Jerome B Zeldis

Celgene, Summit, New Jersey, United States

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Publications (75)782.22 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Pomalidomide is a second generation IMiD (immunomodulatory agent) that has recently been granted approval by the Food and Drug Administration for treatment of relapsed multiple myeloma after prior treatment with two antimyeloma agents, including lenalidomide and bortezomib. A simple and robust HPLC assay with fluorescence detection for pomalidomide over the range of 1-500ng/mL has been developed for application to pharmacokinetic studies in ongoing clinical trials in various other malignancies. A liquid-liquid extraction from human plasma alone or pre-stabilized with 0.1% HCl was performed, using propyl paraben as the internal standard. From plasma either pre-stabilized with 0.1% HCl or not, the assay was shown to be selective, sensitive, accurate, precise, and have minimal matrix effects (<20%). Pomalidomide was stable in plasma through 4 freeze-thaw cycles (<12% change), in plasma at room temperature for up to 2h for samples not pre-stabilized with 0.1% HCl and up to 8h in samples pre-stabilized with 0.1% HCl, 24h post-preparation at 4°C (<2% change), and showed excellent extraction recovery (∼90%). This is the first reported description of the freeze/thaw and plasma stability of pomalidomide in plasma either pre-stabilized with 0.1% HCl or not. The information presented in this manuscript is important when performing pharmacokinetic analyses. The method was used to analyze clinical pharmacokinetics samples obtained after a 5mg oral dose of pomalidomide. This relatively simple HPLC-FL assay allows a broader range of laboratories to measure pomalidomide for application to clinical pharmacokinetics.
    Journal of pharmaceutical and biomedical analysis 01/2014; 92C:63-68. · 2.45 Impact Factor
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    ABSTRACT: Pomalidomide is a second generation IMiD (immunomodulatory agent) that has recently been granted approval by the Food and Drug Administration for treatment of relapsed multiple myeloma after prior treatment with two antimyeloma agents, including lenalidomide and bortezomib. A simple and robust HPLC assay with fluorescence detection for pomalidomide over the range of 1–500 ng/mL has been developed for application to pharmacokinetic studies in ongoing clinical trials in various other malignancies. A liquid–liquid extraction from human plasma alone or pre-stabilized with 0.1% HCl was performed, using propyl paraben as the internal standard. From plasma either pre-stabilized with 0.1% HCl or not, the assay was shown to be selective, sensitive, accurate, precise, and have minimal matrix effects (<20%). Pomalidomide was stable in plasma through 4 freeze–thaw cycles (<12% change), in plasma at room temperature for up to 2 h for samples not pre-stabilized with 0.1% HCl and up to 8 h in samples pre-stabilized with 0.1% HCl, 24 h post-preparation at 4 °C (<2% change), and showed excellent extraction recovery (∼90%). This is the first reported description of the freeze/thaw and plasma stability of pomalidomide in plasma either pre-stabilized with 0.1% HCl or not. The information presented in this manuscript is important when performing pharmacokinetic analyses. The method was used to analyze clinical pharmacokinetics samples obtained after a 5 mg oral dose of pomalidomide. This relatively simple HPLC-FL assay allows a broader range of laboratories to measure pomalidomide for application to clinical pharmacokinetics.
    Journal of Pharmaceutical and Biomedical Analysis. 01/2014; 92:63–68.
