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American Journal of Hematology 01/2013; · 4.67 Impact Factor
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Darrell J White,
Nizar J Bahlis,
Deb C Marcellus,
Andrew Belch,
A Keith Stewart,
Christine Chen,
Michael J Kovacs,
David A Macdonald, Donna E Reece,
Tony Reiman,
Erica Harnett,
Ralph M Meyer,
Judy-Anne W Chapman,
Stephen Couban
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ABSTRACT: BACKGROUND: We conducted a phase II trial that evaluated the tolerability and efficacy of combining lenalidomide with melphalan in previously untreated patients with multiple myeloma who were not candidates for autologous stem cell transplantation. METHODS: After a run-in phase of 6 patients, we planned to conduct a randomized phase II selection-design trial that assessed 2 dose levels of lenalidomide, given days 1 to 21, combined with melphalan, given days 1 to 4, and every 28 days. Planned doses of melphalan were 9 mg/m(2)/d and respective doses of lenalidomide were 10 and 20 mg/d (M9L10 and M9L20). Coprimary endpoints were the frequency of dose-limiting Planned doses of melphalan were 9 mg/m(2)/d and respective doses of lenalidomide were 10 and 20 mg/d (M9L10 and M9L20). toxicities (DLT) and complete response (CR). RESULTS: Four patients received M9L10; all experienced DLTs, which resulted in closure of this cohort. When using the same schedule, we then sequentially tested M6L10 (melphalan 6 mg/m(2) on days 1 to 4 and lenalidomide 10 mg/d on days 1 to 21 every 28 days) (6 patients), M4L15 (melphalan 4 mg/m(2) on days 1 to 4 and lenalidomide 15 mg/d on days 1 to 21 every 28 days) (6 patients), and M5L10 (melphalan 5 mg/m(2) days 1 to 4 and lenalidomide 10 mg/d days 1 to 21 every 28 days) (34 patients). In each cohort, the DLT endpoint was reached because of severe and prolonged hematologic toxicity. At the final dose level, M5L10, 20 of 27 patients experienced DLTs within their first 3 cycles; among 10 patients who received at least 6 cycles, none achieved a CR. CONCLUSIONS: Combining lenalidomide plus melphalan without prednisone is associated with substantial hematologic toxicity that precludes cyclical administration of adequate drug doses.
Clinical lymphoma, myeloma & leukemia 11/2012;
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ABSTRACT: Abstract Background The combination of lenalidomide, bortezomib, and dexamethasone (RVD) has shown excellent efficacy in relapsed or refractory (RRMM) multiple myeloma patients. The aim of our study was to assess the efficacy and toxicity profile of RVD for patients with advanced RRMM. Methods We retrospectively reviewed the records of all RRMM patients treated with RVD between 03/09-12/11. Thirty patients received ≥ 1 full cycle of RVD. Primary endpoints were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results After a median of 5 cycles (1-16), VGPR was seen in 10%, PR in 36.7% and SD in 13.3% (ORR of 46.7%). Disease progression occurred in 21 patients at a median of 3 months (range 1.41-4.59). Eight patients (26%) experienced grade 3/4 adverse events, including anemia, neutropenia, muscle weakness, and pneumonia. No patient experienced worsening peripheral neuropathy. Conclusions Although RVD has been previously shown to be effective in RRMM, the ORR and PFS we observed were affected by very advanced disease status and heavy prior exposure to novel agents. Nevertheless, six of these RRMM patients experienced a benefit of ≥6 months, suggesting synergism of this immunomodulatory derivative/proteasome inhibitor combination and/or re-establishment of drug sensitivity by an emergent myeloma clone.
