%0 Journal Article
%~ PubMed
%A Gibson, J
%A Iland, H J
%A Larsen, S R
%A Brown, C M S
%A Joshua, D E
%T Leukaemias into the 21st century - part 2: the chronic leukaemias.
%B Internal Medicine Journal
%D 2013
%C Australia, United Kingdom, Netherlands, United States
%I Wiley-Blackwell Publishing Asia
%V 43
%N 5
%P 484-494
%@ 1445-5994
%X 
%Z FOR Codes: 111206


%0 Journal Article
%~ PubMed
%A Brown, Ross
%A Kabani, Karieshma
%A Favaloro, James
%A Yang, Shihong
%A Ho, P Joy
%A Gibson, John
%A Fromm, Phillip
%A Suen, Hayley
%A Woodland, Narelle
%A Nassif, Najah
%A Hart, Derek
%A Joshua, Douglas
%T CD86+ or HLA-G+ myeloma cells are associated with poor prognosis and once acquired by trogocytosis create novel Tregacq cells.
%B Blood
%D 2012
%C United States
%I American Society of Hematology
%V 120
%N 10
%P 2055-2063
%@ 0006-4971
%X The transfer of membrane proteins between cells during contact, known as trogocytosis, can create novel cells with a unique phenotype and altered function. We demonstrate that trogocytosis is more common in multiple myeloma (MM) than chronic lymphocytic leukaemia (CLL) and Waldenstrom''s macroglobulinaemia (WM); that T cells are more likely to be recipients than B or NK cells; that trogocytosis occurs independently of either the TCR receptor or HLA compatibility and that following trogocytosis, T cells with acquired antigens can become novel regulators of T cell proliferation. We screened 168 patients with MM and found that CD86 and HLA-G were antigens commonly acquired by T cells from malignant plasma cells. CD3(+)CD86(acq+) and CD3(+) HLA-G(acq+) cells were more prevalent in bone marrow than peripheral blood samples. The presence of either CD86 or HLA-G on malignant plasma cells was associated with a poor prognosis. CD38(++)side population (SP) cells expressed HLA-G, suggesting that these putative myeloma stem cells could generate immune tolerance. HLA-G(+) T cells had a regulatory potency similar to natural Tregs, thus providing another novel mechanism for MM to avoid effective immune surveillance.
%Z FOR Codes: 110709 111206


%0 Journal Article
%~ PubMed
%A Brown, C M S
%A Larsen, S R
%A Iland, H J
%A Joshua, D E
%A Gibson, J
%T Leukaemias into the 21st century: part 1: the acute leukaemias.
%B Internal Medicine Journal
%D 2012
%C Australia
%I Wiley-Blackwell Publishing Asia
%V 42
%N 11
%P 1179-1186
%@ 1445-5994
%X 
%Z FOR Codes: 110202 111206


%0 Journal Article
%~ PubMed
%A Hsu, D C
%A Wilkenfeld, P
%A Joshua, D E
%T Multiple myeloma
%B BMJ (Online)
%D 2012
%C United Kingdom
%I BMJ Group
%V 344
%N 7840
%P d7953
%@ 0959-8146
%X 
%Z FOR Codes: 110399


%0 Journal Article
%~ PubMed
%A Hsu, Danny C
%A Wilkenfeld, Peter
%A Joshua, Douglas E
%T Multiple myeloma.
%B BMJ
%D 2012
%C United Kingdom
%I BMJ Group
%V 344
%N 
%P d7953
%@ 1756-1833
%X 
%Z FOR Codes: 110399


%0 Journal Article
%~ PubMed
%A Ling, Silvia C W
%A Lau, Edwin K K
%A Al-Shabeeb, Ammira
%A Nikolic, Angela
%A Catalano, Albert
%A Iland, Harry
%A Horvath, Noemi
%A Ho, P Joy
%A Harrison, Simon
%A Fleming, Shaun
%A Joshua, Douglas E
%A Allen, John D
%T Response of myeloma to the proteasome inhibitor bortezomib is correlated with the unfolded protein response regulator XBP-1.
%B Haematologica
%D 2012
%C Italy
%I Fondazione Ferrata Storti
%V 97
%N 1
%P 64-72
%@ 1592-8721
%X Multiple myeloma, a malignancy of the antibody-secreting plasma cells, remains incurable by current therapy. However, the proteasome inhibitor bortezomib and other new drugs are revolutionizing its treatment. It remains unclear why myelomas are peculiarly sensitive to bortezomib, or what causes primary or acquired resistance. The ''unfolded protein response'' is necessary for folding and assembly of immunoglobulin chains in both normal and malignant plasma cells, as well as for the disposal of incorrectly folded or unpaired chains via the ubiquitin-proteasome pathway. We tested the hypothesis that levels of transcription factor XBP-1, a major regulator of the unfolded protein response, predict response to bortezomib.
%Z FOR Codes: 1112


