Bayesian Network Meta-Analysis (NMA): Safety of Bortezomib, Thalidomide or Lenalidomide Containing Regimens for Transplant Ineligible Multiple Myeloma (MM) Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3030-3030 ◽  
Author(s):  
Toshihisa Satta ◽  
Norihiro Yamaguchi ◽  
Adriana Malone ◽  
James Talcott ◽  
Ajai Chari
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Individual Patient Data ◽  
Controlled Trial ◽  
Patient Data ◽  
Institutional Research ◽  
Sufficient Data ◽  
Phase 3 ◽  
Mesh Terms ◽  
Better Than

Abstract Background MM is a diagnosis of the elderly, with a median age of 70. Novel agents, such as proteasome inhibitors (bortezomib, V), and immunomodulatory agents (thalidomide, T; lenalidomide, R) have improved response rates and survival in transplant-ineligible patients; however, the disease is incurable and relapse is inevitable. Since older patients are particularly vulnerable to adverse events (AEs), the safety profile, particularly of multidrug regimens, is one of the most important considerations in treatment selection. While numerous phase 3 studies have been done in this patient population, each study is limited to a comparison of no more than 2 or 3 regimens. Given the cost and time to conduct phase 3 studies, Bayesian NMA is a powerful tool that has been used to extract additional information from precious resources. The goal of our study is to compare the safety and preliminary efficacy of induction regimens for transplant ineligible MM patients using data from published phase 3 studies. Methods To identify phase 3 clinical trials comparing induction regimens in transplant ineligible patients, we conducted a systematic literature search using Pubmed, Google Scholar, Embase, ASH and ASCO meeting abstracts with the MeSH terms "multiple myeloma", "randomized controlled trial" and "bortezomib" or "lenalidomide" or "thalidomide" or equivalent. 18 trials met our inclusion criteria. Among these trials, 9 trials did not have sufficient data on AEs (neutropenia, thrombocytopenia, venous thromboembolism and neuropathy grade 3 or higher by CTCAE) to be statistically analyzed. Data were pooled and reported as odds ratio (OR) for the 9 trials incorporated in the analysis. Bayesian NMA under the random-effects model was performed with STATA ver. 14.0. Results Because MP was the most frequently incorporated regimen in the 9 studies, it was utilized as the reference for NMA. The pooled OR of treatment A to have AEs compared to treatment B and 95 % confidence interval (CI) is presented in the table. The pooled OR of Rd 18 compared to MP was 0.57 and statistically significant. Continuous Rd (Rd) and VTP trended towards less AEs than MP (pooled OR 0.63 and 0.6, respectively) but were not statistically significant. The remaining regimens trended to have more AEs than MP. Rd, Rd 18 and VTP were associated with significantly less AEs than VMP with OR 0.31, 0.29, 0.3 respectively. Existing evidence has demonstrated that the triplet regimens MPT, MPR and VMP have longer progression free survival (PFS) than MP. Rd is better than MPT and VMPT is better than VMP in terms of PFS. There is no head to head comparison to determine the best regimen among Rd, MPT, VMP, VMPT. We are contacting primary researchers of original trials to obtain individual patient data in order to conduct NMA for PFS and cost effectiveness. Conclusion Rd and VTP trend safer than MP and are significantly safer than VMP. Based on the systematic review, we do not have sufficient data to select the best regimen in terms of PFS. Further statistical analysis for efficacy will be available upon receipt of individual patient data. Disclosures Chari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Other: Institutional Research Funding; Novartis: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding.

Melphalan and Prednisone (MP) Versus Melphalan, Prednisone and Thalidomide (MPT) as Initial Therapy for Previously Untreated Elderly and/or Transplant Ineligible Patients with Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 615-615 ◽  
Author(s):  
Prashant Kapoor ◽  
S. Vincent Rajkumar ◽  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
David Dingli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Elderly Patients ◽  
Randomized Controlled Trials ◽  
Research Funding ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Patient Data ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
The Impact