Leukemia & lymphoma 08/2012; · 2.40 Impact Factor
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American Journal of Hematology 04/2012; 87(8):822-3. · 4.67 Impact Factor
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Meaghan L Khan,
Craig B Reeder,
Shaji K Kumar,
Marthy Q Lacy, Donna E Reece,
Angela Dispenzieri,
Morie A Gertz,
Phillip Greipp,
Suzanne Hayman,
Steven Zeldenhurst,
David Dingli,
John Lust,
Stephen Russell,
Kristina M Laumann,
Joseph R Mikhael,
P Leif Bergsagel,
Rafael Fonseca,
S Vincent Rajkumar,
A Keith Stewart
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ABSTRACT: Novel agents are considered standard components of induction therapy for newly diagnosed patients with multiple myeloma. We retrospectively compared the results of three consecutive phase 2 clinical trials; RD (lenalidomide/dexamethasone, n=34), CRD (cyclophosphamide/lenalidomide/dexamethasone, n=53) and CyBorD (cyclophosphamide/bortezomib/dexamethasone, n=63) (N=150). Response rates after four cycles of treatment were: ≥near complete response (nCR), 12% vs. 2% vs. 41%, P<0·0001 and very good partial response or better, 35% vs. 30% vs. 65%, P=0·0003, respectively. With all cycles of therapy considered, ≥nCR was 35%, 15% and 41%, P=0·006. However, there is no evidence that one regimen produced superior progression-free survival (PFS) (median: 3·2 vs. 2·3 vs. 2·7years, P=0·11) or overall survival (3-year: 88% vs. 79% vs. 88%, P=0·23). Transplantation did not impact PFS (median: 2·7 vs. 2·3 years, P=0·41) but was associated with improved OS (3-year: 93% vs. 75%, P≤0·001). High genetic risk patients (n=40) had earlier relapse despite lenalidomide or bortezomib (median: 2·1 vs. 2·7years, P=0·45). Grade 3/4 toxicities were least with CyBorD while CRD had most toxicity. In conclusion, CyBorD demonstrated superior responses and less frequent serious toxicity but more neuropathy when compared to RD and CRD. Importantly, 80% of patients treated with modern therapeutic approaches are alive at 4years.
British Journal of Haematology 11/2011; 156(3):326-33. · 4.94 Impact Factor
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ABSTRACT: High-dose chemotherapy with autologous stem cell transplantation (ASCT) can achieve excellent clinical responses in patients with POEMS syndrome (Jimenez Zepeda et al., Blood 2010;116:2403; Gertz et al., Am J Hematol 2005;79:319-328; Gherardi et al., Ann Neurol 1994;35:501-505; Gattinoni et al., Nat Rev Immunol 2006;6:383-393; Salem et al., J Immunol 2009;182:2030-2040; Salem et al., Cancer Immunol Immunother 2010;59:341-353; Salem et al., Cell Immunol 2010;261:134-143). However, High-dose melphalan with ASCT should be considered carefully due to its treatment-related morbidity (Vuckovic et al., Blood 2003;101:2314-2317), especially in patients with poor performance status owing to polyneuropathy and multiorgan involvement, such as cardiac, respiratory, and renal failure. Significant increases in the concentration of circulating macrophage colony-stimulating factor, erythropoietin, IL-6, and TNF-α, reach near maximal values at approximately day +12, predating neutrophil engraftment, and clinically manifest with fever, rash and edema (Dispenzieri et al., Eur J Haematol 2008;80:397-406). Depending on the definition used, approximately 50% of patients satisfied criteria for engraftment syndrome (ES) (Vuckovic et al., Blood 2003;101:2314-2317). ES occurs in 27-47% of patients who undergo ASCT; mortality rate is reported from 8% to 18% (Gattinoni et al., Nat Rev Immunol 2006;6:383-393; Vuckovic et al., Blood 2003;101:2314-2317). We have therefore reviewed our experience with ASCT in patients with POEMS syndrome who were treated with cyclophosphamide and prednisone as induction therapy followed by cyclophosphamide mobilization with an emphasis on treatment-related morbidity and frequency of ES. Our study confirms that ASCT is a feasible and efficacious treatment for patients with POEMS syndrome. In addition, the use of CP followed by cyclophosphamide mobilization decreases the incidence of PES leading to less morbidity and mortality rates.
