D E Reece

The Princess Margaret Hospital, Toronto, Ontario, Canada

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Publications (213)1124.91 Total impact

  • Leukemia & lymphoma 09/2015; DOI:10.3109/10428194.2015.1091927 · 2.89 Impact Factor
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    ABSTRACT: Background: Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma. Methods: In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival. Results: Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients. Conclusions: Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797.).
    New England Journal of Medicine 06/2015; 373(7). DOI:10.1056/NEJMoa1505654 · 55.87 Impact Factor
  • Nuchanan Areethamsirikul · Donna E Reece
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    ABSTRACT: The development of a SPM has become an important issue in myeloma management, given the remarkable improvement in survival afforded by the introduction of novel agents. Treatment with immunomodulatory derivatives, specifically lenalidomide, has recently been identified as a potential risk factor for SPM in several studies, especially in the maintenance setting. We review potential mechanisms for development of SPM, incidence of SPM with different treatment regimens, risk factors associated with SPM and features of SPM after myeloma therapy. The incidence of SPM is discussed in the context of different settings in which lenalidomide is used during the course of the disease. No clear evidence indicates that lenalidomide alone is associated with SPM in the absence of other risk factors. Routine cancer surveillance, lifestyle modification to avoid cancer risk factors and prompt evaluation if new symptoms occur should be emphasized to patients who are on continuous myeloma therapy.
    Leukemia & lymphoma 05/2015; DOI:10.3109/10428194.2014.974043 · 2.89 Impact Factor
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    ABSTRACT: Cyclophosphamide, bortezomib and dexamethasone (CyBorD) is a highly active three-drug induction regimen for untreated transplant-eligible multiple myeloma patients. Although CyBorD has been evaluated only in the phase 2 setting in a limited number of patients, its high efficacy and ease of administration have led to its widespread use. Given that clinical trial efficacy can overestimate real-life effectiveness, we reviewed our institutional experience with 109 newly diagnosed patients who were treated with CyBorD in a non-clinical trial setting. After a median of four cycles, overall response rate (ORR) and very good partial response rate or better (⩾VGPR) were 95 and 66%, respectively, comparable to phase 2 studies of CyBorD and other three/four-drug induction regimens. All patients subsequently underwent successful stem cell collection and upgraded responses to ORR 98% and ⩾VGPR 79% post transplant. At a median follow-up of 19.8 months after diagnosis, the 2-year OS probability was 95.3% (95%CI: 89-98). The presence of concurrent plasmacytoma at diagnosis was the only prognostic factor predicting poorer survival (HR=5.56; 95%CI: 0.92-33.74; P=0.03). CyBorD was well-tolerated, with no severe peripheral neuropathy and minimal hematologic toxicity. Therefore, CyBorD is a convenient, well-tolerated, highly effective induction regimen in preparation for autologous SCT in real-life clinical practice.Bone Marrow Transplantation advance online publication, 19 January 2015; doi:10.1038/bmt.2014.288.
    Bone Marrow Transplantation 01/2015; 50(3). DOI:10.1038/bmt.2014.288 · 3.57 Impact Factor
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    ABSTRACT: Abstract Post-Autologous stem cell transplant (ASCT) studies have demonstrated that absolute lymphocyte count (ALC) recovery is associated with prolonged survival in some hematological malignancies. To assess whether ALC recovery has prognostic significance in patients with MM undergoing single ASCT, we conducted a retrospective analysis of ALC at different time-points in patients with MM. 769 consecutive patients who underwent single ASCT from January 2000 to December 2007 were evaluated. An ALC of ≥ 1400 cells/µL at day-0, day-15 and day-90 significantly correlated with a better OS (median OS of 111, 90.7 and 84months versus 74, 70.5, and 65 months, respectively, p<0.001 for all time-points). Multivariate analysis showed ALC is an independent prognostic factor for OS after ASCT. In conclusion, ALC is a surrogate marker of the host immune system that correlates with better survival in MM patients undergoing single ASCT. Immunomodulatory drugs, vaccination strategies and cellular therapies in MM should be investigated.