Abstract Abstract 615 Background: Trials comparing efficacy of standard melphalan prednisone (MP) therapy with MP plus thalidomide (T) in the transplant ineligible, elderly patients with multiple myeloma have provided conflicting evidence. While there is greater agreement with regard to superior response rates (RR) with the addition of T to MP in elderly patients, the impact on progression free survival (PFS) and overall survival (OS) is less clear with some trials showing an improvement in PFS and/or OS with MPT and others demonstrating no difference in outcomes. We performed a systematic review to integrate the existing outcome data related to the efficacy of MP vs. MPT using a meta-analytic approach. Methods: A comprehensive search of electronic database through July 31st, 2009 was performed for publications, abstracts and presentations to identify randomized controlled trials (RCTs) comparing MP with MPT. A meta-analysis was performed by pooling results on clinical endpoints of RR, PFS and OS reported in all the identified RCTs under a random effects model. We did not have access to individual patient data from these trials. Results: Overall, five prospective RCTs (3 published articles and 2 abstracts) comparing MP with MPT regimen and comprising a total of 1571 patients were identified. For the endpoints of OS and PFS, data were extractable only from 4 RCTs (abstract by Gulbrandsen et al. was excluded). The Bregg and Egger funnel plot for OS demonstrated a symmetric distribution (P = 0.6) indicating no significant publication bias. The test of heterogeneity among all RCTs was statistically significant in the estimate of RR (tau2=0.21; chi2=16.33; p=0.003 (df=4); I2 = 75.5%), but not significant for the estimates of PFS (tau2=0.01; chi2=4.61; p=0.2 (df=3); I2 = 34.9%), and OS (tau2=0.02; chi2=5.53; p=0.14 (df=3); I2 = 45.8%). As expected, the pooled odds ratio of responding to treatment with MP versus MPT was 0.307 (P<0.001) indicating that MP was worse than MPT in achieving at least a partial response. The pooled hazard ratios (HR) for PFS and OS were 1.59 (p<0.001) and 1.34 (p=0.006), respectively (see table for forest plots) in favor of MPT. Conclusion: Our meta-analysis implies that in previously untreated, transplant ineligible elderly patients with multiple myeloma, the addition of thalidomide to melphalan-prednisone demonstrates improved RR, PFS and OS compared with the use of melphalan-prednisone alone. Although the results from a comprehensive individual patient data pooled analysis would give a more precise estimate, our analysis suggests that MPT is superior to MP in terms of response and survival. Disclosures: Dispenzieri: Celgene: Research Funding. Gertz:Celgene: Honoraria. Kumar:celgene, genzyme, millennium, novartis, bayer: Research Funding; genzyme: Membership on an entity's Board of Directors or advisory committees.

Vantage 088: Vorinostat in Combination with Bortezomib in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Global, Randomized Phase 3 Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 811-811 ◽  
Author(s):  
Meletios Athanasios Dimopoulos ◽  
Sundar Jagannath ◽  
Sung-Soo Yoon ◽  
David S. Siegel ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
New Zealand ◽  
Board Of Directors ◽  
Histone Deacetylase ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 3 ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Chemotherapy Agents

