osteopontin, macrophage inflammatory protein-1α), dickkopf-1 protein, bone resorption and formation markers, whereas its effect on angiogenesis was assessed by measuring serum vascular endothelial growth factor, angiogenin, angiopoietin-2 and basic fibroblast growth factor, after four cycles and at the study end. A total of 62 patients were enrolled. The overall response rate was 66%: CR 13%, vgPR 27% and PR 26%. Median time to response was 35 days and median time to progression was 9.3 months. Common adverse events included cytopenias, peripheral neuropathy and infections. No patient experienced deep-vein thrombosis. VMDT reduced angiogenic cytokines, osteoclast regulators, dickkopf-1 and bone resorption. We conclude that VMDT with intermittent thalidomide is an active and well-tolerated regimen for relapsed/refractory myeloma, affecting abnormal bone remodeling and angiogenesis.Leukemia (2008) 22, 2247–2256; doi:10.1038/leu.2008.235; published online 4 September 2008 [ABSTRACT FROM AUTHOR]

Immunomodulatory drugs (IMiDs) and bortezomib have been recently used in the management of patients with both newly diagnosed and relapsed/refractory multiple myeloma. Except of their direct anti-myeloma effect, these agents also alter the interactions between myeloma cells and marrow microenvironment. Several recent studies have investigated their potential effect on myeloma bone disease. Preclinical studies have demonstrated that IMiDs reduce osteoclast formation and function in vitro. Clinical studies have confirmed that thalidomide reduces markers of bone resorption, while lenalidomide induces osteoclast arrest in myeloma patients. However, IMiDs seem to have no effect on osteoblast exhaustion present in myeloma. The proteasome inhibitor bortezomib restores abnormal bone remodeling through the inhibition of osteoclast function and the increase in osteoblast differentiation and activity in vitro. In myeloma patients, bortezomib reduces biochemical markers of bone resorption and normalizes the RANKL/osteoprotegerin ratio, while at the same time increases bone formation markers reducing levels of dickkopf-1 protein. Whether these effects are direct and not only a consequence of the agents' antimyeloma activity is not totally clear. This review summarizes all available data for these attractive agents that combine potent anti-myeloma activity with beneficial effects on bone and may alter the way of management of myeloma-related bone disease.Leukemia (2007) 21, 1875–1884; doi:10.1038/sj.leu.2404843; published online 5 July 2007 [ABSTRACT FROM AUTHOR]

Progressive renal failure is one of the main complications in HbS/β-thalassemia (HbS/β-thal). Early identification of patients at high risk of developing renal failure is of great importance as it may allow specific measures to delay the progression of renal damage and thus reduce the incidence of end-stage renal failure and mortality. Early predictors of renal impairment in HbS/β-thal remain to explore. Within this context, we studied 87 compound HbS/β-thal patients (36 males/51 females; median age 39 years) and 30 healthy controls. In addition to conventional renal biochemistries we measured serum cystatin-C (Cys-C), urine N-acetyl-β-D-glucosaminidase (NAG) excretion and serum and urinary β2-microglobulin (β2-M). Cystatin-C, NAG and serum β2-M levels were higher in patients than controls. The incidence of patients with high levels of Cys-C, NAG, and β2-M was 32.1, 74.7, and 70.1% respectively, while only 6.8% of patients had increased serum creatinine levels. Cystatin-C and serum β2-M showed a strong correlation with creatinine clearance and age, while NAG positively correlated with proteinuria. An inverse correlation was also shown between hemoglobin and β2-M, NAG, and Cys-C levels. Seven patients with proteinuria received therapy with angiotensin-converting enzyme (ACE) inhibitors. Changes of poteinuria positively correlated with NAG levels. These results indicate that Cys-C is an accurate marker of renal dysfunction, and urinary NAG excretion can be considered as a reliable index of the tubular toxicity, and possible predictor of proteinuria and eventual renal impairment in HbS/β-thal patients. Furthermore, NAG measurement may be used for monitoring ACE-inhibitors therapy in HbS/β-thal patients with proteinuria.Kidney International (2006) 69, 2037–2042. doi:10.1038/sj.ki.5000248; published online 22 February 2006 [ABSTRACT FROM AUTHOR]

The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. β2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.Leukemia (2005) 19, 1969–1976. doi:10.1038/sj.leu.2403890; published online 4 August 2005 [ABSTRACT FROM AUTHOR]

