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Background Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA).Methods KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (

With the availability of novel agents, the overall survival (OS) in patients diagnosed with multiple myeloma (MM) has improved over the last decade. Data on 40,294 MM patients in the years from 1973 to 2003 were obtained from the Surveillance, Epidemiology, and End Results Program (SEER) of the US National Cancer Institute. Statistical analyses evaluating gender, race, age, and year of diagnosis were performed using univariate and multivariate Cox regression models for the OS endpoint. The mean patient age at diagnosis was 68.3 years. Mean survival was 30 months (median = 19 months). Asian/Pacific Islander race was associated with an improved OS, HR 0.90 (CI 0.86-0.95, P < 0.001). American Indian/Alaska Native race was associated with a decreased OS, HR 1.18 (CI 1.01-1.38, P = 0.040). Multivariate analysis did not reveal statistically significant differences in OS between patients in the white and black race (P = 0.709). Younger age (age <65, and 65-75) was associated with improved OS when compared with patients >75 years of age (all P < 0.001). Recent treatment decades (1983-1992 and 1993-2003) were associated with improved OS on multivariate analysis with HR 0.88 (CI 0.88-0.89, P < 0.001) and HR 0.83 (CI 0.81-0.85, P < 0.001), respectively. As the largest population analysis to date, this study reveals a statistically significant improvement in OS for patients who were treated in more recent decades, even before the availability of novel agents. Patients who were <65 years of age and Asian/Pacific Islander race groups exhibited superior levels of OS, whereas American Indian/Alaska Native groups had decreased OS.

Variants of factor XI containing Gln226 to Arg (Q226 to R) and Ser248 to Asn (S248 to N) substitutions were first identified in an African American family with a history of excessive bleeding. The substitutions have recently been identified in unrelated individuals, suggesting they are relatively common. Both amino acids are located in the third apple domain of factor XI, an area implicated in binding interactions with factor IX and activated platelets. Recombinant factor XI-R226 and factor XI-N248 were compared with wildtype factor XI in assays for factor IX activation or platelet binding. Factor XI-R226 activates factor IX with a MichaelisMenten constant (K m ) about 5-fold greater than wild-type protein. The catalytic efficiency of factor IX activation is similar to wild-type protein, however, due to an increase in the turnover number (k cat ) for the reaction. Iodinated factor XI-N248 binds to activated platelets with a dissociation constant (K d ) more than 5-fold higher than wild-type protein (55 nM and 10 nM, respectively). Activation of factor XI-N248 by thrombin in the presence of activated platelets is slower and does not progress to the same extent as activation of the wild-type protein under similar conditions. Factor XI-N248 activates factor IX normally in a purified protein system and has relatively normal activity in activated partial thromboplastin time (aPTT) assays. Factor XI-N248 is the first factor XI variant described with a clear functional difference compared with wild-type protein. Importantly, the defect in platelet binding IntroductionCoagulation factor XI is the zymogen of a plasma protease that contributes to hemostasis by activating factor IX. 1 In congenital factor XI deficiency in humans, low plasma activity is almost always associated with a comparable loss of antigen (cross-reactive material-negative [CRM Ϫ ] deficiency). 2,3 Few factor XI-deficient patients with low activity and disproportionately high circulating levels of factor XI antigen (CRM ϩ deficiency) have been reported, 4-6 and the genetic abnormalities in these individuals have not been determined. This distinguishes factor XI deficiency from hemophilias A and B (deficiency of factor VIII or IX, respectively) and von Willebrand disease, where many circulating dysfunctional variants have been described. 7 Another peculiarity of factor XI deficiency that distinguishes it from hemophilia is the poor correlation between plasma factor XI activity and bleeding symptoms. 6,8,9 It is likely that several factors are responsible for this phenomenon. One possibility is that commonly used in vitro tests for factor XI activity do not accurately measure properties of the protein most important for in vivo hemostasis.Previously, we reported 2 amino acid substitutions in factor XI (Q226R and S248N), identified in an African American with a history of excessive bleeding and a modest deficiency in plasma factor XI activity. 10 This patient is a compound heterozygote, with the amino acid substitutions residing on separate alleles. The ...