    Leukemia and Lymphoma 01/2015; DOI:10.3109/10428194.2014.1003057 · 2.89 Impact Factor
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    ABSTRACT: Objectives: Approximately 15% of patients with multiple myeloma (MM) exhibit a t(4;14) translocation, which often results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3). This study evaluated the efficacy and safety of dovitinib, an RTK inhibitor with in vitro inhibitory activity against FGFR, in patients with relapsed or refractory MM with or without t(4;14) translocation. Methods: Adult patients with relapsed or refractory MM who had received ≥2 prior regimens were enrolled in this multicenter, 2-stage, phase 2 trial. Patients were grouped based on their t(4;14) status. Dovitinib (500 mg/day orally) was administered on a 5-days-on/2-days-off schedule. The primary endpoint was overall response rate by local investigator review (per International Myeloma Working Group criteria). In non-responding patients, treatment could continue with the addition of low-dose dexamethasone. Results: In total, 43 patients (median age, 63 years) were enrolled (13 t(4;14) positive, 26 t(4;14) negative, and 4 t(4;14) status non-interpretable). Patients had received a median of 5 prior regimens. Median duration of treatment was 8.7 weeks in the t(4;14)-positive group and 3.7 weeks in the t(4;14)-negative group. None of the patients on dovitinib had objective responses. The stable disease rate was 61.5% in the t(4;14)-positive group and 34.6% in the t(4;14)-negative group. Overall, 39 patients (90.7%) had adverse events suspected to be related to study drug, most commonly diarrhea (60.5%), nausea (58.1%), vomiting (46.5%), and fatigue (32.6%). Conclusion: Dovitinib showed no single-agent activity in relapsed or refractory MM but may stabilize disease in some t(4;14)-positive patients.
    European Journal Of Haematology 11/2014; 95(4). DOI:10.1111/ejh.12491 · 2.07 Impact Factor
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    ABSTRACT: The role of auto-SCT in the treatment of multiple myeloma (MM) in the era of novel agents continues to evolve. It is now clear that the depth of response and clinical outcomes have significantly improved as a result of the combination of these strategies. However, not all patients with MM who undergo auto-SCT are able to sustain a meaningful response and 20% of patients relapse shortly after auto-SCT. In this study, we aimed to assess the impact of early relapse (ER) after auto-SCT on OS for MM patients undergoing single auto-SCT who had received novel agent-based induction regimens. All consecutive patients with MM undergoing single auto-SCT from January 2002 to September 2012 who had novel induction therapy were evaluated. A total of 184 patients were identified. The median OS and PFS for the group of transplanted patients were 93 and 25.4 months, respectively. Median time to relapse was 17.2 months with 40% having relapsed at the time of analysis. ER (<12 months post auto-SCT) was seen in 27 (36%) out of 75 patients who had relapsed, and median OS was significantly shorter than in those with non-ER. Multivariate analysis showed ER as the major independent prognostic factor for OS. On the basis of these findings, we conclude that not only attainment of a good response, but sustainability of it, appears to be a major prognostic variable in MM in the era of novel therapy. Patients with ER post auto-SCT should biologically be characterized in prospective studies to better understand the mechanisms of resistance associated with this particular entity.Bone Marrow Transplantation advance online publication, 27 October 2014; doi:10.1038/bmt.2014.237.
    Bone Marrow Transplantation 10/2014; 50(2). DOI:10.1038/bmt.2014.237 · 3.57 Impact Factor
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    ABSTRACT: Venous thromboembolism (VTE) has an increased incidence in patients with multiple myeloma (MM), especially during chemotherapy. Mechanisms including upregulation of procoagulant factors, such as factor VIII, have been postulated. The National Cancer Institute of Canada Clinical Trials Group MY.10 phase III clinical trial compared thalidomide-prednisone to observation for 332 patients with MM post-autologous stem cell transplantation (ASCT), with a primary endpoint of overall survival and various secondary endpoints including the incidence of VTE. One hundred and fifty-three patients had biomarker data, including D-dimer, factor VIII and thrombin anti-thrombin (TAT) levels collected post-ASCT at baseline and 2 months after intervention investigating in-vivo thrombin generation. Differences between the time-points included a significant reduction over time in D-dimer, factor VIII and TAT levels in the observation group and sustained elevation of D-dimer, significant increase in factor VIII and reduction in TAT levels in the thalidomide-prednisone group. Eight VTE events were reported in this subset of study patients, all in the thalidomide-prednisone arm, with a trend to increase in D-dimer levels over time in those patients with VTE. This study provides physiological and clinical evidence for an increased risk of VTE associated with thalidomide-prednisone maintenance therapy post-ASCT for MM.