The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) system has a major role in the pathogenesis of bone disease in myeloma (MM). The effect of autologous stem cell transplantation (ASCT) on bone turnover in MM was evaluated in 51 patients (35M/16F). Markers of bone resorption (NTX, TRACP-5b), bone formation (bone-alkaline phosphatase (bALP), osteocalcin), OPG and sRANKL were measured pre- and every month post-ASCT. The median follow-up period was 12 months. Four patients were transplanted in CR, 44 were transplanted in PR and three patients had progressive/resistant disease. All patients received bisphosphonates both pre- and post-ASCT. At baseline the majority of patients had increased NTX, TRACP-5b levels, and sRANKL/OPG ratio, while markers of bone formation were strongly suppressed. ASCT produced a significant reduction of sRANKL/OPG ratio, with a concomitant decrease of NTX, and TRACP-5b levels, starting the second month post-ASCT. Bone formation markers, osteocalcin and bALP, started to increase after the 9th and 11th month post-ASCT, respectively, while the increase of OPG preceded this. These results provide biochemical evidence that ASCT normalizes the abnormal bone resorption in MM patients possibly through the decrease of RANKL/OPG ratio, while bone formation requires a longer period to return to normal.Leukemia (2004) 18, 1420-1426. doi:10.1038/sj.leu.2403423 Published online 24 June 2004 [ABSTRACT FROM AUTHOR]

A case of disseminated Aspergillus terreus infection in a patient with prolonged neutropenia after stem cell transplant for myeloma is reported. The isolate was resistant to amphotericin B in vitro, and the patient was successfully managed with surgical debridement and the recently licensed antifungal agent caspofungin. There are many challenges associated with treating invasive aspergillosis, particularly that due to A. terreus, and the early use of caspofungin should be considered. [ABSTRACT FROM AUTHOR]

High-dose therapy with autologous stem cell transplantation (ASCT) has become the treatment of choice for symptomatic eligible patients with multiple myeloma (MM). We report our centre experience and analyse retrospectively the prognostic influence of pretransplant characteristics and transplant modalities on response and survival. A total of 127 MM patients (median age: 55.2 years) were transplanted between 1994 and 2001. In all, 69 patients had IgG, 28 IgA, 23 light chain, one IgD and six non secretory MM. At the time of autograft, 6% of patients were in complete remission (CR), 73% in partial remission (PR), 12% showed minor response to previous treatment and 9% had stable or refractory disease. Prior to autograft, 79% of cases had received only one line of chemotherapy and 21% two or more lines. All patients received PBSC support after conditioning with 200?mg/m2 melphalan alone (100 patients) or melphalan and TBI (27 patients). We evaluated the influence of age (using as cutoff value the ages of 55, 60 and 65 years), type of MM, status pre- and post-ASCT, number of lines of previous regimens, time of ASCT from diagnosis, year of autograft, dose of reinfused CD34+ cells, plasma cell infiltration and ?2-microglobulin at diagnosis on overall (OS) and progression-free survivals (PFS) to define patients with better prognosis. Following ASCT, 15% of patients were in CR and 81% in PR, while only two patients progressed. Median OS and PFS from transplantation were 50.4 and 23.5 months, respectively. Median OS from diagnosis was 79.7 months. Transplant-related mortality was 2.3%. Low levels of ?2-microglobulin and the achievement of CR post-transplant correlated with longer PFS (P<0.03 and <0.01, respectively). The median PFS was 36.1, 23.9, 21.1 and 16.4 months for nonsecretory, IgG, IgA and light chain subtypes, respectively. Age was not an important prognostic factor at a cutoff value of 55 or 60 years. We conclude that... [ABSTRACT FROM AUTHOR]

