Bortezomib-Based Therapy without Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma Patients with t(4;14): A Canadian National Trial,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3982-3982
Author(s):  
Donna E. Reece ◽  
Giovanni Piza Rodriguez ◽  
David Szwajcer ◽  
Leonard A Minuk ◽  
Mariela Pantoja ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Disease Progression ◽  
Induction Therapy ◽  
Research Funding ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Newly Diagnosed

Abstract Abstract 3982 Newly diagnosed multiple myeloma (MM) patients (pts) with t(4;14) identified by FISH who undergo a single ASCT after older induction regimens have a median progression-free survival (PFS) of only 8–9 months (mos) and median overall survival (OS) of 18 mos (Chang H, et al. Bone Marrow Transplan t 2005; 36: 793; Gertz M, et al. Blood 2005; 106: 2837). Given the efficacy of bortezomib in t(4;14) disease, we designed a phase II study based on this agent in which ASCT was not performed as part of first-line therapy. Pts received induction therapy with four 21-day cycles of pegylated liposomal doxorubicin 30 mg/m2on day 4, bortezomib 1.3 mg/m2on days 1, 4, 8, 11 and dexamethasone 40 mg on days 1–4, 8–11, 15–18 of cycle 1 and on days 1–4 and 11–14 of cycles 2–4 (DBD), followed by post-induction therapy with eight 28-day cycles of oral cyclophosphamide 300 mg/m2on days 1, 8, 15, 22, bortezomib 1.5 mg/m2 on days 1,8,15 and prednisone 100 mg q 2 days (CyBor-P). Maintenance therapy with dexamethasone 40 mg/weekly was then administered until disease progression. Although elective stem cell collection was recommended after induction therapy, routine ASCT was not performed in the absence of disease progression. Between February 2008-May 2011, 383 newly diagnosed MM pts were screened for t(4;14) in 8 Canadian centers, and 43 (11.2%) were found to be positive by FISH. Five did not meet the CRAB criteria for symptomatic MM, 7 were ineligible, 3 declined participation and 28 were entered onto study. One of these was later determined to have a variant abnormality of chromosome 4, but not t(4;14), and underwent ASCT after induction therapy; this pt is included in the safety analysis only. The median age was 60 years (range 42–69) and 63% were male. The median percent of nuclei positive for t(4;14) by FISH in the initial bone marrow (unpurified) was 26% (range 2–62), serum β2-microglobulin 239 nmol/L (range 43–1695) and albumin 36 g/L (range 28–48); ten pts had ISS stage 1,10 had stage 2 and 7 had stage 3 MM. Immunoglobulin subtype included IgGκ in 7, IgAκ in 6, IgAλ in 6, IgGλ in 5 and IgMλ in 1. Using modified uniform criteria, the best response in 23 evaluable pts includes: sCR in 6 (26%), CR in 4 (17%), VGPR in 9 (39%), PR in 2 (9%) and SD in 2 (9%). Median F/U is 13.5 mos (range 1.2–35); 6 have progressed at median of 3 mos on study (range 1–11). Four pts have died (due to progression in 3 and complex medical problems/consent withdrawal in 1 in VGPR). SAEs were reported in 7 pts; only 6 pts (21%) developed grade 2 peripheral neuropathy, which necessitated dose reductions of bortezomib in 4. The actuarial 2-yr PFS is 47.7% (95%CI 25.9–87.9%), median PFS is 23. 2 months and 2-yr OS is 76.8% (95%CI 58.3–100%); the median OS has not yet been reached. We conclude: 1) the incidence of t(4;14) by FISH in newly-diagnosed MM pts is 11.2%; which appears to be lower than the 15% anticipated 2) 11.6% of these are asymptomatic; 3) this bortezomib-based regimen is well-tolerated; 4) the overall response rate (sCR + CR + VGPR + PR) is 91% with 82% achieving ≥ VGPR and 43% ≥ CR; 5) the PFS and OS with this approach compare favorably with those seen with older studies of single or double ASCT, and even with some recently reported trials using more modern induction regimens before ASCT, in pts with t(4;14); and 6) the use of more effective maintenance therapy, including agents targeting the aberrations associated with t(4;14), would be of interest in future trials. Disclosures: Reece: Millennium: Research Funding; Otsuka: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol, Meyers, Squibb: Honoraria, Research Funding; Amgen: Honoraria. Off Label Use: Bortezomib regimens other than VMP (boretzomib, melphalan and prednisone)for initial therapy of myeloma. Piza Rodriguez:Celgene: Unrestricted educational grant; Otsuka: Honoraria. Belch:Ortho/Janssen: Honoraria; Celgene: Honoraria. White:Celgene: Consultancy, Honoraria, Research Funding; Ortho/Janssen: Honoraria, Research Funding. Chen:Celgene: Research Funding. Kukreti:Celgene: Honoraria.