%0 Journal Article
%~ PubMed
%A Ho, P Joy
%A Brown, Ross D
%A Spencer, Andrew
%A Jeffels, Melinda
%A Daniher, Daniel
%A Gibson, John
%A Joshua, Douglas E
%T Thalidomide consolidation improves progression-free survival in myeloma with normal but not up-regulated expression of fibroblast growth factor receptor 3: analysis from the Australasian Leukaemia and Lymphoma Group MM6 clinical trial.
%B Leukemia & Lymphoma
%D 2012
%C Switzerland
%I Informa Healthcare
%V 53
%N 9
%P 1728-1734
%@ 1029-2403
%X The translocation t(4;14) is associated with a poor prognosis in myeloma, but its effect in the setting of new drugs such as thalidomide, bortezomib and lenalidomide continues to be investigated, and the role of candidate genes such as FGFR3 (fibroblast growth factor receptor 3) is not yet clarified. In the Australasian Leukaemia and Lymphoma Group (ALLG) MM6 randomized study comparing consolidation thalidomide and prednisolone with prednisolone alone following autologous stem cell transplant, patients on consolidation thalidomide and prednisolone had superior progression-free (PFS) and overall survival (OS). We now show that thalidomide consolidation benefited both t(4;14)-positive (PFS 29 vs. 17 months, p =0.03) and -negative (52 vs. 24 months, p =0.04) disease. PFS for patients with normal FGFR3 expression was significantly better than for those with up-regulated FGFR3 (31 vs. 21 months, p =0.02). Consolidation thalidomide conferred an improved PFS in patients with normal FGFR3 expression (41 vs. 19 months, p =0.02), but there was no improvement in patients with up-regulated FGFR3 (31 vs. 29 months, p =0.76). We conclude that consolidation thalidomide may mitigate the poor prognostic effect of t(4;14), and improves PFS in normal but not up-regulated FGFR3 expression. Thus the level of FGFR3 expression provides additional prognostic information to t(4;14) in myeloma induction and consolidation therapy.
%Z FOR Codes: 110202


%0 Journal Article
%~ PubMed
%A Brown, Ross
%A Suen, Hayley
%A Favaloro, James
%A Yang, Shihong
%A Ho, P Joy
%A Gibson, John
%A Joshua, Douglas
%T Trogocytosis generates acquired regulatory T cells adding further complexity to the dysfunctional immune response in multiple myeloma.
%B Oncoimmunology
%D 2012
%C United States
%I Landes Bioscience
%V 1
%N 9
%P 1658-1660
%@ 2162-4011
%X 
%Z FOR Codes: 1107


%0 Journal Article
%~ PubMed
%A Mo, Sui-Lin
%A Li, Jia
%A Loh, Yen S
%A Brown, Ross D
%A Smith, Adrian L
%A Chen, Yuling
%A Joshua, Douglas
%A Roufogalis, Basil D
%A Li, George Q
%A Fan, Kei
%A Ng, Michelle C H
%A Sze, Daniel Man-Yuen
%T Factors influencing the abundance of the side population in a human myeloma cell line.
%B Bone Marrow Research
%D 2011
%C United States
%I Hindawi Publishing Corporation
%V 2011
%N 
%P 1-8
%@ 2090-3006
%X Side population (SP) refers to a group of cells, which is capable to efflux Hoechst 33342, a DNA-binding dye. SP cells exist both in normal and tumor tissues. Although SP abundance has been used as an indicator for disease prognostic and drug screening in many research projects, few studies have systematically examined the factors influencing SP analysis. In this study we aim to develop a more thorough understanding of the multiple factors involved in SP analysis including Hoechst 33342 staining and cell culture. RPMI-8226, a high SP percentage (SP%) human myeloma cell line was employed here. The results showed that SP% was subject to staining conditions including: viable cell proportion, dye concentration, staining cell density, incubation duration, staining volume, and mix interval. In addition, SP% was highest in day one after passage, while dropped steadily over time. This study shows that both staining conditions and culture duration can significantly affect SP%. In this case, any conclusions based on SP% should be interpreted cautiously. The relation between culture duration and SP% suggests that the incidence of SP cells may be related to cell proliferation and cell cycle phase. Maintaining these technical variables consistently is essential in SP research.
%Z FOR Codes: 111504