HIV-related bone marrow changes are consistent with myelodysplastic features (MDF). Their pathogenesis may differ from primary myelodysplastic syndromes (MDS) and is associated with various factors including the virus itself or the antiretroviral therapy. In order to evaluate the differences between HIV-related MDF and MDS, the morphological changes in peripheral blood and bone marrow, cytogenetic analysis and the response to anaemia treatment were studied in 158 HIV+ patients with haemophilia and the results were compared with those of 61 patients with primary MDS (31 with RA, 10 with RARS, 11 with RAEB, three with RAEB-t and six with CMML). The eligibility criteria for patients with MDS were primary MDS, Hb levels < 10 g dL[sup -1], and no significant organ disease. The peripheral blood and bone marrow examination revealed MDF in 44 HIV-infected haemophilic patients (27.8%). The median time from seroconversion was 12.5 years and the mean time under AZT therapy was 44.1 months. Nineteen of these patients (43.1%) had Hb levels < 10 g dL[sup -1], while neutropenia and thrombocytopenia were observed in 29.5% and 25%, respectively. Every patient of this study with Hb < 10 g dL[sup -1] received erythropoietin (Epo). There were statistically significant morphological alterations between HIV-related MDF and MDS: hypocellularity, plasmatocytosis and eosinophilia were more pronounced in HIV haemophiliacs with MDF, while dysplasia of erythroblasts, megakaryocytes and granulocytes was more frequent in MDS patients. No HIV haemophilic patient with MDF had more than 5% blasts in the bone marrow nor did any develop RAEB or acute leukaemia during the period of this study. The cytogenetic analysis was normal in HIV-infected patients with haemophilia whereas 42.6% of patients with MDS had an abnormal karyotype. Complete erythroid response was achieved with Epo administration in 84.2% of HIV+ haemophilic patients with anaemia compared to 19.7% of patients with MDS... [ABSTRACT FROM AUTHOR]

Myelofibrosis is not frequent in systematic lupus erythematosus (SLE). A review in the literature reveals that the coo-incidence is rather hire since there are only a few papers reporting this combination. The female patient described hereby, presented with thrombocytopenia: following investigation, the diagnosis of SLE was established and bone marrow examination revealed an increase of marrow reticulin. Treatment with steroids reversed both thrombocytopenia and fibrosis. [ABSTRACT FROM AUTHOR]

Presents the case study of a person diagnosed with acute myeloid leukemia and ataxia-telangiectasia. Genetic aspects of ataxia-telangiectasia; Analysis of the patient's peripheral blood smear; Quantitative analysis of immunoglobulins; Detection of chromosomal translocation in the patient.

• This EHA-ESMO Clinical Practice Guideline provides key recommendations on the management of multiple myeloma. • Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe. • Key treatment recommendations are provided for both newly diagnosed myeloma patients and patients with relapsed/refractory disease. • Recommendations for the treatment of plasma cell leukaemia, solitary plasmacytoma and smouldering myeloma are also provided. • Key recommendations for myeloma complications, including bone disease and renal impairment, are included. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding a study on bone mineral density (BMD) which indicates that BMD increases in the patients having a relapsed multiple myeloma who received the combination of dexamethasone (VD) and zoledronic acid (ZA).

A response by E. Terpos and O. Sezer to a letter to the editor about their article "The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma" is presented.

Multiple myeloma (MM) is the second most common hematological malignancy, with an incidence of 6/100 000 in Europe. Interactions between myeloma cells and the microenvironment are essential for MM cell survival. Better knowledge of disease biology has led to the introduction of novel agents for the management of myeloma patients. Patients with asymptomatic MM may remain stable for a long time without any therapy, and treatment is needed only in symptomatic disease. Patients who are eligible for high-dose therapy and autologous stem cell transplantation (ASCT) are usually treated with bortezomib- or immunomodulatory drug (IMiD)-based regimens as induction therapy pre-ASCT. In elderly patients, the combination of melphalan and prednisone with either thalidomide (MPT) or bortezomib (MPV) is considered as the standard of care in this setting. Novel agent-based therapies are used for the management of relapsed/refractory disease. However, previous therapies, age, comorbidities and drug safety have to be taken into consideration before deciding the appropriate therapy for patients with relapsed/refractory myeloma. Patients with renal impairment or with extended bone disease may be treated with bortezomib-based regimens, while patients with pre-existing peripheral neuropathy may be treated with lenalidomide-based combinations. Maintenance therapy with thalidomide can be administered post-ASCT; however, caution is needed due to thalidomide toxicity. [ABSTRACT FROM AUTHOR]