Abstract Abstract 811 Introduction: Vorinostat (VOR), an oral inhibitor of histone deacetylase class I and class II proteins, regulates genes and proteins involved in tumor growth and survival. The synergistic effects of VOR and bortezomib (BTZ) have been shown in preclinical studies and were confirmed in independent phase 1 trials in patients with relapsed/refractory multiple myeloma (MM), producing objective response rates (ORRs) of up to 42% and overall clinical benefit of up to 90%. Materials and methods: Eligible patients were aged ≥ 18 years, had measurable secretory MM, had received 1 to 3 prior systemic anti-myeloma regimens, and had an Eastern Cooperative Oncology Group status ≤ 2. Previous exposure to BTZ and the presence of extracellular plasmacytoma were allowed per protocol, but patients with prior resistance to BTZ were excluded. Patients were randomized 1:1 to receive 21-day cycles of BTZ (1.3 mg/m2 intravenously; days 1, 4, 8, and 11) in combination with oral VOR 400 mg/d, or matching placebo, on days 1 to 14. Additional use of corticosteroids for the treatment of MM was not allowed during the trial. Patients were treated until disease progression, unacceptable toxicities, or withdrawal from the study. The primary endpoint for this trial was progression-free survival (PFS; occurrence of 412 PFS events). Secondary and exploratory endpoints included ORR (≥ partial response), clinical benefit response (ORR + minimal response), overall survival, time to progression, patient-reported outcomes questionnaires (QLQ-C30, QLQ-MY20), and safety/tolerability of this novel drug combination. Responses and progression were determined according to the European Bone and Marrow Transplantation Group criteria and will be confirmed by an Independent Adjudication Committee. Results: Between January 2009 and January 2011, 637 patients were enrolled from 174 centers in 33 countries across the globe making this trial one of the largest studies conducted in patients with relapsed/refractory myeloma. Median age of the study population was 62 years (range, 29–86 years). Of the enrolled patients, 59% were male and 56% were Caucasian. Patients had received a median of 2 prior regimens (range, 1–3). Prior anti-myeloma agents included BTZ (24%), thalidomide (56%), lenalidomide (13%), melphalan (56%), and stem cell transplantation (35%). As of July 2011, 635 patients had received study medication, with a median exposure of 7 cycles (mean: 7.6 cycles; range 1–30 cycles). Reported median exposure to BTZ monotherapy in previous phase 3 trials was approximately 5 cycles. Conclusions: The study passed the protocol-specified futility analyses by the independent data monitoring committee in November 2010. Database lock is anticipated in November 2011, and top-line data on primary and secondary endpoints will be available at the meeting. Disclosures: Dimopoulos: Celgene, Ortho-Biotech: Consultancy, Honoraria. Off Label Use: Vorinostat, an inhibitor of histone deacetylase, is approved in the US for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. Vorinostat is currently under investigation for the treatment of relapsed malignant pleural mesothelioma, relapsed/refractory B cell lymphoma (in combination with other chemotherapy agents), and relapsed/refractory multiple myeloma (in combination with bortezomib and other chemotherapy agents). Jagannath:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Yoon:Celgene: Consultancy; NK Bio: Consultancy. Siegel:Millennium: Honoraria, Research Funding, Speakers Bureau; Merck: Honoraria. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Hajek:Celgene: Honoraria; Janssen: Honoraria; Merck: Educational lecture. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees. Rosiñol:Celgene: Honoraria; Janssen-Cilag: Honoraria. Blacklock:New Zealand Bone Marrow Donor Registry: Consultancy, Employment; Mercy Hospital, Auckland New Zealand: Consultancy; Leukaemia and Blood Foundation, New Zealand: Consultancy, Membership on an entity's Board of Directors or advisory committees; Middlemore Hospital: Employment, Research Funding. Goldschmidt:Amgen, Novartis, Chugai: Research Funding; Janssen-Cilag, Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Merck: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reece:Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Graef:Merck: Employment. Houp:Merck Research Laboratories: Employment. Sun:Merck & Co., Inc.: Employment. Eid:Merck Research Laboratories: Employment. Anderson:Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy; Acetylon: founder.

