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Christoph J Heuck,
Jackie Szymonifka,
Emily Hansen,
John D Shaughnessy,
Saad Z Usmani,
Frits van Rhee,
Elias Anaissie, Bijay Nair,
Sarah Waheed,
Yazan Alsayed,
Nathan Petty,
Clyde Bailey,
Joshua Epstein,
Antje Hoering,
John Crowley,
Bart Barlogie
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ABSTRACT: Because dexamethasone remains a key component of myeloma therapy, we wished to examine the impact of baseline and relapse expression levels of the glucocorticoid receptor gene NR3C1 on survival outcomes in the context of treatment with or without thalidomide.
We investigated the clinical impact of gene expression profiling (GEP)-derived expression levels of NR3C1 in 351 patients with GEP data available at baseline and in 130 with data available at relapse, among 668 subjects accrued to total therapy 2 (TT2).
Low NR3C1 expression levels had a negative impact on progression-free survival (PFS; HR, 1.47; P = 0.030) and overall survival (OS; HR, 1.90; P = 0.002) in the no-thalidomide arm. Conversely, there was a significant clinical benefit of thalidomide for patients with low receptor levels (OS: HR, 0.54; P = 0.015; PFS: HR, 0.54; P = 0.004), mediated most likely by thalidomide's upregulation of NR3C1. In the context of both baseline and relapse parameters, post-relapse survival (PRS) was adversely affected by low NR3C1 levels at relapse in a multivariate analysis (HR, 2.61; P = 0.012).
These findings justify the inclusion of NR3C1 expression data in the work-up of patients with myeloma as it can significantly influence the choice of therapy and, ultimately, OS. The identification of an interaction term between thalidomide and NR3C1 underscores the importance of pharmacogenomic studies in the systematic study of new drugs. Clin Cancer Res; 18(19); 5499-506. ©2012 AACR.
Clinical Cancer Research 08/2012; 18(19):5499-506. · 7.74 Impact Factor
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Sarah Waheed,
Alan Mitchell,
Saad Usmani,
Joshua Epstein,
Shmuel Yaccoby, Bijay Nair,
Rudy Van Hemert,
Edgardo Angtuaco,
Tracy Brown,
Twyla Bartel,
James McDonald,
Elias Anaissie,
Frits van Rhee,
John Crowley,
Bart Barlogie
[show abstract]
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ABSTRACT: Background. Multiple myeloma causes major morbidity resulting from osteolytic lesions that can be detected by metastatic bone surveys. Magnetic resonance imaging and positron emission tomography can detect bone marrow focal lesions long before development of osteolytic lesions.Design and Methods: Using data from patients enrolled in Total Therapy 3 for newly diagnosed myeloma (N=303), we analyzed associations of these imaging techniques with baseline standard laboratory variables assessed before initiating treatment. Of 270 patients with complete imaging data, 245 also had gene expression profiling data. Results. Osteolytic lesions detected on metastatic bone surveys correlated with focal lesions detected by magnetic resonance imaging and positron emission tomography, although, in two-way comparisons, focal lesion counts based on both magnetic resonance imaging and positron emission tomography tended to be greater than those based on metastatic bone survey. Higher numbers of focal lesions detected by magnetic resonance imaging and positron emission tomography were positively linked to high serum concentrations of C-reactive protein, gene-expression-profiling-defined high risk, and the Proliferation molecular subgroup. Positron emission tomography focal lesion maximum standardized unit values were significantly correlated with gene-expression-profiling-defined high risk and higher numbers of focal lesions detected by positron emission tomography. Interestingly, four genes associated with high-risk disease (related to cell cycle and metabolism) were linked to counts of focal lesions detected by magnetic resonance imaging and positron emission tomography. Conclusions. Collectively, our results demonstrate significant associations of all three imaging techniques with tumor burden and, especially, disease aggressiveness captured by gene-expression-profiling-risk designation. (clinicaltrials.gov identifier: NCT00081939).