  • Proceedings of the National Academy of Sciences 12/2013; · 9.81 Impact Factor
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    ABSTRACT: A previous interim report of MM-011, the first study that combined lenalidomide with anthracycline-based chemotherapy followed by lenalidomide maintenance for relapsed and/or refractory multiple myeloma (RRMM), showed promising safety and activity. We report the long-term outcomes of all 76 treated patients with follow-up ≥5 years. This single-center phase I/II study administered lenalidomide (10 mg on days 1-21 of every 28-day cycle), intravenous liposomal doxorubicin (40 mg/m(2) on day 8), dexamethasone (40 mg on days 8-11), and intravenous vincristine (2 mg on day 8). After 4-6 planned induction cycles, lenalidomide maintenance therapy was given at the last tolerated dose until progression, with or without 50 mg prednisone every other day. The median number of previous therapies was 3 (range, 1-7); 49 (64.5%) patients had refractory disease. Forty-three (56.6%) patients received maintenance therapy. Grade 3/4 adverse events occurred during induction and maintenance therapy in 48.7% and 25.6% of patients, respectively. Four (5.3%) treatment-related deaths occurred during induction. Responses were seen in 53.0% (at least partial response) and 71.2% (at least minor response) of patients. Overall, median progression-free survival and overall survival were 10.5 and 19.0 months, respectively; in patients with refractory disease these values were 7.5 and 11.3 months, respectively. Lenalidomide with anthracycline-based chemotherapy followed by maintenance lenalidomide provided durable control in patients with RRMM. (ClinicalTrials.gov number, NCT00091624).
    American Journal of Hematology 11/2013; · 4.00 Impact Factor
  • American Journal of Hematology 05/2013; · 4.00 Impact Factor
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    ABSTRACT: We report results of a phase II trial of combination of melphalan, lenalidomide, and dexamethasone for the treatment of AL amyloidosis. The primary objectives were tolerability and hematologic response rate; secondary objectives were organ responses and survival. Treatment protocol consisted of melphalan 5mg/m2/day for 4 days, lenalidomide 10mg/day for 21 days and dexamethasone 20-40mg once a week every 28 days for a total of 12 cycles. Sixteen subjects were enrolled; of which 14 completed at least 3 cycles and were evaluable for response. Grade 3/4 toxicities were experienced by 88% (n=14), the most common being myelosuppression (n=7). Dose reductions occurred in 85% (n=12/14) of subjects. Hematologic partial and complete responses were achieved by 43% (n=6/14) and 7% (n=1/14) respectively. The median overall survival has not been reached and median progression-free survival is 24 months. In conclusion, this combination is associated with significant myelosuppression leading to dose modifications and producing minor hematologic responses in AL amyloidosis. http://clinicaltrials.gov/ct2/show/NCT00679367.
    Haematologica 11/2012; · 5.94 Impact Factor
  • The Lancet Oncology 07/2012; · 25.12 Impact Factor
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    ABSTRACT: The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL. Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1-21 of each 28-day cycle. 375 mg/m(2) intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until disease progression, stem-cell transplantation, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00294632. 52 patients were enrolled between Feb 10, 2006 and July 30, 2009, 14 in phase 1 and 44 (including six patients who received the MTD of lenalidomide in the phase 1 portion) in phase 2. The MTD was 20 mg lenalidomide. One patient who was treated with 25 mg lenalidomide developed a grade 4 non-neutropenic infection and died. In the phase 2 portion of the study, grade 3-4 haematological toxicities included neutropenia (29 patients), lymphopenia (16 patients), leucopenia (13 patients), and thrombocytopenia (ten patients). There were only two episodes of febrile neutropenia. Among 44 patients in phase 2, 25 (57%) had an overall response: 16 (36%) had a complete response and nine (20%) had a partial response. The median response duration was 18·9 months (95% CI 17·0 months to not reached [NR]). The median progression-free survival was 11·1 months (95% CI 8·3 to 24·9 months), and the median overall survival was 24·3 months (19·8 months to NR). Five of 14 patients who had received bortezomib treatment before enrolment achieved an overall response. Oral lenalidomide plus rituximab is well tolerated and effective for patients with relapsed or refractory MCL. Celgene.