Background: Bisphosphonates (BPs) prevent, reduce, and delay multiple myeloma (MM)-related skeletal complications. Intravenous pamidronate and zoledronic acid, and oral clodronate are used for the management of MM bone disease. The purpose of this paper is to review the current evidence for the use of BPs in MM and provide European Union-specific recommendations to support the clinical practice of treating myeloma bone disease. Design and methods: An interdisciplinary, expert panel of specialists on MM and myeloma-related bone disease convened for a face-to-face meeting to review and assess the evidence and develop the recommendations. The panel reviewed and graded the evidence available from randomized clinical trials, clinical practice guidelines, and the body of published literature. Where published data were weak or unavailable, the panel used their own clinical experience to put forward recommendations based solely on their expert opinions. Results: The panel recommends the use of BPs in MM patients suffering from lytic bone disease or severe osteoporosis. Intravenous administration may be preferable; however, oral administration can be considered for patients unable to make hospital visits. Dosing should follow approved indications with adjustments if necessary. In general, BPs are well tolerated, but preventive steps should be taken to avoid renal impairment and osteonecrosis of the jaw (ONJ). The panel agrees that BPs should be given for 2 years, but this may be extended if there is evidence of active myeloma bone disease. Initial therapy of ONJ should include discontinuation of BPs until healing occurs. BPs should be restarted if there is disease progression. Conclusions: BPs are an essential component of MM therapy for minimizing skeletal morbidity. Recent retrospective data indicate that a modified dosing regimen and preventive measures can greatly reduce the incidence of ONJ. [ABSTRACT FROM AUTHOR]

A correction to the article "The combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide is an effective regimen for relapsed/refractory myeloma and is associated with improvement of abnormal bone metabolism and angiogenesis" by E. Terpos, E. Kastritis, M. Roussou, D. Heath, D. Christoulas, N. Anagnostopoulos, E. Eleftherakis-Papaiakovou, K. Tsionos, P. Croucher and M. A. Dimopoulos published online on September 4, 2008 is presented.

High-dose therapy with autologous stem cell therapy (ASCT) has become the treatment of choice for eligible patients with myeloma. We analysed retrospectively the prognostic influence of pre-transplant characteristics and transplant modalities on response and survival in 211 myeloma patients who were transplanted in our centre between 1994 and 2004. All patients received peripheral blood stem cell support after conditioning with melphalan alone (183 patients), or melphalan and total blood irradiation (28 patients). We evaluated the influence of age, type of multiple myeloma, status prior and post ASCT, previous treatment regimens, time of ASCT from diagnosis, year of autograft, dose of re-infused CD34+ cells, plasma cell infiltration and β2-microglobulin at diagnosis on overall survival (OS) and event-free survival (EFS) to define patients with better prognosis. Median OS and EFS from transplantation were 50.9 and 20.1 months, respectively. Median OS from diagnosis was 68.8 months. Transplant-related mortality was 1.4%. Lower β2-microglobulin levels, achievement of complete remission (CR) post transplant and lower plasma cell infiltration at diagnosis and transplant correlated with longer EFS and OS, whereas CR at transplant and low international prognostic index at transplant correlated with better EFS. Higher CD34+ cell dose correlated with improved OS. We conclude that ASCT is safe and effective and the outcome is independent of age, time from diagnosis, previous treatment and conditioning regimen.Bone Marrow Transplantation (2006) 37, 731–737. doi:10.1038/sj.bmt.1705307; published online 27 February 2006 [ABSTRACT FROM AUTHOR]

Purpose: The investigation of a semi-quantitative index in the pelvis to assess for diffuse bone marrow (BM) [18F]-FDG uptake and the investigation of PET skeletal patterns in multiple myeloma (MM) patients, in accordance with prognostic markers, clonal plasma cell (cPC) morphology, and response to therapy. Methods: We prospectively analyzed [18F]-FDG PET/CT in 90 MM patients (newly diagnosed, 60; relapsed/refractory, 30). Among other PET/CT parameters, we calculated the ratio SUVmax pelvis/liver and examined for correlations with known MM prognostic parameters, cPC morphology (good vs. low/intermediate differentiation), and response to therapy. Results: SUVmax pelvis/liver ratio was significantly lower for the group of good differentiation vs. intermediate/low differentiation cPCs (p < 0.001) and showed a positive correlation with BM infiltration rate, β2 microglobulin, serum ferritin, international staging system (ISS), and revised ISS; no significant correlation was found with hemoglobin. A cutoff value of 1.1 showed an excellent specificity (99%) and high sensitivity (76%) for diffuse BM involvement (AUC 0.94; p < 0.001). Mixed pattern and appendicular involvement correlated with poor prognostic features while normal pattern, found in 30% of patients, correlated with good prognostic features. Presence of ≥ 10 focal lesions negatively predicted for overall response (p < 0.05; OR 4.8). The CT component improved the diagnostic performance of PET. Conclusion: This study showed, for the first time, that cPC morphology and markers related with MM biology, correlate with SUVmax pelvis/liver index, which could be used as a surrogate marker for BM assessment and disease prognosis; PET patterns correlate with MM prognostic features and response rates. [ABSTRACT FROM AUTHOR]

