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dexamethasone post autologous hematopoietic cell transplantation in patients with multiple myeloma: a single-center experience
Abstracts 706 Clinical features and treatment outcomes of patients with Necrobiotic Xanthogranuloma (NXG) associated with monoclonal gammopathies (MG) Larissa Higgins, M.B., B.Ch, BAO,2 Wilson Gonsalves, MD,1 Shaji Kumar, MD,1 S. Vincent Rajkumar, MD,1 Francis Buadi, MD,1 Martha Lacy, MD,1 Angela Dispenzieri, MD,1 David Dingli, MD, PhD,1 John Lust, MD, PhD,1 Prashant Kapoor, MD,1 Nelson Leung, MD,1 Yi Lin, MD, PhD,1 Robert Kyle, MD,1 Morie Gertz, MD,1 Ronald Go, MD1 1
Mayo Clinic, Rochester; 2Galway University Hospital
Background: NXG is a rare chronic granulomatous disorder of the skin associated with MG. Due to its rarity, data on response to various therapies are limited. Objective: To describe the clinical features in patients with NXG and MG as well as their response to treatment. Setting: Single tertiary medical care center. Patients: 35 patients with NXG and coexisting MG from 1994-2015. Results: The median age at diagnosis was 56 years (range: 26e88). Most patients had a plasma cell dyscrasia (28 MGUS; 5 smoldering myeloma) while 2 had CLL. The most common monoclonal (M) protein was IgG kappa (60%). The median M-spike was 1.1 g/dL (range: 0e3). The most common site of NXG was periocular (66%). The treatments were heterogeneous and included excision, intra-lesional injection, radiotherapy and systemic treatment. The types of systemic treatment used and clinical response are reported
Table No of patientsA
Response rateB
Chlorambucil+/-Steroids
5
1/5 (20%)
Melphalan/Steroids
3
0/3 (0%)
Cytoxan/Steroids
4
0/4 (0%)
Cladribine
3
1/3 (33%)
Vincristine/doxorubicin/dexamethasone
2
0/2 (0%)
High dose therapy with stem cell rescue
3
2/3 (67%)
Thalidomide+/-Steroids
11
4/11 (36%)
Lenalidomide+/-Steroids
14
7/14 (50%)
Treatment Chemotherapy
Novel agents
Bortezomib+/-Steroids
4
1/4 (25%)
Bortezomib/Lenalidomide/Dexamethasone
1
1/1 (100%)
Intravenous immunoglobulin
4
2/4 (50%)
11
4/11 (36%)
Rituximab
6
1/6 (17%)
AntibioticsC
3
0/3 (0%)
6
0/6 (0%)
Systemic steroids alone
D
Immunosuppressants A
B
Amongst the 35 patients in this study; Response rate: Improvement in NXG skin disease; Antibiotics: Fluoroquinolones/Tetracycline; DImmunosuppressants: Cyclosporine/Methotrexate/Plaquenil
C
in the Table. Median follow up was 46 months (range: 4e234) and the median survival was not reached but at the time of analysis 80% were still alive. At last follow-up, 80% of patients had signs of either clinical improvement or stable skin disease. Eight patients (23%) had disease progression to multiple myeloma at a median of 67 months (Range: 21 e 107). Conclusions: We report the clinical findings and treatment outcomes of the largest series of patients with NXG associated with MG. Cutaneous clinical benefit can be achieved with various systemic agents used in the treatment of lymphoproliferative malignancies.