%0 Journal Article
%~ PubMed
%A Mitsiades, Constantine S
%A Davies, Faith E
%A Laubach, Jacob P
%A Joshua, Douglas
%A San Miguel, Jesus
%A Anderson, Kenneth C
%A Richardson, Paul G
%T Future Directions of Next-Generation Novel Therapies, Combination Approaches, and the Development of Personalized Medicine in Myeloma.
%B Journal of clinical oncology : official journal of the American Society of Clinical Oncology
%D 2011
%C United States
%I American Society of Clinical Oncology
%V 29
%N 14
%P 1916-23
%@ 1527-7755
%X Despite tangible progress in recent years, substantial therapeutic challenges remain in multiple myeloma (MM), particularly for patients at high risk for early relapse or death and for those with advanced multi-drug resistant disease and refractoriness to currently available combination regimens. Addressing these challenges requires identification of novel classes of anti-MM agents, their incorporation into safe and more effective combination regimens, and development of efficient algorithms to select the most appropriate therapeutic options for the clinical and molecular features of individual patients at a given time during their disease. Ideally, these goals can be facilitated by preclinical identification of the "driver" molecular lesions on which different myeloma subtypes exquisitely depend, and by informative preclinical models simulating the clinical setting(s) in which trials will be conducted. Large prospective studies of patients treated uniformly with contemporary clinical regimens are essential, but there is also a major need for flexibility in studying new regimens in the future. Long-term patient follow-up and integrated annotation of clinical (safety and efficacy) and correlative (molecular, biochemical, etc) data are also critical. Novel molecular profiling techniques will likely identify more clinically and biologically discrete subsets of patients with recurrent, even if infrequent, lesions. This molecular heterogeneity, combined with the increasing numbers of candidate therapeutic targets and respective investigational agents, may pose formidable challenges for the development and implementation of personalized medicine in MM. This review discusses these challenges, as well as potential strategies to address them, with the aim of making significant improvement in the clinical outcome of patients with MM.
%Z FOR Codes: 110399


%0 Journal Article
%~ PubMed
%A Khoo, Teh Liane
%A Vangsted, Annette Juul
%A Joshua, Douglas
%A Gibson, John
%T Interferon-alpha in the treatment of multiple myeloma.
%B Current Drug Targets
%D 2011
%C Netherlands
%I Bentham Science Publishers Ltd.
%V 12
%N 3
%P 437-446
%@ 1873-5592
%X Interferons are soluble proteins produced naturally by cells in response to viruses. It has both anti-proliferative and immunomodulating properties and is one of the first examples of a biological response modifier use to treat the haematological malignancy multiple myeloma. Interferon has been used in this clinical practice for over thirty years. However, despite considerable efforts, numerous clinical trials and two large meta-analysis, its exact role in the management of multiple myeloma still remains unclear. Its role in the treatment of multiple myeloma has been as a single induction agent, a co-induction agent with other chemotherapy regimens, and as maintenance therapy after conventional chemotherapy or complete remission after autologous or allogeneic transplantation. Interferon as a single induction agent or co-induction agent with other chemotherapy agents appears only to have minimal benefit in myeloma. Its role as maintenance therapy in the plateau phase of myeloma also remains uncertain. More recently, the use of interferon must now compete with the "new drugs"--thalidomide, lenalidomide and bortezomib in myeloma treatment. Will there be a future role of interferon in the treatment of multiple myeloma or will interferon be resigned to the history books remains to be seen.
%Z FOR Codes: 60108 60108


%0 Journal Article
%~ PubMed
%A Brown, Ross D
%A Langshaw, Mark R
%A Uhr, Elaine J
%A Gibson, John N
%A Joshua, Douglas E
%T The impact of mandatory fortification of flour with folic acid on the blood folate levels of an Australian population.
%B Medical Journal of Australia
%D 2011
%C Australia
%I Australasian Medical Publishing Company Pty. Ltd.
%V 194
%N 2
%P 65-67
%@ 0025-729X
%X To determine the impact that mandatory fortification with folic acid of wheat flour used in breadmaking has had on the blood folate levels of an Australian population since it was introduced in September 2009.
%Z FOR Codes: 1103


%0 Journal Article
%~ PubMed
%A Reid, S
%A Yang, S
%A Brown, R
%A Kabani, K
%A Aklilu, E
%A Ho, P J
%A Woodland, N
%A Joshua, D
%T Characterisation and relevance of CD138-negative plasma cells in plasma cell myeloma.
%B International journal of laboratory hematology
%D 2010
%C United Kingdom, Unit
%I Wiley-Blackwell Publishing Ltd.
%V 32
%N 6 Pt 1
%P e190-6
%@ 1751-5521
%X The use of CD138 to isolate CD138(+) plasma cells (PCs) from plasma cell myeloma (PCM) patients'' bone marrow samples has been used extensively in myeloma research. We sought to highlight the problem with this selection process, by demonstrating that a subpopulation of CD138??? plasma cells exists which is not included in these analyses.
%Z FOR Codes: 110399 110701 110701