Haematologica 06/2012; · 6.42 Impact Factor
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Saad Z Usmani,
Christoph Heuck,
Alan Mitchell,
Jackie Szymonifka, Bijay Nair,
Antje Hoering,
Yazan Alsayed,
Sarah Waheed,
Sajjad Haider,
Alejandro Restrepo,
Frits van Rhee,
John Crowley,
Bart Barlogie
[show abstract]
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ABSTRACT: Background. Extramedullary disease is an uncommon manifestation in multiple myeloma and can either accompany newly diagnosed disease or can develop with disease progression or relapse. We evaluated the impact of this disease feature on patient outcome in the context of novel agents. Design and Methods. We analyzed clinical and biological features of extramedullary disease in 936 patients with multiple myeloma enrolled in Total Therapy protocols, 240 patients in non-Total Therapy protocols, and 789 non-protocol patients, all of whom had baseline PET scans to document extramedullary disease at diagnosis and its subsequent development at the time of disease progression or relapse.Results. The most common sites for extramedullary disease at diagnosis were skin and soft tissue whereas liver involvement was the striking feature in extramedullary disease at disease relapse or progression. Regardless of therapy, extramedullary disease was associated with shorter progression-free and overall survival, as well presence of anemia, thrombocytopenia, elevated serum LDH, cytogenetic abnormalities, and high-risk features in 70- and 80-gene risk models in univariate analysis. Multivariate analysis with logistic regression revealed that this disease feature was more prevalent in patients with elevated centrosome index by gene expression profiling, as well as myeloma molecular subtypes that are more prone for relapse. These include MF subtype (also called MAF subtype, associated with over expression of MAF gene seen with chromosome translocation 14;16 or translocation 14;20, respectively) and PR subtype (also called "Proliferation" subtype, associated with overexpression of pro-proliferative genes). Conclusions. These data show that extramedullary disease is more prevalent in genomically defined high risk multiple myeloma and is associated with a shorter progression free survival and overall survival, even in the era of novel agents.All clinical trials included in the analyses were registered with www.clinicaltrials.gov.
Haematologica 06/2012; · 6.42 Impact Factor
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Saad Z Usmani,
Rachel Sexton,
Antje Hoering,
Christoph J Heuck, Bijay Nair,
Sarah Waheed,
Yazan Al Sayed,
Nabeel Chauhan,
Nisar Ahmad,
Shebli Atrash,
Nathan Petty,
Frits van Rhee,
John Crowley,
Bart Barlogie
[show abstract]
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ABSTRACT: Thalidomide and lenalidomide constitute an important part of effective myeloma therapy. Recent data from the Intergroup Francophone du Myélome, Cancer and Leukemia Group B, and Gruppo Italiano Malattie Ematologiche dell Adulto MM-015 trials suggest that lenalidomide maintenance therapy is associated with a higher incidence of second primary malignancies (SPMs), including both hematologic and solid malignancies. In the present study, we analyzed data from the Total Therapy 2 (TT2) trial, along with the 2 Total Therapy 3 (TT3) trials. TT2 patients were assigned randomly to either a control group (no thalidomide) or to the experimental group (thalidomide during induction, between transplantations, and during consolidation and maintenance). The 2 TT3 trials used thalidomide and bortezomib during induction, before and in consolidation after tandem melphalan-based transplantation; TT3A applied VTD (bortezomib, thalidomide, dexamethasone) in the first year of maintenance and TD for 2 more years, whereas TT3B used VRD (bortezomib, lenalidomide, dexamethasone) maintenance for 3 years. The cumulative incidence of SPMs did not differ significantly among the TT trial components when measured from enrollment (P = .78) or from initiation of maintenance (P = .82). However, a pairwise comparison of the TT2 arms suggested a lower incidence of hematologic SPMs in the thalidomide maintenance arm (hazard ratio = 0.38; P = .09). These trials are registered at www.clinicaltrials.gov as NCT00573391 (TT2), NCT00081939 (TT3A), and NCT00572169 (TT3B).
