نتائج البحث - "Robert Z. Orlowski"

1

Updated Analysis of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma (NDMM): The Phase 3 Maia Study

المصدر: Kumar, S K, Facon, T, Usmani, S Z, Plesner, T, Orlowski, R Z, Touzeau, C, Basu, S, Bahlis, N J, Goldschmidt, H, O'Dwyer, M E, Venner, C P, Weisel, K, Hulin, C, Karlin, L, Preis, M, Broyl, A, Renwick, W, Hansson, M, Krevvata, M, Wang, J, Van Rampelbergh, R, Ukropec, J, Uhlar, C M, Kobos, R & Perrot, A 2020, ' Updated Analysis of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma (NDMM) : The Phase 3 Maia Study ', Blood, vol. 136, no. Suppl. 1, pp. 24-26 . https://doi.org/10.1182/blood-2020-134847Test

مصطلحات موضوعية: Oncology, medicine.medical_specialty, business.industry, Immunology, Daratumumab, Cell Biology, Hematology, Newly diagnosed, medicine.disease, Biochemistry, Transplant ineligible, Internal medicine, medicine, In patient, business, Multiple myeloma, Dexamethasone, Lenalidomide, medicine.drug

الوصف: Introduction: Daratumumab (DARA) is a human, CD38-targeting, IgG1κ monoclonal antibody approved as monotherapy in relapsed/refractory multiple myeloma (RRMM) and in combination with standard of care for RRMM and NDMM. The addition of DARA to standard-of-care regimens in phase 3 studies has consistently improved progression-free survival (PFS) and led to deep and durable responses, including higher rates of minimal residual disease (MRD) negativity compared with standard of care. In the primary analysis of the phase 3 MAIA study (median follow-up, 28.0 mo), D-Rd vs Rd significantly improved PFS and MRD-negativity rates in transplant-ineligible NDMM (Facon T, N Engl J Med 2019). With longer follow-up (36.4 mo), D-Rd maintained a PFS benefit and deeper and more durable responses vs Rd alone (Bahlis N, Blood 2019. 134[Suppl 1]:1875). Here, we report updated efficacy and safety findings from MAIA after approximately 4 years of follow-up. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age ≥65 years or comorbidities were randomly assigned (1:1) to receive Rd ± DARA. Stratification factors included International Staging System stage (ISS [I vs II vs III]), region (North America vs other), and age ( Results: A total of 737 patients were randomized (D-Rd, n = 368; Rd, n = 369). Patient baseline characteristics were well balanced between the two treatment arms. Median (range) age was 73 (45-90) years, with 44% of patients ≥75 years of age. 27%, 43%, and 29% of all patients were ISS stage I, II, and III, respectively. Among 642 patients evaluable for FISH/karyotyping analysis, 86% had standard and 14% had high cytogenetic risk. After a median follow-up of 47.9 months, 176 (48%) and 273 (75%) patients discontinued study treatment in the D-Rd vs Rd groups, respectively, with 85 (23%) and 113 (31%) patients discontinuing treatment due to progressive disease. PFS remained improved for D-Rd vs Rd (median, not reached [NR] vs 34 mo; HR, 0.54; 95% CI, 0.43-0.67; P Grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) occurring in ≥10% of patients were neutropenia (53%/37%), pneumonia (18%/11%), anemia (16%/21%), lymphopenia (16%/11%), hypokalemia (12%/10%), leukopenia (11%/6%), and cataract (11%/10%); grade 3/4 infection rates were 40%/29%. The most common serious TEAE was pneumonia (17%/11%). 11% of patients in the D-Rd arm and 22% in the Rd arm discontinued treatment due to an adverse event. The complete updated data set will be presented at the meeting with additional efficacy endpoints, including MRD-negativity rate. Conclusion : After 48 months follow up, the addition of DARA to Rd continues to demonstrate a superior PFS benefit. More patients continued to have deeper and more durable responses with D-Rd vs Rd alone. No new safety concerns were observed with longer follow-up. These results continue to support the use of D-Rd in the first line of treatment for patients with transplant-ineligible NDMM. Disclosures Kumar: Sanofi: Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; Celgene/BMS: 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; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Karyopharm: Consultancy; Merck: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; MedImmune: Research Funding; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Adaptive Biotechnologies: Consultancy. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Usmani:Abbvie: Consultancy; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Other; GSK: Consultancy, Research Funding; Merck: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Array Biopharma: Research Funding. Plesner:Janssen: Consultancy. Orlowski:Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding. Bahlis:BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Genentech: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Goldschmidt:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Incyte: Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Mundipharma GmbH: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Molecular Partners: Research Funding; Merck Sharp and Dohme (MSD): Research Funding. O'Dwyer:Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Research Funding; Carrick Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy; ONK Therapeutics: Consultancy, Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Weisel:Adaptive: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Karlin:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; Sanofi: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Preis:Janssen: Other: for factor XI inhibitor. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Hansson:Amgen, Celgene, Takeda, Janssen Cilag: Consultancy. Krevvata:Janssen: Current Employment. Wang:Janssen: Current Employment. Van Rampelbergh:Janssen: Current Employment. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Uhlar:Janssen: Current Employment, Current equity holder in publicly-traded company. Kobos:Janssen: Current Employment, Current equity holder in publicly-traded company. Perrot:Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5896bbe9c1a891d488ec422553d253f1Test
https://doi.org/10.1182/blood-2020-134847Test

