Efficacy and safety of long-term treatment with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma.

Data from two randomized pivotal, phase 3 trials evaluating the combination of lenalidomide and dexamethasone in relapsed/refractory multiple myeloma (RRMM) were pooled to characterize the subset of patients who achieved long-term benefit of therapy (progression-free survival ⩾ 3 years). Patients with long-term benefit of therapy (n = 45) had a median duration of treatment of 48.1 months and a response rate of 100%. Humoral improvement (uninvolved immunoglobulin A) was more common in patients with long-term benefit of therapy (79% vs 55%; P = 0.002). Significant predictors of long-term benefit of therapy in multivariate analysis were age < 65 years (P = 0.03), ß2-microglobulin <2.5 mg/l (P = 0.002) and fewer prior therapies (P = 0.002). The exposure-adjusted incidence rate (EAIR) of grade 3-4 neutropenia was lower in patients with long-term benefit of therapy (13.9 vs 38.2 per 100 patient-years). The EAIR for invasive second primary malignancy was the same in patients with long-term benefit of therapy and other patients (1.7 per 100 patient-years). These findings indicate that patients with RRMM can experience long-term benefit with lenalidomide and dexamethasone treatment with manageable side effects.

Alendronate and atrial fibrillation: a meta-analysis of randomized placebo-controlled clinical trials.

UNLABELLED: In this meta-analysis of all Merck-conducted, placebo-controlled clinical trials of alendronate, the occurrence of AF was uncommon, with most studies reporting two or fewer events. Across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious AF was observed. INTRODUCTION: To explore the incidence of atrial fibrillation (AF) and other cardiovascular endpoints in clinical trials of alendronate. METHODS: All double-blind, placebo-controlled studies of alendronate 5, 10, or 20 mg daily, 35 mg once-weekly, 35 mg twice-weekly, and 70 mg once-weekly of at least 3 months duration conducted by Merck were included in this meta-analysis. The primary method of analysis was exact Poisson regression. Estimated relative risk (RR) of alendronate versus placebo and the associated 95% confidence interval was derived from a model that included number of episodes with factors for treatment group and study and an offset parameter for number of person-years on study. RESULTS: Of 41 studies considered, 32 met all criteria for inclusion in the analysis (participants-9,518 alendronate, 7,773 placebo). Estimated RR for all AF events was 1.16 (95% CI = 0.87, 1.55; p = 0.33). Most trials had two or fewer AF events. The RR of AF classified as a serious adverse event was 1.25 (95% CI = 0.82, 1.93; p = 0.33), but became 0.97 (95% CI = 0.51, 1.85) when the clinical fracture cohort of the Fracture Intervention Trial was excluded, indicating that results were driven by events in that study. Estimated RRs for other cardiovascular endpoints were less than 1. CONCLUSIONS: The incidence of atrial fibrillation was low in Merck clinical trials of alendronate and was not significantly increased in any single trial nor in the meta-analysis. Based on this analysis, alendronate use does not appear to be associated with an increased risk of atrial fibrillation.

Impact of lenalidomide dose on progression-free survival in patients with relapsed or refractory multiple myeloma.

This analysis assessed the effect of lenalidomide on progression-free survival (PFS). Patients with relapsed or refractory multiple myeloma (RRMM) who received lenalidomide plus dexamethasone in the MM-009 and MM-010 trials were pooled and those who had not progressed and were still receiving lenalidomide at 12 months were included. The median follow-up of surviving patients was 48 months. Of 353 patients who received lenalidomide plus dexamethasone, 116 (33%) had not progressed. Overall, 52 patients (45%) had no dose reductions, 25 (22%) had dose reductions ≥12 months and 39 (34%) had dose reductions before 12 months. Patients who had dose reductions ≥12 months had a significantly longer median PFS than those who had reductions before 12 months (P=0.007) or no dose reductions (P=0.039) (not reached vs 28.0 vs 36.8 months, respectively). In a multivariate Cox regression model, dose reduction ≥12 months was an independent predictor of improved PFS (hazard ratio, 0.47; 95% confidence interval, 0.23-0.98) after adjusting for patient characteristics. The data suggest that to achieve maximum PFS benefit, patients with RRMM should be treated for ≥12 months with full-dose lenalidomide plus dexamethasone. Thereafter, patients may benefit from lower-dose continued therapy; prospective studies are needed to confirm these findings.