707 Consolidation with bortezomib/lenalidomide/dexamethasone post autologous hematopoietic cell transplantation in patients with multiple myeloma: a single-center experience Imane Abou Dalle, MD,1 Mohamed A. Kharfan-Dabaja, MD,2 Ali Bazarbachi, MD, PhD,1 Jean El Cheikh, MD1 1
Bone Marrow Transplantation Program and Division of Hematology
and Oncology, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon; 2Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA
Purpose: High-dose therapy (HDT) combined with autologous stem cell transplantation is a standard front-line treatment strategy for patients with newly diagnosed multiple myeloma (MM). Unfortunately, a number of patients will eventually relapse, emphasizing the need for new treatment options or strategies to improve outcomes in these patients. We propose that incorporating active novel agents early in the disease course using bortezomib, lenalidomide, and dexamethasone (VRD) as consolidation post autologous transplantation might improve long-term outcomes by treating residual disease at an early chemo sensitive stage. Patients and Methods: This study was conducted at the American university of Beirut Medical Center, Lebanon. We identified 24 patients with MM who received an autologous transplant between January 2013 and December 2014, and received consolidation treatment with VRD afterwards. Of note, 50% of patients received VRD pretransplant induction. The conditioning regimen consisted of melphalan 200mg/m2 in 24 patients and bortezomib was added to the conditioning in 2 of them. The consolidation regimen consisted of bortezomib 1.3 mg/m2 I.V. (days 1, 8, 15 and 22 of each 28-day cycle), lenalidomide 25 mg orally daily for 21 days every 28 days, dexamethasone 20 mg total orally (days 1, 8, 15 and 22 of each 28day cycle) for a total of 2 cycles. Patients and disease characteristics are summarized in Table 1. Results: Median age at transplantation was 54 (35-67) years. At time of transplant, only 1 (4%) patient was in complete remission (CR). Median time from diagnosis to transplant was 10.5 (3-29) months. The median number of days to reach an ANC more than 500/mm3 post-transplant was 11 (8-18) days. VRD consolidation therapy was initiated at a median of 55
Clinical Lymphoma, Myeloma & Leukemia September 2015
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Abstracts (24-84) days from transplantation. In total, 23 (96%) patients completed 2 cycles of VRD. One patient could not receive bortezomib during cycle 2 because of severe peripheral neuropathy. At a median post-transplant follow up of 17 (2-27) months, all patients were still alive, among whom 15 (62%) achieved deeper responses. Five (21%) patients had disease progression after a median of 8 months post-transplantation. Conclusion: VRD consolidation is feasible and appears to improve outcomes in patients with MM. These encouraging findings warrant further confirmation in a prospective randomized trial.
708 Pharmacogenomics of Bortezomib in Multiple Myeloma Patients Reveals that the Ubiquitin Ligase SCF-Skp2 Promotes Drug Resistance James J. Driscoll,1,2,3 Ehsan Malek4 1
The Vontz Center for Molecular Studies, University of Cincinnati
College of Medicine, Cincinnati, OH; 2Division of Hematology and Oncology; University of Cincinnati College of Medicine, Cincinnati, OH; 3University of Cincinnati Cancer Institute, Cincinnati, OH; 4Case Western Reserve University, Cleveland, OH
Table 1 Patients characteristics Variables Number of patients Median (range) age, years Gender Disease subtype
Pre-transplant induction therapy
Prior lines of therapy Disease status at transplantation
Conditioning regimen
Median (range) time from diagnosis to transplant Median (range) time from transplantation to initiation of consolidation VRD Response attained post VRD consolidation Median (range) follow up from transplantation
Results 24 54 (35-67) Male¼16 (67%) IgG¼13 (54%) IgA¼6 (25%) FLC (kappa or lambda)¼4 (17%) Other¼1 (4%) VRD¼12 (50%) VTD¼4 (17%) VD¼4 (17%) Others¼4 (17%) 1line¼14 (58%) >1 line¼10 (42%) CR¼1 (4%) VGPR¼9 (38%) PR¼14 (58%) Melphalan 200 mg/m2¼ 22 (92%) Melphalan 200 mg/m2+bortezomib¼2 (8%) 10.5 (3-29) months 55 (24-84) days
Additional response¼15 (62%) SD¼4 (17%) PD¼5 (21%) 17 (2-27) months
Abbreviations: CR: complete remission, VGPR: very good partial response, PR: partial response, SD: stable disease, PD: progressive disease.