2

Outcomes in Patients with AL (Light-Chain) Cardiac Amyloidosis

المؤلفون: Krina K. Patel, Donna M. Weber, Taha Al-Juhaishi, Elisabet E. Manasanch, Regan Murphy, Qaiser Bashir, Samer A. Srour, Jeremy Ramdial, Gregory P. Kaufman, Hans C. Lee, Robert Z. Orlowski, Chitra Hosing, Sheeba K. Thomas, Uday R. Popat, Richard E. Champlin, Yago Nieto, Muzaffar H. Qazilbash, Mahmoud R. Gaballa, Neeraj Saini

المصدر: Blood. 136:11-13

مصطلحات موضوعية: Cardiac response, Response rate (survey), medicine.medical_specialty, business.industry, Immunology, Small sample, Cell Biology, Hematology, Biochemistry, Nyha class, Peripheral blood, Baseline characteristics, Family medicine, Medicine, In patient, business, Bristol-Myers

الوصف: Background: Cardiac involvement by light chain amyloidosis (AL) is generally associated with an unfavorable outcome. Bortezomib-based induction, and high-dose melphalan followed by autologous hematopoietic stem cell transplantation (auto-HCT) in eligible patients is associated with best long-term outcomes. We report the outcome of cardiac AL patients who underwent auto-HCT at our institution. Methods: We retrospectively reviewed all patients with cardiac AL who received auto-HCT between January 1997 and December 2018 at our institution. Hematologic and cardiac organ responses were evaluated according to the Consensus Guidelines for AL (R Comenzo et al. Leukemia 2012). Revised Mayo staging system was used for cardiac staging (S Kumar et al. JCO 2012). Progression free survival (PFS) and overall survival (OS) were calculated from the date of transplant. Survival was estimated using Kaplan Meier method and compared using log rank test. Cox proportional hazard models were used for adjusted survival analysis. Results: 57 patients were identified and baseline characteristics summarized in Table 1. Thirty eight patients (67%) at diagnosis and 17 (30%) at auto-HCT were evaluable by the revised Mayo staging system. Eleven (19%), 14 (25%), 17 (30%), and 13 (23%) patients had stage 1, 2, 3 and 4 disease, respectively, while the stage was unknown in 2 (3%) patients. Twenty-four (42%) patients received induction with a combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD), 14 (25%) received bortezomib and dexamethasone, and 2 (3%) received other bortezomib-based induction (Table 1). Based on hematologic response criteria, 3 (5%), 15 (27%) and 22 (39%) patients achieved complete response (CR), a very good partial response (VGPR), or partial response (PR) to induction, with an overall response rate (ORR) of 71%. All patients underwent peripheral blood stem cell (PBSC) mobilization with filgrastim, with or without plerixafor. Thirty-nine (68%) patients received melphalan 200mg/m2 and 18 (32%) received melphalan 140mg/m2 as preparative regimen. Nineteen patients (33%) received maintenance therapy post auto-HCT. One-hundred day and 1-year post auto-HCT non-relapse mortality rate was 5% (3 patients). Best post auto-HCT hematologic ORR was 92%, with 19 (34%), 20 (35%), and 13 (23%) patients achieving CR, VGPR and PR, respectively. Based on the consensus guidelines for cardiac response in AL using NT-proBNP or NYHA class, 51 patients (89%) had a cardiac organ response at their last evaluation (Table 2). Median follow up in surviving patients was 32.9 months (range 5.1 - 140.6). The 