American Journal of Hematology 06/2011; 86(10):873-5. · 4.67 Impact Factor
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Andrzej J Jakubowiak,
Kent A Griffith, Donna E Reece,
Craig C Hofmeister,
Sagar Lonial,
Todd M Zimmerman,
Erica L Campagnaro,
Robert L Schlossman,
Jacob P Laubach,
Noopur S Raje, [......],
Melissa A Mietzel,
Colleen K Harvey,
Sandra M Wear,
Jennifer C Barrickman,
Craig L Tendler,
Dixie-Lee Esseltine,
Susan L Kelley,
Mark S Kaminski,
Kenneth C Anderson,
Paul G Richardson
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ABSTRACT: This phase 1/2 trial evaluated combination lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (RVDD) in newly diagnosed multiple myeloma (MM) patients. Patients received RVDD at 4 dose levels, including the maximum tolerated dose (MTD). Patients with a very good partial response or better (≥ VGPR) after cycle 4 proceeded to autologous stem cell transplantation or continued treatment. The primary objectives were MTD evaluation and response to RVDD after 4 and 8 cycles. Seventy-two patients received a median of 4.5 cycles. The MTDs were lenalidomide 25 mg, bortezomib 1.3 mg/m(2), pegylated liposomal doxorubicin 30 mg/m(2), and dexamethasone 20/10 mg, as established with 3-week cycles. The most common adverse events were fatigue, constipation, sensory neuropathy, and infection; there was no treatment-related mortality. Response rates after 4 and 8 cycles were 96% and 95% partial response or better, 57% and 65% ≥ VGPR, and 29% and 35% complete or near-complete response, respectively. After a median follow-up of 15.5 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated 18-month PFS and OS were 80.8% and 98.6%, respectively. RVDD was generally well tolerated and highly active, warranting further study in newly diagnosed MM patients. This trial was registered at www.clinicaltrials.gov as NCT00724568.
Blood 05/2011; 118(3):535-43. · 9.90 Impact Factor
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Donna E Reece,
Ute Hegenbart,
Vaishali Sanchorawala,
Giampaolo Merlini,
Giovanni Palladini,
Joan Bladé,
Jean-Paul Fermand,
Hani Hassoun,
Leonard Heffner,
Robert A Vescio,
Kevin Liu,
Christopher Enny,
Dixie-Lee Esseltine,
Helgi van de Velde,
Andrew Cakana,
Raymond L Comenzo
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ABSTRACT: This first prospective phase 2 study of single-agent bortezomib in relapsed primary systemic AL amyloidosis evaluated the recommended (maximum planned) doses identified in phase 1 testing (1.6 mg/m² once weekly [days 1, 8, 15, and 22; 35-day cycles]; 1.3 mg/m² twice weekly [days 1, 4, 8, and 11; 21-day cycles]). Among all 70 patients enrolled in the study, 44% had ≥ 3 organs involved, including 73% and 56% with renal and cardiac involvement. In the 1.6 mg/m² once-weekly and 1.3 mg/m² twice-weekly groups, the hematologic response rate was 68.8% and 66.7% (37.5% and 24.2% complete responses, respectively); median time to first/best response was 2.1/3.2 and 0.7/1.2 months, and 78.8% and 75.5% had response durations of ≥ 1 year, respectively. One-year hematologic progression-free rates were 72.2% and 74.6%, and 1-year survival rates were 93.8% and 84.0%, respectively. Outcomes appeared similar in patients with cardiac involvement. Among all 70 patients, organ responses included 29% renal and 13% cardiac responses. Rates of grade ≥ 3 toxicities (79% vs 50%) and discontinuations/dose reductions (38%/53% vs 28%/22%) resulting from toxicities appeared higher with 1.3 mg/m² twice-weekly versus 1.6 mg/m² once-weekly dosing. Both bortezomib dose schedules represent active, well-tolerated regimens in relapsed AL amyloidosis. This study was registered at www.clinicaltrials.gov as #NCT00298766.
Blood 05/2011; 118(4):865-73. · 9.90 Impact Factor
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Donna E Reece
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ABSTRACT: One of the major efforts to improve the results of intensive therapy and autologous stem cell transplantation (ASCT) in multiple myeloma involves the integration of novel agents into the transplantation sequence. This can include their administration before, during, and after the transplantation procedure. Several phase 2 and 3 studies have evaluated the use of novel agents as part of induction therapy before transplantation to produce higher response rates and progression-free survival (PFS). Similarly, posttransplantation maintenance-or consolidation-with these agents consistently improves PFS. Survival benefits have been more difficult to demonstrate, although one trial using bortezomib before and after transplantation and a second using lenalidomide as maintenance have shown significantly longer survival times. This article reviews the different regimens used with ASCT, with an emphasis on randomized trials.