Montelukast and bronchial inflammation in asthma: a randomised, double-blind placebo-controlled trial.

BACKGROUND: Examination of bronchoalveolar lavage, induced sputum, and peripheral blood indicate that cysteinyl leukotriene receptor blockers decrease inflammatory cells in asthma but these do not examine airway tissue per se. OBJECTIVES: Our objective was to determine the effect of montelukast, a leukotriene receptor antagonist, on airway tissue inflammatory cells by direct bronchoscopic examination of the bronchial mucosa. METHODS: Adult subjects with mild asthma (pre-bronchodilator FEV(1)> or =70% predicted; PC(20) of < or =4 mg/mL) were given 10mg/day oral montelukast (N=38) or placebo (N=37) for 6 weeks. Bronchial mucosal eosinophils and mast cells were identified and counted. RESULTS: Change from baseline in numbers of biopsy EG2+ ("activated") eosinophils was the primary endpoint; numbers of total (chromotrope 2R+) eosinophils and (tryptase+) mast cells were secondary. Unexpectedly, there were many patients with zero EG2+ eosinophils at baseline. There was a within-group decrease in EG2+ cells, from 13.54 cells/mm (at baseline) to 0.79 cells/mm at 6 weeks in the montelukast group (LS mean change; 95% confidence interval=-13.59 [-25.45, -1.74]cells/mm; P<0.05), a change not observed in the placebo group (-1.17 [-13.26, 10.91]cells/mm; NS). The zero-inflated Poisson statistical model demonstrated that montelukast significantly reduced post-treatment EG2+ cells by 80% compared with placebo (95% CI [70.6-86.8%]; P<0.0001). The data for total eosinophils showed similar changes. The reduction in mast cell numbers was 12% (95% CI [7.9, 16.0]; P<0.0001). CONCLUSION: Direct examination of airway tissue confirms that montelukast decreases the number of eosinophils and mast cells in asthma.

Predictors of recurrence for patients with small (one centimeter or less) localized breast cancer (T1a,b N0 M0).

BACKGROUND: The frequency of small (< or = 1 cm) axillary lymph node negative invasive breast cancers (T1a,b N0 M0) is increasing because of wider implementation of breast cancer screening. Identification of prognostic factors for these patients has been based largely on retrospective pathology review. The authors analyzed histologic factors recorded in the original pathology reports to determine predictors of recurrence for patients with T1a,b N0 M0 breast cancer. METHODS: Two hundred eighteen patients were studied. Potential prognostic factors including measured millimeter tumor size in three dimensions, histologic grade, nuclear grade, and presence or absence of lymphatic vessel invasion were documented prospectively in routine surgical pathology reports of a large community (nonuniversity based) hospital. Follow-up was performed annually by the tumor registry. RESULTS: With a median follow-up of 6.9 years (range, 3-15.8 years), overall recurrence free survival was 93%. Poor nuclear grade (hazard ratio, 5.8; 95% confidence interval, 1.70-19.82; P = 0.004) and lymphatic vessel invasion (hazard ratio, 4.6; 95% confidence interval, 1.34-15.61; P = 0.01) were independent predictors of recurrence. Only 10% of patients had cancers with both poor nuclear grade and lymphatic vessel invasion and their 67% 7-year recurrence free survival (RFS) rate was significantly lower than the 92% RFS rate observed for patients with one of these two factors (P = 0.007) and the 99% RFS for patients with neither poor risk factor (P = 0.0001). CONCLUSIONS: The combination of poor nuclear grade and lymphatic vessel invasion identifies a very small subset (10%) of patients with T1a,b N0 M0 breast cancer with a significant relapse risk that warrants consideration of adjuvant systemic therapy. However, the majority of patients with T1a,b N0 M0 breast cancer have an exceptionally good prognosis.