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53. S873 EFFICACY OF QUADRUPLET KCRD (CARFILZOMIB, CYCLOPHOSPHAMIDE, LENALIDOMIDE AND DEXAMETHASONE) INDUCTION FOR NEWLY DIAGNOSED MYELOMA PATIENTS: ANALYSIS OF THE MYELOMA XI STUDY BY MOLECULAR RISK

Author

Pawlyn, C., primary, Kaiser, M., additional, Davies, F., additional, Cairns, D., additional, Striha, A., additional, Hockaday, A., additional, Kishore, B., additional, Garg, M., additional, Williams, C., additional, Karunanithi, K., additional, Lindsay, J., additional, Jones, J., additional, Jenner, M., additional, Russell, N., additional, Cook, G., additional, Drayson, M., additional, Owen, R., additional, Gregory, W., additional, Morgan, G., additional, and Jackson, G., additional

Published
2019
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60. Neutral tumor evolution in myeloma is associated with poor prognosis

Author

Johnson, DC, Lenive, O, Mitchell, J, Jackson, G, Owen, R, Drayson, M, Cook, G, Jones, JR, Pawlyn, C, Davies, FE, Walker, BA, Wardell, C, Gregory, WM, Cairns, D, Morgan, GJ, Houlston, RS, and Kaiser, MF

Abstract

Recent studies suggest that the evolutionary history of a cancer is important in forecasting clinical outlook. To gain insight into the clonal dynamics of multiple myeloma (MM) and its possible influence on patient outcome we analysed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase III trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory therapy (IMiD). By analysing mutant allele frequency distributions in tumors we found that 17-20% of MM is under neutral evolutionary dynamics. These tumors are associated with poorer patient survival in non-intensively treated patients, consistent with reduced therapeutic efficacy of micro-environment modulating IMiD drugs. Our findings provide evidence that knowledge of the evolutionary history of MM has relevance for predicting patient outcome and personalising therapy.

Published
2017

61. Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial

Author

Jones, J R, Cairns, D A, Gregory, W M, Collett, C, Pawlyn, C, Sigsworth, R, Striha, A, Henderson, R, Kaiser, M F, Jenner, M, Cook, G, Russell, N H, Williams, C, Pratt, G, Kishore, B, Lindsay, J, Drayson, M T, Davies, F E, Boyd, K D, Owen, R G, Jackson, G H, and Morgan, G J

Subjects
Adult, Aged, 80 and over, Male, Vorinostat, fungi, Neoplasms, Second Primary, Kaplan-Meier Estimate, Middle Aged, Hydroxamic Acids, Disease-Free Survival, Thalidomide, Bortezomib, Risk Factors, Antineoplastic Combined Chemotherapy Protocols, Humans, Original Article, Female, Multiple Myeloma, Lenalidomide, Oligopeptides, Aged
Abstract

We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4–1.0%), 2.3% (95% CI 1.6–2.7%) and 3.8% (95% CI 2.9–4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2–26.4%), compared with 6.5% (95% CI 0.2–12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.

Published
2016

62. Myasthenia gravis and elderly people

Author

Schon, F., Drayson, M., and Thompson, R.A.

Subjects
Croydon, England -- Health aspects, Aged -- Diseases -- Health aspects, Myasthenia gravis -- Demographic aspects -- Health aspects, Health, Psychology and mental health, Seniors, Social sciences, Diseases, Demographic aspects, Health aspects
Abstract

Introduction The usually cited pattern of myasthenia gravis (MG) is that the incidence is 2-4/million [1-4] with a peak age of onset in women in the twenties and a less [...]