Blood 06/2012; 120(8):1597-600. · 9.90 Impact Factor
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John D Shaughnessy,
Pingping Qu,
Saad Usmani,
Christoph J Heuck,
Qing Zhang,
Yiming Zhou,
Erming Tian,
Ichiro Hanamura,
Frits van Rhee,
Elias Anaissie,
Joshua Epstein, Bijay Nair,
Owen Stephens,
Ryan Williams,
Sarah Waheed,
Yazan Alsayed,
John Crowley,
Bart Barlogie
[show abstract]
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ABSTRACT: Gene expression profiling (GEP) of purified plasma cells 48 hours after thalidomide and dexamethasone test doses showed these agents' mechanisms of action and provided prognostic information for untreated myeloma patients on Total Therapy 2 (TT2). Bortezomib was added in Total Therapy 3 (TT3), and 48 hours after bortezomib GEP analysis identified 80 highly survival-discriminatory genes in a training set of 142 TT3A patients that were validated in 128 patients receiving TT3B. The 80-gene GEP model (GEP80) also distinguished outcomes when applied at baseline in both TT3 and TT2 protocols. In context of our validated 70-gene model (GEP70), the GEP80 model identified 9% of patients with a grave prognosis among those with GEP70-defined low-risk disease and 41% of patients with favorable prognosis among those with GEP70-defined high-risk disease. PMSD4 was 1 of 3 genes common to both models. Residing on chromosome 1q21, PSMD4 expression is highly sensitive to copy number. Both higher PSMD4 expression levels and higher 1q21 copy numbers affected clinical outcome adversely. GEP80 baseline-defined high risk, high lactate dehydrogenase, and low albumin were the only independent adverse variables surviving multivariate survival model. We are investigating whether second-generation proteasome inhibitors (eg, carfilzomib) can overcome resistance associated with high PSMD4 levels.
Blood 05/2011; 118(13):3512-24. · 9.90 Impact Factor
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Xin Li,
Wen Ling,
Angela Pennisi,
Yuping Wang,
Sharmin Khan,
Mohammad Heidaran,
Ajai Pal,
Xiaokui Zhang,
Shuyang He,
Andy Zeitlin,
Stewart Abbot,
Herbert Faleck,
Robert Hariri,
John D Shaughnessy,
Frits van Rhee, Bijay Nair,
Bart Barlogie,
Joshua Epstein,
Shmuel Yaccoby
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ABSTRACT: Human placenta has emerged as a valuable source of transplantable cells of mesenchymal and hematopoietic origin for multiple cytotherapeutic purposes, including enhanced engraftment of hematopoietic stem cells, modulation of inflammation, bone repair, and cancer. Placenta-derived adherent cells (PDACs) are mesenchymal-like stem cells isolated from postpartum human placenta. Multiple myeloma is closely associated with induction of bone disease and large lytic lesions, which are often not repaired and are usually the sites of relapses. We evaluated the antimyeloma therapeutic potential, in vivo survival, and trafficking of PDACs in the severe combined immunodeficiency (SCID)-rab model of medullary myeloma-associated bone loss. Intrabone injection of PDACs into nonmyelomatous and myelomatous implanted bone in SCID-rab mice promoted bone formation by stimulating endogenous osteoblastogenesis, and most PDACs disappeared from bone within 4 weeks. PDACs inhibitory effects on myeloma bone disease and tumor growth were dose-dependent and comparable with those of fetal human mesenchymal stem cells (MSCs). Intrabone, but not subcutaneous, engraftment of PDACs inhibited bone disease and tumor growth in SCID-rab mice. Intratumor injection of PDACs had no effect on subcutaneous growth of myeloma cells. A small number of intravenously injected PDACs trafficked into myelomatous bone. Myeloma cell growth rate in vitro was lower in coculture with PDACs than with MSCs from human fetal bone or myeloma patients. PDACs also promoted apoptosis in osteoclast precursors and inhibited their differentiation. This study suggests that altering the bone marrow microenvironment with PDAC cytotherapy attenuates growth of myeloma and that PDAC cytotherapy is a promising therapeutic approach for myeloma osteolysis.
Stem Cells 02/2011; 29(2):263-73. · 7.78 Impact Factor
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[show abstract]
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ABSTRACT: Myeloma survival varies markedly with International Staging System classification, presence of cytogenetic abnormalities, and, especially, gene expression profiling-based risk and delTP53 status, whose collective impact has not been examined in the context of specific therapies.