Bortezomib-Based Therapy, without Stem Cell Transplantation, for Newly Diagnosed Multiple Myeloma Patients with t(4;14).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3861-3861
Author(s):  
Donna E. Reece ◽  
Giovanni Piza Rodriguez ◽  
Andrew Belch ◽  
David Szwajcer ◽  
Mariela Pantoja ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Induction Therapy ◽  
Research Funding ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Newly Diagnosed ◽  
Post Induction

Abstract Abstract 3861 Poster Board III-797 Previous studies have reported that multiple myeloma (MM) patients (pts) with t(4;14) identified by FISH who are treated with a single ASCT as part of first-line therapy have worse outcomes than those lacking this adverse cytogenetic marker; two trials have described a median progression-free survival (PFS) of only 8-9 months and median overall survival (OS) of 18 mos in this setting (Chang H, et al. Bone Marrow Transplant 2005; 36: 793; Gertz M, et al. Blood 2005; 106: 2837). Since the novel agent bortezomib appears to have efficacy in patients with t(4;14), we designed a phase II protocol in which pts receive induction with pegylated liposomal doxorubicin, bortezomib and dexamethasone (DBD) x 4 cycles, followed by post-induction therapy with oral cyclophosphamide 300 mg/m2 days 1,8 15, 22 with bortezomib 1.5 mg/m2 days 1,8,15 and prednisone 100 mg q 2 days of a 28-day cycle (CyBor-P) x 8 additional cycles. Maintenance therapy with dexamethasone (dex) 40 mg/month was then administered until progression. Although elective stem cell collection was recommended after induction, routine ASCT was not performed in the absence of disease progression. Between February 2008-August 2009, 153 newly diagnosed MM pts were screened for t(4;14) in 7 Canadian centers, and 14 (9%) were found to be positive by FISH. Four did not meet the critieria for symptomatic MM, 2 had received ≥ 2 mos of prior therapy while 8 were entered onto study. One of these was later determined to have a variant abnormality of chromosome 4 but not t(4;14) and underwent ASCT after induction; this pt is included in the safety analysis only. The median age was 56 (49-69) and 43% were male. The median percent nuclei positive for t(4;14) was 30% (10-41%), serum β2-microglobulin 394 nmol/L (190-1695) and albumin 34 g/L (28-39); one pt had ISS stage 1,3 had stage 2 and 3 had stage 3 MM. Immunoglobulin subtype included IgGκ in 2 and IgAκ in 2 and IgAλ in 3. All pts have completed DBD induction, with the best response in the 7 evaluable pts consisting of PR in 2 and VGPR in 5; one in PR progressed quickly after induction and has achieved nCR after D-PACE followed by ASCT and lenalidomide maintenance. Four are receiving post-induction therapy with CyBor-P currently, with VGPR in 3 and PR in 1. No SAEs or grade3/4 neutropenia or thrombocytopenia has occurred; other toxicities were mild, with grade 2 skin toxicity noted in 37.5% and grade 2 neurotoxicity observed in 7.4%. All pts are alive at a median follow-up (F/U) of 8 mos (2-11), and 6 (86%) are free of progression. We conclude: 1) the incidence of t(4;14) in newly diagnosed MM pts appears to be lower than the 15% anticipated; 2) 28% of newly diagnosed pts with this entity have asymptomatic MM; 3) preliminarily, DBD induction has resulted in ≥ PR in all pts although 1 progressed quickly; 4) this bortezomib-based regimen is very well-tolerated; 5) longer F/U is required to determine the PFS and OS with this approach. Disclosures: Reece: Ortho Biotech: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Use of bortezomib as part of initial therapy with pegylated liposomal doxorubicin and dexamethasone. Piza Rodriguez:Ortho Biotech: Honoraria. Belch:Ortho Biotech: Honoraria, Research Funding. Shustik:Ortho Biotech: Honoraria. Bahlis:Ortho Biotech: Honoraria; Celgene: Honoraria. White:Ortho Biotech: Honoraria, Research Funding. Chen:Ortho Biotech: Honoraria. Kukreti:Celgene: Honoraria. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Trudel:Ortho Biotech: Honoraria, Research Funding.

Outcomes of Multiple Myeloma Patients with Del 17p Undergoing Autologous Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-22
Author(s):  
Iuliana Vaxman ◽  
Alissa Visram ◽  
Prashant Kapoor ◽  
Abdullah S. Al Saleh ◽  
Shaji K. Kumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Advisory Board ◽  
Newly Diagnosed ◽  
Immunomodulatory Agents