    British Journal of Haematology 10/2014; 168(4). DOI:10.1111/bjh.13176 · 4.71 Impact Factor
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    ABSTRACT: Numerous studies have reported the feasibility and safety of autologous SCT (ASCT) in patients with multiple myeloma (MM) and mild to moderate renal impairment, but there are limited data in dialysis-dependent patients. In this retrospective study, we reviewed the toxicities and efficacy outcomes of 33 MM patients with dialysis-dependent renal failure who underwent ASCT at our institution from 1998 to 2012. The most common grade 3 non-hematologic toxicities were mucositis (49%), infection (15%) and bleeding (6%). Atrial dysrhythmias (24%) and delirium (30%) of all grades were also common. Hematologic toxicities included febrile neutropenia (88%); and RBC and platelet transfusions were required by 71 and 100% of patients, respectively. Transplant-related mortality (TRM) was high at 15%, predominantly caused by septic shock. Response to ASCT was at least VGPR (very good PR) in 50%, PR in 46.2% and stable disease (SD) in 3.8%. Median OS was 5.6 years, comparable to our overall institutional data. Overall, seven patients became dialysis independent. We conclude that ASCT can be an effective treatment for dialysis-dependent MM patients, with high response rates and survival. However, toxicities and a high TRM are observed indicating that further studies are needed to enhance the safety of this approach.Bone Marrow Transplantation advance online publication, 6 October 2014; doi:10.1038/bmt.2014.226.
    Bone Marrow Transplantation 10/2014; 50(1). DOI:10.1038/bmt.2014.226 · 3.57 Impact Factor
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    ABSTRACT: CAN2007 was the first prospective phase 1/2 study of once- and twice-weekly single-agent bortezomib in relapsed primary systemic AL amyloidosis. Seventy patients were treated, including 18 and 34 patients at the maximum planned doses on the once- and twice-weekly schedules, respectively. This pre-specified final analysis provides mature response and long-term outcomes data after 3 years' additional follow-up since the last report. In the once-weekly 1.6 mg/m(2) and twice-weekly 1.3 mg/m(2) bortezomib groups, final hematologic response rates were 68.8% and 66.7%, respectively; 80% of patients in each group sustained their response for ≥1 year. One-year progression-free rates were 72.2% and 76.8%. Median overall survival (OS) was 62.1 months and not reached; 4-year OS rates were 75.0% and 63.0%. A low baseline difference in kappa/lambda free light-chain level was associated with higher hematologic complete response rates and longer OS. At data cut-off, 40 (57%) patients had received subsequent therapy, including 19 (27%) retreated with bortezomib, 11 (58%) of whom achieved complete or partial hematologic responses. Four patients received prolonged bortezomib for between 3.5 and 5.6 years, with no new safety concerns, highlighting the feasibility of long-term therapy. Single-agent bortezomib produced durable hematologic responses and promising long-term OS in relapsed AL amyloidosis. The study is registered to www.clinicaltrials.gov as NCT00298766.