%0 Journal Article
%~ PubMed
%A Li, Jia
%A Sze, Daniel M-Y
%A Brown, Ross D
%A Cowley, Mark J
%A Kaplan, Warren
%A Mo, Sui-Lin
%A Yang, Shihong
%A Aklilu, Esther
%A Kabani, Karieshma
%A Loh, Yen S
%A Yamagishi, Tetsuo
%A Chen, Yuling
%A Ho, P Joy
%A Joshua, Douglas E
%T Clonal expansions of cytotoxic T cells exist in the blood of patients with Waldenstrom's Macroglobulinaemia but exhibit anergic properties and are eliminated by nucleoside analogue therapy.
%B Blood
%D 2010
%C United States
%I American Society of Hematology
%V 115
%N 17
%P 3580-8
%@ 0006-4971
%X T cells contribute to host-tumor interactions in patients with monoclonal gammopathies. Expansions of CD8(+)CD57(+) T-cell receptor Vbeta-positive (TCRVbeta(+))-restricted cytotoxic T-cell (CTL) clones are found in 48% of patients with multiple myeloma and confer a favorable prognosis. We now report that CTL clones with varying TCRVbeta repertoire are present in 70% of patients with Waldenstr??m macroglobulinemia (WM; n = 20). Previous nucleoside analog (NA) therapy, associated with increased incidence of transformation to aggressive lymphoma, significantly influenced the presence of TCRVbeta expansions (chi(2) = 11.6; P < .001), as 83% of patients without (n = 6) and only 7% with (n = 14) TCRVbeta expansions had received NA. Clonality of CD3(+)CD8(+)CD57(+)TCRVbeta(+)-restricted CTLs was confirmed by TCRVbeta CDR3 size analysis and direct sequencing. The differential expression of CD3(+)CD8(+)CD57(+)TCRVbeta(+) cells was profiled using DNA microarrays and validated at mRNA and protein level. By gene set enrichment analysis, CTL clones expressed not only genes from cytotoxic pathways (GZMB, PRF1, FGFBP2) but also genes that suppress apoptosis, inhibit proliferation, arrest cell-cycle G1/S transition, and activate T cells (RAS, CSK, and TOB pathways). Proliferation tracking after stimulation confirmed their anergic state. Our studies demonstrate the incidence, NA sensitivity, and nature of clonal CTLs in WM and highlight mechanisms that cause anergy in these cells.
%Z FOR Codes: 110704 110709


%0 Journal Article
%~ PubMed
%A Berenson, James R
%A Anderson, Kenneth C
%A Audell, Robert A
%A Boccia, Ralph V
%A Coleman, Morton
%A Dimopoulos, Meletios A
%A Drake, Matthew T
%A Fonseca, Rafael
%A Harousseau, Jean-Luc
%A Joshua, Douglas
%A Lonial, Sagar
%A Niesvizky, Ruben
%A Palumbo, Antonio
%A Roodman, G David
%A San-Miguel, Jesus F
%A Singhal, Seema
%A Weber, Donna M
%A Zangari, Maurizio
%A Wirtschafter, Eric
%A Yellin, Ori
%A Kyle, Robert A
%T Monoclonal gammopathy of undetermined significance: a consensus statement.
%B British Journal of Haematology
%D 2010
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 150
%N 1
%P 28-38
%@ 1365-2141
%X On February 25, 2009, a panel of international experts on plasma cell dyscrasia and skeletal disease met to discuss monoclonal gammopathy of undetermined significance (MGUS). This non-malignant B-cell disorder is the most common plasma cell dyscrasia and is associated with an increased risk of developing serious B-cell disorders. Individuals with MGUS also have an increased risk of osteoporosis and osteopenia associated with an increased likelihood of developing fractures especially in the vertebral column, peripheral neuropathy and thromboembolic events. The goal of the meeting was to develop a consensus statement regarding the appropriate tests to screen, evaluate and follow-up patients with MGUS. The panel also addressed the identification and treatment of MGUS-related skeletal problems, thromboembolic events and neurological complications. The following consensus statement outlines the conclusions and marks the first time that a consensus statement for the screening and treatment of MGUS has been clearly stated.
%Z FOR Codes: 110202