    The Lancet Oncology 06/2012; 13(7):716-23. · 25.12 Impact Factor
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    ABSTRACT: Tuberculosis (TB) is responsible for significant morbidity and mortality worldwide. Even after successful microbiological cure of TB, many patients are left with residual pulmonary damage that can lead to chronic respiratory impairment and greater risk of additional TB episodes due to reinfection with Mycobacterium tuberculosis. Elevated levels of the proinflammatory cytokine tumor necrosis factor-α and several other markers of inflammation, together with expression of matrix metalloproteinases, have been associated with increased risk of pulmonary fibrosis, tissue damage, and poor treatment outcomes in TB patients. In this study, we used a rabbit model of pulmonary TB to evaluate the impact of adjunctive immune modulation, using a phosphodiesterase-4 inhibitor that dampens the innate immune response, on the outcome of treatment with the antibiotic isoniazid. Our data show that cotreatment of M. tuberculosis infected rabbits with the phosphodiesterase-4 inhibitor CC-3052 plus isoniazid significantly reduced the extent of immune pathogenesis, compared with antibiotic alone, as determined by histologic analysis of infected tissues and the expression of genes involved in inflammation, fibrosis, and wound healing in the lungs. Combined treatment with an antibiotic and CC-3052 not only lessened disease but also improved bacterial clearance from the lungs. These findings support the potential for adjunctive immune modulation to improve the treatment of pulmonary TB and reduce the risk of chronic respiratory impairment.
    American Journal Of Pathology 07/2011; 179(1):289-301. · 4.60 Impact Factor
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    ABSTRACT: In patients with chronic lymphocytic leukemia (CLL), treatment with lenalidomide induces a unique, previously uncharacterized, immune response called tumor flare reaction (TFR). The clinical significance of this reaction remains unknown. Forty-five patients with CLL who were treated with lenalidomide in a phase 2 clinical trial were evaluated for the clinical features, intensity, and duration of TFR. Correlation was made with tumor response and the immune cellular microenvironment. Steroids for the prophylaxis of TFR was not given to patients in Group A (n = 29) whereas patients in Group B (n = 16) received low-dose prednisone as well as a slow dose escalation of lenalidomide for the prevention of TFR. Thirty (67%) patients experienced a TFR, with a grade 2 or 3 reaction (according to National Cancer Institute Common Toxicity Criteria [version 3.0]) observed in 33% of patients (47% in Group A and 9% in Group B; P = .05). The median time to onset of the TFR was 6 days, and was longer in the patients receiving prophylaxis (4 days vs 9 days, respectively; P = .01). A complete response was observed in 7 of 30 (23%) patients with TFR and 1 of 15 (7%) patients without TFR. The median progression-free survival was 19.9 months and 19.4 months, respectively, for patients with versus those without TFR (P = .92). TFR is a unique immune-mediated phenomenon noted with lenalidomide treatment only in patients with CLL that correlates with clinical response. It can be effectively managed with anti-inflammatory agents.
    Cancer 05/2011; 117(10):2127-35. · 5.20 Impact Factor
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    ABSTRACT: Lenalidomide is an immunomodulatory agent used to treat plasma cell dyscrasias. We previously observed worsening of kidney function in a high proportion of patients with AL amyloidosis during lenalidomide treatment. The objective of this study is to characterize alterations in kidney function among patients with AL amyloidosis undergoing treatment with lenalidomide. This is a secondary analysis of an ongoing clinical trial at a single referral centre. Forty-one patients with AL amyloidosis received lenalidomide with or without dexamethasone in monthly cycles. Kidney dysfunction was defined as ≥ 50% increase in serum creatinine. Severe kidney dysfunction was defined as ≥ 100% increase in serum creatinine. Recovery of renal function was defined as a return of serum creatinine to within 25% of the pre-treatment value or discontinuation of dialysis. Twenty-seven of 41 patients (66%) developed kidney dysfunction during lenalidomide treatment. The kidney dysfunction was severe in 13 of these patients (32%); four of whom required initiation of dialysis (10%). The median time to kidney dysfunction after starting lenalidomide was 44 days (interquartile range 15-108 days). Four of eight patients without underlying renal amyloidosis developed kidney dysfunction. Patients with severe kidney dysfunction were older and had a higher frequency of underlying renal amyloidosis, greater urinary protein excretion, and lower serum albumin. Recovery of renal function occurred in 12 patients (44%). Among patients with AL amyloidosis, worsening of kidney function occurs frequently during lenalidomide treatment. While a causal role of the drug has not been established, our findings suggest that kidney function should be monitored closely during treatment with this drug.