    Blood 09/2014; 124(16). DOI:10.1182/blood-2014-04-568329 · 10.45 Impact Factor
  • Y Yang · Y Chen · M N Saha · J Chen · K Evans · L Qiu · D Reece · G An Chen · H Chang
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    ABSTRACT: Multiple myeloma (MM) is incurable in virtually all patients due to the presence of innate and emergent drug-resistance. To identify potential drug resistance mechanisms in MM we used iTRAQ mass spectrometry (MS) to compare protein expression profiles of drug resistant (RPMI 8226R5) and sensitive (RPMI 8226 S) isogenic cell lines. We identified selective overexpression of MARCKS in drug resistant R5 cells. MARCKS overexpression was also observed in several drug-resistant human myeloma cell lines (HMCLs) and in drug resistant primary MM samples. Functionally, inhibition of MARCKS phosphorylation by Enzastaurin or knockdown of the gene by RNAi significantly enhanced the sensitivity of resistant HMCLs and primary MM samples to bortezomib and to other anti-myeloma drugs, providing evidence that MARCKS can modulate drug response. Mechanistically, pMARCKS was found to function as an E2F-1 co-factor to regulate SKP2 transcription. pMARCKS promoted cell cycle progression by facilitating SKP2 expression, suppressing p27(Kip1) and potentially counteracting drug-induced cell cycle arrest by promoting Cyclin E/CDK2 activity. Importantly, MARCKS knockdown in combination with bortezomib treatment overcame bortezomib resistance and significantly inhibited tumor growth and prolonged host survival in a MM xenograft model. These data provide a rationale for therapeutic targeting of pMARCKS to improve the outcome of patients with refractory/relapsed MM.Leukemia accepted article preview online, 02 September 2014. doi:10.1038/leu.2014.255.
    Leukemia 09/2014; 29(3). DOI:10.1038/leu.2014.255 · 10.43 Impact Factor
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    ABSTRACT: This single institution, open label Phase I-II dose escalation trial evaluated the safety and efficacy of the combination of lenalidomide (Revlimid®), cyclophosphamide and prednisone (CPR) in patients with relapsed/refractory multiple myeloma. The maximal administered dose of CPR consisted of cyclophosphamide 300 mg/m2 on day 1, 8, and 15, lenalidomide 25 mg on d 1–21 and prednisone 100 mg every other day in a 28-d cycle. Between November 2007 and June 2009, 32 patients were entered in cohorts of three at three dose levels. The median age was 64 years, 59% were male, with a median two prior regimens. Responding patients could stay on treatment until progression. The full-dose CPR regimen produced no dose-limiting toxicity and was delivered for a median of 16 months (3·5–65 months) with acceptable safety and tolerance. The overall response rate (≥ partial response) was 94% at a median follow up of 28 months. The median progression-free survival was 16·1 months [95% confidence interval (CI); 10·9–22·5 months], while the median overall survival was 27·6 months (95% CI; 16·8–36·6 months). Only the beta-2 microglobulin level at protocol entry correlated with a better survival (P = 0·047). These observations compare favourably with other 2- and 3- drug combinations for relapsed/refractory myeloma, and suggest that CPR should be evaluated further in the setting of relapsed/refractory disease, or in newly diagnosed patients.
    British Journal of Haematology 08/2014; 168(1). DOI:10.1111/bjh.13100 · 4.71 Impact Factor
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    ABSTRACT: Patients with multiple myeloma (MM) who relapse after autologous transplantation have limited therapeutic options. We conducted a prospective, multicenter, Phase IIa study to investigate the safety and efficacy of intravenous (IV) busulfan (Bu) in combination with bortezomib as a conditioning regimen for a second autotransplant. Because a safe Bu exposure was unknown in patients receiving this combination, Bu was initially targeted to a total area under the concentration–time curve (AUC) of 20,000 μM*min. As no concentration-limiting toxicity was observed in six patients, this Bu exposure was utilized in the following treatment cohort (n=24). Individualized Bu dose, based on test dose 0.8 mg/kg pharmacokinetics [PK], was administered daily for 4 consecutive days starting 5 days before transplant, followed by a single dose of bortezomib (1.3 mg/m2) 1 day before transplantation. The total mean dose of IV Bu (including the test dose and 4-day administration) was 14.2 mg/kg (standard deviation=2.48; range 8.7–19.2). Confirmatory PK demonstrated that only 2 of 30 patients who underwent transplantation were dosed outside the Bu AUC target and dose adjustments were made for the last two doses of IV Bu. The median age was 59 years (range, 48–73). Median time from first to second transplant was 28.0 months (range, 12–119). Of 26 evaluable patients, 10 patients attained a partial response (PR) or better at 3 months post-transplantation, with two patients attaining a complete response. At 6 months post-transplantation, five of 12 evaluable patients had maintained or improved their disease status. Median progression-free survival was 191 days, whereas median overall survival was not reached during the study period. The most common grade 3–4 toxicities were febrile neutropenia (50.0%) and stomatitis (43.3%). One transplant-related death was observed. A combination of dose-targeted IV Bu and bortezomib induced PR or better in a third of patients with MM who underwent a second autotransplant, with acceptable toxicity.