Published
1996

64. Minimal residual disease following autologous stem cell transplant in myeloma: impact on outcome is independent of induction regimen

Author

de Tute, R. M., primary, Rawstron, A. C., additional, Gregory, W. M., additional, Child, J. A., additional, Davies, F. E., additional, Bell, S. E., additional, Cook, G., additional, Szubert, A. J., additional, Drayson, M. T., additional, Jackson, G. H., additional, Morgan, G. J., additional, and Owen, R. G., additional

Published
2015
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65. High versus attenuated dose dexamethasone has little effect on the speed or depth of response to induction therapy for myeloma

Author

Giles, H., primary, Ferretti, L., additional, Cook, M., additional, Aung, Y.S., additional, Yadav, P., additional, Cockwell, P., additional, Pinney, J., additional, Davies, F.E., additional, Gregory, W.M., additional, Owen, R.G., additional, Jackson, G.H., additional, Child, J.A., additional, Morgan, G.J., additional, and Drayson, M., additional

Published
2015
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67. Presentation free light chain levels and age are the strongest predictors of renal function in newly diagnosed multiple myeloma patients

Author

Yadav, P., primary, Cockwell, P., additional, Cook, M., additional, Pinney, J., additional, Giles, H., additional, Aung, Y.S., additional, Gregory, W.M., additional, Owen, R.G., additional, Davies, F.E., additional, Jackson, G.H., additional, Child, A., additional, Morgan, G.J., additional, and Drayson, M., additional

Published
2015
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69. The quadruplet KCRD (carfilzomib, cyclophosphamide, lenalidomide, and dexamethasone) is safe and well tolerated as induction therapy for newly diagnosed, transplant eligible, myeloma patients

Author

Pawlyn, C., primary, Davies, F., additional, Cairns, D., additional, Collett, C., additional, Jones, J., additional, Kaiser, M., additional, Chalmers, A., additional, Striha, A., additional, Milligan, D., additional, Lindsay, J., additional, Chapman, C., additional, Allotey, D., additional, Shafeek, S., additional, Karunanithi, K., additional, Cook, G., additional, Russell, N., additional, Drayson, M., additional, Owen, R., additional, Gregory, W., additional, Jackson, G., additional, and Morgan, G., additional

Published
2015
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72. Guidelines for the correct determination of second primary malignancies in myeloma trials

Author

Jones, J., primary, Cairns, D., additional, Sigsworth, R., additional, Collett, C., additional, Pawlyn, C., additional, Striha, A., additional, Melchor, L., additional, Kaiser, M., additional, Drayson, M., additional, Davies, F., additional, Gregory, W., additional, Boyd, K., additional, Owen, R., additional, Jackson, G., additional, and Morgan, G., additional

Published
2015
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74. Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate

Author

Khanim, F., Davies, N., Veliça, P., Hayden, R., Ride, J., Pararasa, C., Chong, M.G., Gunther, U., Veerapen, N., Winn, P., Farmer, R., Trivier, E., Rigoreau, L., Drayson, M., Bunce, C., Khanim, F., Davies, N., Veliça, P., Hayden, R., Ride, J., Pararasa, C., Chong, M.G., Gunther, U., Veerapen, N., Winn, P., Farmer, R., Trivier, E., Rigoreau, L., Drayson, M., and Bunce, C.

Abstract

Background: We and others have identified the aldo-keto reductase AKR1C3 as a potential drug target in prostate cancer, breast cancer and leukaemia. As a consequence, significant effort is being invested in the development of AKR1C3-selective inhibitors. Methods: We report the screening of an in-house drug library to identify known drugs that selectively inhibit AKR1C3 over the closely related isoforms AKR1C1, 1C2 and 1C4. This screen initially identified tetracycline as a potential AKR1C3-selective inhibitor. However, mass spectrometry and nuclear magnetic resonance studies identified that the active agent was a novel breakdown product (4-methyl(de-dimethylamine)-tetracycline (4-MDDT)). Results: We demonstrate that, although 4-MDDT enters AML cells and inhibits their AKR1C3 activity, it does not recapitulate the anti-leukaemic actions of the pan-AKR1C inhibitor medroxyprogesterone acetate (MPA). Screens of the NCI diversity set and an independently curated small-molecule library identified several additional AKR1C3-selective inhibitors, none of which had the expected anti-leukaemic activity. However, a pan AKR1C, also identified in the NCI diversity set faithfully recapitulated the actions of MPA. Conclusions: In summary, we have identified a novel tetracycline-derived product that provides an excellent lead structure with proven drug-like qualities for the development of AKR1C3 inhibitors. However, our findings suggest that, at least in leukaemia, selective inhibition of AKR1C3 is insufficient to elicit an anticancer effect and that multiple AKR1C inhibition may be required.