%0 Journal Article
%~ PubMed
%A Nath, Christa E
%A Shaw, Peter J
%A Trotman, Judith
%A Zeng, Lihua
%A Duffull, Stephen B
%A Hegarty, Gareth
%A McLachlan, Andrew J
%A Gurney, Howard
%A Kerridge, Ian
%A Kwan, Yiu Lam
%A Presgrave, Peter
%A Tiley, Campbell
%A Joshua, Douglas
%A Earl, John
%T Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy.
%B British Journal of Clinical Pharmacology
%D 2010
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 69
%N 5
%P 484-497
%@ 1365-2125
%X WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * There has been one previous population pharmacokinetic analysis of total melphalan given as a short infusion in 84 adults (mixed diagnoses) and creatinine clearance and body size were found to be important determinants of total melphalan clearance. Dose and exposure to total melphalan were found to correlate with the development of mucositis. WHAT THIS STUDY ADDS * This is the largest population pharmacokinetic study on melphalan conducted to date. It is the first conducted in a uniform patient population (patients with multiple myeloma) and the first in which both total and unbound melphalan pharmacokinetics are examined. Factors found to be important determinants of total and unbound plasma clearance of melphalan were creatinine clearance, fat free mass and haematocrit. Haematocrit has not previously been identified as an influential covariate in any previous study. The importance of total and unbound melphalan exposure on transplant outcome was demonstrated by preliminary pharmacodynamic results showing significant associations with melphalan-related toxicity. A preliminary analysis of the association with disease response showed promising trends, but will be examined in more detail with longer follow-up of the whole cohort. AIMS To i) investigate the pharmacokinetics of total and unbound plasma melphalan using a population approach, ii) identify clinical factors that affect melphalan disposition and iii) evaluate the role of melphalan exposure in melphalan-related toxicity and disease response. METHODS Population pharmacokinetic modelling (using NONMEM) was performed with total and unbound concentration-time data from 100 patients (36-73 years) who had received a median 192 mg m(-2) melphalan dose. Model derived estimates of total and unbound melphalan exposure (AUC) in patients with serious melphalan toxicity and those who had a good disease response (>/=90% decrease in paraprotein concentrations) were compared using the Mann-Whitney test. RESULTS A two compartment model generated population mean estimates for total and unbound melphalan clearance (CL) of 27.8 and 128 l h(-1), respectively. Estimated creatinine clearance, fat free mass and haematocrit were important determinants of total and unbound CL, reducing the inter-individual variability in total CL from 34% to 27% and in unbound CL from 42% to 30%. Total AUC (range 4.9-24.4 mg l(-1) h) and unbound AUC (range 1.0-6.5 mg l(-1) h) were significantly higher in patients who had oral mucositis (>/=grade 3) and long hospital admissions (P < 0.01). Patients who responded well had significantly higher unbound AUC (median 3.2 vs. 2.8 mg l(-1) h, P < 0.05) when assessed from diagnosis to post-melphalan and higher total AUC (median 21.3 vs. 13.4 mg l(-1) h, P= 0.06), when assessed from pre- to post-melphalan. CONCLUSIONS Creatinine clearance, fat free mass and haematocrit influence total and unbound melphalan plasma clearance. Melphalan exposure is related to melphalan toxicity while the association with efficacy shows promising trends that will be studied further.
%Z FOR Codes: 699


%0 Journal Article
%~ PubMed
%A Dispenzieri, A
%A Kyle, R
%A Merlini, G
%A Miguel, J S
%A Ludwig, H
%A Hajek, R
%A Palumbo, A
%A Jagannath, S
%A Blade, J
%A Lonial, S
%A Dimopoulos, M
%A Comenzo, R
%A Einsele, H
%A Barlogie, B
%A Anderson, K
%A Gertz, M
%A Harousseau, J L
%A Attal, M
%A Tosi, P
%A Sonneveld, P
%A Boccadoro, M
%A Morgan, G
%A Richardson, P
%A Sezer, O
%A Mateos, M V
%A Cavo, M
%A Joshua, D
%A Turesson, I
%A Chen, W
%A Shimizu, K
%A Powles, R
%A Rajkumar, S V
%A Durie, B G M
%A , International Myeloma Working Group
%T International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders.
%B Leukemia
%D 2009
%C United Kingdom
%I Nature Publishing Group
%V 23
%N 2
%P 215-224
%@ 1476-5551
%X The serum immunoglobulin-free light chain (FLC) assay measures levels of free kappa and lambda immunoglobulin light chains. There are three major indications for the FLC assay in the evaluation and management of multiple myeloma and related plasma cell disorders (PCD). In the context of screening, the serum FLC assay in combination with serum protein electrophoresis (PEL) and immunofixation yields high sensitivity, and negates the need for 24-h urine studies for diagnoses other than light chain amyloidosis (AL). Second, the baseline FLC measurement is of major prognostic value in virtually every PCD. Third, the FLC assay allows for quantitative monitoring of patients with oligosecretory PCD, including AL, oligosecretory myeloma and nearly two-thirds of patients who had previously been deemed to have non-secretory myeloma. In AL patients, serial FLC measurements outperform PEL and immunofixation. In oligosecretory myeloma patients, although not formally validated, serial FLC measurements reduce the need for frequent bone marrow biopsies. In contrast, there are no data to support using FLC assay in place of 24-h urine PEL for monitoring or for serial measurements in PCD with measurable disease by serum or urine PEL. This paper provides consensus guidelines for the use of this important assay, in the diagnosis and management of clonal PCD.
%Z FOR Codes: 111299


