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Alina S Gerrie,
Joseph R Mikhael,
Lu Cheng,
Haiyan Jiang, Vishal Kukreti,
Tony Panzarella,
Donna Reece,
Keith A Stewart,
Young Trieu,
Suzanne Trudel,
Christine I Chen
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ABSTRACT: Dexamethasone ± thalidomide with infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide [D(T)PACE] is generally reserved as salvage therapy for aggressive multiple myeloma (MM) or plasma cell leukaemia (PCL) resistant to conventional therapies. The efficacy and durability of this potentially toxic regimen in this setting is unclear. We identified 75 patients who received D(T)PACE for relapsed/refractory MM at two tertiary care centres: Princess Margaret Hospital, Toronto and Mayo Clinic Arizona. At time of D(T)PACE, 16 patients had PCL and three patients had leptomeningeal disease. Patients were heavily pretreated (median three prior regimens, range 1-12; prior autologous stem cell transplant [ASCT] 33%). Overall response rate was 49% (very-good partial response 16%, partial response 33%) with stable disease in an additional 36%. Median progression-free survival (PFS) was 5·5 months (95% confidence interval [CI]:4·3-9·8); overall survival (OS) 14·0 months (95% CI:8·7-19·3). Thirty-five patients proceeded to ASCT or clinical trial, with median PFS for this subset of 13·4 months (95% CI:7·7-20·1) and OS 20·5 months (95% CI:14·8-63·8). D(T)PACE is an effective salvage therapy for heavily pretreated MM patients. Although the overall response rate of 49% in this poor prognosis cohort is reasonable, the PFS is short, suggesting the best role for D(T)PACE is in bridging to definitive therapy, such as transplantation.
British Journal of Haematology 04/2013; · 4.94 Impact Factor
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American Journal of Hematology 01/2013; · 4.67 Impact Factor
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ABSTRACT: BACKGROUND: The goal of induction in younger MM patients is to improve performance status and symptoms, enabling autologous stem cell transplantation (ASCT). It is unclear whether intensification of induction regimens improves post transplant outcomes. PATIENTS AND METHODS: We studied 178 MM patients who received conservative steroid-based induction therapy without novel agents before ASCT between 2000 and 2006 and correlated induction parameters (rapidity of response, need for salvage induction therapy, depth of response) with transplant outcomes. RESULTS: Fifty-three percent of patients achieved at least a partial response by cycle 2 (early responders). Rapidity of induction response did not translate into a significant difference in post transplant progression-free survival (PFS) (20.7 vs. 20.0 months; P = .24) or overall survival (OS) (64.4 vs. 51.3 months, respectively; P = .13). In 41 patients (23%) the first induction regimen failed, but they responded to salvage and proceeded to ASCT. They had inferior PFS (15.6 vs. 21.8 months; P = .008) and OS (43.5 vs. 69.4 months; P = .0004) post transplant compared with those requiring 1 regimen. CONCLUSION: Rapid response to induction therapy does not correlate with PFS or OS post ASCT when using a conservative steroid-based induction regimen. Patients in whom this initial induction fails have worse post transplant outcomes, thus the upfront use of intensive therapies with novel agents should be considered.
Clinical lymphoma, myeloma & leukemia 10/2012;
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Journal of Clinical Oncology 09/2012; · 18.37 Impact Factor
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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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David S Siegel,
Thomas Martin,
Michael Wang,
Ravi Vij,
Andrzej J Jakubowiak,
Sagar Lonial,
Suzanne Trudel, Vishal Kukreti,
Nizar Bahlis,
Melissa Alsina, [......],
George Somlo,
Jeffrey Zonder,
Kevin Song,
A Keith Stewart,
Edward Stadtmauer,
Lori Kunkel,
Sandra Wear,
Alvin F Wong,
Robert Z Orlowski,
Sundar Jagannath
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ABSTRACT: Carfilzomib is a next-generation, selective proteasome inhibitor being evaluated for the treatment of relapsed and refractory multiple myeloma. In this open-label, single-arm phase 2 study (PX-171-003-A1), patients received single-agent carfilzomib 20 mg/m(2) intravenously twice weekly for 3 of 4 weeks in cycle 1, then 27 mg/m(2) for ≤ 12 cycles. The primary endpoint was overall response rate (≥ partial response). Secondary endpoints included clinical benefit response rate (≥ minimal response), duration of response, progression-free survival, overall survival, and safety. A total of 266 patients were evaluable for safety, 257 for efficacy; 95% were refractory to their last therapy; 80% were refractory or intolerant to both bortezomib and lenalidomide. Patients had median of 5 prior lines of therapy, including bortezomib, lenalidomide, and thalidomide. Overall response rate was 23.7% with median duration of response of 7.8 months. Median overall survival was 15.6 months. Adverse events (AEs) were manageable without cumulative toxicities. Common AEs were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Thirty-three patients (12.4%) experienced peripheral neuropathy, primarily grades 1 or 2. Thirty-three patients (12.4%) withdrew because of an AE. Durable responses and an acceptable tolerability profile in this heavily pretreated population demonstrate the potential of carfilzomib to offer meaningful clinical benefit. This trial was registered at www.clinicaltrials.gov as #NCT00511238.