Published
2014

77. The serotonin transporter (SLC6A4) is present in B-cell clones of diverse malignant origin: probing a potential anti-tumor target for psychotropics

Author

Meredith, E. J., Holder, M. J., Chamba, A., Challa, A., Drake-Lee, A., Bunce, C. M., Drayson, M. T., Pilkington, G., Blakely, R. D., Dyer, M. J., Barnes, N. M., and Gordon, J.

Subjects
Apoptosis/drug effects, Fluoxetine/pharmacology, N-Methyl-3,4-methylenedioxyamphetamine/pharmacology, Serotonin Plasma Membrane Transport Proteins/*analysis/drug effects/physiology, Psychotropic Drugs/*pharmacology, Clomipramine/pharmacology, Cell Line, Tumor, P-Glycoprotein/analysis, Humans, Proto-Oncogene Proteins c-bcl-2/analysis/physiology, Fenfluramine/pharmacology, Burkitt Lymphoma/*chemistry/drug therapy, Antineoplastic Agents/*pharmacology, Lymphoma, B-Cell/*chemistry/drug therapy
Abstract

Following our previous description of the serotonin transporter (SERT) acting as a conduit to 5-hydroxytryptamine (5-HT)-mediated apoptosis, specifically in Burkitt's lymphoma, we now detail its expression among a broad spectrum of B cell malignancy, while exploring additional SERT substrates for potential therapeutic activity. SERT was readily detected in derived B cell lines with origins as diverse as B cell precursor acute lymphoblastic leukemia, mantle cell lymphoma, diffuse large B cell lymphoma, and multiple myeloma. Concentration and timecourse kinetics for the antiproliferative and proapoptotic activities of the amphetamine derivatives fenfluramine (an appetite suppressant) and 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") revealed them as being similar to the endogenous indoleamine. A tricyclic antidepressant, clomipramine, instead mirrored the behavior of the selective serotonin reuptake inhibitor fluoxetine, both being effective in the low micromolar range. A majority of neoplastic clones were sensitive to one or more of the serotonergic compounds. Dysregulated bcl-2 expression, either by t(14;18)(q32;q21) translocation or its introduction as a constitutively active transgene, provided protection from proapoptotic but not antiproliferative outcomes. These data indicate a potential for SERT as a novel anti-tumor target for amphetamine analogs, while evidence is presented that the seemingly more promising antidepressants are likely impacting malignant B cells independently of the transporter itself. Faseb Journal

Published
2005

79. Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate

Author

Khanim, F, primary, Davies, N, additional, Veliça, P, additional, Hayden, R, additional, Ride, J, additional, Pararasa, C, additional, Chong, M G, additional, Gunther, U, additional, Veerapen, N, additional, Winn, P, additional, Farmer, R, additional, Trivier, E, additional, Rigoreau, L, additional, Drayson, M, additional, and Bunce, C, additional

Published
2014
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80. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: A report of the International Myeloma Working Group

Author

Kyle, R.A. Child, J.A. Anderson, K. Barlogie, B. Bataille, R. Bensinger, W. Bladé, J. Boccadoro, M. Dalton, W. Dimopoulos, M. Djulbegovic, B. Drayson, M. Durie, B. Facon, T. Fonseca, R. Gahrton, G. Greipp, P. Harousseau, J.L. Harrington, D. Hussein, M. Joshua, D. Ludwig, H. Morgan, G. Oken, M. Powles, R. Richardson, P. Roodman, D. San Miguel, J. Shimizu, K. Shustik, C. Sirohi, B. Sonneveld, P. Tricot, G. Turesson, I. Van Ness, B. Vesole, D. Weber, D. Westin, J. Wheatley, K.