Phase 1 Study of the Investigational Proteasome Inhibitor Ixazomib Alone or in Combination with Lenalidomide–Dexamethasone (Rd) in Japanese Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5752-5752 ◽  
Author(s):  
Hiroshi Handa ◽  
Kenshi Suzuki ◽  
Takaaki Chou ◽  
Takafumi Matsushima
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Japanese Patients ◽  
M Protein ◽  
Phase 3 ◽  
Grade 3 ◽  
Ongoing Phase

Background Ixazomib is the first oral proteasome inhibitor to be investigated clinically for the treatment of MM. Phase 1 studies have shown single-agent activity and manageable toxicities in RRMM (Kumar et al. Blood 2014) and phase 1/2 studies have suggested the feasibility and activity of weekly oral ixazomib plus Rd in previously untreated MM (Kumar et al. ASH 2012; Richardson et al. ASH 2013). These findings have led to ongoing phase 3 trials of weekly ixazomib 4 mg + Rd in RRMM and previously untreated MM. However, the early-phase studies were conducted in Western pts. This phase 1, open-label multicenter study aimed to determine the safety, tolerability, and pharmacokinetics (PK) of weekly ixazomib alone or with Rd in Japanese pts with RRMM (Japic Clinical Trials Information no. 121822). Methods Primary objectives were to evaluate the safety and tolerability, including dose-limiting toxicities (DLTs) and adverse events (AEs), and the PK of ixazomib alone or with Rd. A secondary objective was evaluation of antitumor activity. Japanese pts aged ≥20 years with RRMM who had received at least 2 prior regimens, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. All had measurable disease and ECOG performance status of 0–2. Pts with grade ≥2 peripheral neuropathy or grade ≥2 diarrhea at study entry were excluded. Pts received ixazomib 4 mg on days 1, 8, and 15 of 28-day cycles, alone or with Rd (lenalidomide 25 mg on days 1–21, dexamethasone 40 mg on days 1, 8, 15, and 22), per the regimen used in the ongoing phase 3 trials. AEs were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points prior to and after dosing on days 1 and 15 of cycle 1. Responses were assessed per IMWG uniform response criteria. Results Fourteen pts were enrolled; 8 (57%) were male, median age was 62.5 yrs (range 53–71), 4 pts were aged ≥65 yrs, median number of prior therapies was 7. Seven pts received single-agent ixazomib and 7 received ixazomib + Rd. One pt in each cohort was excluded from the DLT-evaluable population. Two patients experienced DLTs in cycle 1: 1 pt receiving single-agent ixazomib had grade 4 thrombocytopenia and grade 3 diarrhea, hypertension, hypokalemia, hyponatremia, and nausea; 1 pt in the ixazomib + Rd cohort had grade 4 thrombocytopenia and neutropenia. All events were considered treatment-related. At data cut-off (Jan 6 2014), 6 pts remained on treatment and 8 had discontinued due to: progressive disease (PD; n=3), AEs (n=3), symptomatic deterioration, and protocol violation (each n=1). At data cut-off, pts (n=14) had received a median of 6 cycles of ixazomib (range 1–21); the 7 pts in the ixazomib + Rd cohort had received a median of 4 cycles (range 1–12) of ixazomib + Rd. Thirteen (93%) pts experienced treatment-related AEs; the most common were neutropenia (71%), thrombocytopenia (71%), leukopenia (64%), lymphopenia (57%), and diarrhea (50%). There were no cases of peripheral neuropathy. Nine (64%) pts had grade ≥3 AEs; the most common were lymphopenia (50%), neutropenia (43%), and thrombocytopenia (36%). Two (14%) pts (single-agent cohort) had serious AEs (grade 2 bronchitis in 1 pt, and grade 4 thrombocytopenia and grade 3 hypokalemia in 1 pt). Three pts discontinued due to AEs; 1 due to diarrhea in the single-agent cohort, and 1 due to neutropenia and 1 due to thrombocytopenia in the ixazomib + Rd cohort. There were no deaths. PK data showed ixazomib was rapidly absorbed with a Tmax at 1.08–1.83 hrs. Terminal half-life (geometric mean) was 5.7 days for single-agent ixazomib and 5.2 days for ixazomib + Rd. There were no substantial differences in the ixazomib PK profile between the two cohorts. Thirteen pts were response-evaluable. One pt (ixazomib + Rd cohort) had a partial response; at data cut-off, this pt remained in response with a 100% M-protein reduction (unconfirmed VGPR) and duration of response of ~10.8 months. Seven pts had stable disease (including 3 with M-protein reductions of 25–50%), 2 had PD, and 3 were not assessable. Conclusions These data suggest that ixazomib 4 mg alone or with Rd is feasible and tolerable in Japanese pts with RRMM. The AEs were manageable, reflecting the AE profile seen in Western populations, supporting the use of this dose and schedule in Japanese pts. Disclosures Handa: Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding. Off Label Use: Investigational agent ixazomib for the treatment of Japanese patients with relapsed and/or refractory multiple myeloma.. Matsushima:Takeda Pharmaceutical Company Limited : Employment.