    Biology of Blood and Marrow Transplantation 08/2014; 20(12). DOI:10.1016/j.bbmt.2014.08.007 · 3.40 Impact Factor
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    ABSTRACT: We conducted a systematic review to determine the appropriate use of bortezomib alone or in combination with other agents in patients with multiple myeloma (mm). We searched medline, embase, the Cochrane Library, conference proceedings, and the reference lists of included studies. We analyzed randomized controlled trials and systematic reviews if they involved adult mm patients treated with bortezomib and if they reported on survival, disease control, response, quality of life, or adverse effects. Twenty-six unique studies met the inclusion criteria. For patients with previously untreated mm and for candidates for transplantation, we found a statistically significant benefit in time to progression [hazard ratio (hr): 0.48, p < 0.001; and hr: 0.63, p = 0.006, respectively] and a better response with a bortezomib than with a non-bortezomib regimen (p < 0.001). Progression-free survival was longer with bortezomib and thalidomide than with thalidomide alone (p = 0.01). In non-candidates for transplantation, a significant benefit in overall survival was observed with a bortezomib regimen (hr compared with a non-bortezomib regimen: 0.61; p = 0.008), and in transplantation candidates receiving bortezomib, the response rate was improved after induction (p = 0.004) and after a first transplant (p = 0.016). In relapsed or refractory mm, overall survival (p = 0.03), time to progression (hr: 1.82; p = 0.000004), and progression-free survival (hr: 1.69; p = 0.000026) were significantly improved with bortezomib and pegylated liposomal doxorubicin (compared with bortezomib alone), and bortezomib monotherapy was better than dexamethasone alone (hr: 0.77; p = 0.027). Bortezomib combined with thalidomide and dexamethasone was better than either bortezomib monotherapy or thalidomide with dexamethasone (p < 0.001). In previously untreated or in relapsed or refractory mm patients, bortezomib-based therapy has improved disease control and, in some patients, overall survival.
    08/2014; 21(4):e573-603. DOI:10.3747/co.21.1798
  • Leukemia and Lymphoma 06/2014; 56(1):1-11. DOI:10.3109/10428194.2014.893304 · 2.89 Impact Factor

Publication Stats

8k Citations
1,124.91 Total Impact Points


  • 2002–2015
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2003–2014
    • University Health Network
      • • Department of Medical Oncology
      • • Department of Laboratory Hematology
      • • Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2003–2013
    • University of Toronto
      • Department of Laboratory Medicine and Pathobiology
      Toronto, Ontario, Canada
  • 2011
    • University of Michigan
      Ann Arbor, Michigan, United States
    • University of Pennsylvania
      • Department of Medicine
      Philadelphia, PA, United States
  • 2008
    • Emory University
      Atlanta, Georgia, United States
  • 1995–2005
    • University of Kentucky
      • Markey Cancer Center
      Lexington, Kentucky, United States
  • 1990–2000
    • University of British Columbia - Vancouver
      • Division of Hematology
      Vancouver, British Columbia, Canada
  • 1999
    • Washington University in St. Louis
      San Luis, Missouri, United States
    • Cleveland State University
      Cleveland, Ohio, United States
  • 1996
    • Vancouver Community College
      Vancouver, British Columbia, Canada
  • 1986–1996
    • Vancouver General Hospital
      • Department of Pathology and Laboratory Medicine (UBC)
      Vancouver, British Columbia, Canada