Subjects
immune system diseases, hemic and lymphatic diseases
Abstract

The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations. In monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy, unattributed/unassociated (MG[u]), the monoclonal protein is < 30 g/1 and the bone marrow clonal cells < 10% with no evidence of multiple myeloma, other B-cell proliferative disorders or amyloidosis. In asymptomatic (smouldering) myeloma the M-protein is ≥ 30 g/1 and/or bone marrow clonal cells ≥ 10% but no related organ or tissue impairment (ROTI)(end-organ damage), which is typically manifested by increased calcium, renal insufficiency, anaemia, or bone lesions (CRAB) attributed to the plasma cell proliferative process. Symptomatic myeloma requires evidence of ROTL Non-secretory myeloma is characterized by the absence of an M-protein in the serum and urine, bone marrow plasmacytosis and ROTI. Solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas (± recurrent) are also defined as distinct entities. The use of these criteria will facilitate comparison of therapeutic trial data. Evaluation of currently available prognostic factors may allow better definition of prognosis in multiple myeloma.

Published
2003

81. Up-regulation of steroid sulphatase activity in HL60 promyelocytic cells by retinoids and 1alpha,25-dihydroxyvitamin D3

Author

Hughes, P J, Twist, L E, Durham, J, Choudhry, M A, Drayson, M, Chandraratna, R, Michell, R H, Kirk, C J, and Brown, G

Subjects
17-Hydroxysteroid Dehydrogenases, Base Sequence, Estrone, Reverse Transcriptase Polymerase Chain Reaction, Cell Differentiation, HL-60 Cells, Tretinoin, Up-Regulation, Calcitriol, Receptors, Estrogen, Enzyme Induction, polycyclic compounds, Humans, Steryl-Sulfatase, RNA, Messenger, Oxidation-Reduction, Cell Division, Research Article, Arylsulfatases, DNA Primers
Abstract

HL60 promyeloid cells express both classes of oestrogen receptor (ERalpha and ERbeta). We show that hydrolysis of oestrone sulphate by steroid sulphatase is a major source of oestrone in HL60 cells, and that most of the released oestrone is not metabolized further to 17beta-oestradiol. Treatment of HL60 cells with retinoids or 1alpha,25-dihydroxyvitamin D3 increased steroid sulphatase mRNA and activity in parallel with the induction of CD11b, an early marker of myeloid differentiation that is expressed before the differentiating cells stop proliferating. Use of agonists and antagonists against retinoid receptor-alpha and retinoid receptor-X revealed that both classes of retinoid receptor can drive steroid sulphatase up-regulation. Steroid sulphatase activity fluctuates during the cell cycle, being highest around the transition from G1 to S phase. During the differentiation of HL60 cells induced by all-trans-retinoic acid or 1alpha,25-dihydroxyvitamin D3, there is increased conversion of 17beta-oestradiol into oestrone by an oxidative 17beta-hydroxysteroid dehydrogenase. Treatment of Caco-2 colon adenocarcinoma cells with all-trans-retinoic acid or 1alpha,25-dihydroxyvitamin D3 also increases 17beta-oestradiol oxidation to oestrone. An increase in local oestrone production therefore occurs in multiple cell types following treatment with retinoids and 1alpha,25-dihydroxyvitamin D3. The possible involvement of locally produced oestrogenic steroids in regulating the proliferation and differentiation of myeloid cells is discussed.

Published
2001

84. Does zoledronic acid (ZOL) reduce skeletal-related events (SREs) and improve progression-free survival (PFS) in patients (Pts) with multiple myeloma (MM) with or without bone disease? MRC myeloma IX study results.