S54
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Clinical Lymphoma, Myeloma & Leukemia September 2015
Context: While the clinical benefit of Bortezomib in multiple myeloma (MM) remains unchallenged, many patients do not respond to therapy and drug resistance develops nearly uniformly. We employed a pharmacogenomic approach to identify genes expressed at higher levels in tumor cells from MM patients that did not respond to Bortezomib and that were correlated with reduced progression-free survival (PFS) and overall survival (OS). Objective: We sought to identify actionable therapeutic targets to overcome Bortezomib-resistance and to then identify novel small molecules that inhibited key targets. Design: Gene expression datasets from newly diagnosed and relapsed/refractory MM patients were analyzed to identify genes that correlated with reduced PFS and OS in patients that did not respond specifically to Bortezomib. Setting: Bioinformatic and pharmacogenomic analyses were performed using MM patient genetic and clinical outcome results. In vitro and in vivo studies using MM cell lines, patient samples and mouse models validated the ability of novel small molecules to overcome Bortezomib-resistance. Patients: Datasets and clinical outcome information obtained from MM patients with relapsed and/or refractory disease that had been enrolled in the APEX and CREST trials and treated with either Bortezomib or Dexamethasone (GSE9782) were analyzed as well as datasets from newly diagnosed, symptomatic patients randomized to induction therapy with either Bortezomib, Doxorubicin, Dexamethasone (PAD) or Vincristine, Doxorubicin, Dexamethasone (VAD) in the HOVON-65/GMMG-HD4 trial (dataset GSE5900). Main Outcome Measures: Expression of the E3 ubiquitin ligase SCF-Skp2 was correlated with the reduced PFS and OS of Bortezomib-resistant MM patients with statistical significance. Results: CUL1 and COMMD1, critical effectors of SCF-Skp2 activity, were expressed at higher levels in Bortezomib-resistant patients. We identified a novel compound, DT204, that inactivated SCF-Skp2 and when combined with Bortezomib synergistically induced apoptosis and reduced the viability of Bortezomib-resistant cells. Bortezomib treatment with DT204 reduced the growth of xenotransplanted myeloma cells in mouse models and prolonged host survival. Conclusions: We demonstrate that the SCFSkp2-p27 axis represents a major determinant in the ability of Bortezomib to induce apoptosis and provide a proof-of-concept to target SCFSkp2 as a strategy to overcome therapeutic resistance and to enhance efficacy of Bortezomib-based therapies in MM. Keywords: Multiple Myeloma, Pharmacogenomics, Bortezomib, Proteasome.
Mayo Clinic, Rochester; 2Galway University Hospital
Background: NXG is a rare chronic granulomatous disorder of the skin associated with MG. Due to its rarity, data on response to various therapies are limited. Objective: To describe the clinical features in patients with NXG and MG as well as their response to treatment. Setting: Single tertiary medical care center. Patients: 35 patients with NXG and coexisting MG from 1994-2015. Results: The median age at diagnosis was 56 years (range: 26e88). Most patients had a plasma cell dyscrasia (28 MGUS; 5 smoldering myeloma) while 2 had CLL. The most common monoclonal (M) protein was IgG kappa (60%). The median M-spike was 1.1 g/dL (range: 0e3). The most common site of NXG was periocular (66%). The treatments were heterogeneous and included excision, intra-lesional injection, radiotherapy and systemic treatment. The types of systemic treatment used and clinical response are reported
Table No of patientsA
Response rateB
Chlorambucil+/-Steroids
5
1/5 (20%)
Melphalan/Steroids
3
0/3 (0%)
Cytoxan/Steroids
4
0/4 (0%)
Cladribine
3
1/3 (33%)
Vincristine/doxorubicin/dexamethasone
2
0/2 (0%)
High dose therapy with stem cell rescue
3
2/3 (67%)
Thalidomide+/-Steroids
11
4/11 (36%)
Lenalidomide+/-Steroids
14
7/14 (50%)
Treatment Chemotherapy
Novel agents
Bortezomib+/-Steroids
4
1/4 (25%)
Bortezomib/Lenalidomide/Dexamethasone
1
1/1 (100%)
Intravenous immunoglobulin
4
2/4 (50%)
11
4/11 (36%)
Rituximab
6
1/6 (17%)
AntibioticsC
3
0/3 (0%)
6
0/6 (0%)
Systemic steroids alone
D
Immunosuppressants A
B
Amongst the 35 patients in this study; Response rate: Improvement in NXG skin disease; Antibiotics: Fluoroquinolones/Tetracycline; DImmunosuppressants: Cyclosporine/Methotrexate/Plaquenil
C
in the Table. Median follow up was 46 months (range: 4e234) and the median survival was not reached but at the time of analysis 80% were still alive. At last follow-up, 80% of patients had signs of either clinical improvement or stable skin disease. Eight patients (23%) had disease progression to multiple myeloma at a median of 67 months (Range: 21 e 107). Conclusions: We report the clinical findings and treatment outcomes of the largest series of patients with NXG associated with MG. Cutaneous clinical benefit can be achieved with various systemic agents used in the treatment of lymphoproliferative malignancies.