Final Analysis of Overall Survival from the Phase 3 Panorama 1 Trial of Panobinostat Plus Bortezomib and Dexamethasone Versus Placebo Plus Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3026-3026 ◽  
Author(s):  
Jesús F. San-Miguel ◽  
Vania T.M. Hungria ◽  
Sung-Soo Yoon ◽  
Meral Beksac ◽  
Meletios A. Dimopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Final Analysis ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Study Therapy

Abstract Introduction: Panobinostat is a potent pan-deacetylase inhibitor (pan-DACi) that targets key aberrations in multiple myeloma (MM) cell biology, including epigenetics and protein metabolism. In the phase 3 clinical trial PANORAMA 1, panobinostat in combination with bortezomib and dexamethasone (PAN-BTZ-Dex) led to a statistically significant and clinically relevant increase in progression-free survival of approximately 4 months compared with that with placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex). Further analyses of patient outcomes by prior treatment demonstrated that the magnitude of PFS benefit was greatest among patients who received at least 2 prior regimens, including bortezomib and an immunomodulatory drug (IMiD; PAN-BTZ-Dex [n = 73]: 12.5 months [95% CI, 7.3-14.0 months]; Pbo-BTZ-Dex [n = 74]: 4.7 months (95% CI, 3.7-6.1 mo; HR 0.47 [95% CI, 0.32-0.72]). These data supported the regulatory approvals of PAN-BTZ-Dex for the treatment of patients with multiple myeloma who received at least 2 prior regimens, including bortezomib and an IMiD. Here we present the final analysis of overall survival (OS) for the entire patient population and among patients who received at least 2 prior regimens, including bortezomib and an IMiD. Methods: The study design for the PANORAMA 1 trial was described previously (San-Miguel. Lancet Oncol. 2014;15:1195-206). The key secondary endpoint was OS. As of June 29, 2015, the 415 events required to conduct the final analysis of OS had been observed. Kaplan-Meier estimation was utilized for OS analyses for the entire population (N = 768), the pre-specified subgroup of patients who received prior bortezomib and IMiD (n = 193), and patients who received at least 2 prior regimens including bortezomib and an IMiD (n = 147). Results: The median OS of patients who received PAN-BTZ-Dex in the overall population was 40.3 months (95% CI, 35.0-44.8 months) vs 35.8 months (95% CI, 29.0-40.6 months) for the Pbo-BTZ-Dex arm with HR 0.94 [95% CI, 0.78-1.14], P = .5435 (Fig 1A). The percentage of patients in each arm who received post-study therapy was 37.7% in the PAN-BTZ-Dex arm and 48.8% in the Pbo-BTZ-Dex arm. The median OS of patients who received at least 2 prior lines, including bortezomib and an IMiD, was 25.5 months (95% CI, 19.6-34.3 months) in the PAN-BTZ-Dex arm vs 19.5 months (95% CI, 14.1-32.5 months) in the Pbo-BTZ-Dex arm (Fig. 1B). The proportion of patients in this subgroup who received post-study therapy was 35.6% in the PAN-BTZ-Dex arm and 66.2% in the Pbo-BTZ-Dex arm. Conclusion: For the overall PANORAMA 1 study population, patients in the PAN-BTZ-Dex arm demonstrated an increase in median OS of 4.5 months vs patients in the Pbo-BTZ-Dex arm, but this result was not statistically significant (P = .5435). Median OS was also slightly longer for the PAN-BTZ-Dex arm among the more heavily pretreated subgroup of patients who received at least 2 prior regimens, including bortezomib and an IMiD. A higher percentage of patients on the Pbo-BTZ-Dex arm received post-study therapy vs the PAN-BTZ-Dex arm, which may have confounded the OS results. In summary, PAN-BTZ-Dex demonstrates statistically significant increases in PFS vs Pbo-BTZ-Dex in patients with relapsed or relapsed and refractory MM; however, this did not translate to a statistically significant increase in OS. Future trials will plan to focus on further optimization of dose and schedule of panobinostat and bortezomib to improve outcome, as well as novel combinations with other agents, including IMiDs and next-generation proteasome inhibitors. Figure 2. Figure 2. Disclosures Beksac: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Speakers Bureau. Dimopoulos:Janssen: Honoraria; Janssen-Cilag: Honoraria; Onyx: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Jedrzejczak:Onconova: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siritanaratkul:Pfizer: Research Funding; Roche: Research Funding; Novartis: Research Funding; Janssen-Cilag: Research Funding. Schlossman:Millennium: Consultancy. Hou:Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Sopala:Novartis Pharma: Employment, Equity Ownership. Bengoudifa:Novartis: Employment. Corrado:Novartis: Employment, Equity Ownership. Richardson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