    Nephrology Dialysis Transplantation 03/2011; 26(3):881-6. · 3.37 Impact Factor
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    ABSTRACT: Lenalidomide (REVLIMID), an immunomodulatory compound targeting both cancer cells and their microenvironment, has substantial activity in several difficult-to-manage hematological malignancies. In previously treated multiple myeloma, lenalidomide produces high-quality responses combined with sustained disease control. Recently, several randomized studies have demonstrated a clinical benefit of continuous lenalidomide treatment in newly diagnosed multiple myeloma. In many patients with refractory anemia associated with lower risk myelodysplastic syndromes and a 5q chromosome deletion, lenalidomide leads to transfusion independence, considerably improving quality of life. It has a manageable safety profile, and its oral formulation reduces the burden on patients. Several phase III trials are ongoing in other indications currently underserved by conventional therapy, such as chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and prostate cancer. Several early-stage studies are exploring lenalidomide alone and in combination across different hematological malignancies, solid tumors, and immune-related disorders.
    Annals of the New York Academy of Sciences 03/2011; 1222:76-82. · 4.38 Impact Factor
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    Blood 12/2010; 116(23):5071-2. · 9.78 Impact Factor
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    ABSTRACT: In two randomized phase III trials (MM-009 and MM-010), lenalidomide plus dexamethasone significantly prolonged time to progression and overall survival (OS) in patients with relapsed/refractory multiple myeloma compared with dexamethasone alone. In both trials the treatment was continued until disease progression or unacceptable toxicity. We conducted a subanalysis to determine if continuing therapy after achieving≥partial response (PR) improved survival. Data were collected on 212 patients who were treated with lenalidomide plus dexamethasone and achieved≥PR. Kaplan-Meier survival estimates were compared between patients on continued treatment versus patients discontinuing therapy because of adverse events, withdrawal of consent, or other reasons. Time-dependent multivariate regression analyses were used to determine the benefit of continuing treatment with lenalidomide. A total of 174 patients received continued treatment until disease progression or death, and 38 patients discontinued therapy without progression. There was a trend toward longer median OS in patients who continued therapy (50.9 months vs. 35.0 months; P=.0594). When controlling for the number of previous antimyeloma therapies, β2-microglobulin levels, and Durie-Salmon stage (which adversely affected survival in these patients), continued lenalidomide treatment (HR, 0.137; 95% CI, 0.045-0.417; P=.0005) or each additional cycle of lenalidomide (HR, 0.921; 95% CI, 0.886-0.957; P<.0001) were both associated with longer survival. Continued lenalidomide treatment until disease progression after achievement of ≥PR is associated with a significant survival advantage when controlling for patient characteristics. These findings should be confirmed in a prospectively designed trial.
    Clinical lymphoma, myeloma & leukemia 10/2010; 11(1):38-43.