707 Consolidation with bortezomib/lenalidomide/dexamethasone post autologous hematopoietic cell transplantation in patients with multiple myeloma: a single-center experience Imane Abou Dalle, MD,1 Mohamed A. Kharfan-Dabaja, MD,2 Ali Bazarbachi, MD, PhD,1 Jean El Cheikh, MD1 1
Bone Marrow Transplantation Program and Division of Hematology
and Oncology, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon; 2Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA
Purpose: High-dose therapy (HDT) combined with autologous stem cell transplantation is a standard front-line treatment strategy for patients with newly diagnosed multiple myeloma (MM). Unfortunately, a number of patients will eventually relapse, emphasizing the need for new treatment options or strategies to improve outcomes in these patients. We propose that incorporating active novel agents early in the disease course using bortezomib, lenalidomide, and dexamethasone (VRD) as consolidation post autologous transplantation might improve long-term outcomes by treating residual disease at an early chemo sensitive stage. Patients and Methods: This study was conducted at the American university of Beirut Medical Center, Lebanon. We identified 24 patients with MM who received an autologous transplant between January 2013 and December 2014, and received consolidation treatment with VRD afterwards. Of note, 50% of patients received VRD pretransplant induction. The conditioning regimen consisted of melphalan 200mg/m2 in 24 patients and bortezomib was added to the conditioning in 2 of them. The consolidation regimen consisted of bortezomib 1.3 mg/m2 I.V. (days 1, 8, 15 and 22 of each 28-day cycle), lenalidomide 25 mg orally daily for 21 days every 28 days, dexamethasone 20 mg total orally (days 1, 8, 15 and 22 of each 28day cycle) for a total of 2 cycles. Patients and disease characteristics are summarized in Table 1. Results: Median age at transplantation was 54 (35-67) years. At time of transplant, only 1 (4%) patient was in complete remission (CR). Median time from diagnosis to transplant was 10.5 (3-29) months. The median number of days to reach an ANC more than 500/mm3 post-transplant was 11 (8-18) days. VRD consolidation therapy was initiated at a median of 55
Clinical Lymphoma, Myeloma & Leukemia September 2015
- S53
Abstracts (24-84) days from transplantation. In total, 23 (96%) patients completed 2 cycles of VRD. One patient could not receive bortezomib during cycle 2 because of severe peripheral neuropathy. At a median post-transplant follow up of 17 (2-27) months, all patients were still alive, among whom 15 (62%) achieved deeper responses. Five (21%) patients had disease progression after a median of 8 months post-transplantation. Conclusion: VRD consolidation is feasible and appears to improve outcomes in patients with MM. These encouraging findings warrant further confirmation in a prospective randomized trial.