%0 Journal Article
%~ PubMed
%A Palumbo, A
%A Sezer, O
%A Kyle, R
%A Miguel, J S
%A Orlowski, R Z
%A Moreau, P
%A Niesvizky, R
%A Morgan, G
%A Comenzo, R
%A Sonneveld, P
%A Kumar, S
%A Hajek, R
%A Giralt, S
%A Bringhen, S
%A Anderson, K C
%A Richardson, P G
%A Cavo, M
%A Davies, F
%A Bladé, J
%A Einsele, H
%A Dimopoulos, M A
%A Spencer, A
%A Dispenzieri, A
%A Reiman, T
%A Shimizu, K
%A Lee, J H
%A Attal, M
%A Boccadoro, M
%A Mateos, M
%A Chen, W
%A Ludwig, H
%A Joshua, D
%A Chim, J
%A Hungria, V
%A Turesson, I
%A Durie, B G M
%A Lonial, S
%A , IMWG
%T International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation.
%B Leukemia
%D 2009
%C United Kingdom
%I Nature Publishing
%V 23
%N 10
%P 1716-30
%@ 1476-5551
%X In 2005, the first guidelines were published on the management of patients with multiple myeloma (MM). An expert panel reviewed the currently available literature as the basis for a set of revised and updated consensus guidelines for the diagnosis and management of patients with MM who are not eligible for autologous stem cell transplantation. Here we present recommendations on the diagnosis, treatment of newly diagnosed non-transplant-eligible patients and the management of complications occurring during induction therapy among these patients. These guidelines will aid the physician in daily clinical practice and will ensure optimal care for patients with MM.
%Z FOR Codes: 111299


%0 Journal Article
%~ PubMed
%A Giralt, S
%A Stadtmauer, E A
%A Harousseau, J L
%A Palumbo, A
%A Bensinger, W
%A Comenzo, R L
%A Kumar, S
%A Munshi, N C
%A Dispenzieri, A
%A Kyle, R
%A Merlini, G
%A San Miguel, J
%A Ludwig, H
%A Hajek, R
%A Jagannath, S
%A Blade, J
%A Lonial, S
%A Dimopoulos, M A
%A Einsele, H
%A Barlogie, B
%A Anderson, K C
%A Gertz, M
%A Attal, M
%A Tosi, P
%A Sonneveld, P
%A Boccadoro, M
%A Morgan, G
%A Sezer, O
%A Mateos, M V
%A Cavo, M
%A Joshua, D
%A Turesson, I
%A Chen, W
%A Shimizu, K
%A Powles, R
%A Richardson, P G
%A Niesvizky, R
%A Rajkumar, S V
%A Durie, B G M
%A , IMWG
%T International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100).
%B Leukemia
%D 2009
%C United Kingdom
%I Nature Publishing
%V 23
%N 10
%P 1904-1912
%@ 1476-5551
%X Multiple myeloma is the most common indication for high-dose chemotherapy with autologous stem cell support (ASCT) in North America today. Stem cell procurement for ASCT has most commonly been performed with stem cell mobilization using colony-stimulating factors with or without prior chemotherapy. The target CD34+ cell dose to be collected as well as the number of apheresis performed varies throughout the country, but a minimum of 2 million CD34+ cells/kg has been traditionally used for the support of one cycle of high-dose therapy. With the advent of plerixafor (AMD3100) (a novel stem cell mobilization agent), it is pertinent to review the current status of stem cell mobilization for myeloma as well as the role of autologous stem cell transplantation in this disease. On June 1, 2008, a panel of experts was convened by the International Myeloma Foundation to address issues regarding stem cell mobilization and autologous transplantation in myeloma in the context of new therapies. The panel was asked to discuss a variety of issues regarding stem cell collection and transplantation in myeloma especially with the arrival of plerixafor. Herein, is a summary of their deliberations and conclusions.
%Z FOR Codes: 111299


%0 Journal Article
%~ PubMed
%A Dickinson, M
%A Prince, H M
%A Kirsa, S
%A Zannettino, A
%A Gibbs, S D J
%A Mileshkin, L
%A O'Grady, J
%A Seymour, J F
%A Szer, J
%A Horvath, N
%A Joshua, D E
%T Osteonecrosis of the jaw complicating bisphosphonate treatment for bone disease in multiple myeloma: an overview with recommendations for prevention and treatment.
%B Internal medicine journal
%D 2009
%C Australia, United Kingdom, Netherlands, United States
%I Wiley-Blackwell Publishing Asia
%V 39
%N 5
%P 304-316
%@ 1445-5994
%X Osteonecrosis of the Jaw (ONJ) is a recently recognised and potentially highly morbid complication of bisphosphonate therapy in the setting of metastatic malignancy, including myeloma. Members of the Medical and Scientific Advisory Group of the Myeloma Foundation of Australia formulated guidelines for the management of bisphosphonates around the issue of ONJ, based on the best available evidence in June 2008. Prior to commencement of therapy, patients should have an oral health assessment and be educated about the risks of ONJ. Dental assessment should occur 6 monthly during therapy. If tooth extraction is required, sufficient time should be allowed for complete healing to occur prior to commencement of bisphosphonate. As the risk of ONJ increases with duration of bisphosphonate therapy, we recommend annual assessment of dose with modification to 3 monthly i.v. therapy or to oral therapy with clodronate for those with all but the highest risk of skeletal-related event. Established ONJ should be managed conservatively; a bisphosphonate "drug holiday" is usually indicated and invasive surgery should generally be avoided. These recommendations will assist with clinical decision making for myeloma patients who are at risk of bisphosphonate-associated ONJ.
%Z FOR Codes: 111299