Hematology 01/2011; 2011:197-204. · 1.49 Impact Factor
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Donna E Reece,
David H Vesole,
Smriti Shrestha,
Mei-Jie Zhang,
Waleska S Pérez,
Angela Dispenzieri,
Gustavo A Milone,
Muneer Abidi,
Harold Atkins,
Asad Bashey, [......],
Gregory A Hale,
Shaji Kumar,
Robert A Kyle,
Hillard M Lazarus,
Philip L McCarthy,
Santiago Pavlovsky,
Vivek Roy,
Daniel J Weisdorf,
Peter H Wiernik,
Parameswaran N Hari
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ABSTRACT: Immunoglobulin D (IgD) and IgM multiple myeloma represent uncommon immunoglobulin isotypes, accounting for 2% and 0.5% of cases, respectively. Limited information is available regarding the prognosis of these isotypes, but they have been considered to have a more aggressive course than the more common immunoglobulin G (IgG) and IgA isotypes. In particular, the outcome after autologous hematopoietic stem cell transplantation (auto-HCT) has not been well defined.
Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 36 patients with IgD and 11 patients with IgM myeloma among 3578 myeloma patients who received intensive therapy and auto-HCT over a 10-year period.
The progression-free and overall survival probabilities at 3 years were 38% (95% CI, 21%-56%) and 69% (95% CI, 51%-84%) for IgD myeloma, and 47% (95% CI, 17%-78%) and 68% (95% CI, 36%-93%), respectively, for IgM disease. Although formal statistical analysis was limited by the small sample size, these results were comparable to those for IgG and IgA patients autografted during the same time period. Transplantation-related mortality and disease relapse/progression of myeloma were also similar for all isotypes.
This analysis demonstrates comparable outcomes in all immunoglobulin isotypes. Therefore, auto-HCT should be offered to eligible patients with IgD and IgM myeloma.
Clinical lymphoma, myeloma & leukemia 12/2010; 10(6):458-63.
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Craig B Reeder, Donna E Reece,
Vishal Kukreti,
Christine Chen,
Suzanne Trudel,
Kristina Laumann,
Joseph Hentz,
Nicholas A Pirooz,
Jesus G Piza,
Rodger Tiedemann,
Joseph R Mikhael,
Peter L Bergsagel,
Jose F Leis,
Rafael Fonseca,
Alexander K Stewart
Blood 04/2010; 115(16):3416-7. · 9.90 Impact Factor
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Donna E Reece,
Dan Sullivan,
Sagar Lonial,
Ann F Mohrbacher,
Gurkamal Chatta,
Chaim Shustik,
Howard Burris,
Karthik Venkatakrishnan,
Rachel Neuwirth,
William J Riordan,
Michael Karol,
Lisa L von Moltke,
Milin Acharya,
Peter Zannikos,
A Keith Stewart
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ABSTRACT: Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses.
Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m(2), days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected.
Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102-112 L/h for first dose; 15-32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m(2) group.
Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m(2) doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.
Cancer Chemotherapy and Pharmacology 03/2010; 67(1):57-67. · 2.83 Impact Factor
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Donna E Reece
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ABSTRACT: Many recent trials have been undertaken that incorporate novel agents into the treatment of newly diagnosed multiple myeloma patients. This review highlights the current status of different approaches to initial therapy in the era of novel drugs.
The therapy of newly diagnosed patients with multiple myeloma is still usually based on age and eligibility for autologous stem cell transplantation (ASCT). In older patients, several randomized trials have evaluated the addition of a novel agent to oral melphalan and prednisone, while novel agents have been incorporated before, during and after ASCT in younger individuals. Newer investigational approaches that are not age-dependent include continuous myeloma suppression with dexamethasone plus an immunomodulatory derivative, or the use of multiple cycles of combination regimens followed by a treatment break or maintenance therapy. Updated information is now also available regarding the use of nonmyeloablative allogeneic transplantation. The biologic heterogeneity of myeloma is most easily measured in the clinic by fluorescence in-situ hybridization (FISH) cytogenetics, and the detection of adverse cytogenetics is beginning to influence treatment decisions.