3-year PFS was 53.5% [95% CI 38.6-68.4%], and 3-year OS was 67.8% [53.9-81.7%]. On univariate analysis, melphalan 200 vs. 140 (p=0.017, HR 0.387 95%CI 0.178- 0.844) was associated with a better PFS, but none of the variables had an impact on PFS or OS on a multivariate Cox regression analysis, perhaps due to a small sample size. Conclusion: In this retrospective analysis we showed that in transplant-eligible patients with advanced cardiac AL, high-dose melphalan and auto-HCT is associated with a low (5%) NRM, an organ response rate of almost 90%, and a 3-year OS of almost 70%. Disclosures Bashir: Takeda: Other: Advisory Board, Research Funding; Acrotech: Research Funding; Celgene: Research Funding; StemLine: Research Funding; KITE: Other: Advisory Board; Purdue: Other: Advisory Board; Amgen: Other: Advisory Board. Nieto:Secura Bio: Other: Grant Support; Astra Zeneca: Other: Grant Support; Novartis: Other: Grant Support; Affimed: Consultancy, Other: Grant Support. Hosing:NKARTA Inc.: Consultancy. Popat:Bayer: Research Funding; Novartis: Research Funding. Lee:Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Genentech: Consultancy; Daiichi Sankyo: Research Funding; Sanofi: Consultancy; Regeneron: Research Funding. Patel:Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Janssen: Consultancy, Research Funding; Nektar: Consultancy, Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Manasanch:Merck: Research Funding; Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria; Quest Diagnostics: Research Funding; Adaptive Biotechnologies: Honoraria; JW Pharma: Research Funding; Novartis: Research Funding; BMS: Honoraria; Sanofi: Research Funding. Thomas:X4 Pharma: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Pharmacyclics: Other: Advisory Boards. Kaufman:Karyopharm: Honoraria; Janssen: Research Funding; Bristol Myers Squibb: Research Funding. Orlowski:Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties. Champlin:Takeda: Patents & Royalties; Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy; Omeros: Consultancy; Johnson and Johnson: Consultancy; Actinium: Consultancy. Qazilbash:Bioclinica: Consultancy; Amgen: Research Funding; Angiocrine: Research Funding; Bioline: Research Funding; Janssen: Research Funding.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::ddc41c501011a8221f58c6a08cee33b4Test
https://doi.org/10.1182/blood-2020-143209Test

3

Meaningful Changes in Patient-Reported Outcomes in Relation to Best Clinical Response and Disease Progression: Post Hoc Analyses from MAIA

المصدر: Perrot, A, Facon, T, Kumar, S, Plesner, T, Orlowski, R Z, Moreau, P, Bahlis, N J, Basu, S, Nahi, H, Hulin, C, Quach, H, Goldschmidt, H, O'Dwyer, M E, Venner, C P, Weisel, K, Mace, J R, Raje, N S, Tiab, M, Macro, M, Frenzel, L, Leleu, X, Liu, K, Fastenau, J, Gries, K S, Ho, K F, Mistry, P, Tromp, B, Delioukina, M, Vermeulen, J & Usmani, S Z 2021, ' Meaningful Changes in Patient-Reported Outcomes in Relation to Best Clinical Response and Disease Progression : Post Hoc Analyses from MAIA ', Blood, vol. 138, no. Suppl. 1, 4095 . https://doi.org/10.1182/blood-2021-150369Test

مصطلحات موضوعية: medicine.medical_specialty, Post hoc, Relation (database), business.industry, Internal medicine, Immunology, Disease progression, medicine, In patient, Cell Biology, Hematology, business, Biochemistry