Introduction High risk (HR) multiple myeloma (MM) constitutes approximately 25 % of newly diagnosed patients and is a subgroup of MM patients that is variably defined. Patients with 17p deletion are considered HR and their optimal treatment approach has not been determined. Various strategies have been suggested to improve outcomes in MM patients harboring del 17p, including tandem transplants. Recently, the long-term outcomes of the phase 3 EMN02 trial were published with the study group receiving bortezomib, cyclophosphamide and dexamethasone (VCd) induction prior to transplant. There are no data demonstrating that tandem transplant is applicable to the US population using induction containing immunomodulatory agents and bortezomib. Aim To report on outcomes of newly diagnosed MM patients with del 17p that underwent autologous stem cell transplantation (ASCT). Methods Retrospective study of all consecutive newly diagnosed MM patient with del 17p that underwent ASCT at Mayo Clinic, Rochester, Minnesota. Patients were defined by the Mayo Medical Lab as 17p deleted and included if they met the following criteria: If 50 cells in the bone marrow sample and 10 cells with the deletion were identified (20%) or if the bone marrow sample had between 20-50 total cells and 20% cells with the deletion were identified. We excluded patients that relapsed prior to ASCT (as those patients were excluded in the EMN02 trial), patients that underwent ASCT more than 12 months from the diagnosis and patients that underwent tandem ASCT (defined as two consecutive ASCT within 180 days of each other without relapse in between). Consolidation treatment was defined as treatment given after transplant for up to six 28-day cycles and maintenance was defined as all treatment given after ASCT for more than 6 months. Combined maintenance was defined as maintenance regimens that included two novel agents. Results 116 patients with MM and 17p deletion underwent ASCT at Mayo Clinic between January 2013 and April 2020. The median age at diagnosis was 62 (IQR 57-68, range 34-76) years. Forty-five (39%) patients were over 65 years. Nine patients (8%) had triple-hit MM and 34 (29%) had double-hit MM. Median follow-up of the survivors was 33 months (IQR 21-54). Consolidation therapy was given to 36 patients (31%) and maintenance was given to 91 patients (78%). Seven patients relapsed before day 100. There was no difference in the OS (P=0.72) or PFS (P=0.1) between patients that received VRd (bortezomib, lenalidomide and dexamethasone) versus VCd (bortezomib, cyclophosphamide and dexamethasone) induction (Figure 1). When comparing patients that received proteasome inhibitors (PIs)+ immunomodulatory agents (IMiDs) as induction to patients that received VCd induction, PFS was longer for patients that received the PIs + IMiDs (HR 0.53 P=0.04, 95% CI=0.3-0.98) (Figure 2), however there was no OS difference (P=0.61). Maintenance therapy was given to 94 patients (81%). There was no OS (P=0.34) or PFS (P=0.36) difference between IMiD based and PI based maintenance, but there was a PFS advantage to patients that received two drug maintenance (HR= 0.41, P=0.037, 95% CI 0.14-0.95) (Figure 2). The median OS and PFS of the entire cohort were not reached and 29 months, respectively. Conclusions The outcomes of our patients were similar to that of the single arm ASCT in the EMN02 trial, and no difference in outcomes were found between patients that received VRd and VCd induction, suggesting that tandem transplants should be considered for 17p deleted MM patients. Dual novel agent maintenance therapy is important in improving outcome. Disclosures Kapoor: Celgene: Honoraria; GlaxoSmithKline: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Janssen: Research Funding. Kumar:Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Tenebio: Other, Research Funding; Adaptive Biotechnologies: Consultancy; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Novartis: Research Funding; Carsgen: Other, Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; MedImmune: Research Funding. Dispenzieri:Pfizer: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Alnylam: Research Funding; Intellia: Research Funding; Celgene: Research Funding. Dingli:Alexion: Consultancy; Sanofi-Genzyme: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; Millenium: Consultancy; Karyopharm Therapeutics: Research Funding; Rigel: Consultancy; Apellis: Consultancy. Gertz:DAVA oncology: Speakers Bureau; Proclara: Other; Abbvie: Other; Physicians Education Resource: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Appellis: Other: personal fee; Research to Practice: Other; Ionis/Akcea: Other: personal fee; Celgene: Other; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Annexon: Other: personal fee; Alnylam: Other: personal fee; Prothena: Other: personal fee; Janssen: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Aurora Bio: Other; Springer Publishing: Patents & Royalties; Sanofi: Other; Amgen: Other: personal fee.

Sequential Approach with Bortezomib as Induction Before Autologous Transplantation, Followed by Lenalidomide as Consolidation-Maintenance in Untreated Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3419-3419 ◽  
Author(s):  
Francesca Gay ◽  
Patrizia Falco ◽  
Claudia Crippa ◽  
Anna Marina Liberati ◽  
Francesca Patriarca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Advisory Committee ◽  
Research Funding ◽  
Response Rate ◽  
Autologous Transplantation ◽  
Pegylated Liposomal Doxorubicin ◽  
Newly Diagnosed ◽  
Sequential Approach ◽  
Grade 3

