Publications (64)530.46 Total impact
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Article: Multiple Myeloma, Version 1.2013.
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ABSTRACT: These NCCN Guidelines Insights highlight the important updates/changes specific to the management of relapsed or progressive disease in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include the addition of new regimens as options for salvage therapy and strategies to mitigate the adverse effects and risks associated with newer regimens for the treatment of multiple myeloma.Journal of the National Comprehensive Cancer Network: JNCCN 01/2013; 11(1):11-17. · 4.41 Impact Factor -
Article: Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2013.
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ABSTRACT: These NCCN Guidelines Insights highlight the important updates/changes specific to the management of Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma. These include the addition of regimens containing novel agents as primary and salvage therapy options, inclusion of the updated summary of response categories and criteria from the sixth international workshop on Waldenström's Macroglobulinemia, and a section on management of peripheral neuropathy in the accompanying discussion.Journal of the National Comprehensive Cancer Network: JNCCN 10/2012; 10(10):1211-1219. · 4.41 Impact Factor -
Article: Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy.
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ABSTRACT: Multiple myeloma is one of numerous malignancies characterized by increased glucose consumption, a phenomenon with significant prognostic implications in this disease. Few studies have focused on elucidating the molecular underpinnings of glucose transporter (GLUT) activation in cancer, knowledge that could facilitate identification of promising therapeutic targets. To address this issue, we performed gene expression profiling studies involving myeloma cell lines and primary cells as well as normal lymphocytes to uncover deregulated GLUT family members in myeloma. Our data demonstrate that myeloma cells exhibit reliance on constitutively cell surface-localized GLUT4 for basal glucose consumption, maintenance of Mcl-1 expression, growth, and survival. We also establish that the activities of the enigmatic transporters GLUT8 and GLUT11 are required for proliferation and viability in myeloma, albeit because of functionalities probably distinct from whole-cell glucose supply. As proof of principle regarding the therapeutic potential of GLUT-targeted compounds, we include evidence of the antimyeloma effects elicited against both cell lines and primary cells by the FDA-approved HIV protease inhibitor ritonavir, which exerts a selective off-target inhibitory effect on GLUT4. Our work reveals critical roles for novel GLUT family members and highlights a therapeutic strategy entailing selective GLUT inhibition to specifically target aberrant glucose metabolism in cancer.Blood 03/2012; 119(20):4686-97. · 9.90 Impact Factor -
Article: A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma.
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ABSTRACT: This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 + 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow-derived plasma cells was reliably saturated (≥ 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens.Blood 12/2011; 120(3):552-9. · 9.90 Impact Factor -
Article: Multiple myeloma.
Journal of the National Comprehensive Cancer Network: JNCCN 10/2011; 9(10):1146-83. · 4.41 Impact Factor -
Article: Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study
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ABSTRACT: Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T0). The median age at diagnosis was 58 years, and time from diagnosis to T0 was 3.3 years. Following T0, 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0–8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (44%) including partial response in 69 (32%). The median overall survival and event-free survival from T0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.Keywords: multiple myeloma; relapse; natural history; survivalLeukemia 07/2011; 26(1):149-157. · 9.56 Impact Factor -
Article: Alkaline phosphatase variation during carfilzomib treatment is associated with best response in multiple myeloma patients.
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ABSTRACT: The ubiquitin-proteasome pathway regulates bone formation through osteoblast differentiation. We analyzed variation alkaline phosphatase (ALP) during carfilzomib treatment. Data from 38 patients enrolled in the PX-171-003 and 29 patients in PX-171-004 studies, for patients with relapsed/refractory myeloma, were analyzed. All patients received 20 mg/m(2) of carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Sixty-seven patients from ALP data were evaluable. In PX-171-003, the ORR (>PR) was 18% and the clinical benefit response (CBR; >MR) was 26%, while in PX-171-004, the ORR was 35.5% overall and 57% in bortezomib-naive patients. ALP increment from baseline was statistically different in patients who achieved ≥ VGPR compared with all others on Days 1 (P = 0.0049) and 8 (P = 0.006) of Cycle 2. In patients achieving a VGPR or better, ALP increased more than 15 units per liter at Cycle 2 Day 1 over baseline. An ALP increase over the same period of time was seen in 26%, 13% and 11% of patients achieving PR, MR, and SD, respectively. This retrospective analysis of patients with relapsed or refractory myeloma treated with single-agent carfilzomib indicates that early elevation in ALP is associated with subsequent myeloma response.European Journal Of Haematology 06/2011; 86(6):484-7. · 2.61 Impact Factor -
Article: Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3.