• The clinical course of advanced cancer for many patients with bone metastases can be transformed through optimum multidisciplinary management. • Bone-targeted agents significantly reduce skeletal morbidity in patients with bone metastases across tumour types and should be part of standard treatment. • Treatment-induced bone loss increases fracture risk and may require use of a bone-targeted agent in addition to lifestyle modifications. • The addition of a bisphosphonate to standard adjuvant therapies for postmenopausal early breast cancer reduces bone recurrence and improves survival. [ABSTRACT FROM AUTHOR]

Background: The novel proteasome inhibitor carfilzomib alone or in combination with other agents is already one of the standard therapies for relapsed and/or refractory multiple myeloma (MM) patients and produces impressive response rates in newly diagnosed MM as well. However, carfilzomib-related cardiovascular adverse events (CVAEs) - including hypertension (all grades: 12.2%; grade ≥3: 4.3%), heart failure (all grades: 4.1%; grade ≥3: 2.5%) and ischemic heart disease (all grades: 1.8%; grade ≥3: 0.8%) - may lead to treatment suspensions. At present, there are neither prospective studies nor expert consensus on the prevention, monitoring and treatment of CVAEs in myeloma patients treated with carfilzomib.Methods: An expert panel of the European Myeloma Network in collaboration with the Italian Society of Arterial Hypertension and with the endorsement of the European Hematology Association aimed to provide recommendations to support health professionals in selecting the best management strategies for patients, considering the impact on outcome and the risk-benefit ratio of diagnostic and therapeutic tools, thereby achieving myeloma response with novel combination approaches whilst preventing CVAEs.Results: Patients scheduled to receive carfilzomib need a careful cardiovascular evaluation before treatment and an accurate follow-up during treatment.Conclusions: A detailed clinical assessment before starting carfilzomib treatment is essential to identify patients at risk for CVAEs, and accurate monitoring of blood pressure and of early signs and symptoms suggestive of cardiac dysfunction remains pivotal to safely administer carfilzomib without treatment interruptions or dose reductions. [ABSTRACT FROM AUTHOR]

Aim: Haemophilia A and B are associated with reduced bone mineral density (BMD). The aim of this study was to assess circulating sclerostin and dickkopf‐1 (Dkk‐1), (inhibitors of osteoblastic differentiation), as well as the receptor activator of nuclear factor kB ligand (RANKL)/osteoprotegerin (OPG) system (the major regulator of osteoclastogenesis), in patients with haemophilia (PWH), their possible correlations with clinical risk factors and the effect of ibandronate on these markers. Methods: Eighty‐nine male PWH (mean age 45.9 ± 15.3 years) and 30 age‐matched healthy male controls participated. BMD was assessed by DXA. Sclerostin, Dkk‐1, RANKL and OPG were measured in serum of patients, controls, as well as in ten patients receiving oral ibandronate (150 mg/mo), at baseline and after 12 months. Results: Patients with haemophilia had lower circulating sclerostin (median ± IQR: 47.4 ± 26.93 vs 250 ± 250 pmol/L, P < .001), Dkk‐1 (21.24 ± 17.18 vs 26.16 ± 15.32pg/mL, P = .04) and higher levels of RANKL (0.23 ± 0.03 vs 0.04 ± 0.03 pmol/L, P = .001), RANKL/OPG ratio (0.063 ± 0.25 vs 0.005 ± 0.11, P = .001) compared with controls. Patients with low BMD had higher OPG concentrations compared to those with normal BMD. Sclerostin and RANKL/OPG correlated positively with BMD. Patients with severe haemophilia had lower sclerostin concentrations compared with those with mild or moderate disease. The degree of arthropathy negatively correlated with sclerostin and Dkk‐1 levels. PWH who received ibandronate showed a decrease in serum Dkk‐1 without any significant effect on sclerostin and RANKL/OPG. Conclusions: Patients with haemophilia present increased osteoclastic activity coupled with compensatory increased osteoblastic activity. Ibandronate did not affect RANKL/OPG ratio, but it decreased Dkk‐1. [ABSTRACT FROM AUTHOR]