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    Blood 09/2010; 116(11):1990-1. · 9.78 Impact Factor
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    ABSTRACT: This retrospective pooled analysis of two phase III trials (MM-009/MM-010) compared clinical outcomes of patients who achieved a complete response or very good partial response to treatment with lenalidomide plus dexamethasone with the outcomes of those who only achieved a partial response. Patients (n=353) received lenalidomide (25 mg/day for 21 days of each 28-day cycle) plus dexamethasone (40 mg on days 1-4, 9-12, and 17-20 for four cycles, and only on days 1-4 after the first four cycles). Time to response, duration of response, time-to-progression, overall survival, and adverse events were investigated for patients who had a complete or very good partial response and compared with those of patients who had a partial response. At the time of unblinding, 32% of patients had achieved a complete or very good partial response and 28% had a partial response. Half (50.5%) of the patients who had a partial response as their initial response achieved a complete or very good partial response with further treatment. The probability of achieving a complete or very good partial response with continued lenalidomide treatment decreased with delayed achievement of a partial response (by cycle 4 versus later); however, it remained clinically significant. With an extended follow-up of 48 months, the median response duration, time-to-progression, and overall survival were longer in patients with a complete or very good partial response than in those with a partial response (24.0 versus 8.3 months, P<0.001; 27.7 versus 12.0 months, P<0.001; not reached versus 44.2 months, P=0.021, respectively). The benefit of a complete or very good partial response was independent of when it was achieved. Continuing treatment with lenalidomide plus dexamethasone to achieve best response, in the absence of disease progression and toxicity, provided deeper remissions and greater clinical benefit over time for patients in this study.
    Haematologica 05/2010; 95(10):1738-44. · 5.94 Impact Factor
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    ABSTRACT: Lenalidomide and other new agents are improving survival of multiple myeloma patients. This review describes current data on lenalidomide in myeloma and how the unique properties of lenalidomide may lend its use in new settings, such as maintenance and preventive therapy. This review covers the activity of lenalidomide in multiple myeloma, efficacy in both newly diagnosed and relapsed/refractory patients, how to manage effectively common adverse events observed with lenalidomide, and its potential use in new settings based on clinical trials published up to 2009. This review describes the mechanism of action of lenalidomide in myeloma which provides the basis for its clinical use in newly diagnosed, relapsed/refractory, and high-risk smoldering myeloma in combination with other agents. Strategies to reduce or effectively manage myelosuppression and thromboembolic events, the main adverse events associated with lenalidomide plus dexamethasone therapy, are also described. Lenalidomide is an oral immunomodulatory drug that is highly effective in treating multiple myeloma, has a favorable safety profile and is now being evaluated as maintenance therapy, preventive therapy and in combination with other new agents.
    Expert Opinion on Pharmacotherapy 04/2010; 11(5):829-42. · 2.86 Impact Factor
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    ABSTRACT: Cancer and its treatment can induce subjective and objective evidence of diminished functional capacity encompassing physical fatigue and cognitive impairment. Dexmethylphenidate (D-MPH; the D-isomer of methylphenidate) was evaluated for treatment of chemotherapy-related fatigue and cognitive impairment. A randomized, double-blind, placebo-controlled, parallel-group study evaluated the potential therapeutic effect and safety of D-MPH in the treatment of patients with chemotherapy-related fatigue. Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue Subscale (FACIT-F) total score at Week 8 was the primary outcome measure. One hundred fifty-four patients (predominantly with breast and ovarian cancers) were randomized and treated. Compared with placebo, D-MPH-treated subjects demonstrated a significant improvement in fatigue symptoms at Week 8 in the FACIT-F (P=0.02) and the Clinical Global Impression-Severity scores (P=0.02), without clinically relevant changes in hemoglobin levels. Cognitive function was not significantly improved. There was a higher rate of study drug-related adverse events (AEs) (48 of 76 [63%] vs. 22 of 78 [28%]) and a higher discontinuation rate because of AEs (8 of 76 [11%] vs. 1 of 78 [1.3%]) in D-MPH-treated subjects compared with placebo-treated subjects. The most commonly reported AEs independent of study drug relationship in D-MPH-treated subjects were headache, nausea, and dry mouth, and in placebo-treated subjects were headache, diarrhea, and insomnia. D-MPH produced significant improvement in fatigue in subjects previously treated with cytotoxic chemotherapy. Further studies with D-MPH or other agents to explore treatment response in chemotherapy-associated fatigue should be considered.