The authors examined overall survival (OS), event-free survival (EFS), and complete response duration (CRD) in Total Therapy 2 with randomization to a control or thalidomide arm and in Total Therapy 3 with added bortezomib. Among 612 patients with complete data sets, multivariate analyses were used to investigate the relative contributions to OS, EFS, and CRD of International Staging System stage, cytogenetic abnormalities, and gene expression profiling-derived risk and delTP53 status, in the context of the 3 Total Therapy regimens.
Whereas gene expression profiling risk segregated outcomes within all 3 International Staging System stages, International Staging System 3 conferred inferior prognosis only in low-risk myeloma, whereas the grave prognosis of high-risk disease was International Staging System-independent. After adjusting for gene expression profiling-defined high risk and delTP53 in multivariate analysis, International Staging System 3 and cytogenetic abnormalities both retained independent adverse implications for OS, EFS, and CRD. Among the 86% with low-risk disease, cytogenetic abnormalities and delTP53 both affected all 3 endpoints negatively, whereas the International Staging System 3 effect was limited to OS. Total Therapy 3 improved survival outcomes beyond results obtained with Total Therapy 2.
In the genomic era, standard laboratory variables, such as International Staging System stage and presence of cytogenetic abnormalities, continue to impact survival after adjusting for gene expression profiling risk and delTP53 status, providing a basis for stratification in our current practice of gene expression profiling risk-based treatment assignment.
Cancer 10/2010; 117(5):1001-9. · 4.77 Impact Factor
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Frits van Rhee,
Jackie Szymonifka,
Elias Anaissie, Bijay Nair,
Sarah Waheed,
Yazan Alsayed,
Nathan Petty,
John D Shaughnessy,
Antje Hoering,
John Crowley,
Bart Barlogie
[show abstract]
[hide abstract]
ABSTRACT: The impact of cumulative dosing and premature drug discontinuation (PMDD) of bortezomib (V), thalidomide (T), and dexamethasone (D) on overall survival (OS), event-free survival (EFS), time to next therapy, and post-relapse survival in Total Therapy 3 were examined, using time-dependent methodology, relevant to induction, peritransplantation, consolidation, and maintenance phases. Univariately, OS and EFS were longer in case higher doses were used of all agents during induction, consolidation (except T), and maintenance (except V and T). The favorable OS and EFS impact of D induction dosing provided the rationale for examining the expression of glucocorticoid receptor NR3C1, top-tertile levels of which significantly prolonged OS and EFS and rendered outcomes independent of D and T dosing, whereas T and D, but not V, dosing was critical to outcome improvement in the bottom-tertile NR3C1 setting. PMDD of V was an independent highly adverse feature for OS (hazard ratio = 6.44; P < .001), whereas PMDD of both T and D independently imparted shorter time to next therapy. The absence of adverse effects on postrelapse survival of dosing of any VTD components and indeed a benefit from V supports the use up-front of all active agents in a dose-dense and dose-intense fashion, as practiced in Total Therapy 3, toward maximizing myeloma survival.
Blood 08/2010; 116(8):1220-7. · 9.90 Impact Factor
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Bijay Nair
Oncology (Williston Park, N.Y.) 08/2010; 24(9):836. · 1.03 Impact Factor
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ABSTRACT: The Total Therapy 3 trial 2003-33 enrolled 303 newly diagnosed multiple myeloma patients and was noted to provide superior clinical outcomes compared with predecessor trial Total Therapy 2, especially in gene expression profiling (GEP)-defined low-risk disease. We report here on the results of successor trial 2006-66 with 177 patients, using bortezomib, lenalidomide, and dexamethasone maintenance for 3 years versus bortezomib, thalidomide, and dexamethasone in year 1 and thalidomide/dexamethasone in years 2 and 3 in the 2003-33 protocol. Overall survival (OS) and event-free survival (EFS) plots were super-imposable for the 2 trials, as were onset of complete response and complete response duration (CRD), regardless of GEP risk. GEP-defined high-risk designation, pertinent to 17% of patients, imparted inferior OS, EFS, and CRD in both protocols and, on multivariate analysis, was the sole adverse feature affecting OS, EFS, and CRD. Mathematical modeling of CRD in low-risk myeloma predicted a 55% cure fraction (P < .001). Despite more rapid onset and higher rate of CR than in other molecular subgroups, CRD was inferior in CCND1 without CD20 myeloma, resembling outcomes in MAF/MAFB and proliferation entities. The robustness of the GEP risk model should be exploited in clinical trials aimed at improving the notoriously poor outcome in high-risk disease.