الوصف: Introduction: In oncology clinical trials, overall survival (OS) is considered the gold standard efficacy endpoint. However, in multiple myeloma, the prolonged survival times and availability of multiple salvage therapies render it difficult to rely on OS as a primary endpoint. Instead, progression-free survival (PFS) or clinical response can be a relevant biomarker. At the same time, some health technology assessment bodies will only consider evidence based on patient-relevant endpoints, such as morbidity, mortality, and health-related quality of life (HRQoL), within their benefit assessments. Patient-reported outcomes (PROs) provide insights into how a treatment affects HRQoL, including symptoms and functioning. In the phase 3 MAIA trial, daratumumab, lenalidomide, and dexamethasone (D-Rd) demonstrated a significantly prolonged PFS and rapid and sustained improvements in PROs compared with lenalidomide and dexamethasone (Rd) alone at a median follow-up of 28 months. Updated results with longer follow-up confirmed a continued PFS benefit, deepening best clinical responses, and a significant OS benefit with D-Rd. Here, we report the results of analyses exploring the relationship between clinical efficacy endpoints and PROs in the MAIA trial. Methods: In MAIA (NCT02252172), TIE patients with NDMM were randomized to D-Rd or Rd until disease progression (PD) or unacceptable side effects. Clinical response and PD were defined per the International Myeloma Working Group uniform response criteria. PROs were assessed at baseline, on day 1 of cycles 3, 6, 9, and 12 for year 1, every 6 months thereafter until PD, or at end of treatment and at 8 and 16 weeks post-progression using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30). The current analyses were conducted on patients with a baseline PRO assessment and ≥1 post-baseline PRO assessment using a clinical cutoff date of February 19, 2021. Patients from both treatment groups were pooled and stratified by best clinical response. For PROs, the threshold for clinically meaningful change from baseline was defined a priori as ≥10 points based on published literature. Analyses were conducted for the global health status (GHS), fatigue, and pain scales of the EORTC QLQ-C30. The proportions of patients with clinically meaningful improvement in these PROs from baseline at any time while on treatment were calculated for and compared across best clinical response subgroups. For this analysis, patients were censored at the time of PD or discontinuation of therapy. Results were summarized with odds ratios and 95% confidence intervals. Additionally, the proportions of patients with clinically meaningful worsening in PROs from baseline at the time of and post-progression were also calculated for those who had PD. No adjustments were made for multiplicity. Nominal P-values are presented. Results: Best clinical response at a median follow-up of 56.2 months for the 710 patients included in this analysis is shown in the Table. For GHS, fatigue, and pain, the proportion of patients who reported clinically meaningful improvement from baseline increased with increasing depth of best clinical response. Odds ratios comparing best clinical response vs stable disease reflect this relationship and are shown in the Figure. Of the 264 patients who experienced PD and had PRO data at the time of or post-progression, 38.6%, 54.9%, and 39.4% reported meaningful worsening of GHS, pain, and fatigue, respectively, at the time of or post-progression. Conclusions: Patients with deeper best clinical response were more likely to report meaningful improvements in PROs. Patients who experienced PD reported worsening of GHS and symptoms at the time of or following progression. These analyses provide evidence of the association between key clinical efficacy endpoints and PROs and demonstrate the patient relevance of these clinical endpoints. Figure 1 Figure 1. Disclosures Perrot: Abbvie: Honoraria; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kumar: Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Plesner: Takeda: Research Funding; Genentech: Other: Advisor, Research Funding; Oncopeptides: Other: Advisor, Research Funding; AbbVie: Other: Advisor, Research Funding; CSL Behring: Other: Advisor; Janssen: Other: Advisor, Research Funding; Celgene: Other: Advisor, Research Funding; Genmab: Research Funding. Orlowski: Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Moreau: Abbvie: Honoraria; Oncopeptides: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Bahlis: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Honoraria. Nahi: XNK Therapeutics AB: Consultancy. Hulin: abbvie: Honoraria; Celgene/BMS: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Quach: Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldschmidt: GSK: Honoraria; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; Johns Hopkins University: Other: Grant; Mundipharma: Research Funding; MSD: Research Funding; Molecular Partners: Research Funding. O'Dwyer: Bristol Myers Squibb: Research Funding; ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Venner: Amgen: Research Funding; Celgene: Research Funding; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; BMS: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Macro: Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; GSK: Honoraria; Celgen/BMS: Honoraria; Sanofi: Honoraria. Leleu: Sanofi: Honoraria; Roche: Honoraria; Pierre Fabre: Honoraria; Oncopeptides: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Other: Non-financial support. Liu: Janssen: Current Employment, Current equity holder in publicly-traded company. Fastenau: Janssen: Current Employment, Current equity holder in publicly-traded company. Gries: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Ho: DRG Abacus: Consultancy; Emalex Biosciences: Consultancy; Janssen: Consultancy. Mistry: Janssen: Current Employment, Current equity holder in publicly-traded company. Tromp: Janssen: Current Employment, Current equity holder in publicly-traded company. Delioukina: Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company. Usmani: Amgen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy; Array BioPharma: Consultancy, Research Funding; GSK: Consultancy, Research Funding; EdoPharma: Consultancy; SkylineDX: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e39fb8beb1fde49685e379c18c4cbd22Test
https://doi.org/10.1182/blood-2021-150369Test