Abstract Abstract 3419 Poster Board III-307 Background Bortezomib induction before autologous stem cell transplantation (ASCT) has shown its efficacy in newly diagnosed multiple myeloma (MM) patients, both in association with dexamethasone alone (Harousseau JL, et al. Blood 110, 2007, abstr 450) and in combination with doxorubicin and dexamethasone (Popat R, et al. Br J Haematol 141:512-516, 2008). Lenalidomide, a less toxic and more potent thalidomide-derivative, lacks the neurotoxic effects of the parent drug and represents an optimal agent to include in maintenance regimens. Aims These observations provided the rationale for investigating a sequential approach including bortezomib as induction and lenalidomide as consolidation-maintenance in MM patients undergoing ASCT. Methods A hundred and two newly diagnosed patients aged 65–75 years were enrolled in 17 Italian centers. Induction (PAD) included four 21-day cycles of bortezomib (1.3 mg/m2 days 1,4,8,11), pegylated-liposomal-doxorubicin (30 mg/m2 day 4), and dexamethasone (40 mg/day: cycle 1, days 1–4, 8–11, 15–18; cycles 2–4, days 1–4). Autologous transplantation was tandem melphalan 100 mg/m2 (MEL100) followed by stem-cell support. After ASCT, patients received consolidation with four 28-day cycles of lenalidomide (25 mg/day days 1–21 every 28 days) plus prednisone (50 mg every other day) (LP), followed by maintenance (L) with lenalidomide alone (10 mg/day days 1–21 every 28 days) until relapse. Primary endpoints were safety (incidence of grade 3–4 adverse events [AEs]) and efficacy (response rate). Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Time-to-event estimates analysis was performed using the Kaplan-Meier method. Results Very good partial response (VGPR) or better was 58% after PAD induction and increased to 82% after MEL100 and to 86% during LP-L. Complete response (CR) rate was 13% after PAD induction, increased to 38% after MEL100 and to 66% during LP-L. After a median follow-up of 2 years, the 2-year PFS was 69%, the 2-year time-to-progression was 75% and the 2-year OS was 86%. During PAD induction, main grade 3–4 AEs were thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%); treatment-related mortality was 3%. During consolidation-maintenance grade 3–4 AEs included neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%). Consolidation-maintenance treatment was well tolerated: only 4% of patients required Granulocyte-colony stimulating factor support and no patient required platelet transfusion; dermatological toxicity was easily manageable with dose-reduction and supportive therapy; no treatment-related deaths were reported. Updated results will be presented at the meeting. Conclusion This is the first phase II study in newly diagnosed MM patients to date, where a sequential approach including bortezomib as induction, and lenalidomide as post ASCT consolidation-maintenance was explored. Treatment was correlated with an increase in response rate and in the depth of response (CR rate) and was generally well tolerated. These data suggest that this is a safe and effective regimen for newly diagnosed MM patients. Randomized trials are needed to confirm these results. Disclosures Patriarca: Celgene: Honoraria; Janssen Cilag: Honoraria. Bringhen:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Janssen Cilag : Consultant, advisory committee, Research Funding; Celgene: Consultant, advisory committee, Research Funding; Pharmion: Consultant, advisory committee, Research Funding. Palumbo:Celgene: Honoraria; Janssen Cilag: Honoraria.

Lenalidomide Is a Highly Effective Maintenance Therapy in Myeloma Patients of All Ages; Results of the Phase III Myeloma XI Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1143-1143 ◽  
Author(s):  
Graham H Jackson ◽  
Faith E Davies ◽  
Charlotte Pawlyn ◽  
David A Cairns ◽  
Alina Striha ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Disease Progression ◽  
Induction Therapy ◽  
Research Funding ◽  
Patient Choice ◽  
Phase Iii ◽  
Induction Treatment ◽  
Second Primary ◽  
Newly Diagnosed ◽  
Support Research

Abstract Background Lenalidomide is an effective treatment for myeloma and has been studied in a range of combination regimens worldwide. The results of these studies have suggested that prolonged exposure to lenalidomide is important to improve outcomes both as a maintenance agent post-transplant (Attal M et al NEJM 2012, McCarthy et al NEJM 2012) and in the transplant ineligible population (Palumbo A et al NEJM 2012, Benboubker L et al NEJM 2014). In the Myeloma XI study, the largest of its kind, we explored the use of oral lenalidomide continued to disease progression compared to no therapy in both newly diagnosed transplant eligible (TE) and transplant non-eligible (TNE) populations. Here we present the results of this maintenance randomization, which demonstrate the efficacy and safety of maintenance lenalidomide. Methods The Myeloma XI study is a Phase III, UK-based, multicenter, open-label, parallel group, randomized controlled trial for newly diagnosed symptomatic myeloma patients of all ages and includes a maintenance comparison of lenalidomide versus no maintenance. Newly diagnosed symptomatic myeloma patients both TE and TNE were enrolled to the study. Induction treatment in both pathways was with thalidomide or lenalidomide plus cyclophosphamide and dexamethasone, with appropriate dose reductions for TNE patients. TE patients proceded to a standard melphalan 200mg/m2 transplant. Patients were randomized to either maintenance lenalidomide or observation after achieving maximum response (TNE) or at 100 days after transplant (TE). Lenalidomide was administered at a dose of 10mg daily in 21/28 day cycles until disease progression. Dose adjustments for renal impairment and following AEs were permitted. The primary endpoints for the maintenance randomization were progression-free (PFS) and overall survival. Secondary endpoints included response, toxicity and PFS2. Time-to-event endpoints were measured from maintenance randomization. This abstract summarizes a preliminary analysis, final data will be presented at the meeting. The median follow up in this analysis is 26 months [IQR 12-41]. Results A total of 1550 patients, 828 TE and 722 TNE, median age 61 and 74 years, respectively, were randomized between lenalidomide (n=857) and no maintenance (n=693). The arms were well-balanced for clinical features and response to induction therapy (e.g. ISS stage III: 27% vs 23%, VGPR/CR: 73% vs 73%). The maintenance randomization has met its primary endpoint demonstrating a 55% reduction in risk of progression or death for lenalidomide compared to no maintenance (HR 0.45 [95%CI 0.39-0.52], median PFS 37 vs 19 months, p<0.0001) This significant improvement was observed in each pathway TE: HR 0.46 [95%CI 0.36-0.58], median PFS 60 vs 28 months, p<0.0001. TNE: HR 0.44 [95%CI 0.36-0.53], median PFS 26 vs 12 months, p<0.0001. The benefit of lenalidomide maintenance on PFS persisted across risk subgroups and was independent of induction therapy and response. An exploratory analysis of 132 patients stopping lenalidomide treatment for reasons other than disease progression (91 toxicity, 28 patient choice and 13 clinician choice) shows that patients receiving greater than 12 months of treatment have an improved median PFS compared to those stopping earlier (HR 0.35 [95%CI 0.18-0.68], 49 vs 31 months, p<0.0015). At this time 445 patients continue to receive lenalidomide maintenance on study. Of patients who have stopped therapy, only 21.5% did so due to toxicity. Relevant grade 3/4 adverse events were: neutropenia 35%, thrombocytopenia 7.4%, anaemia 4.4%, peripheral neuropathy 1.4%. Venous thromboembolism occurred in 2.3%. Second primary malignancy (SPM) data was collected and the relationship with maintenance therapy reviewed. 72 SPM were observed (24 no maintenance, 48 lenalidomide). Haematologic malignancy crude incidence was 0.3% vs. 0.9%. While we found a slight excess of SPM in older patients these were mostly non-invasive and did not impact the outcome benefit demonstrated. Conclusion The use of maintenance lenalidomide treatment results in highly significant improvements in PFS for patients of all ages and should be standard of care. On behalf of the NCRI Haem-Onc CSG Disclosures Jackson: Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau. Davies:Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Pawlyn:Takeda Oncology: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support. Jones:Celgene: Honoraria, Research Funding. Kishore:celgene: Other: travel grant. Garg:Janssen: Other: Travel support, Research Funding, Speakers Bureau; Takeda: Other: Travel support; Novartis: Other: Travel support, Research Funding. Williams:Takeda: Honoraria, Other: Travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel support, Speakers Bureau. Karunanithi:Celgene: Other: Travel support, Research Funding; Janssen: Other: Travel support, Research Funding. Lindsay:Janssen: Consultancy; Novartis: Other: Travel support; Takeda: Other: Travel support; BMS: Consultancy, Other: Travel support; Celgene: Honoraria, Other: Travel support. Jenner:Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel support; Amgen: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau. Kaiser:BMS: Consultancy, Other: Travel Support; Takeda: Consultancy, Other: Travel Support; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Chugai: Consultancy. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Owen:Takeda: Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Other: Travel support. Morgan:Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding; Univ of AR for Medical Sciences: Employment; Celgene: Consultancy, Honoraria, Research Funding.