Blood 05/2010; 115(21):4168-73. · 9.90 Impact Factor
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Yiming Zhou,
Lijuan Chen,
Bart Barlogie,
Owen Stephens,
Xiaosong Wu,
David R Williams,
Marie-Astrid Cartron,
Frits van Rhee, Bijay Nair,
Sarah Waheed,
Mauricio Pineda-Roman,
Yazan Alsayed,
Elias Anaissie,
John D Shaughnessy
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ABSTRACT: MicroRNAs (miRNAs) are noncoding RNAs that regulate global gene expression. miRNAs often act synergistically to repress target genes, and their dysregulation can contribute to the initiation and progression of a variety of cancers. The clinical relationship between global expression of miRNA and mRNA in cancer has not been studied in detail. We used whole-genome microarray analyses of CD138-enriched plasma cells from 52 newly diagnosed cases of multiple myeloma to correlate miRNA expression profiles with a validated mRNA-based risk stratification score, proliferation index, and predefined gene sets. In stark contrast to mRNAs, we discovered that all tested miRNAs were significantly up-regulated in high-risk disease as defined by a validated 70-gene risk score (P < 0.01) and proliferation index (P < 0.05). Increased expression of EIF2C2/AGO2, a master regulator of the maturation and function of miRNAs and a component of the 70-gene mRNA risk model, is driven by DNA copy number gains in MM. Silencing of AGO2 dramatically decreased viability in MM cell lines. Genome-wide elevated expression of miRNAs in high-risk MM may be secondary to deregulation of AGO2 and the enzyme complexes that regulate miRNA maturation and function.
Proceedings of the National Academy of Sciences 04/2010; 107(17):7904-9. · 9.68 Impact Factor
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John D Shaughnessy,
Yiming Zhou,
Jeff Haessler,
Frits van Rhee,
Elias Anaissie, Bijay Nair,
Sarah Waheed,
Yazan Alsayed,
Joshua Epstein,
John Crowley,
Bart Barlogie
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[hide abstract]
ABSTRACT: Contrary to Total Therapy (TT) 2 for multiple myeloma patients, FGFR3- translocation bore no adverse effects on outcome in TT3 with added bortezomib. Del TP53, another poor-risk feature in TT2 and present in 10% of 441 patients treated, was examined for its prognostic consequences in TT3. Not affecting rate or duration of complete response, TP53 haplo-insufficiency also did not compromise, in the 83% with genomically defined low-risk myeloma, survival or event-free survival. FGFR3+ and FGFR3- molecular subgroups fared worse in the presence of del TP53 when applying TT2 but not TT3. Thus, the prognostic implications of del TP53 were protocol-, genome-defined risk- and molecular subgroup-dependent.
British Journal of Haematology 09/2009; 147(3):347-51. · 4.94 Impact Factor
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Antje Hoering,
John Crowley,
John D Shaughnessy,
Klaus Hollmig,
Yazan Alsayed,
Jackie Szymonifka,
Sarah Waheed, Bijay Nair,
Frits van Rhee,
Elias Anaissie,
Bart Barlogie
[show abstract]
[hide abstract]
ABSTRACT: Landmark analyses are used to investigate the importance for survival of achieving complete response (CR), an important initial goal of myeloma therapy. With median times to CR in Total Therapy (TT) trials of approximately 1 year, this approach excludes a sizeable fraction of patients dying before such a landmark. To permit inclusion of all trial participants, we investigated the prognostic implications of both onset and duration of CR as time-dependent variables. Superseding the adverse effects of cytogenetic abnormalities and other standard prognostic parameters, both failure to achieve CR (non-CR) and, especially, loss of CR (los-CR) were independently associated with inferior survival in TT1, TT2, and TT3 protocols. In the context of gene array-defined risk, available in TT2 and TT3 subsets, both los-CR and non-CR terms were retained in the survival model as dominant adverse variables, stressing the prognostic importance of sustaining CR status, especially in high-risk disease.