Clinical trials have established the superiority of regimens containing novel agents in the initial management of myeloma, although a number of questions remain about the optimal strategy.
Current opinion in hematology 08/2009; 16(4):306-12. · 5.19 Impact Factor
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Donna E Reece,
Vaishali Sanchorawala,
Ute Hegenbart,
Giampaolo Merlini,
Giovanni Palladini,
Jean-Paul Fermand,
Robert A Vescio,
Xiangyang Liu,
Yusri A Elsayed,
Andrew Cakana,
Raymond L Comenzo
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ABSTRACT: New treatment options are required for primary systemic AL amyloidosis (AL). This phase 1 dose-escalation component of a phase 1/2 study in relapsed AL aimed to determine the maximum tolerated dose (MTD) of bortezomib once weekly (0.7-1.6 mg/m(2); days 1, 8, 15, and 22; 35-day cycles) and twice weekly (0.7-1.3 mg/m(2); days 1, 4, 8, and 11; 21-day cycles) and assess preliminary hematologic responses. Thirty-one patients with relapsed AL were enrolled across 7 cohorts. Dose-limiting toxicity included grade 3 congestive heart failure in 2 patients (1 at once weekly, 1.6 mg/m(2), and 1 at twice weekly, 1.0 mg/m(2)). MTD was not defined for either schedule; the maximum doses of 1.6 mg/m(2) (once weekly) and 1.3 mg/m(2) (twice weekly) are being used in phase 2 evaluation. Most commonly reported toxicities on both schedules included gastrointestinal events, fatigue, and nervous system disorders. Discontinuations and dose reductions for toxicity were reported in 12 and 4 patients, respectively. No treatment-related deaths occurred. Hematologic responses occurred in 15 (50%) of 30 evaluable patients, including 6 (20%) complete responses. Median time to first response was 1.2 months. Once-weekly and twice-weekly bortezomib appear generally well tolerated in relapsed AL, with promising hematologic responses. This study is registered with http://ClinicalTrials.Gov under identifier NCT00298766.
Blood 07/2009; 114(8):1489-97. · 9.90 Impact Factor
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Christine Chen, Donna E Reece,
David Siegel,
Ruben Niesvizky,
Ralph V Boccia,
Edward A Stadtmauer,
Rafat Abonour,
Paul Richardson,
Jeffrey Matous,
Shaji Kumar,
Nizar J Bahlis,
Melissa Alsina,
Robert Vescio,
Steven E Coutre,
Dennis Pietronigro,
Robert D Knight,
Jerome B Zeldis,
Vincent Rajkumar
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ABSTRACT: Lenalidomide gained Food and Drug Administration (FDA) approval for treatment of patients with relapsed or refractory multiple myeloma (MM) in combination with dexamethasone in June 2006. In April 2005, the FDA and patient advocacy groups requested an expanded access programme to both provide lenalidomide to patients likely to benefit and obtain additional safety information. Relapsed/refractory MM patients received lenalidomide 25 mg/d (days 1-21) and dexamethasone 40 mg/d (days 1-4, 9-12, and 17-20 of cycles 1-4; days 1-4 only from cycle 5 onwards), in 4-week cycles until disease progression, study drug discontinuation, or lenalidomide approval. Of the 1438 patients enrolled, approximately 60% were male, median age was 64 years, and 61.7% had Durie-Salmon stage III disease. Median time on study was 15.4 weeks (range: 0.1-49.1) and median dose was 25 mg. The most common adverse events (AEs) were haematological (49%), gastrointestinal (59%), and fatigue (55%). The most common grade > or =3 AEs were haematological (45%), fatigue (10%), and pneumonia (7%). The most common serious AEs were pneumonia (8%), pyrexia (4%), and deep-vein thrombosis (3%). Primary cause of death was disease progression (10%). Safety data confirmed known AEs of lenalidomide plus dexamethasone therapy in patients with relapsed/refractory MM.