    Journal of pain and symptom management 11/2009; 38(5):650-62. · 2.42 Impact Factor
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    ABSTRACT: Lenalidomide is a novel immunomodulatory agent with antiproliferative activities. Given its efficacy in a wide range of hematologic malignancies, we conducted a phase II trial (NHL-001) of single-agent lenalidomide in indolent non-Hodgkin's lymphoma (NHL). Patients with relapsed/refractory indolent NHL were eligible, with no limit on the number of previous therapies. Oral lenalidomide 25 mg was self-administered once daily on days 1 to 21 of every 28-day cycle for up to 52 weeks as tolerated, or until disease progression. The primary end point was objective response rate (ORR), with secondary end points of duration of response (DR), progression-free survival (PFS), and safety. Forty-three enrolled patients were assessable for response and safety. Patients received a median of three prior systemic therapies (range, 1 to 17) and half were refractory to last therapy. ORR was 23% (10 of 43), including a 7% complete response (CR) or unconfirmed CR rate. Twenty-seven percent (six of 22) of patients with follicular lymphoma grade 1 or 2, and 22% (four of 18) with small lymphocytic lymphoma responded to therapy. Median DR was not reached, but was longer than 16.5 months with seven of 10 responses ongoing at 15 to 28 months. Median PFS for the whole group was 4.4 months (95% CI, 2.5 to 10.4 months). Adverse events were predictable and manageable; the most common grade 3 or 4 adverse events were neutropenia (30% and 16%, respectively) and thrombocytopenia (14% and 5%, respectively). Oral lenalidomide monotherapy produces durable responses with manageable adverse events in patients with relapsed/refractory indolent NHL, warranting further investigation of treatment for indolent NHL.
    Journal of Clinical Oncology 10/2009; 27(32):5404-9. · 18.04 Impact Factor
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    ABSTRACT: We present a pooled update of two large, multicenter MM-009 and MM-010 placebo-controlled randomized phase III trials that included 704 patients and assessed lenalidomide plus dexamethasone versus dexamethasone plus placebo in patients with relapsed/refractory multiple myeloma (MM). Patients in both studies were randomized to receive 25 mg daily oral lenalidomide or identical placebo, plus 40 mg oral dexamethasone. In this pooled analysis, using data up to unblinding (June 2005 for MM-009 and August 2005 for MM-010), treatment with lenalidomide plus dexamethasone significantly improved overall response (60.6 vs 21.9%, P<0.001), complete response rate (15.0 vs 2.0%, P<0.001), time to progression (median of 13.4 vs 4.6 months, P<0.001) and duration of response (median of 15.8 months vs 7 months, P<0.001) compared with dexamethasone-placebo. At a median follow-up of 48 months for surviving patients, using data up to July 2008, a significant benefit in overall survival (median of 38.0 vs 31.6 months, P=0.045) was retained despite 47.6% of patients who were randomized to dexamethasone-placebo receiving lenalidomide-based treatment after disease progression or study unblinding. Low beta(2)-microglobulin and low bone marrow plasmacytosis were associated with longer survival. In conclusion, these data confirm the significant response and survival benefit with lenalidomide and dexamethasone.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2009; 23(11):2147-52. · 10.16 Impact Factor

Publication Stats

6k Citations
782.22 Total Impact Points

Institutions

  • 2005–2011
    • Celgene
      Summit, New Jersey, United States
    • University of South Florida
      Tampa, Florida, United States
  • 2010
    • Hospital Universitario de Salamanca
      Helmantica, Castille and León, Spain
  • 2009
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2008
    • University of Texas MD Anderson Cancer Center
      • Department of Lymphoma and Myeloma
      Houston, TX, United States
  • 2003–2007
    • Peter MacCallum Cancer Centre
      • Division of Haematology and Medical Oncology
      Melbourne, Victoria, Australia
  • 2002–2006
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, MA, United States
  • 2001
    • Rush University Medical Center
      Chicago, Illinois, United States