The conclusions of this study validated dental extractions and use of dentures as risk factors for ONJ development. Ibandronate and pamidronate at the dosages and frequency used in this study seem to exhibit a safer drug profile concerning ONJ complication; however, randomized controlled trials are needed to validate these results. Before initiation of a bisphosphonate, patients should have a comprehensive dental examination. Patients with a challenging dental situation should have dental care attended to before initiation of these drugs.

Background Selinexor with dexamethasone has demonstrated activity in patients with heavily pretreated multiple myeloma (MM). In a phase 1b/2 study, the combination of oral selinexor with the proteasome inhibitor (PI) bortezomib, and dexamethasone (SVd) induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. The aim of this trial was to evaluate the clinical benefit of weekly SVd versus standard bortezomib and dexamethasone (Vd) in patients with previously treated MM.Methods This phase 3, randomised, open label trial was conducted at 123 sites in 21 countries.Patients who were previously treated with one to three lines of therapy, including PIs were randomised (1:1) to selinexor (100 mg once-weekly) plus bortezomib (1•3 mg/m 2 once-weekly) and dexamethasone (20 mg twice-weekly) [SVd] or bortezomib (1•3 mg/m 2 twice-weekly) and dexamethasone (20 mg 4 times per week) [Vd]. Randomisation was done using interactive response technology and stratified by previous PI therapy, lines of treatment, and MM stage. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population.Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562.

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Our large, multicenter trial showed that the non-stem-cell toxic DRC regimen is an active, well-tolerated treatment for symptomatic patients with WM.

Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-jB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma Bortezomib is a proteasome inhibitor that is currently indicated for patients with multiple myeloma (MM) who have received at least one prior therapy. Although the anti-myeloma effect of bortezomib has been clearly demonstrated, its effect on bone metabolism is still unclear. In addition to increased bone resorption, bone formation is suppressed in patients with myeloma (Silvestris et al, 2004). There are recent reports that bortezomib may increase serum alkaline phosphatase activity, which is consistent with enhanced osteoblast function (Shimazaki et al, 2005;Zangari et al, 2005). However, knowledge of the molecular mechanisms that are involved and the effect bortezomib also has on bone resorption is still lacking. Dickkopf-1 (DKK-1) protein is an inhibitor of Wnt signalling that participates in osteoblast dysfunction in MM (Tian et al, 2003). The receptor activator of nuclear factor-kappa B ligand (RANKL), RANK and osteoprotegerin (OPG) system is considered the final mediator of osteoclastogenesis as well as osteoclast activation in myeloma [Terpos et al, 2003a]. Therefore, this study aimed to evaluate the effect bortezomib has on RANKL and DKK-1 serum levels in MM patients and determine if this correlates to markers of bone metabolism. Patients and methods PatientsThirty-four myeloma patients who had relapsed after previous therapies were evaluated ( SummaryThe effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf-1 (DKK-1), soluble receptor activator of nuclear factor-jB ligand (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of type-I collagen (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b); bone-alkaline phosphatase and osteocalcin were reduced. Serum DKK-1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK-1, sRANKL, CTX, and TRACP-5b after four cycles, and dramatically increased bone-alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK-1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma.

Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. We showed that MM patients had increased serum hepcidin, which inversely correlated with hemoglobin, suggesting that hepcidin contributes to MMrelated anemia. Searching for hepcidininducing cytokines in MM, we quantified the stimulation of hepcidin promoterluciferase activity in HuH7 cells by MM sera. MM sera activated the hepcidin promoter significantly more than did normal sera. We then examined the role of bone morphogenetic proteins (BMPs) and interleukin-6 (IL-6), the major transcriptional regulators of hepcidin. Mutations in both BMP-responsive elements abrogated the activation dramatically, while mutations in the IL-6-responsive signal transducer and activator of transcription 3-binding site (STAT3-BS) had only a minor effect. Cotreatment with anti-BMP-2/4 or noggin-Fc blocked the promoter induction with all MM sera, anti-IL-6 blocked it with a minority of sera, whereas anti-BMP-4, -6, or -9 antibodies had no effect. BMP-2-immunodepleted MM sera had decreased promoter stimulatory capacity, and BMP-2 concentrations in MM sera were significantly higher than in normal sera. Our results demonstrate that BMP-2 is a major mediator of the hepcidin stimulatory activity of MM sera. (Blood. 2010;116(18):3635-3644) IntroductionMultiple myeloma (MM) is a malignant plasma cell disorder that accounts for approximately 10% of all hematologic cancers. 1 The disease is characterized by monoclonal proliferation of plasma cells together with overproduction of a monoclonal antibody, 2 often accompanied by anemia, hypercalcemia, renal insufficiency, or bone lesions. 3 Approximately 97% of MM patients develop anemia during the course of their illness, and 70% are anemic at diagnosis. The anemia is usually normocytic/normochromic, 4 serum-iron levels are normal to low, serum ferritin is high, and hemosiderin is prominent in bone marrow macrophages. 5 This suggests than iron release from reticuloendothelial macrophages is impaired, consistent with anemia of inflammation. 6 The main mediator of anemia of inflammation is the ironregulatory hormone, hepcidin. Hepcidin is produced by hepatocytes and acts on the iron exporter, ferroportin. Binding of hepcidin to ferroportin induces the internalization and degradation of ferroportin, thereby preventing cellular iron efflux and causing retention of iron, mainly inside enterocytes, macrophages, and hepatocytes. 7 Pathologic induction of hepcidin by inflammation causes hypoferremia, restricting the iron supply for erythropoiesis and, eventually, causing anemia. The interleukin-6 (IL-6)-hepcidin axis was shown to be important for inflammation-related hypoferremia. 8 However, in chronic inflammation, IL-6-independent pathways may also induce hepcidin mRNA. 9 Recently, 2 studies described the involvement of hepcidin in anemia of MM in humans. We reported that patients with stage III MM (n ϭ 44) at diagnosis had higher urinar...

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