British Journal of Haematology 05/2009; 146(2):164-70. · 4.94 Impact Factor
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Asad Bashey,
Waleska S Pérez,
Mei-Jie Zhang,
Kenneth C Anderson,
Karen Ballen,
James R Berenson,
L Bik To,
Rafael Fonseca,
César O Freytes,
Robert Peter Gale, [......],
Hillard M Lazarus,
Dipnarine Maharaj,
Philip L McCarthy,
Gustavo A Milone,
Stephen Nimer,
Santiago Pavlovsky, Donna E Reece,
Gary Schiller,
David H Vesole,
Parameswaran Hari
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ABSTRACT: Relapse is the overwhelming cause of treatment failure after autologous transplantation for multiple myeloma (MM). For patients with a syngeneic donor, twin transplants provide a healthy graft that is free of myeloma. The relative impact of the graft on posttransplant relapse can be estimated by comparing risk of relapse after hematopoietic cell transplantation from genetically identical twins versus autotransplants because confounding differences in minor or major histocompatibility antigens are absent in the syngeneic transplant setting. Outcomes of 43 subjects who received twin transplants for MM were compared to 170 matched autotransplant recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Multivariate analysis was performed by fitting a Cox model stratified on matched pairs. The matched transplant patients studied were similar with respect to subject-, disease-, and transplant-related characteristics. Cumulative incidence of relapse/progression was significantly lower, and progression-free survival (PFS) was significantly higher following twin transplants. In multivariate analysis, the probability of relapse/progression was lower in twins (relative risk [RR] = 0.49, 95% confidence interval [CI] 0.28-0.86, P = .011). Twin transplants have a significantly lower relapse risk than autotransplants in MM, suggesting that graft composition may impact outcomes following high-dose chemotherapy.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2008; 14(10):1118-24. · 3.15 Impact Factor
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Shaji Kumar,
Waleska S Pérez,
Mei-Jie Zhang,
Karen Ballen,
Asad Bashey,
L Bik To,
Christopher N Bredeson,
Mitchell S Cairo,
Gerald J Elfenbein,
César O Freytes, [......],
Martha Q Lacy,
Hillard M Lazarus,
Philip L McCarthy,
Gustavo A Milone,
Jan S Moreb,
Santiago Pavlovsky, Donna E Reece,
David H Vesole,
Peter H Wiernik,
Parameswaran Hari
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ABSTRACT: Nonsecretory myeloma (NSM) accounts for <5% of cases of multiple myeloma (MM). The outcome of these patients following autologous stem cell transplantation (ASCT) has not been evaluated in clinical trials. We compared the outcomes after ASCT for patients with NSM reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1989 and 2003, to a matched group of 438 patients (4 controls for each patient) with secretory myeloma (SM). The patients were matched using propensity scores calculated using age, Durie-Salmon stage, sensitivity to pretransplant therapy, time from diagnosis to transplant, and year of transplant. Disease characteristics were similar in both groups at diagnosis and at transplant except higher risk of anemia, hypoalbuminemia, and marrow plasmacytosis (in SM) and plasmacytoma (more in NSM). Cumulative incidence of treatment-related mortality (TRM), relapse, progression-free survival (PFS), and overall survival (OS) were similar between the groups. In multivariate analysis, based on a Cox model stratified on matched pairs and adjusted for covariates not considered in the propensity score, we found no difference in outcome between the NSM and SM groups. In this large cohort of patients undergoing ASCT, we found no difference in outcomes of patients with NSM compared to those with SM.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2008; 14(10):1134-40. · 3.15 Impact Factor
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ABSTRACT: The combination of oral weekly cyclophosphamide and alternate day prednisone is a convenient regimen for relapsed/refractory multiple myeloma (MM), and we sought to improve its efficacy by adding bortezomib, a proteasome inhibitor with proven antimyeloma activity.
We conducted a phase I-II trial evaluating six dose levels to define the maximum tolerated dose (MTD) of this combination in relapsed/refractory MM. An additional 10 patients were evaluated at the highest dose level reached.