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ABSTRACT: A panel of members of the 2009 International Myeloma Workshop developed guidelines for standard investigative workup of patients with suspected multiple myeloma. Both serum and urine should be assessed for monoclonal protein. Measurement of monoclonal protein both by densitometer tracing and/by nephelometric quantitation is recommended, and immunofixation is required for confirmation. The serum-free light chain assay is recommended in all newly diagnosed patients with plasma cell dyscrasias. Bone marrow aspiration and/or biopsy along with demonstration of clonality of plasma cells are necessary. Serum β(2)-microglobulin, albumin, and lactate dehydrogenase are necessary for prognostic purposes. Standard metaphase cytogenetics and fluorescent in situ hybridization for 17p, t(4;14), and t(14;16) are recommended. The skeletal survey remains the standard method for imaging screening, but magnetic resonance imaging frequently provides valuable diagnostic and prognostic information. Most of these tests are repeated during follow-up or at relapse.Blood 02/2011; 117(18):4701-5. · 9.90 Impact Factor -
Article: How I treat elderly patients with myeloma.
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ABSTRACT: The clinical approach to older patients with myeloma has to be modified to take into account comorbidities and the likelihood of higher treatment-related toxicity. Individualization of management and adequate supportive therapy are important to obtain the best response while minimizing adverse effects. Corticosteroids, novel agents, conventional cytotoxic agents, and high-dose chemotherapy with autotransplantation (modalities used in younger patients) are also used in older patients, although the elderly undergo transplantation less frequently. The sequential use of active agents singly and in different combinations has improved response rates and survival of all patients with myeloma, including the elderly.Blood 09/2010; 116(13):2215-23. · 9.90 Impact Factor -
Article: Monoclonal gammopathy of undetermined significance: a consensus statement.
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ABSTRACT: 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.British Journal of Haematology 07/2010; 150(1):28-38. · 4.94 Impact Factor -
Article: NCCN clinical practice guidelines in oncology: multiple myeloma.
Journal of the National Comprehensive Cancer Network: JNCCN 10/2009; 7(9):908-42. · 4.41 Impact Factor -
Article: Targeting Glucose Consumption and Autophagy in Myeloma with the Novel Nucleoside Analogue 8-Aminoadenosine
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ABSTRACT: Multiple myeloma, an incurable plasma cell malignancy, is characterized by altered cellular metabolism and resistance to apoptosis. Recent connections between glucose metabolism and resistance to apoptosis provide a compelling rationale for targeting metabolic changes in cancer. In this study, we have examined the ability of the purine analogue 8-aminoadenosine to acutely reduce glucose consumption by regulating localization and expression of key glucose transporters. Myeloma cells counteracted the metabolic stress by activating autophagy. Co-treatment with inhibitors of autophagy results in marked enhancement of cell death. Glucose consumption by drug-resistant myeloma cells was unaffected by 8-aminoadenosine, and accordingly, no activation of autophagy was observed. However, these cells can be sensitized to 8-aminoadenosine under glucose-limiting conditions. The prosurvival autophagic response of myeloma to nutrient deprivation or to nucleoside analogue treatment has not been described previously. This study establishes the potential of metabolic targeting as a broader means to kill and sensitize myeloma and identifies a compound that can achieve this goal.Journal of Biological Chemistry 09/2009; 284(39):26816-26830. · 4.77 Impact Factor -
Article: Targeting glucose consumption and autophagy in myeloma with the novel nucleoside analogue 8-aminoadenosine.
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ABSTRACT: Multiple myeloma, an incurable plasma cell malignancy, is characterized by altered cellular metabolism and resistance to apoptosis. Recent connections between glucose metabolism and resistance to apoptosis provide a compelling rationale for targeting metabolic changes in cancer. In this study, we have examined the ability of the purine analogue 8-aminoadenosine to acutely reduce glucose consumption by regulating localization and expression of key glucose transporters. Myeloma cells counteracted the metabolic stress by activating autophagy. Co-treatment with inhibitors of autophagy results in marked enhancement of cell death. Glucose consumption by drug-resistant myeloma cells was unaffected by 8-aminoadenosine, and accordingly, no activation of autophagy was observed. However, these cells can be sensitized to 8-aminoadenosine under glucose-limiting conditions. The prosurvival autophagic response of myeloma to nutrient deprivation or to nucleoside analogue treatment has not been described previously. This study establishes the potential of metabolic targeting as a broader means to kill and sensitize myeloma and identifies a compound that can achieve this goal.Journal of Biological Chemistry 08/2009; 284(39):26816-30. · 4.77 Impact Factor -
Article: Regression of cardiac amyloid after autologous stem-cell transplantation.
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ABSTRACT: Primary cardiac amyloid has a dismal prognosis and most treatments are experimental with highly variable results. Although autologous stem-cell transplant in conjunction with high-dose chemotherapy has yielded regression of amyloid in other body tissues, the presence of cardiac involvement contraindicates stem-cell transfer due to high treatment mortality. We describe the successful treatment of cardiac amyloid using autologous stem-cell transplantation and the resultant regression of the cardiac amyloid.The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 08/2009; 28(7):746-8. · 3.54 Impact Factor -
Article: Optimizing the CD34 + cell dose for reduced-intensity allogeneic hematopoietic stem cell transplantation.
