A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma

BACKGROUND Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been shown in preclinical and phase 1 studies to have antimyeloma activity. METHODS In this multicenter, open-label, nonrandomized, phase 2 trial, we enrolled 202 patients with relapsed myeloma that was refractory to the therapy they had received most recently. Patients received 1.3 mg of bortezomib per square meter of body-surface area twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles (24 weeks). In patients with a suboptimal response, oral dexamethasone (20 mg daily, on the day of and the day after bortezomib administration) was added to the regimen. The response was evaluated according to the criteria ofthe European Group for Blood and Marrow Transplantation and confirmed by an independent review committee. RESULTS Of 193 patients who could be evaluated, 92 percent had been treated with three or more ofthe major classes of agents for myeloma, and in 91 percent, the myeloma was refractory to the therapy received most recently. The rate of response to bortezomib was 35 percent, and those with a response included 7 patients in whom myeloma protein became undetectable and 12 in whom myeloma protein was detectable only by immuno-fixation. The median overall survival was 16 months, with a median duration of response of 12 months. Grade 3 adverse events included thrombocytopenia (in 28 percent of patients), fatigue (in 12 percent), peripheral neuropathy (in 12 percent), and neutropenia (in 11 percent). Grade 4 events occurred in 14 percent of patients. CONCLUSIONS Bortezomib, a member of a new class of anticancer drugs, is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy

Periodontitis and atherosclerotic cardiovascular disease: Consensus report of the Joint EFP/ AAP Workshop on Periodontitis and Systemic Diseases

© 2013 European Federation of Periodontology and American Academy of Periodontology.Background: This consensus report is concerned with the association between periodontitis and atherosclerotic cardiovascular disease (ACVD). Periodontitis is a chronic multifactorial inflammatory disease caused by microorganisms and characterized by progressive destruction of the tooth supporting apparatus leading to tooth loss; as such, it is a major public health issue. Aims: This report examined biological plausibility, epidemiology and early results from intervention trials. Plausibility: Periodontitis leads to entry of bacteria in the blood stream. The bacteria activate the host inflammatory response by multiple mechanisms. The host immune response favors atheroma formation, maturation and exacerbation. Epidemiology: In longitudinal studies assessing incident cardiovascular events, statistically significant excess risk for ACVD was reported in individuals with periodontitis. This was independent of established cardiovascular risk factors. The amount of the adjusted excess risk varies by type of cardiovascular outcome and across populations by age and gender. Given the high prevalence of periodontitis, even low to moderate excess risk is important from a public health perspective. Intervention: There is moderate evidence that periodontal treatment: (i) reduces systemic inflammation as evidenced by reduction in C-reactive protein (CRP) and improvement of both clinical and surrogate measures of endothelial function; but (ii) there is no effect on lipid profiles - supporting specificity. Limited evidence shows improvements in coagulation, biomarkers of endothelial cell activation, arterial blood pressure and subclinical atherosclerosis after periodontal therapy. The available evidence is consistent and speaks for a contributory role of periodontitis to ACVD. There are no periodontal intervention studies on primary ACVD prevention and there is only one feasibility study on secondary ACVD prevention. Conclusions: It was concluded that: (i) there is consistent and strong epidemiologic evidence that periodontitis imparts increased risk for future cardiovascular disease; and (ii) while in vitro, animal and clinical studies do support the interaction and biological mechanism, intervention trials to date are not adequate to draw further conclusions. Well-designed intervention trials on the impact of periodontal treatment on prevention of ACVD hard clinical outcomes are needed.Link_to_subscribed_fulltex

Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma

Bortezomib, a proteasome inhibitor with efficacy in multiple myeloma, is associated with thrombocytopenia, the cause and kinetics of which are different from those of standard cytotoxic agents. We assessed the frequency, kinetics, and mechanism of thrombocytopenia following treatment with bortezomib 1.3 mg/m2 in 228 patients with relapsed and/or refractory myeloma in 2 phase 2 trials. The mean platelet count decreased by approximately 60% during treatment but recovered rapidly between treatments in a cyclic fashion. Among responders, the pretreatment platelet count increased significantly during subsequent cycles of therapy. The mean percent reduction in platelets was independent of baseline platelet count, M-protein concentration, and marrow plasmacytosis. Plasma thrombopoietin levels inversely correlated with platelet count. Murine studies demonstrated a reduction in peripheral platelet count following a single bortezomib dose without negative effects on megakaryocytic cellularity, ploidy, or morphology. These data suggest that bortezomib-induced thrombocytopenia is due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors. The exact mechanism underlying bortezomib-induced thrombocytopenia remains unknown but it is unlikely to be related to marrow injury or decreased thrombopoietin production