Thirty-seven patients were treated on this study. The MTD was not defined. Both of the highest dose levels of bortezomib tested (1.3 mg/m(2) on days 1, 4, 8, and 11 and 1.5 mg/m(2) on days 1, 8, and 15, each on a 28-day cycle) could be safely given with cyclophosphamide 300 mg/m(2) per week and prednisone. At these dose levels, the overall response rate was 95% (complete responses [CR] plus partial response plus minimal response), with CR observed in more than 50% of patients. The weekly bortezomib regimen resulted in fewer instances of grade 3 thrombocytopenia and grade 1 to 2 peripheral neuropathy; the 1-year progression-free and overall survival probabilities with this dose level were 83% (95% CI, 73% to 96%) and 100%, respectively.
Weekly bortezomib 1.5 mg/m(2) plus oral cyclophosphamide and prednisone produces an unprecedented response rate and encouraging 1-year survival in relapsed/refractory patients with MM. Further evaluation of this promising regimen is warranted both in relapsed and newly diagnosed disease.
Journal of Clinical Oncology 10/2008; 26(29):4777-83. · 18.37 Impact Factor
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Donna E Reece
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ABSTRACT: Many changes have been incorporated into the approach to multiple myeloma over the last few years, due to improvements in our understanding of the disease biology. New diagnostic and prognostic criteria from the International Myeloma Working Group have clarified the initial clinical approach to this disease. The prognostic impact of chromosomal abnormalities is now recognized, and the detection of specific abnormal cytogenetics is beginning to influence therapeutic decisions. The introduction of the novel agents thalidomide, bortezomib and lenalidomide has expanded treatment options at different points in the disease course; these agents are being evaluated in conjunction with conventional chemotherapy and stem cell transplantation. This report highlights some of the key recent findings in multiple myeloma, and describes areas for future research.
Blood Reviews 12/2007; 21(6):301-14. · 5.36 Impact Factor
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Athanasios Anagnostopoulos,
Parameswaran N Hari,
Waleska S Pérez,
Karen Ballen,
Asad Bashey,
Christopher N Bredeson,
César O Freytes,
Robert Peter Gale,
Morie A Gertz,
John Gibson,
Hartmut Goldschmidt,
Hillard M Lazarus,
Philip L McCarthy, Donna E Reece,
David H Vesole,
Sergio A Giralt
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ABSTRACT: The role of hematopoietic stem cell transplantation (SCT) in Waldenstrom's macroglobulinemia (WM) has not been extensively studied. To determine the potential for long-term disease control using SCT in WM, we performed a retrospective review of 36 patients with WM who received autologous (n = 10) or allogeneic (n = 26) SCT and were reported to the Center for International Blood and Marrow Transplant Research between 1986 and 2002. The following outcomes were described: nonrelapse mortality (NRM), relapse, progression-free survival (PFS), and overall survival (OS). Median age at the time of SCT was 51 years (range, 30-76 years), and median time from initial treatment to SCT was 29 months (range, 2-198 months). A total of 78% of the patients had 2 or more previous chemotherapy regimens, and 52% had disease resistant to salvage chemotherapy. In the allogeneic SCT group, 58% of the patients received myeloablative conditioning regimens containing total body irradiation (TBI), and of the allograft recipients, 19% received nonmyeloablative/reduced-intensity conditioning. After a median follow-up of 65 months, 15 of the 36 patients (42%) are alive. Primary disease accounted for 29% of the deaths in the allogeneic SCT group and 25% of the deaths in the autologous SCT group. The relapse rate at 3 years was 29% (95% confidence interval [CI], 14%-48%) in the allogeneic group and 24% (95% CI, 4%-54%) in the autologous group. PFS at 3 years was 31% (95% CI, 14%-50%) in the allogeneic group and 65% (95% CI, 32%-91%) in the autologous group; OS was 46% (95% CI, 27%-65%) in the allogeneic group and 70% (95% CI, 40%-93%) in the autologous group. NRM at 3 years was 40% (95% CI, 23%-59%) in the allogeneic group and 11% (95% CI, 0-36%) in the autologous group. Autologous SCT is a safe and feasible treatment option for patients with WM, especially for those who present with adverse prognostic factors. Allogeneic SCT carries a much higher (40%) risk of NRM and should not be considered outside the context of a clinical trial.
Biology of Blood and Marrow Transplantation 09/2006; 12(8):845-54. · 3.87 Impact Factor