Phase 2 Study of Carfilzomib, Thalidomide, and Low-Dose Dexamethasone As Induction/Consolidation in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma, the Carthadex Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1141-1141 ◽  
Author(s):  
Ruth Wester ◽  
Bronno van der Holt ◽  
Emelie Asselbergs ◽  
Mark van Duin ◽  
Sonja Zweegman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Induction Therapy ◽  
Research Funding ◽  
Fixed Dose ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
Standard Risk

Abstract Introduction A phase 2 dose escalation trial of Carfilzomib in combination with Thalidomide and Dexamethasone (KTd) for induction and consolidation in newly diagnosed, transplant-eligible patients with multiple myeloma (MM). We report the results of 4 dose levels. Methods In this multicenter, open-label, phase 2 trial, transplant-eligible patients aged between 18 and 65 years with previously untreated symptomatic MM were included. Patients were treated with 4 cycles of escalating dose of Carfilzomib + fixed-dose thalidomide and dexamethasone (KTd) for induction therapy. The dose of Carfilzomib was 20 mg/m2 i.v. on days 1, 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 and 16 of cycles 2 to 4. Thalidomide dose was 200 mg orally on days 1 through 28 and Dexamethasone 40 mg orally on days 1, 8, 15 and 22. Carfilzomib was escalated to 20/36 mg/m2 in cohort 2, to 20/45 mg/m2 in cohort 3 and to 20/56 mg/m2 in cohort 4. Induction was followed by stem cell harvest after Cyclophosphamide priming (2 to 4 mg/m2) and G-CSF. Hereafter patients received high-dose Melphalan (HDM, 200mg/m2) and autologous stem cell transplantation followed by consolidation treatment with 4 cycles of KTd in the same schedule except a lower dose of Thalidomide (50mg). The primary endpoint was response after induction therapy and overall, specifically complete response (CR) and very good partial response (VGPR). Secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). Results All 111 patients with a median follow-up of 55, 42, 35 and 28 months, in cohorts 1 to 4, respectively were included in the analysis. Median age was 58 years. ISS stages I/II/III were 41%/34%/23%, respectively, R-ISS stages I/II/III/unknown were 23%/59%/9%/9%, respectively. Of 111 patients, 9 patients stopped treatment during/after induction, 8 patients after cyclophosphamide priming or HDM and 9 patients during consolidation because of toxicity (n=9), non-eligibility for further treatment (n=6), progression (n=5), refusal (n=2) or other reasons (n=4). Overall response rate for all cohorts was 95%. Response after induction was CR/sCR in 18% of patients, ≥ VGPR in 66% of patients, ≥ PR in 94% of patients. After HDM the CR/sCR rate increased to 31% and after consolidation to 64%. Responses between cohorts were in general comparable. See Table 1. Response based on risk status by ISS/FISH in either cohort and accumulated did not show a difference in CR/sCR rate after consolidation between standard-risk (67%) and high risk defined as t(4;14) and/or del17p and/or add1q and/or ISS3 (60%). OS at 30 months was comparable between standard risk and high risk, 91% versus 90%. PFS at 30 months for standard risk and high risk was 79% and 62%, logrank p=0.02 (HR=2.3, 95% CI=1.1-4.5). PFS at 30 months per cohort was 70% (95% CI, 55% to 81%), 70% (95% CI, 45% to 85%), 80% (95% CI, 56% to 92%) and 62% (95% CI, 32% to 82%) in cohorts 1,2, 3 and 4, respectively, and 71% (95% CI, 61% to 79%) in all patients. OS at 30 months per cohort was 90% (95% CI, 77% to 96%), 90% (95% CI, 66% to 97%), 95% (95% CI, 71% to 99%) and 88% (95% CI, 58% to 97%) respectively, and 91% (95% CI, 83% to 95%) in all patients. Gene expression profiling using the Affymetrix U133 Plus 2.0 GeneChips was performed on purified tumor cells for 49 patients. Using the prognostic classifier EMC92 a high-risk group of patients (16%) was identified versus standard risk (in terms of OS: logrank p=0.06 (HR=3.7, 95% CI=0.8-16.8), and in terms of PFS: logrank p=0.14 (HR=2.1, 95% CI=0.8-6.0)). Safety analysis for all 111 patients showed non-hematological grade 3 and 4 toxicity, mainly respiratory disorders (in 15%), GI disorders (13%) and skin lesions (10%). Toxicity between cohorts did not show a significant difference. Cardiac adverse events were limited and included heart failure (n=2 at 27 mg/m2), hypertension (n=2) and chest pain (n=1 at 45mg/m2). Conclusion Carfilzomib, thalidomide, dexamethasone (KTd) is an effective regimen, with increasing CR percentages following KTd consolidation. With escalated doses of Carfilzomib responses and toxicity were comparable to standard dose of 27 mg/m2. Disclosures Zweegman: Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kersten:Celgene: Research Funding; Amgen: Honoraria. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Broijl:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