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ABSTRACT: Low CD34 + cell doses increase allograft-related mortality and very high doses increase the risk of graft-versus-host disease. The optimum CD34 + cell dose remains undefined. The effect of the CD34 + cell dose based on ideal weight was analyzed in 130 patients with hematologic malignancies undergoing reduced-intensity allogeneic blood cell transplantation in the context of factors known to affect the outcome: chemosensitivity, donor age, lactate dehydrogenase (LDH), human leukocyte antigen (HLA) match, performance status, and platelet count. The survival of patients receiving >8 x 10(6)/kg CD34 + cells was not significantly different from those receiving <6. The outcome of those receiving 6-8 x 10(6)/kg CD34 + cells was significantly better than the rest. This superiority was confirmed in multivariable analysis. Among patients receiving <or=8 x 10(6)/kg CD34 + cells, an increasing number of infused cells was associated with higher overall survival in a continuous fashion (Risk ratio (RR) 0.8759; p = 0.045). Cell dose based on actual weight did not correlate with survival. The number of CD34 + cells infused, a potentially modifiable factor, affects survival after reduced-intensity allogeneic transplantation. We recommend a CD34 + cell dose of 6-8 x 10(6) per kg ideal body weight to optimize outcome. The possible adverse effect of higher cell doses (>8) needs further confirmation.Leukemia & lymphoma 07/2009; 50(9):1434-41. · 2.40 Impact Factor -
Article: The relationship between the serum free light chain assay and serum immunofixation electrophoresis, and the definition of concordant and discordant free light chain ratios.
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ABSTRACT: "Stringent" complete remission in myeloma has been defined by a normal serum free light chain ratio (SFLCR) in addition to the standard criteria for CR. 2648 serial samples from 122 IgG or IgA myeloma patients were studied to explore the relationship between SFLCR and serum immunofixation electrophoresis (SIFE). SFLCR was normal in 34% of cases with positive SIFE and abnormal in 66%. SFLCR was normal in 69% of cases with negative SIFE and abnormal in 31%. When evaluated with SIFE as the benchmark, the sensitivity of SFLCR was 66% and specificity was 69%. These findings were unchanged when abnormal SFLCR values were classified as concordant (< 0.26 for lambda disease and > 1.65 for kappa) or discordant (< 0.26 for kappa disease and > 1.65 for lambda). Additional studies are required to determine the temporal relationship between SFLCR normalization and paraprotein clearance. Until then, the role of SFLCR in defining response remains controversial.Blood 06/2009; 114(1):38-9. · 9.90 Impact Factor -
Article: Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma.
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ABSTRACT: Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.Blood 06/2009; 114(4):772-8. · 9.90 Impact Factor -
Article: Yttrium-90 ibritumomab tiuxetan doses calculated to deliver up to 15 Gy to critical organs may be safely combined with high-dose BEAM and autologous transplantation in relapsed or refractory B-cell non-Hodgkin's lymphoma.
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ABSTRACT: To determine the maximum-tolerated radiation-absorbed dose (RAD) to critical organs delivered by yttrium-90 ((90)Y) ibritumomab tiuxetan in combination with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy with autologous transplantation. Eligible patients had relapsed or refractory CD20+ non-Hodgkin's lymphoma (NHL). Individualized (90)Y activities were based on dosimetry and were calculated to deliver cohort-defined RAD (1 to 17 Gy) to critical organs with three to six patients per cohort. The therapeutic dose of (90)Y ibritumomab tiuxetan was followed by high-dose BEAM and autologous transplantation. Forty-four patients were treated. Thirty percent of patients had achieved less than a partial remission to their most recent therapy and would not have been eligible for autologous transplantation at most centers. The toxicity profile was similar to that associated with high-dose BEAM chemotherapy. Two dose-limiting toxicities occurred at the 17 Gy dose level, which made 15 Gy the recommended maximum-tolerated RAD. Although eight patients received at least twice the conventional dose of 0.4 mCi/kg, a weight-based strategy at 0.8 mCi/kg would have resulted in a wide range of RAD; nearly 25% of patient cases would have received 17 Gy or more, and many would have received less than 10 Gy. With a median follow-up of 33 months for all patients, the estimated 3-year progression-free and overall survivals were 43% and 60%, respectively. Dose-escalated (90)Y ibritumomab tiuxetan may be safely combined with high-dose BEAM with autologous transplantation and has the potential to be more effective than standard-dose radioimmunotherapy. Careful dosimetry is required to avoid toxicity and undertreatment.Journal of Clinical Oncology 05/2009; 27(10):1653-9. · 18.37 Impact Factor -
Article: Outcome of high-dose cytarabine-based induction therapy followed by hematopoietic stem cell transplantation in acute myeloid leukemia: influence of karyotype.