Solitary plasmacytoma is an infrequent form of plasma cell dyscrasia that presents as a single mass of monoclonal plasma cells, located either extramedullary or intraosseous. In some patients, a bone marrow aspiration can detect a low monoclonal plasma cell infiltration which indicates a high risk of early progression to an overt myeloma disease. Before treatment initiation, whole body positron emission tomography-computed tomography or magnetic resonance imaging should be performed to exclude the presence of additional malignant lesions. For decades, treatment has been based on high-dose radiation, but studies exploring the potential benefit of systemic therapies for high-risk patients are urgently needed. In this review, a panel of expert European hematologists updates the recommendations on the diagnosis and management of patients with solitary plasmacytoma. [ABSTRACT FROM AUTHOR]

The article evaluates the importance of focal lesions in spine magnetic resonance imaging (MRI) for the identification of patients with asymptomatic multiple myeloma at high risk of progression. At least one in six patients with more than one focal lesion are found to have one of the other high-risk features. Patients with more than one focal lesion is noted to have a median time of 13 months to progression. Spine MRI is considered useful as an imaging modality of choice.

The article discusses the risk of fracture in patients with haemophilia (PWH) with associated low bone mineral density, regarding prevalence, potential pathogenetic mechanisms and future perspectives. Topics considered include the most common fracture sites and the average age at the time of sustaining a fracture, factors that contributes to increased fracture risk in PWH, and the use of Fracture Risk Assessment Tool (FRAX) in adults with haemophilia older than 40 years old.

Paroxysmal nocturnal hemoglobinuria (PNH) or Marchiafava-Micheli disease is an acquired clonal hematopoietic stem cell disorder that few clinicians or even hematologists have followed throughout its full natural history and clinical course. The molecular and biochemical background of PNH was elucidated at the end of the last century following nordecades of research. Over 180 somatic mutations of the X-linked gene PIG-A in hematopoietic stem cells have been implicated in the pathogenesis of PNH, resulting in impairment of the biosynthetic pathway of the glycosyl-phosphatidyl-inositol (GPI) molecule, which is a glycoprotein mechanism for membrane anchoring. PNH is the first and single example of acquired autoimmune hemolytic anemia with a negative Coombs' test. It is based on a red cell membrane defect with normal morphology, which leads to paroxysmal episodes of hemoglobinuria, with dark-coloured urine most noticeable in the morning. The red cell membrane deficiency of CD55 and CD59, GPI-anchored complement regulatory proteins, adequately explains the symptom of chronic intravascular hemolysis with hemosidirinuria, although the pathogenesis of thromboembolic events in unusual sites and bone marrow failure, which complement the characteristic clinical triad of PNH manifestations, still remains obscure. This review summarizes the available scientific elements of the unique molecular and biochemical defect of PNH and describes the underlying pathogenetic pathways that lead to its clinical manifestations. [ABSTRACT FROM AUTHOR]

Recent developments have led to remarkable improvements in the assessment and treatment of patients with multiple myeloma (MM). New technologies have become available to precisely evaluate the biology and extent of the disease, including information about cytogenetics and genetic abnormalities, extramedullary manifestations and minimal residual disease. New, more effective drugs have been introduced into clinical practice, which enable clinicians to significantly improve the outcome of patients but also pose new challenges for the prevention and management of their specific side effects. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of patients, as access to the most sophisticated advances may vary depending on local circumstances. Here, we propose the minimal requirements and possible options for diagnosis, monitoring and treatment of patients with multiple myeloma. [ABSTRACT FROM AUTHOR]

Recent developments have led to remarkable improvements in the assessment and treatment of patients with multiple myeloma (MM). New technologies have become available to precisely evaluate the biology and extent of the disease, including information about cytogenetics and genetic abnormalities, extramedullary manifestations and minimal residual disease. New, more effective drugs have been introduced into clinical practice, which enable clinicians to significantly improve the outcome of patients but also pose new challenges for the prevention and management of their specific side effects. Given these various new options and challenges, it is important to identify the minimal requirements for diagnosis and treatment of patients, as access to the most sophisticated advances may vary depending on local circumstances. Here, we propose the minimal requirements and possible options for diagnosis, monitoring and treatment of patients with multiple myeloma. [ABSTRACT FROM AUTHOR]