scholarly journals Lenalidomide Compared to Ixazomib Maintenance in Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3776-3776
Author(s):  
Eunice Lai ◽  
Yu Yang Soon ◽  
Ainsley Ryan Yan Bin Lee ◽  
Shi Yin Wong ◽  
Cinnie Yentia Soekojo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Meta Analysis ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Risk Of Bias ◽  
Newly Diagnosed ◽  
Maintenance Strategies

Abstract Background Maintenance therapy is considered a standard of care in transplant eligible (TE) and non transplant eligible (NTE) patients with newly diagnosed multiple myeloma (NDMM). While immunomodulators (IMID) and proteasome inhibitors (PI) have been proposed as maintenance therapy options, there are no randomised trials (RCTs) directly comparing these agents in the maintenance setting. The IMID lenalidomide (Len) and the PI ixazomib (Ixa) have been compared against placebo as maintenance strategies in NDMM. We present a network meta-analysis (NMA) of RCTs comparing the efficacy and safety of Len and Ixa maintenance therapies in NDMM. Methods We searched various biomedical databases for eligible studies evaluating Len or Ixa against placebo/ observation as maintenance therapy in patients with NDMM from date of inception through November 2020. The primary outcome was progression-free survival (PFS). Secondary outcomes include overall survival (OS) and adverse events (AE). The Cochrane risk of bias tool version 2.0 was used to assess trial quality. A Bayesian NMA model was used to assess the relative effects of competing treatments on PFS and OS outcomes. Adverse events were assessed using the synthesis without meta-analysis (SWIM) approach due to variability in the toxicity scoring criteria. The GRADE approach was used to rate the certainty of the evidence. This study is registered with PROSPERO, CRD42021226157. Results We identified eight studies including 3229 transplant eligible (TE) and 1689 non transplant eligible (NTE) patients. All studies were judged to have low risk of bias. Len but not Ixa was associated with statistically significant improvement in PFS when compared to placebo in TE (Len: Hazard Ratio (HR) 0.46, 95% Credible Interval (CrI) 0.35-0.56, high certainty; Ixa: HR 0.72, 95% CrI 0.46-1.13, moderate certainty) and NTE (Len: HR 0.46, 95% CrI 0.29-0.75, high certainty; Ixa: HR 0.69, 95% CrI 0.43-1.18, moderate certainty). Bayesian modelling demonstrated a 97% and 93% probability that Len resulted in superior PFS compared to Ixa in TE and NTE patients respectively. Both Len and Ixa were not associated with statistically significant improvement in OS compared to placebo in TE and NTE patients. There was no significant effect modification on the effect of Len vs placebo and Ixa vs placebo by cytogenetics status, use of proteasome inhibitors for induction or duration of maintenance therapies for PFS and/or OS outcomes. Len were judged to have a higher incidence of second malignancies and grade 3 or 4 neutropenia than Ixa while Ixa was judged to have a higher incidence of thrombocytopenia than Len. Conclusions Maintenance therapy with Len may provide a larger PFS benefit than Ixa regardless of type of induction therapy and cytogenetic risk in patients with NDDM. The differing toxicity profile of these agents is also an important consideration for treatment decisions. RCTs directly comparing these maintenance strategies are warranted. Figure 1 Figure 1. Disclosures Ooi: Jansen: Honoraria; Teva Pharmaceuticals: Honoraria; GSK: Honoraria; Abbvie: Honoraria; Amgen: Honoraria. Chng: Sanofi: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Amgen: Honoraria; BMS/Celgene: Honoraria, Research Funding; Johnson and Johnson: Honoraria, Research Funding; Pfizer: Honoraria.