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ABSTRACT: One-hundred-twenty consecutive adult patients aged 15-69 years (median 40) with acute myeloid leukemia (AML) excluding t(15;17) received induction therapy comprising idarubicin, high-dose cytarabine and etoposide. Planned post-induction treatment included two courses of moderate-intensity consolidation therapy followed by stem cell transplantation. 11 patients (9%) died during induction therapy. The complete remission (CR) rate with a single cycle of induction therapy was 71%. The overall CR rate, after salvage chemotherapy but excluding allogeneic transplantation for primary refractory disease, was 82%. CR rates with one cycle of therapy for patients with good, intermediate and poor karyotype were 96, 72 and 41%, respectively (P<0.0001). The impact of karyotype on the overall CR rate was also significant (96 vs. 88 vs. 59%; P=0.001). Overall, 84 of 98 patients (86%) attaining CR underwent autologous (n=59), allogeneic (n=23) or syngeneic (n=2) hematopoietic stem cell transplantation in first CR. The 5-year overall survival (OS) of 43% (95% CI: 34-52%) was significantly influenced by the karyotype: good 73%, intermediate 41%, and poor 18% (P=0.0001). These data suggest that the sequence of therapy employed is active in AML, but additional steps are needed to improve the outcome of patients with intermediate- and high-risk cytogenetic abnormalities.Leukemia & lymphoma 01/2009; 49(12):2284-90. · 2.40 Impact Factor -
Article: Pharmacovigilance and reporting oversight in US FDA fast-track process: bisphosphonates and osteonecrosis of the jaw.
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ABSTRACT: More than half of all serious adverse reactions are identified 7 or more years after a drug receives approval from the US Food and Drug Administration (FDA). In 2002, 9 months after the intravenous bisphosphonate zoledronic acid received regulatory approval for marketing, the FDA received reports of nine patients with cancer, who were treated with zoledronic acid, who unexpectedly developed osteonecrosis of the jaw. During the next 2 years, three oral surgeons described 104 patients with cancer with osteonecrosis of the jaw in the medical literature and identified intravenous bisphosphonate therapy as being common to the care of these patients. In subspecialty medical, radiology, and dental journals, case reports and case series described clinical features of osteonecrosis of the jaw in patients with cancer who were treated with bisphosphonates. Manufacturer-sponsored epidemiological studies reported the first estimates of the incidence of this toxic effect, ranging from 0.1% to 1.8%. By contrast, independent epidemiological efforts from clinicians and the International Myeloma Foundation reported incidence estimates between 5% and 10%. Between 2003 and 2005, warnings about the risks of bisphosphonate-associated osteonecrosis were disseminated by national regulatory agencies, the manufacturers of bisphosphonates, and the International Myeloma Foundation. From 2006, independent clinical recommendations for diagnosis, prevention, and treatment of this toxic effect have been disseminated by manufacturers, national regulatory authorities, the International Myeloma Foundation, and medical specialty organisations. Furthermore, independent efforts by pharmaceutical manufacturers, dental and medical professionals, a non-profit organisation (the International Myeloma Foundation), patients, and regulatory authorities has led to the rapid identification and dissemination of safety information for this serious adverse reaction. Better coordination of safety-related pharmacovigilance initiatives is now needed.The lancet oncology 01/2009; 9(12):1166-72. · 14.47 Impact Factor
Top co-authors
Top Journals
- Blood (7)
- Blood (6)
- Cancer (6)
- British Journal of Haematology (4)
- New England Journal of Medicine (3)
Institutions
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2008–2010
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Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, IL, USA
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2009
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Harvard University
Boston, MA, USA -
University of Texas MD Anderson Cancer Center
- Department of Experimental Therapeutics
Houston, TX, USA
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2003–2009
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Dana-Farber Cancer Institute
- Department of Medical Oncology
Boston, MA, USA -
Northwestern University
- • Feinberg School of Medicine
- • Division of Hematology/Oncology
Evanston, IL, USA
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2002–2009
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Royal Marsden Hospital
London, ENG, United Kingdom
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2007
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Northwestern Memorial Hospital
Chicago, IL, USA -
Roswell Park Cancer Institute
Buffalo, NY, USA
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2006
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Emory University
- Winship Cancer Institute
Atlanta, GA, USA -
Charité Universitätsmedizin Berlin
- Department of Pediatrics, Division of Oncology and Hematology
Berlin, Land Berlin, Germany
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2005
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Indiana Blood and Marrow Transplantation
Indianapolis, IN, USA
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2004
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University of South Carolina
- Department of Internal Medicine
Columbia, SC, USA
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