Carfilzomib,lenalidomide, dexamethasone,and cyclophosphamide (KRdc) as induction therapy for transplant-eligible,newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial

BackgroundCarfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy.Methods and findingsThe Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51–0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19–5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10⁻⁵ bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world.ConclusionsThe KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy.Trial registrationClinicalTrials.gov ISRCTN49407852.

Graham Jackson and co-workers study a combination induction treatment including carfilzomib for patients with transplant-eligible myeloma.     

Metabolism of glyphosate in an Arthrobacter sp. GLP-1

The metabolism of glyphosate [N-(phosphonomethyl)glycine] in a bacterium tentatively identified as an Arthrobacter sp., capable of growth on this herbicide as its sole phosphorus source, has been investigated using solid-state NMR techniques as well as radiotracer analysis. The pathway involves the conversion of glyphosate to glycine, a C1 unit and phosphate. The phosphonomethyl carbon is specifically incorporated into the amino acids serine, cysteine, methionine, and histidine, as well as into purine bases and thymine, indicating the involvement of tetrahydrofolate in single-carbon transfer reactions. Glycine derived from glyphosate is utilized in purine and protein biosynthesis. This pathway for glyphosate degradation in a gram-positive bacterium is similar to that previously reported for Pseudomonas sp. PG2982 [Jacob et al. (1985) J. Biol. Chem. 260, 5899-5905] and is distinct from that reported for soil metabolism of glyphosate where aminomethylphosphonic acid has been shown to be a major metabolite. Preliminary evidence is presented which indicates that the conversion of glyphosate to glycine and the C1 unit involves the intermediate formation of sarcosine. Thus, the primary event in glyphosate degradation by Arthrobacter sp. GLP-1 is the cleavage of its C-P bound. This report constitutes the first demonstration of the metabolism of glyphosate in a gram-positive bacterium.     

Taxonomic notes on the paper wasps of the genus Ropalidia in the Indian subcontinent (Hymenoptera: Vespidae)

The taxonomy of Ropalidia wasps in the Indian subcontinent is revised, recognizing 26 species in the subcontinent. Their diagnostic characteristics are summarized in a key to species. New synonymies proposed in the present study are: R. bicolorata shiva Das and Gupta, 1989 under R. bicolorata van der Vecht, 1962; R. colorata sordida van der Vecht, 1941 under R. colorata van der Vecht, 1941; R. rodialipa Lambert and Narendran, 2005 and R. anupama Lambert and Narendran, 2005, both under R. cyathiformis Fabricius, 1804; R. jacobsoni flavoscutellata Das and Gupta, 1989, and R. bangalorica Lambert and Narendran, 2005, both under R. jacobsoni du Buysson, 1908; R. travancorica Lambert and Narendran, 2005, under R. marginata Lepeletier, 1836; R. sridharani Lambert and Narendran, 2005, under R. rufocollaris Cameron, 1900; Ropalidia rufoplagiata nursei van der Vecht, 1941 under R. rufoplagiata Cameron, 1905; Icaria lugubris Smith, 1858, under R. sumatrae Weber, 1801; and a revised synonymy is Icaria pendula Smith, 1857, under R. variegata Smith, 1852. The new replacement name Ropalidia kasaragodensis Lambert and Narendran is proposed for R. indica Lambert and Narendran, 2005, non van der Vecht, 1941.     

Fungitoxicity of some higher plants againstRhizoctonia solani

Summary Leaves ofChenopodium ambrosioides exhibited strong fungitoxicity against the mycelial growth ofRhizoctonia solani causing damping off diseases of some seedlings. Minimum inhibitory concentration of the fungitoxic constituent isolated in form of essential oil, was found to be 1000 ppm at which it was fungicidal in nature. It exhibited broad range of antifungal activity and did not show any phytotoxicity on the germination and seedling growth ofPhaseolus aureus.     

Stimulation of immune suppressive CD34+ cells from normal bone marrow by Lewis lung carcinoma tumors

 Progressive growth of metastatic Lewis lung carcinoma (LLC-LN7) tumors is associated with increased levels of bone-marrow-derived CD34⁺ cells having natural suppressor (NS) activity toward T cells. The present studies determined whether tumor-derived products are responsible for this induction of NS activity. Culturing normal bone marrow cells with LLC-LN7-conditioned medium (LLC-CM) or with recombinant granulocyte/macrophage-colony-stimulating factor (GM-CSF) resulted in the appearance of NS activity. The development of NS activity coincided with a prominent increase in the levels of CD34⁺ cells. That the CD34⁺ cells were responsible for the NS activity of the bone marrow cultures containing LLC-CM was shown by the loss of NS activity when CD34⁺ cells were depleted. The stimulation of CD34⁺ NS cells by LLC-CM was attributed to tumor production of GM-CSF, since neutralization of GM-CSF within the LLC-CM reduced its capacity to increase CD34⁺ cell levels. Studies also showed that the induction of CD34⁺ NS cells by LLC-CM and GM-CSF could be overcome by including in the cultures an inducer of myeloid differentiation, 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]. These results demonstrate that the mechanism by which the LLC-LN7 tumors stimulate increased levels of CD34⁺ NS cells from normal bone marrow is by their production of GM-CSF and that this can be blocked with the myeloid differentiation inducer 1,25(OH)₂D₃. Received: 8 December 1997 / Accepted: 27 February 1998     

Unilateral naris occlusion and the rat accessory olfactory bulb

Blocking airflow through half of the nasal cavity during early life results in a 25% reduction in the size of the ipsilateral main olfactory bulb. The present study indicates that the size of the accessory bulb is relatively unaffected by the procedure.