Autologous Stem Cell Transplant: A Cost Effective and Efficacious Treatment for Newly Diagnosed Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2358-2358 ◽  
Author(s):  
Seema Niphadkar ◽  
Indumathy Varadarajan ◽  
Tiffany Pompa ◽  
Kevin Y Hou ◽  
Kathleen Degen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Maintenance Therapy ◽  
Progression Free Survival ◽  
Cost Effective ◽  
Novel Agents ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Optimal Duration ◽  
The Cost

Abstract Background: Induction chemotherapy followed by autologous stem cell transplantation (ASCT) is considered a standard of care for appropriate patients with newly diagnosed multiple myeloma (MM), but with the rapid expansion of available treatments, the role of ASCT has been questioned. Numerous studies have shown an improvement in complete response (CR) and progression free survival (PFS) with ASCT but our study is a cost comparison between novel agents and ASCT. We aimed to compare the cost effectiveness of ASCT versus non-transplant regimens in relation to PFS. Methods: We queried the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (NIS) between 2008 and 2013 using the ICD-9 code 203.00 for MM and V42.81 for ASCT in the primary and secondary diagnosis fields. The analysis included patients who were 18 years or older. We monitored the trends in ASCT with regards to cost of a transplant admission and length of stay (LOS). Cost of hospitalization was adjusted for inflation in reference to the year 2011 and cost to charge ratio. Literature regarding common treatment regimens, response rates, duration of treatment, and PFS was reviewed. The assumption was made that transplant eligible patients that did not undergo transplant would be treated as though they were transplant ineligible. Gay et al 2015 showed a 43.4-month (mo) median PFS with 4 cycles of Rd followed by ASCT and lenalidomide maintenance until progression or toxicity. The cost of novel regimens was estimated using the one month commercial cost described by Roy et al and wholesale acquisition costs for new agents not described by the study which were adjusted using adjunct cost described by the study. A standard weight of 70 kg was used for agents requiring dose calculations. The cost of novel agents for an equivalent duration of 43.4 mo was estimated. Results: A total of 44778 (weighted n=9039) hospitalizations for MM (Male 55.9%, Caucasian 57.9%, peak incidence 65-79 yrs) occurred from 2008-2013. The average length of stay during ASCT admission was 11.4 +/- 0.4 days with a cost of $109,856 +/-5749.83. There has been a 16.89% decrease in LOS and 1.99% increase in the cost of ASCT (p<0.05). Gay et al showed a 43.4 mo PFS with 4 cycles Rd ($46,216) followed by ASCT ($109,856) and lenalidomide maintenance (~35.4 mo $564,453 adjusted for cost of office visits and lab work) for a total of $720,525 Conclusion: Rd + ASCT + R maintenance is efficacious for the treatment of newly diagnosed MM. The cost associated with the induction and transplant represents only 22% of the total cost, whereas lenalidomide maintenance makes up 78%. Considering secondary risks and the cost involved with lenolidomide maintenance, further investigation is warranted regarding the optimal duration of maintenance therapy and resultant progression free survival. It also raises the need for alternative options for maintenance therapy. Bortezomib and ixazomib are both more cost effective options and studies are in progress to assess their efficacy in PFS in the maintenance setting. Studies using novel agents for induction prior to ASCT are ongoing and have yet to reach an optimal duration of therapy. Table 1 shows that most of the novel agents used in combination regimens are more expensive that ASCT. Although most patients would not remain on one of these regimens for 43.4 mo, they would presumably progress through multiple lines of therapy during the 43.4 mo of PFS that ASCT provides. In an era of cost consciousness, ASCT should continue to be an integral component of MM treatment. Disclosures No relevant conflicts of interest to declare.

Role Of Double Stem Cell Transplantation For Newly Diagnosed Multiple Myeloma In The Era Of Novel Agents

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2171-2171
Author(s):  
Shotaro Hagiwara ◽  
Risen Hirai ◽  
Miki Nakamura ◽  
Akira Tanimura ◽  
Masataka Takeshita ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Induction Therapy ◽  
Partial Remission ◽  
Progression Free Survival ◽  
Novel Agents ◽  
Newly Diagnosed ◽  
Free Survival