Towards a Network-Based Molecular Taxonomy of Newly Diagnosed Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 840-840
Author(s):  
Alessandro Lagana ◽  
Ben Readhead ◽  
Deepak Perumal ◽  
Brian Kidd ◽  
Hearn Jay Cho ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Somatic Mutations ◽  
Molecular Taxonomy ◽  
Network Biology ◽  
Cellular Systems ◽  
Biological Processes ◽  
Institutional Research ◽  
Newly Diagnosed ◽  
Integrative Network

Abstract Recent advances in computational biology have led to the development of novel and sophisticated methods to model large datasets measured from complex organisms based on integrative network biology. Networks can provide valuable insight into key biological processes and allow for a deeper understanding of the complexity of cellular systems and disease mechanisms. We developed and applied a network biology approach to infer an improved molecular model and understanding of newly diagnosed multiple myeloma (MM). We constructed the first co-expression network of MM based on RNA-seq data from the current release (IA4) of the Multiple Myeloma Research Foundation (MMRF) CoMMpass Study dataset. The data set consists of 92 samples from newly diagnosed MM patients. Whole Exome Sequencing (WES) data available for 77 out of 92 samples allowed the integration of somatic mutations into the network. Our analysis organized 23,033 genes into 50 co-expression modules. We then evaluated the molecular activity of co-expression modules for concordance with molecular traits. We performed module enrichment analysis against Gene Ontology terms, pathways, chromosome locations, protein-protein interaction networks, MM-associated gene sets and drug-target databases. Analysis of the newly diagnosed multiple myeloma network model (MMNet) revealed known and novel molecular features of multiple myeloma. The integration of MMNet with somatic mutations data unveiled a significant association between mutation burden and the activation of several modules. Fundamental biological processes such as DNA repair, cell cycle, signal transduction, NK-kappaB cascade and MAPK signaling characterized such modules. Interestingly, a number of mutated genes demonstrated pluripotent associations with co-expression module activity. For example, FGFR3 was correlated with expression of several modules, including one enriched for RNA processing and translation-related processes and included the known MM-associated genes FRZB and CCND3. Similarly, the frequently mutated gene DIS3 was significantly associated to five different modules, including the translation-related module and a module enriched for the 1q locus. Our results have identified novel key driver genes that may inform therapy prioritization. The MMNet topology revealed a far greater molecular heterogeneity in primary MM underscoring opportunities to improve the molecular taxonomy of this disease. We identified several modules associating with previously described MM classes, including a module enriched for genes up regulated in the UAMS MS class characterized by spiked expression of WHSC1 and FGFR3. Module connectivity confirmed the central role of both genes, WHSC1 being the top hub gene, i.e. the most connected gene in the module, and FGFR3 being among the top 10 hubs. Consistent with previous findings, this module was characterized by negative correlation with aneuploidy. We found other modules enriched for genes dysregulated in other UAMS classes, such as MF, CD1 and CD2. We also identified several modules associating with relevant biological processes such as apoptosis, cell communication, Wnt and Toll-like receptor signaling. Correlation of modules expression with clinical traits identified insights into genetic subgroups of MM that are not previously described. For examples, we found a module positively correlated to the African American ethnicity. This module was also characterized by enrichment for genes in the fragile regions 5q31 and 6q21. These findings may provide important and exciting insights into the biology of MM among African Americans as they are at increased risk for MM. Our integrative network analysis of the CoMMpass dataset uncovers novel and complex patterns of genomic perturbation, key drivers and associations between clinical traits and genetic markers in newly diagnosed MM patients. Disclosures Chari: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Biotest: Other: Institutional Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jagannath:BMS: Honoraria; MERCK: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Dudley:Ayasdi, Inc: Other: Equity; Personalis: Patents & Royalties; NuMedii, Inc: Patents & Royalties; GlaxoSmithKline: Consultancy; Janssen Pharmaceuticals: Consultancy; Ecoeos, Inc: Other: Equity.