Blood 07/2012; 120(14):2817-25. · 9.90 Impact Factor
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Ravi Vij,
Michael Wang,
Jonathan L Kaufman,
Sagar Lonial,
Andrzej J Jakubowiak,
A Keith Stewart, Vishal Kukreti,
Sundar Jagannath,
Kevin T McDonagh,
Melissa Alsina, [......],
Jeffrey V Matous,
Peter Lee,
Peter Rosen,
Michael Sebag,
David H Vesole,
Lori A Kunkel,
Sandra M Wear,
Alvin F Wong,
Robert Z Orlowski,
David S Siegel
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ABSTRACT: Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m(2) for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m(2) for cycle 1 and then 27 mg/m(2) for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy-17.1% overall (1 grade 3; no grade 4)-in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.
Blood 05/2012; 119(24):5661-70. · 9.90 Impact Factor
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American Journal of Hematology 04/2012; 87(8):822-3. · 4.67 Impact Factor
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ABSTRACT: The role of a second autologous stem cell transplant (ASCT) as salvage therapy is unclear, particularly with the availability of novel agents to treat progressive multiple myeloma (MM). We retrospectively reviewed all MM patients who received a second ASCT as salvage therapy at our center from March 1992 to December 2009. Eighty-one MM patients received a second ASCT for relapsed MM. The median time to relapse after first transplant was 39 months (9.83-100). All patients received reinduction therapy before the second ASCT. The high-dose regimen given before the second ASCT consisted of melphalan (MEL) alone in the majority. Complete response, very good partial response, and partial response were seen in 7.7%, 39.7%, and 50%, respectively, at day 100 post-ASCT; the median time to relapse after the second ASCT was 19 months. Early deaths occurred in 2.6%. Median progression-free survival (PFS) based on the time to myeloma relapse after first ASCT was 9.83 months (relapse ≤ 24 months) and 17.3 months (relapse ≥ 24 months) (P < .05). Median overall survival (OS) was 28.47 months (relapse ≤ 24 months) and 71.3 months (relapse >24 months) (P = .006). Second ASCT is a feasible and safe option for salvage therapy in MM. The best outcome was observed in patients whose time to progression was >24 months after first ASCT, as these patients had a subsequent PFS lasting over 1 year and an OS of almost 6 years.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2011; 18(5):773-9. · 3.15 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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Maurizio Zangari,
Monette Aujay,
Fenghuang Zhan,
Kristina L Hetherington,
Tamara Berno,
Ravi Vij,
Sundar Jagannath,
David Siegel,
A Keith Stewart,
Luhua Wang,
Robert Z Orlowski,
Andrew Belch,
Andrzej Jakubowiak,
George Somlo,
Suzanne Trudel,
Nizar Bahlis,
Sagar Lonial,
Seema Singhal, Vishal Kukreti,
Guido Tricot
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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
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Christine I Chen,
P Leif Bergsagel,
Harminder Paul,
Wei Xu,
Anthea Lau,
Nimisha Dave, Vishal Kukreti,
Ellen Wei,
Chungyee Leung-Hagesteijn,
Zhi Hua Li,
Joseph Brandwein,
Mariela Pantoja,
James Johnston,
Spencer Gibson,
Tiffany Hernandez,
David Spaner,
Suzanne Trudel
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ABSTRACT: Lenalidomide is an oral immunomodulatory drug with multiple effects on the immune system and tumor cell microenvironment leading to inhibition of malignant cell growth. Based on encouraging reports of lenalidomide in relapsed and refractory chronic lymphocytic leukemia (CLL), we investigated the first-line use of single-agent lenalidomide in CLL.