%0 Journal Article
%~ PubMed
%A Brown, Ross D
%A Spencer, Andrew
%A Ho, Phoebe Joy
%A Kennedy, Nola
%A Kabani, Karieshma
%A Yang, Shihong
%A Sze, Daniel M
%A Aklilu, Esther
%A Gibson, John
%A Joshua, Douglas E
%T Prognostically significant cytotoxic T cell clones are stimulated after thalidomide therapy in patients with multiple myeloma.
%B Leukemia and Lymphoma
%D 2009
%C United Kingdom
%I Informa Healthcare
%V 50
%N 11
%P 1860-1864
%@ 1029-2403
%X The expanded T cell clones are associated with a prolonged survival in patients with multiple myeloma. We sought to confirm this prognostic significance in a multicenter patient cohort and investigate the effect of thalidomide on clones and T regulatory cells (T(regs)). Blood was collected from 120 patients enrolled in a Phase III trial of maintenance therapy +/- thalidomide after autologous stem cell transplantation. TCR Vbeta repertoire analysis identified T cell expansions in 48% of patients pre-transplant and 68% after 8-month maintenance. T cell expansions, previously shown to be clonal, were predominantly CD8+ (93%) and all 24 TCR Vbeta families tested were represented. Thalidomide therapy was associated with a significant increase in the incidence of patients with multiple expansions (49% vs. 23%; chi2 = 6.8; p = 0.01). The presence of expansions regardless of therapy was associated with a significantly longer median progression free survival (PFS) (32.1 vs. 17.6 months; chi2 = 5.6; p = 0.02) and overall survival (OS) (chi2 = 3.9; p < 0.05). Median PFS in the thalidomide arm was 50.9 months for patients with expansions and 28.3 months for patients without expansions (chi2 = 19.4; p = 0.0002). Thalidomide did not appear to modulate T(reg) numbers. Expanded T cell clones are prognostically significant and have an impact on progression after thalidomide therapy in a proportion of patients.
%Z FOR Codes: 60199


%0 Journal Article
%~ PubMed
%A Loh, Yen S
%A Mo, Suilin
%A Brown, Ross D
%A Yamagishi, Tetsuo
%A Yang, Shihong
%A Joshua, Douglas E
%A Roufogalis, Basil D
%A Sze, Daniel M-Y
%T Presence of Hoechst low side populations in multiple myeloma.
%B Leukemia & Lymphoma
%D 2008
%C United Kingdom
%I Informa Healthcare
%V 49
%N 9
%P 1813-1816
%@ 1029-2403
%X 
%Z FOR Codes: 110709


%0 Journal Article
%~ PubMed
%A Joshua, Douglas E
%A Brown, Ross D
%A Ho, P Joy
%A Gibson, John
%T Regulatory T cells and Multiple Myeloma.
%B Clinical Lymphoma & Myeloma
%D 2008
%C United States
%I Cancer Information Group
%V 8
%N 5
%P 283-286
%@ 1557-9190
%X Many clinical observations point to active immunologic phenomena in patients with myeloma. These consist of active suppression of the host''s immune system and partially successful attempts by the host''s immune system to suppress the malignant B-cell population. Clinical conditions such as asymptomatic myeloma, which represents clinical presentation in the plateau phase of the disease, plateau establishment after conventional induction therapy without the ongoing need for therapy, and the positive prognostic importance of the presence of clones of cytotoxic T cells in the peripheral blood of some patients, suggest that host-tumor interaction is an active dynamic state. Regulatory T (Treg) cells comprise 5%-10% of peripheral CD4 T cells and are responsible for the control of autoimmune phenomena. Deficiency of the FoxP3 transcription factor, which normally characterizes Treg cells, leads to multiorgan autoimmune disorders in humans and mice. The role of Treg cells in the protection from malignancy is unclear, but their depletion can lead to the induction of tumor rejection in murine models, and their demonstration as tumorinfiltrating lymphocytes in malignancy point to a significant immunomodulator role. In myeloma, host-tumor immune interactions are complex. However, patients can clearly exhibit control of their B-cell malignancy for many years with stability of paraprotein levels, demonstrating a homeostasis between tumor and host. Whether Treg cells are playing a role in this homeostasis is unclear. At present, there is considerable debate in the literature regarding observations such as whether Treg cells are increased or decreased, functional or dysfunctional. In this review, we will discuss the potential importance of Treg cells and their role in myeloma, a disease characterized by a unique set of host-tumor interactions.
%Z FOR Codes: 1107