4

Descriptive Analysis of Isatuximab Use Following Prior Daratumumab in Patients with Relapsed/Refractory Multiple Myeloma

المؤلفون: Krina K. Patel, Elisabet E. Manasanch, Melody R. Becnel, Gregory P. Kaufman, Robert Z. Orlowski, Sheeba K. Thomas, Hans C. Lee, Sandra B. Horowitz, Donna M. Weber, Swami P. Iyer

المصدر: Blood. 136:20-21

مصطلحات موضوعية: medicine.medical_specialty, business.industry, Immunology, Daratumumab, Cell Biology, Hematology, Pomalidomide, medicine.disease, Biochemistry, Thalidomide, Family medicine, Relapsed refractory, medicine, In patient, Elotuzumab, business, Multiple myeloma, medicine.drug, Lenalidomide

الوصف: Background: Anti-CD38 monoclonal antibodies (mAb) like daratumumab (dara) have become integral in managing relapsed/refractory (RR) and newly diagnosed (ND) multiple myeloma (MM). Isatuximab (isa), a newer CD38 mAb, induces direct rather than indirect apoptosis of MM cells. However, little is known about whether the use of one prior CD38 mAb will alter the efficacy of another in subsequent lines of therapy. Methods: All patients (pts) with MM treated at MD Anderson with isa after receiving dara in prior lines of therapy were identified. We conducted a retrospective analysis with data points including patient and disease characteristics, responses to dara, response to isa, the presence of high risk features, and the presence of t(11,14). Results: 9 pts were identified, ages 56-72. 5 pts (55%) were male. 5 pts (55%) were alive at the time of data cutoff. 5 pts were Hispanic, 3 White, and 1 Black. 8 pts (89%) had high risk features as represented by the presence of del17p, t(4,14), t(14,16), t(14,20), p53 mutations, gain 1q, extramedullary disease (EMD), CNS disease, early relapse (within 1 year) after autologous transplant, or an increased (>5%) peripheral blood plasma cells (PBPC). 2 (22%) had t(11,14). 4 (44%) had IgG MM. 2 (22%) with light chain disease, 2 (22%) with IgA MM, and 1 (11%) with IgD MM. Dara was initially used in lines 2-7. Dara combinations with pomalidomide (pom), bortezomib (bor), thalidomide (thal), lenalidomide (len), or carfilzomib (car); and pom combinations that also included elotuzumab (elo) or Cytoxan (cytox) are noted in table 1. Dara was discontinued (dc'd) in 8 pts due to progressive disease (PD) and in 1 pt due to toxicity. 8 pts (89%) experienced a best overall response (ORR) of partial response (PR) to dara; 1 pt had stable disease (SD). All pts received prior len and 8 pts received prior pom at some time during the treatment of MM. All pts received isa in combination with pom/dexamethasone (dex). Best ORR to isa/pom/dex: 5 pt (55%) had PR, 2 pt with minimal response (MR), 1 SD, 1 PD. Median treatment duration of isa/pom/dex was 5 weeks (2-14 weeks) at data cutoff. 3 pts dc'd isa/pom/dex due to infections, and 2 due to later progression. 2 pts remain on therapy. 1 pt chose to dc all MM therapy for quality of life purposes despite PR with isa/pom/dex. 1 pt died from cardiac disease unrelated to MM or treatment. Conclusions: Our current study of heavily pretreated pts with RRMM demonstrates that despite prior anti-CD38 therapy with dara, most patients (77%) experienced a response of MR or better with treatment with another anti-CD38 therapy isa. To our knowledge, this is the first report of outcomes to isa in patients with prior dara therapy. Further long term follow up will be needed to determine the length of response. Additional studies are planned to further evaluate this patient population. Table 1 Disclosures Thomas: Pharmacyclics: Other: Advisory Boards; BMS: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharma: Research Funding; Xencor: Research Funding; Genentech: Research Funding. Iyer:Rhizen: Research Funding; CRISPR: Research Funding; Spectrum: Research Funding; Merck: Research Funding; Curio Biosciences: Honoraria; Target Oncology: Honoraria; Afffimed: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Trillium: Research Funding; Seattle Genetics, Inc.: Research Funding. Patel:Celgene: Consultancy, Research Funding; Cellectis: Research Funding; Nektar: Consultancy, Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Manasanch:Adaptive Biotechnologies: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Takeda: Honoraria; Quest Diagnostics: Research Funding; Merck: Research Funding; JW Pharma: Research Funding; Novartis: Research Funding; Sanofi: Research Funding. Kaufman:Janssen: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Honoraria. Lee:Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy. Orlowski:Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::73d5a45f17ff49bcc7008f58777e9305Test
https://doi.org/10.1182/blood-2020-140526Test