Using a starting dose of lenalidomide 10 mg/d for 21 days of a 28-day cycle and weekly 5-mg dose escalations to a target of 25 mg, we encountered severe toxicities (tumor lysis, fatal sepsis) in the first two patients enrolled. The study was halted and the protocol amended to a more conservative regimen: starting dose of lenalidomide 2.5 mg with monthly escalations to a target dose of 10 mg, and extended tumor lysis prophylaxis and monitoring. Gene expression profiles from patient samples before and after 7 days of lenalidomide were performed.
Twenty-five patients were enrolled on the amended protocol. No further tumor lysis events were reported. Tumor flare was common (88%) but mild. Grade 3 to 4 neutropenia occurred in 72% of patients, with only five episodes of febrile neutropenia. The overall response rate was 56% (no complete responses). Although rapid peripheral lymphocyte reductions were observed, rebound lymphocytoses during the week off-therapy were common. Lenalidomide-induced molecular changes enriched for cytoskeletal and immune-related genes were identified.
Lenalidomide is clinically active as first-line CLL therapy and is well-tolerated if a conservative approach with slow dose escalation is used. A lenalidomide-induced molecular signature provides insights into its immunomodulatory mechanisms of action in CLL.
Journal of Clinical Oncology 12/2010; 29(9):1175-81. · 18.37 Impact Factor
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ABSTRACT: Light chain (AL) amyloidosis has a rare association with non-Hodgkin lymphoma (NHL). Both peritumoral and systemic AL amyloidosis have been reported, but a detailed description of these syndromes is lacking. We describe 10 patients with lymphoma associated AL amyloidosis. NHL patients with peritumoral amyloidosis had low or undetectable levels of monoclonal (M) protein, mostly single organ involvement(lung or soft tissue), and underlying extranodal marginal zone lymphoma, mucosa associated lymphoid tissue subtype. NHL patients with systemic amyloidosis had high levels of M-protein, multiorgan involvement with frequent cardiac involvement, and predominantly underlying lymphoplasmacytic lymphoma. Systemic amyloidosis was associated with inferior outcomes
American Journal of Hematology 10/2010; 85(10):805-8. · 4.67 Impact Factor
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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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Journal of Clinical Oncology 10/2009; 27(33):e194-7. · 18.37 Impact Factor
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ABSTRACT: Multiple myeloma (MM) rarely occurs in patients 40 years of age and younger. This young age has been reported to correlate with improved survival in patients with MM. The objective of this study is to describe presenting features and outcomes of patients < or =40 years of age with MM who undergo autologous stem cell transplantation (ASCT) as first-line treatment, and compare overall survival (OS) and progression free survival (PFS) to patients aged 41-65 years. We performed a retrospective institutional review of all patients < or =40 years of age and 41-65 years of age at the time of diagnosis of MM who had undergone upfront ASCT from January 1, 1990, to July 31, 2007. Thirty-eight patients < or =40 years of age and 608 patients aged 41-65 were identified. There was a high rate of plasma cell leukemia (PCL) in young patients at 11% compared to the reported rate of 2%-4%. At diagnosis, there was an increased rate of renal failure in the young cohort compared to patients aged 41-65 years at 25% versus 16% and Bence Jones proteinuria at 81% versus 51%. The rate of complete or partial response was similar between the groups at 79% and 83% in the young and older cohorts, respectively. Median PFS post-ASCT was 22.0 months (95% confidence interval [CI]: 16.1, 28.0), versus 26.9 months (95% CI: 24.0, 29.8) for patients aged 41-65 years (P = .66). Median OS from date of ASCT was also similar to those over 40 years: 68.1 months (95% CI: 39.0, 97.2) versus 80.7 months (95% CI: 68.1, 93.4); P = .90. Treatment-related mortality (TRM) was low at 2.6% and 2.3% in the young and older cohorts, respectively. Despite previous reports that young age is a positive prognostic marker, our study found OS post-ASCT is equivalent to those aged 41-65 years. This study emphasizes the importance of developing strategies to better the outcomes of young patients with MM.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2009; 15(6):686-93. · 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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Journal of Clinical Oncology 03/2008; 26(4):675-8. · 18.37 Impact Factor