Blood 07/2009; 114(7):1299-305. · 9.90 Impact Factor
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Bijay Nair,
John D Shaughnessy,
Yiming Zhou,
Marie Astrid-Cartron,
Pingping Qu,
Frits van Rhee,
Elias Anaissie,
Yazan Alsayed,
Sarah Waheed,
Klaus Hollmig,
Jackie Szymonifka,
Nathan Petty,
Antje Hoering,
Bart Barlogie
[show abstract]
[hide abstract]
ABSTRACT: We report on prognostic implications for post-relapse survival (PRS) of a gene expression profiling (GEP)-defined risk score at relapse available in 120 myeloma patients previously enrolled in tandem transplantation trial Total Therapy 2. Among the 71 patients with additional GEP baseline information, 3-year PRS was 71% in 40 patients with low risk present both at baseline and relapse contrasting with only 17% in 28 patients with high risk at relapse, 12 of whom with baseline low-risk status fared better than the remainder (P = .08). On multivariate analysis of relapse parameters available in 104 patients, high risk conferred short PRS (hazard ratio = 4.00, P < .001, R(2) = 33%), whereas relapse hyperdiploidy predicted long PRS (hazard ratio = 0.37, P = .022, cumulative R(2) = 41%). In case the initial partial response lasted less than 2 years, relapse low-risk identified 26 patients with superior 3-year PRS of 61% versus 9% among 32 with relapse high-risk (P < .001). Based on its PRS predictive power, GEP analysis should be an integral part of new agent trials in search of better therapy for high-risk myeloma.
Blood 05/2009; 113(26):6572-5. · 9.90 Impact Factor
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ABSTRACT: The clinical significance of cytogenetic abnormalities (CA) present in randomly sampled (RS) or focal lesion (FL) bone marrow sites was examined in 419 untreated myeloma patients. Among 290 patients with gene expression profiling (GEP) data generated from RS sites, GEP-defined high-risk was present in 52% of the RS+/FL+ group but in only 9% of the remainder (P < 0.001). The RS+/FL+ constellation (18%) was an independent predictor of poor survival, also after adjusting for GEP-derived risk and TP53 status (Hazard ratio = 2.42, P = 0.004). The prevalence of high-risk myeloma in the RS+/FL+ group may reflect a dissemination-prone condition not shared by the other three groups.
British Journal of Haematology 03/2009; 145(5):637-41. · 4.94 Impact Factor
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ABSTRACT: Patients with smoking-related cancer have higher risks for recurrence if they continue to smoke.
To encourage cancer patients to quit smoking a motivational pocket calendar with information about smoking and cancer, tips for stopping, and logs for monitoring was distributed among 32 patients, along with a baseline questionnaire.
After 3 months, patients completed a second questionnaire. Twenty-one patients completed both questionnaires; 5 (24%) had quit smoking. The average number of cigarettes smoked per day dropped from 25.3 at baseline to 15.8 (P = .0001).
A pocket calendar appears to be a useful adjunct for smoking cessation.
Journal of Cancer Education 02/2009; 24(3):210-1. · 0.76 Impact Factor
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British Journal of Haematology 01/2009; 145(1):134-7. · 4.94 Impact Factor
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American Journal of Hematology 12/2007; 83(4):345 - 345. · 4.67 Impact Factor
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ABSTRACT: We report here a 57-year-old man treated with etanercept for 6 months for psoriasis who developed myelodysplasia with acute myeloid leukemia. Leukemia cells had distinct karyotype associated with poor prognosis. The patient did not respond to cytosine arabinoside 100 mg/m(2) continuous infusion over 7 days with daunorubicin 45 mg/m(2) daily for 3 days. He also did not respond to salvage induction therapy with gemtuzumab (6 mg/m(2) on day 1 and 4 mg/m(2) on day 8) and intravenous continuous infusion cytosine arabinoside 200 mg/m(2). We review other cases of lymphoma and leukemia associated with tumor necrosis factor inhibitors and suggest mechanisms by which inhibition of the TNF-alpha family may predispose to cancer. We also suggest that all patients being considered for TNF-alpha treatment be screened for hematologic malignancies or premalignancies with blood counts and bone marrow aspirates/biopsies if indicated.
American Journal of Hematology 12/2007; 82(11):1022-4. · 4.67 Impact Factor