Author

Boyd, K., primary, Morgan, G., additional, Davies, F., additional, Wu, P., additional, Gregory, W., additional, Bell, S. E., additional, Szubert, A., additional, Navarro Coy, N., additional, Drayson, M., additional, Owen, R. G., additional, Feyler, S., additional, Ashcroft, J., additional, Ross, F., additional, Byrne, J., additional, Roddie, H., additional, Rudin, C., additional, Cook, G., additional, Jackson, G. H., additional, and Child, J. A., additional

Published
2011
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85. Are there benefits to long-term bisphosphonate treatment in multiple myeloma (MM)? Insights from temporal analyses of zoledronic acid (ZOL) versus clodronate (CLO) in the MRC Myeloma IX Trial.

Author

Davies, F., primary, Morgan, G., additional, Wu, P., additional, Gregory, W., additional, Bell, S. E., additional, Szubert, A., additional, Navarro Coy, N., additional, Drayson, M., additional, Owen, R. G., additional, Feyler, S., additional, Ashcroft, J., additional, Ross, F., additional, Byrne, J., additional, Roddie, H., additional, Rudin, C., additional, Cook, G., additional, Jackson, G. H., additional, Boyd, K., additional, and Child, J. A., additional

Published
2011
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86. Defining the biological subgroup of multiple myeloma patients which benefits maximally from the overall survival (OS) benefit associated with treatment with zoledronic acid (ZOL).

Author

Morgan, G. J., primary, Davies, F., additional, Gregory, W., additional, Bell, S. E., additional, Szubert, A., additional, Navarro Coy, N., additional, Drayson, M., additional, Owen, R. G., additional, Feyler, S., additional, Ashcroft, J., additional, Ross, F., additional, Byrne, J., additional, Roddie, H., additional, Rudin, C., additional, Cook, G., additional, Jackson, G. H., additional, Boyd, K., additional, Child, J. A., additional, and Wu, P., additional

Published
2011
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88. Multiple myeloma

Author

MacLennan, I. C., Drayson, M., and Dunn, J.

Subjects
Research Article
Abstract

Multiple myeloma occurs in over 2000 new patients in England and Wales each year. It presents most frequently as bone pain and patients tend to become dehydrated and may develop renal failure. No available treatment is curative, but about two thirds of patients achieve a stable response with low dose combination chemotherapy. Combination chemotherapy including doxorubicin and carmustine with the alkylating agents cyclophosphamide and melphalan achieve a higher stable response rate than conventional treatment with melphalan and prednisone without additional haematological toxicity. These responses are associated with loss of bone pain and patients remain symptom free for months without further treatment. Relapse occurs on average in a little under two years and, though second responses are frequently obtained, the disease eventually becomes refractory. This paper looks at who should be treated and the benefits that may be expected from the treatments available.

Published
1994

94. Cellular and mucosal immune reactions to mental and cold stress: Associations with gender and cardiovascular reactivity

Author

Willemsen, G., Carroll, D., Ring, C., Drayson, M., Willemsen, G., Carroll, D., Ring, C., and Drayson, M.

Abstract

To examine gender differences in immune reactions to stress and relationships between immune and cardiovascular reactivity, measures of cellular and mucosal immunity and cardiovascular activity were recorded in 77 men and 78 women at rest and in response to active (mental arithmetic) and passive (cold pressor) stress tasks. Both tasks reduced CD4+ T cells and the CD4/8 ratio. Total lymphocytes, NK cells, CD8+ T cells, and secretory immunoglobulin A (sIgA) increased with active stress. Passive stress decreased sIgA. At rest, men had more NK cells, less CD4+ T cells, and fewer neutrophils than women. Mental stress increased sIgA in men but not women. Cardiovascular reactivity to active stress was associated with increases in NK cells. The data support the hypothesis that stress-related increases in lymphocytes are beta-adrenergically mediated, and suggest that the fall in CD4+ T cells may be alpha-adrenergically driven. Mechanisms underlying sIgA reactions are more difficult to determine. Men and women differed in some cell counts, but not in reactivity, although gender influenced sIgA reactions to arithmetic.

Published
2002
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