Low Molecular Weight Heparin for Prevention of Placenta-Mediated Pregnancy Complications: An Individual Patient Data Meta-Analysis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 890-890
Author(s):  
Marc Rodger ◽  
Johanna IP de Vries ◽  
Evelyne Rey ◽  
Jean-Christophe JCG Gris ◽  
Ida Martinelli ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Molecular Weight Heparin ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Risk Difference ◽  
Patient Data ◽  
Low Molecular Weight ◽  
Single Center ◽  
Advisory Committees

Abstract Introduction Placenta-mediated pregnancy complications (PMPC) include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age (SGA) newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality. Affected women are at an elevated risk of recurrence in subsequent pregnancies. We completed a pooled summary-based (i.e. study level) meta-analysis that strongly suggests that low-molecular-weight heparin (LMWH) reduces the risk of recurrent PMPCs. However, our study-level meta-analysis was limited by high clinical and statistical heterogeneity likely due to the inclusion of women with heterogeneous prior PMPCs and trial designs (e.g. single vs multi-center trials). To address these limitations, the trialists agreed to conduct an individual patient data meta-analysis to identify sources of heterogeneity including exploring which patients benefit from LMWH and which outcomes are prevented. Methods We conducted a systematic review to identify randomised controlled trials that were eligible to contribute individual patient data to a meta-analysis to evaluate the effectiveness of LMWH for reducing the risk of PMPC in women with prior PMPCs. The primary outcome was a composite of early-onset or severe pre-eclampsia, birth of an SGA newborn < 5th percentile, late pregnancy loss (> 20 weeks), or placental abruption leading to delivery. Individual patient data from eligible women were re-coded in a prescribed format and combined in a common dataset for analysis. All studies were assessed for risk of bias. Results Data from 1049 women in nine trials were analysed; Participants were mostly Caucasian (88%) with a mean age of 31.518 had thrombophilia. 525 women were randomised to LMWH and 524 to no LMWH. In our primary outcome analysis, LMWH did not significantly reduce the risk of recurrent PMPCs (LMWH 60/459 (13.1%) vs. no LMWH 92/449 (20.5%) p=0.1). Significant heterogeneity was noted between single center and multi-center trials. In multi-center trials, LMWH reduced HELLP (p=0.03) but none of the other secondary outcomes, whereas in single center trials LMWH reduced all of the secondary outcomes. In sub-group analysis, in multi-center trials LMWH reduced the primary outcome in women with prior abruption (p<0.01) but none of the other sub-groups, whereas in single center trials LMWH was beneficial in all the sub-groups (prior pre-eclampsia, prior severe pre-eclampsia, prior early onset pre-eclampsia, prior SGA <10th, prior SGA < 5th and prior abruption). Conclusions In this individual patient data meta-analysis, LMWH does not appear to reduce the risk of recurrent PMPC in women with prior PMPC. Promising results suggest that women with prior abruption may benefit from LMWH but this should be replicated in future multi-center trials. PROSPERO registration:CRD42013006249 Table. Primary Analysis All Studies Multi-Center Studies Single Center Studies Composite outcome Risk difference (95% CI) N=908 -0.07 (-0.16, 0.01)p = 0.10 N=524 -0.01 (-0.11, 0.09) p = 0.89 N=384 -0.17 (-0.21, -0.13) p < .0001 Secondary Outcome Analyses Severe or Early Preeclampsia Risk difference (95% CI) N=946 -0.04 (-0.10, 0.02) p = 0.20 N=562 0.01 (-0.06, 0.07) p = 0.81 N=384 -0.11 (-0.16, -0.07) p <.0001 HELLP Risk difference (95% CI) N=813 -0.02 (-0.04, -0.004) p = 0.01 N=429 -0.01 (-0.02, -0.001) p = 0.03 N=384 -0.04 (-0.07, -0.01) p = 0.02 SGA <10 Risk difference (95% CI) N=913 -0.08 (-0.14, -0.02) p = 0.01 N=529 -0.03 (-0.10, 0.03) p = 0.32 N=384 -0.14 (-0.18, -0.10) p <0.0001 Abruption leading to delivery Risk difference (95% CI) N=945 -0.01 (-0.02, 0.003) p = 0.14 N=561 -0.01 (-0.03, 0.01) p = 0.53 N=384 -0.016 (-0.027, -0.005) p = 0.005 Subgroup Analyses Prior preeclampsia Risk difference (95% CI) N=583 -0.12 (-0.19, -0.04) p = 0.002 N=288 -0.06 (-0.19, 0.06) p = 0.34 N=295 -0.17 (-0.24, -0.11) p <.0001 Prior severe or early onset Preeclampsia Risk difference (95% CI) N=487 -0.10 (-0.19, -0.02) p = 0.02 N=236 -0.04 (-0.19, 0.12) p = 0.65 N=251 -0.17 (-0.23, -0.11) p <.0001 Any prior late loss (2 >12 weeks or 1 >16 weeks) Risk difference (95% CI) N=245 0.001 (-0.11, 0.12) p = 0.98 N=0 Prior SGA < 10 Risk difference (95% CI) N=305 -0.12 (-0.25, 0.01) p = 0.08 N=203 -0.03 (-0.17, 0.10) p = 0.64 N=102 -0.29 (-0.38, -0.20) p <.0001 Prior abruption Risk difference (95% CI) N=281 -0.16 (-0.22, -0.11) p <.0001 N=95 -0.13 (-0.22, -0.04) p = 0.01 N=186 -0.18 (-0.22, -0.14) p <.0001 Disclosures Rodger: Biomerieux: Honoraria, Research Funding. Off Label Use: Low Molecular Weight Heparin to prevent pregnancy complications. de Vries:Pfizer: Research Funding. Rey:Leo Pharma: Other: Travel Grant. Gris:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stago: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Leo Pharma: Consultancy, Speakers Bureau; LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxter: Research Funding; BI: Speakers Bureau; Bayer: Speakers Bureau; BMS: Speakers Bureau. Schleussner:Bayer: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Merck: Research Funding, Speakers Bureau. Middeldorp:GSK/Aspen: Research Funding; Bayer: Consultancy, Speakers Bureau; BI: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Daiichi-Sankyo: Consultancy, Speakers Bureau. Bates:Eli Lilly Canada: Other: I hold the Eli Lilly Canada/May Cohen Chair in Women's Health. Eli Lilly Canada provides unrestricted funding for partial salary support through this Chair. Eli Lilly Canada does not manufacture/distribute drugs relevant to the topic to be discussed..

Safety and Efficacy of Elotuzumab with Lenalidomide/Dexamethasone for Multiple Myeloma in a Japanese Subpopulation Analysis of the Phase 3 Eloquent-2 Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3315-3315
Author(s):  
Kazuteru Ohashi ◽  
Kenshi Suzuki ◽  
Kazutaka Sunami ◽  
Shinsuke Iida ◽  
Shinichiro Okamoto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Research Funding ◽  
Pharmaceutical Research ◽  
Incidence Rates ◽  
Open Label ◽  
Phase 3 ◽  
Safety And Efficacy ◽  
Infusion Reactions ◽  
Adjusted Incidence