Abstract Background Autologous stem cell transplantation (ASCT) has been a part of the standard therapy for newly diagnosed multiple myeloma and several studies showed double ASCT improved the outcome in comparison with single ASCT, especially the patients who failed to achieve very good partial remission (VGPR). Recently, the introduction of novel agents significantly improved the response rate of the treatment for the multiple myeloma. Although ASCT is still crucial for newly diagnosed myeloma patients, the role of the double ASCT is unclear in the era of novel agents. We performed a single institution-based retrospective study. Methods We reviewed the medical records of patients who treated with ASCT for multiple myeloma between January 2001 and April 2013 in National Center for Global Health and Medicine, Tokyo, Japan. The regimen of the remission induction therapy, number of stem cell transplantations, survival after the first ASCT, progression free survival, the response after the induction therapy and the first ASCT were analyzed. Results Since 2001, we performed ASCT for 167 patients. Ninety-three patients were treated with double ASCT, and 2 patients were treated with tandem ASCT–allogeneic SCT. In 127 patients were treated with vincristine, adriamycin, and dexamethasone (VAD) as an induction therapy, and 40 patients were treated with bortezomib and dexamethasone (BD). Very-good-partial-remission (VGPR) or complete remission (CR) was obtained in 25.2%, 34.6% of the patients treated with VAD, and in 45.7%, 54.3% with BD regimen before and after the transplantation respectively. Overall survival (OS) and progression free survival (PFS) did not differ significantly between VAD and BD induction, the estimated 2 year-OS was 89.8% vs. 79.5%, and the 2 year-PFS was 43.2% vs. 63.5% respectively. Double transplantation improved PFS and OS in VAD induction than single transplantation (p=0.000, p=0.002). In BD induction, patients who failed to achieve VGPR or better after the first ASCT, double transplantation improved OS (p=0.010) but not PFS. In both VAD induction and BD, there was no significant survival benefit in double transplantation in patients who achieved VGPR or better. Conclusion The achievement of VGPR or better after the ASCT resulted in significantly better PFS. The role of double transplantation is still crucial for patients with inadequate response after the first ASCT even in the era of novel agents. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Phase II Trial of Bortezomib-Based Induction, Autologous Stem Cell Transplantation, Bortezomib-Based Consolidation, and Bortezomib Maintenance in Newly Diagnosed Multiple Myeloma in Japan

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3305-3305
Author(s):  
Junya Kanda ◽  
Masayuki Kobayashi ◽  
Takeshi Maeda ◽  
Toshiyuki Toshiyuki ◽  
Masaaki Tsuji ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Phase Ii ◽  
Induction Therapy ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Background: Three drug combinations are the standard treatment for newly diagnosed multiple myeloma (NDMM). However, induction, consolidation, and maintenance therapy have not been standardized in Japan. Therefore, in this single arm Phase II study, we evaluated bortezomib-based induction, autologous stem cell transplantation (ASCT), bortezomib-based consolidation, and bortezomib maintenance in transplant eligible NDMM patients and assessed clinical outcomes as well as the minimal residual disease (MRD) status. Methods: Patients received four cycles of CyBorD induction therapy with bortezomib 1.3 mg/m2 and cyclophosphamide 300 mg/m2 on day 1, 8, 15, and 22 and dexamethasone 40 mg on day 1-3, 8-10, 15-17, and 22-24 for the first two cycles and day 1, 8, 15, and 22 for the last two cycles of four 28-day cycles. Peripheral blood stem cells were collected after cyclophosphamide 2 g/m2 for 2 days, which was followed by melphalan 200 mg/m2 and ASCT. Three months after ASCT, patients received consolidation treatment with three cycles of CyBorD identical to the last two cycles of the induction therapy followed by maintenance therapy with bortezomib 1.3 mg/m2 on day 1 and 15 of a 28-day cycle, for 24 months. The primary end-point was the complete response (CR) rate after consolidation therapy and assessed as an interim analysis. Responses were assessed according to the International Myeloma Working Group (IMWG) criteria. MRD was assessed using an allele-specific oligonucleotide real-time quantitative polymerase chain reaction (qPCR). The toxicity was evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Results: From August 2013 to May 2016, 42 (25 male and 17 female) patients with a median age of 58 (range 42-65) years with NDMM were found eligible and enrolled in 15 centers in Japan. The International Staging System (ISS) values were 1 in 17 (40%), 2 in 20 (48%), and 3 in 5 patients (12%). Adverse cytogenetics of 17p deletion, t(4;14), and t(14;16) were observed in 20%, 18%, and 3% of the evaluable patients, respectively. Following four induction cycles of CyBorD, the overall response rate (ORR) was obtained in 71% of patients, including a CR/sCR of 10% and very good partial response (VGPR) of 26%. One of the evaluable 11 patients showed MRD negativity after induction therapy. Four patients discontinued the protocol during the induction therapy because of grade 4 interstitial pneumonia (n = 2), prolonged grade 3 drug eruption (n = 1), and grade 1 delirium (n = 1). Four patients discontinued the protocol due to doctor judgement (inadequate efficacy, n = 2; repetitive infection, n = 1; grade 3 neutropenia, n = 1). A total of 26 of the 42 patients completed ASCT following the protocol and 18 achieved VGPR/CR, including CR in 10 patients. Three of the evaluable 10 patients showed MRD negativity after ASCT. The 2-year overall and progression-free survival rates were 93% (95% confidence interval [CI], 76%-98%) and 81% (95% CI, 51%-94%), respectively (Figure 1). Conclusions: CyBorD with ASCT for NDMM resulted in relatively high CR rates in the investigated Japanese population, although a relatively high incidence of discontinuation of therapy was observed. Dose and schedule modification of induction therapy may be necessary in Japanese populations. Clinical trial information: UMIN000010542. Figure 1. Figure 1. Disclosures Imada: Celgene: Honoraria; Bristol-Meyers Squibb: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Nippon Shinyaku: Honoraria; MSD: Honoraria; Chugai: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Kyowa Hakko Kirin: Honoraria; Shire Japan: Honoraria; Ono: Honoraria; Mundipharma: Honoraria. Takaori-Kondo:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Janssen Pharmaceuticals: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria.

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