Periostin is a secreted extracellular matrix protein preferentially expressed in bone by osteocytes and periosteal osteoblasts. Reduced periostin expression may affect osteoblast differentiation and collagen type I synthesis and predispose to osteoporosis and increased fracture risk. We aimed to evaluate circulating periostin levels in postmenopausal women with low bone mass, their possible correlations with clinical and laboratory parameters, as well as the 3-month effect of zoledronic acid. Serum samples for periostin, 25-hydroxyvitamin D, parathyroid hormone (PTH), C-terminal telopeptide of type I collagen (CTx), and total alkaline phosphatase (tALP) were obtained from 46 postmenopausal women with low bone mass at baseline and 3 months after zoledronic acid infusion and from 30 agematched, postmenopausal controls with normal bone mass at baseline. There was no difference in periostin levels between women with normal and low bone mass (250 ± 15 vs. 272 ± 14 ng/ml, respectively; p = 0.279). Periostin remained essentially unchanged after zoledronic acid infusion (262 ± 18 ng/ml; p = 0.130). Serum periostin levels at baseline were not affected by previous bisphosphonate treatment, and were correlated only to tALP (rs = 0.351; p = 0.018). In multiple linear regression analysis, tALP (B = 3.17; 95 % CI = 0.59-5.79; p = 0.018) was associated with serum periostin levels at baseline, independently from previous anti-osteoporotic treatment, age, body mass index, and 25-hydroxyvitamin D. In conclusion, serum periostin levels do not differ between postmenopausal women with normal and low bone mass and are not affected by zoledronic acid treatment. Women with higher tALP have independently higher periostin levels. [ABSTRACT FROM AUTHOR]

The incidence and severity of renal impairment at the time of diagnosis of myeloma remains unchanged during the past 20 years due to increasing numbers of elderly patients who are diagnosed and treated for myeloma. Novel therapies have improved significantly the survival of patients with severe renal dysfunction and may also decrease the risk of early death which is high in patients with severe renal impairment, especially among older patients.Background Renal impairment (RI) is a common presenting complication of multiple myeloma (MM); the availability of new treatments has improved the outcomes of patients with MM; however, their impact on the survival of patients who present with RI has not been extensively studied. Patients and methods We analyzed the characteristics and outcomes of 1773 consecutive unselected patients who were treated for symptomatic myeloma since January 1990. Results Although there was a significant increase in the proportion of patients of advanced age in the more recent periods, the frequency of RI as well as the proportion of patients who presented with severe RI (eGFR < 30 ml/min/1.73 m2) remained unchanged around 18%. Thus, after adjustment for age, there was a decrease in the risk of severe RI at presentation after 2000. Myeloma response rates (≥PR) to frontline therapy have substantially increased, and this was translated in a significant increase in the median survival. Specifically for patients with severe RI, the median OS has improved from 18 and 19.5 months in the 1990–1994 and 1995–1999 to 29 and 32 months for the periods 2000–2004 and after 2005 (P = 0.005). Severe RI was associated with a high risk of early death (12% versus 7% for patients with moderate RI versus 3% for patients with mild or no RI (P < 0.001), especially among older patients, and has remained unchanged over time. Conclusions There has been a major improvement in the survival of patients with severe RI in the past decade, despite the increasing numbers of patients of advanced age. However, the risk of early death remains high in patients with severe RI, especially in the elderly. [ABSTRACT FROM AUTHOR]

Summary: Activin-A is expressed in bone and seems to regulate osteoclastogenesis. In this study, serum activin-A was increased in postmenopausal women with low bone mass and was positively correlated to age and negatively to lumbar spinal bone mineral density (BMD). Serum activin-A levels did not change 3 months after zoledronic acid infusion. Introduction: The aims of the study were to evaluate prospectively the circulating activin-A levels in postmenopausal women with low bone mass and explore possible correlations with clinical and laboratory data, as well as the 3-month effect of zoledronic acid infusion. Methods: Postmenopausal women with low bone mass assigned to receive zoledronic acid infusion (Patients, n = 47) and age-matched, postmenopausal women with normal bone mass (Controls, n = 27) were recruited on an outpatient basis. Main outcome measurement was serum activin-A levels. Results: Serum activin-A was higher in patients at baseline compared to controls ( p < 0.001) and activin-A in the serum of patients and controls was positively correlated with age (Spearman's coefficient of correlation [rs] = 0.325; p = 0.005) and negatively with lumbar spinal (LS) BMD (rs = −0.425; p < 0.001). In multiple linear regression analysis, only age (B = 8.93; 95 % CI = 4.39-13.46; p < 0.001) was associated with serum activin-A levels at baseline, independent from group (patients or controls), previous anti-osteoporotic treatment, LS BMD and follicle-stimulating hormone. Circulating activin-A levels were not affected 3 months after zoledronic acid infusion. Conclusions: Serum activin-A is increased in postmenopausal women with low bone mass compared with postmenopausal women with normal bone mass and is positively correlated to age and negatively to LS BMD. [ABSTRACT FROM AUTHOR]