Abstract Background: Elotuzumab is an immunostimulatory monoclonal antibody that binds to signaling lymphocytic activation molecule family member 7 (SLAMF7), which is expressed on myeloma and natural killer (NK) cells. Elotuzumab has a dual mode of action: directly activating NK cells and tagging myeloma cells, thereby initiating antibody-dependent cell-mediated cytotoxicity. In the phase 3 ELOQUENT-2 (NCT01239797) trial involving patients (pts) with relapsed/refractory multiple myeloma (RRMM), elotuzumab in combination with lenalidomide/dexamethasone (ELd) was compared with lenalidomide/dexamethasone alone (Ld) and demonstrated improved progression-free survival (PFS; hazard ratio [HR] 0.70, p<0.001) and overall response rate (ORR; 79% vs 66%, p<0.001) (Lonial S et al. N Engl J Med 2015;373:621-31). We assessed the safety and efficacy of elotuzumab in the ELOQUENT-2 Japanese subpopulation. Methods: ELOQUENT-2 was a phase 3, open-label, multicenter trial that enrolled pts with RRMM and 1-3 prior therapies. Pts were randomized 1:1 to elotuzumab (10 mg/kg) plus Ld or Ld in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. All pts received premedication before elotuzumab administration to mitigate infusion reactions. Coprimary endpoints were PFS and ORR. Secondary endpoints and exploratory objectives included overall survival (OS) and safety, respectively. Results: ELOQUENT-2 included 60 Japanese pts in the all-randomized population of 646: 31/321 ELd and 29/325 Ld. The median age was 69 years (range 45-80) in the ELd group and 66 years (range 47-84) in the Ld group. Forty percent (24/60) of pts were refractory to their most recent line of therapy. The median duration of therapy was 22 cycles (range 2-38) in ELd group and 16 cycles (range 3-36) in the Ld group. The data cut-off excluding OS was October 2014; OS was updated October 2015. PFS (ELd vs Ld) was 74% (95% confidence interval [CI]: 55-86) vs 66% (95% CI: 45-80) at 1 year, and 48% (95% CI: 29-65) vs 18% (95% CI: 7-34) at 2 years (Figure). HR for PFS (ELd vs Ld) was 0.51 (95% CI: 0.3-1.1), a 49% reduction in risk of progression/death. Median PFS was 22.2 months (95% CI: 17.5-not estimated [NE]) in the ELd group and 18.5 months (95% CI: 11.1-21.2) in the Ld group. ORR was similar in both groups: 84% (95% CI: 66-95) in the ELd group vs 86% (95% CI: 68-96) in the Ld group. The interim HR for OS between the ELd and Ld groups was 0.81 (95% CI: 0.35-1.87). Survival rates in ELd and Ld pts, respectively, at 1 year were 100% (95% CI: NE-NE) and 97% (95% CI: 78-100); at 2 years, 90% (95% CI: 73-97) and 86% (95% CI 67-94); and at 3 years, 68% (95% CI: 48-81) and 64% (95% CI: 44-79). Grade 3/4 adverse events (AEs) occurring in ≥10% in either groups were neutropenia (ELd 26%, Ld 31%), cataract (ELd 19%, Ld 14%), pneumonia (ELd 19%, Ld 3%), lymphocytopenia (ELd 19%, Ld 3%), decreased appetite (ELd 7%, Ld 14%), anemia (ELd 7%, Ld 10%), hyperglycemia (ELd 7%, Ld 10%), and thrombocytopenia (ELd 3%, Ld 14%). Infections were reported in 81% (25/31) and 79% (23/29) in the ELd and Ld groups, respectively, with exposure-adjusted incidence rates of infection (per 100 person-years) of 172.6 and 183.4, respectively. The incidence of pneumonia was 29% (9/31) vs 7% (2/29) in the ELd and Ld groups, respectively, with exposure-adjusted incidence rates of infection (per 100 person-years) of 16.7 and 4.5, respectively. All pneumonia AEs were reported as serious AEs and were resolved by elotuzumab omission or treatment with antibiotics. No pts discontinued elotuzumab due to pneumonia. Infusion reactions were observed in 4 pts (13%) in the ELd group; all were Grade 1. Conclusions: In the Japanese ELOQUENT-2 population, elotuzumab showed durable efficacy, with improved PFS and ORR, and with acceptable safety. Incidence of pneumonia tended to be higher with ELd vs Ld in the Japanese subanalysis. All cases were manageable, and none led to treatment discontinuation. Within the constraints of a small subgroup, results were consistent between Japanese pts and the overall pt population. Study support: Bristol-Myers Squib, Princeton, New Jersey, USA Disclosures Sunami: Ono Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squibb K.K.: Research Funding; Novartis: Research Funding; Celgene: Honoraria, Research Funding; Takeda: Research Funding; Sanofi: Research Funding; Janssen Pharmaceutical: Research Funding. Iida:Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding. Okamoto:Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Asahi Kasei Pharma Corp.: Research Funding; Alexion Pharmaceuticals, Inc.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Teijin Pharma Limited: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Shionogi & Co., Ltd.: Research Funding; Pfizer Inc.: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Research Funding. Miyoshi:Bristol-Myers Squibb K.K.: Employment. Bleickardt:Bristol-Myers Squibb: Employment. Matsumoto:Celgene: Honoraria; Janssen Pharmaceutical: Honoraria.

Sign in / Sign up

Export Citation Format

Share Document