%0 Journal Article
%~ PubMed
%A Burgess, P
%A Robin, H
%A Langshaw, M
%A Kershaw, G
%A Pathiraja, R
%A Yuen, S
%A Coad, C
%A Xiros, N
%A Mansy, G
%A Coleman, R
%A Brown, R
%A Gibson, J
%A Holman, R
%A Hubbard, J
%A Wick, V
%A Lammers, M
%A Johnson, R
%A Huffman, K
%A Bell, J
%A Ibrahim, A
%A Estepa, F
%A Lovegrove, J
%A Joshua, D
%T Rule based processing of the CD4000, CD3200 and CD Sapphire analyser output using the Cerner Discern Expert Module.
%B International journal of laboratory hematology
%D 2008
%C United Kingdom
%I Wiley-Blackwell
%V 31
%N 0
%P 603-14
%@ 1751-5521
%X The latest version of our Laboratory Information System haematology laboratory expert system that handles the output of Abbott Cell-Dyn Sapphires, CD4000s and a CD3200 full blood count analyser in three high-volume haematology laboratories is described. The three hospital laboratories use Cerner Millennium Version 2007.02 software and the expert system uses Cerner Millennium Discern Expert rules and some small Cerner Command Language in-house programs. The entire expert system is totally integrated with the area-wide database and has been built and maintained by haematology staff members, as has the haematology database. Using patient demographic data, analyser numeric results, analyser error and morphology flags and previous results for the patient, this expert system decides whether to validate the main full blood count indices and white cell differential, or if the analyser results warrant further operator intervention/investigation before verifying, whether a blood film is required for microscopic review and if abnormal results require phoning to the staff treating the patient. The principles of this expert system can be generalized to different haematology analysers and haematology laboratories that have different workflows and different software.
%Z FOR Codes: 110202


%0 Journal Article
%~ PubMed
%A Cooper, C L
%A Joshua, D E
%A Lee, C S
%A Eyers, A A
%A Cooper, W A
%T Extranodal plasmablastic lymphoma arising in mantle cell lymphoma.
%B Histopathology
%D 2007
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 51
%N 6
%P 856-9
%@ 0309-0167
%X 
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Sanders, J
%A Crawford, B
%A Gibson, J
%A Joy Ho, P
%A Iland, H
%A Joshua, D
%T Is there a case for the early use of bisphosphonates in smouldering myeloma and MGUS? (Bisphosphonates in SMM & MGUS).
%B International journal of laboratory hematology
%D 2007
%C United Kingdom
%I Blackwell Publishing Ltd.
%V 29
%N 5
%P 395-397
%@ 1751-5521
%X 
%Z FOR Codes:


%0 Book Section
%A Ling, Silvia
%A Campbell, Lynda J
%A Ho, Joy
%A Gibson, John
%A Joshua, Douglas
%T Molecular Biology, Pathology, and Cytogenetics
%B Clinical Malignant Haematology
%D 2007
%C United States
%I McGraw Hill
%V 
%N 
%P 847-857
%@ 9780071436502
%E Sekeres, Mikkael A.
%E Kalaycio, Matt E.
%E Bolwell, Brian J.
%X 
%Z FOR Codes: 110202 111201


%0 Journal Article
%~ PubMed
%A Osborne, Richard H
%A De Abreu Lourenço, Richard
%A Dalton, Andrew
%A Houltram, Jennifer
%A Dowton, David
%A Joshua, Douglas Edgar
%A Lindeman, Robert
%A Ho, Phoebe Joy
%T Quality of life related to oral versus subcutaneous iron chelation: a time trade-off study.
%B Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research
%D 2007
%C United States
%I Wiley-Blackwell Publishing Inc.
%V 10
%N 6
%P 451-456
%@ 1524-4733
%X OBJECTIVE: To investigate the utility associated with subcutaneous infusion (deferoxamine) compared with once-daily oral administration (deferasirox) of iron chelation therapy. METHODS: Interviews using the time trade-off technique were used to estimate preferences (utility) for health states by finding the point at which respondents were indifferent between a longer but lower quality of life (QoL) and a shorter time in full health. Participants (n = 110) were community-based, 51% women, median age 35 years, from four regions in Sydney, Australia. Respondents rated three health states involving equal outcomes for people with thalassemia but with different treatment modalities for iron chelation; an "anchor state" describing a patient receiving iron chelation without administration mode specified, anchor state plus iron chelation via subcutaneous infusion, and anchor state plus iron chelation through once-daily oral medication. RESULTS: On an interval scale between 0 (death) and 1 (full health), median (interquartile range) utility of 0.80 (0.65-0.95) for the anchor state, 0.66 (0.45-0.87) for subcutaneous infusion, and 0.93 (0.80-0.97) for once-daily oral administration was obtained. The mean (median) difference of 0.23 (0.27) between the two treatments was statistically significant (Wilcoxon-signed rank test, P < 0.001). Subcutaneous infusion was associated with a mean (median) utility 0.13 (0.14) lower than the anchor state (P < 0.001), and once-daily oral treatment had a utility 0.10 (0.13) higher (P < 0.001). CONCLUSION: Community respondents associate oral administration of an iron chelator such as deferasirox with enhanced QoL compared with subcutaneous treatment. Assuming equal safety and efficacy, QoL gains from once-daily oral treatment compared with subcutaneous infusion are significant.
%Z FOR Codes: 110202 110502