708 Pharmacogenomics of Bortezomib in Multiple Myeloma Patients Reveals that the Ubiquitin Ligase SCF-Skp2 Promotes Drug Resistance James J. Driscoll,1,2,3 Ehsan Malek4 1
The Vontz Center for Molecular Studies, University of Cincinnati
College of Medicine, Cincinnati, OH; 2Division of Hematology and Oncology; University of Cincinnati College of Medicine, Cincinnati, OH; 3University of Cincinnati Cancer Institute, Cincinnati, OH; 4Case Western Reserve University, Cleveland, OH
Table 1 Patients characteristics Variables Number of patients Median (range) age, years Gender Disease subtype
Pre-transplant induction therapy
Prior lines of therapy Disease status at transplantation
Conditioning regimen
Median (range) time from diagnosis to transplant Median (range) time from transplantation to initiation of consolidation VRD Response attained post VRD consolidation Median (range) follow up from transplantation
Results 24 54 (35-67) Male¼16 (67%) IgG¼13 (54%) IgA¼6 (25%) FLC (kappa or lambda)¼4 (17%) Other¼1 (4%) VRD¼12 (50%) VTD¼4 (17%) VD¼4 (17%) Others¼4 (17%) 1line¼14 (58%) >1 line¼10 (42%) CR¼1 (4%) VGPR¼9 (38%) PR¼14 (58%) Melphalan 200 mg/m2¼ 22 (92%) Melphalan 200 mg/m2+bortezomib¼2 (8%) 10.5 (3-29) months 55 (24-84) days
Additional response¼15 (62%) SD¼4 (17%) PD¼5 (21%) 17 (2-27) months
Abbreviations: CR: complete remission, VGPR: very good partial response, PR: partial response, SD: stable disease, PD: progressive disease.
S54
-
Clinical Lymphoma, Myeloma & Leukemia September 2015
Context: While the clinical benefit of Bortezomib in multiple myeloma (MM) remains unchallenged, many patients do not respond to therapy and drug resistance develops nearly uniformly. We employed a pharmacogenomic approach to identify genes expressed at higher levels in tumor cells from MM patients that did not respond to Bortezomib and that were correlated with reduced progression-free survival (PFS) and overall survival (OS). Objective: We sought to identify actionable therapeutic targets to overcome Bortezomib-resistance and to then identify novel small molecules that inhibited key targets. Design: Gene expression datasets from newly diagnosed and relapsed/refractory MM patients were analyzed to identify genes that correlated with reduced PFS and OS in patients that did not respond specifically to Bortezomib. Setting: Bioinformatic and pharmacogenomic analyses were performed using MM patient genetic and clinical outcome results. In vitro and in vivo studies using MM cell lines, patient samples and mouse models validated the ability of novel small molecules to overcome Bortezomib-resistance. Patients: Datasets and clinical outcome information obtained from MM patients with relapsed and/or refractory disease that had been enrolled in the APEX and CREST trials and treated with either Bortezomib or Dexamethasone (GSE9782) were analyzed as well as datasets from newly diagnosed, symptomatic patients randomized to induction therapy with either Bortezomib, Doxorubicin, Dexamethasone (PAD) or Vincristine, Doxorubicin, Dexamethasone (VAD) in the HOVON-65/GMMG-HD4 trial (dataset GSE5900). Main Outcome Measures: Expression of the E3 ubiquitin ligase SCF-Skp2 was correlated with the reduced PFS and OS of Bortezomib-resistant MM patients with statistical significance. Results: CUL1 and COMMD1, critical effectors of SCF-Skp2 activity, were expressed at higher levels in Bortezomib-resistant patients. We identified a novel compound, DT204, that inactivated SCF-Skp2 and when combined with Bortezomib synergistically induced apoptosis and reduced the viability of Bortezomib-resistant cells. Bortezomib treatment with DT204 reduced the growth of xenotransplanted myeloma cells in mouse models and prolonged host survival. Conclusions: We demonstrate that the SCFSkp2-p27 axis represents a major determinant in the ability of Bortezomib to induce apoptosis and provide a proof-of-concept to target SCFSkp2 as a strategy to overcome therapeutic resistance and to enhance efficacy of Bortezomib-based therapies in MM. Keywords: Multiple Myeloma, Pharmacogenomics, Bortezomib, Proteasome.