The role of thalidomide, bortezomib and lenalidomide in multiple myeloma patients presenting with renal impairment was evaluated in 133 consecutive newly diagnosed patients who were treated with a novel agent-based regimen. A significant improvement of renal function (renalPR (renal partial response)) was observed in 77% of patients treated with bortezomib, in 55% with thalidomide and in 43% with lenalidomide (P=0.011). In multivariate analysis, bortezomib-based therapy was independently associated with a higher probability of renal response compared with thalidomide- or lenalidomide-based therapy. Other important variables included eGFR (estimated glomerular filtration rate) 30 ml/min, age 65 years and myeloma response. Patients treated with bortezomib achieved at least renalPR in a median of 1.34 months vs 2.7 months for thalidomide and >6 months for lenalidomide-treated patients (P=0.028). In multivariate analysis bortezomib-based therapy, higher doses of dexamethasone (160 mg during the first month of treatment), an eGFR 30 ml/min and age 65 years were independently associated with shorter time to renal response. In conclusion, bortezomib-based therapies may be more appropriate for the initial management of patients with myeloma-related renal failure; however, thalidomide and lenalidomide are also associated with significant probability of improvement of their renal function. [ABSTRACT FROM AUTHOR]

Background:Vascular endothelial growth factor action in tumour angiogenesis is well characterised; nevertheless, it functions as a key element in the promotion of the immune system's evasion by tumours. We sought to investigate the possible direct effect of VEGF on T-cell activation and through which type of VEGF receptor it exerts this effect on cells isolated from ovarian cancer patients' ascites.Methods:T cells isolated from the ascites of ovarian cancer patients were cultured with anti-CD3 and IL-2, with or without VEGF for 14 days and the number of viable T cells was counted. Cytotoxic activity of cultured T cells and expression of VEGF receptor-2 (VEGFR-2), was assayed.Results:The addition of VEGF in cultures significantly reduced the number and proliferation rate of T cells in a dose-dependent manner and CD3+ T cells expressed VEGFR-2 on their surface upon activation. Experiments with specific anti-VEGFR-2 antibodies revealed that the direct suppressive effect of VEGF on T-cell proliferation is mediated by VEGFR-2. We also showed that VEGF significantly reduced the cytotoxic activity of T cells.Conclusion:Our study showed that ascites-derived T cells secrete VEGF and express VEGFR-2 upon activation. Vascular endothelial growth factor directly suppresses T-cell activation via VEGFR-2. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions. [ABSTRACT FROM AUTHOR]

Background: The International Staging System (ISS) is the most widely used staging system for patients with multiple myeloma (MM). However, serum β2-microglobulin increases in renal impairment (RI) and there have been concerns that ISS-3 stage may include ‘up-staged’ MM patients in whom elevated β2-microglobulin reflects the degree of renal dysfunction rather than tumor load. Patients and methods: In order to assess the impact of RI on the prognostic value of ISS, we analyzed 1516 patients with symptomatic MM and the degree of RI was classified according to the Kidney Disease Outcomes Quality Initiative-Chronic Kidney Disease (CKD) criteria. Results: Forty-eight percent patients had stages 3–5 CKD while 29% of patients had ISS-1, 38% had ISS-2 and 33% ISS-3. The frequency and severity of RI were more common in ISS-3 patients. RI was associated with inferior survival in univariate but not in multivariate analysis. When analyzed separately, ISS-1 and ISS-2 patients with RI had inferior survival in univariate but not in multivariate analysis. In ISS-3 MM patients, RI had no prognostic impact either in univariate or multivariate analysis. Results were similar, when we analyzed only patients with Bence-Jones >200 mg/day. Conclusions: ISS remains unaffected by the degree of RI, even in patients with ISS-3, which includes most patients with renal dysfunction. [ABSTRACT FROM PUBLISHER]