5

Update of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant (AuSCT) in Patients (Pts) with Multiple Myeloma (MM)

المصدر: Blood. 136:46-47

مصطلحات موضوعية: Oncology, medicine.medical_specialty, business.industry, Immunology, Phases of clinical research, Cell Biology, Hematology, medicine.disease, Biochemistry, Maintenance therapy, Internal medicine, Medicine, In patient, Elotuzumab, Stem cell, business, Multiple myeloma, medicine.drug, Lenalidomide

الوصف: Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) after AuSCT in pts with MM. Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAM F7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of MM pts who have received 1-3 prior therapies. We report updated results of this phase 2 trial evaluating the efficacy and safety of adding ELO to LEN as maintenance therapy post- AuSCT. Patients and Methods: Between 4/15/2015-1/27/2016, 27 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2, q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=73 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until disease progression (PD). LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity > grade 1 and significant cytopenias (ANC < 1000/mL, platelet count < 100,000/ml). For the 1st 8 weeks, pts The study's primary endpoint is PFS, defined as time from AuSCT to PD or death (whichever occurs first), or censored at date of last contact. Secondary objectives are best response, OS, incidence of second primary malignancies (SPMs) and adverse event (AE) profile. Total enrollment of 100 evaluable pts was completed on 6/5/2019. Patients are followed until death, withdrawal of consent or removal from study. Eligible pts received ≤2 lines of induction therapy, and were 60-210 days post-AuSCT. Results: Pts (n=100) have been treated for a median of 27.5 cycles (4-67). At study entry, 37 (37%) had complete response (CR), 40 (40%) very good partial response (VGPR), 22 (22%) partial response (PR) and 1 (1%) minor response (MR). Best response achieved to date on study is CR in 61 pts (61%), VGPR in 29 pts (29%) and PR in 10 pts (10%). Median time for conversion to CR on study is 1 month. Of pts in CR and tested for minimal residual disease (MRD) to date, 42/48 are negative (flow cytometry on ≥ 2 x106 cells). Eleven of 42 have converted from VGPR to MRD negative CR while on study. With a median follow up of 41 months, 90% of pts (n=90) remain alive. Eighteen pts have had PD; of these, 10 had high-risk cytogenetics. Three died of PD while receiving salvage therapy, 1 of pneumonia, 4 of second malignancies and 1 of unknown cause at another facility. One additional pt died on study in VGPR, after developing acute cerebral encephalopathy with refractory status epilepticus of unclear etiology. Estimated 4 year PFS is 75%. High-risk cytogenetics (n =31) adversely affected PFS (p=0.01); 14/31 pts remain on study. Of 23 pts transitioned to another therapy, median 2nd PFS has not been reached. Grade 3-4 Hematologic AEs (no. of pts/102 pts) were: neutropenia 32% (33), febrile neutropenia 15% (15), thrombocytopenia 7% (7), and anemia 10% (10). Grade 3-4 non-Hematologic AEs (no. of pts): hypophosphatemia 29% (30), respiratory infections 21% (21), diarrhea 15% (15), fatigue 12% (12), peripheral neuropathy 8% (8), other infections 7% (7), myalgias 5% (5), dyspnea 5% (5). SPMs include cutaneous basal and squamous cell carcinomas (8), AML (1), B-cell ALL (1), t-MDS (4), osteosarcoma (1), intra-epidermal adenocarcinoma of the neck (1), mucinous appendiceal neoplasm (1), mucinous epidermoid carcinoma of parotid (1), prostate cancer (1). Renal cell carcinoma was diagnosed in 1 pt, 15 months after removal from study for PD. Conclusions: Lenalidomide-elotuzumab is a well-tolerated maintenance therapy on which 38% of pts have had improvement in quality of response while on therapy, including 27% who converted to CR. SPM rates seem consistent with those observed in CALGB 100104 and IFM 2005-02 trials of lenalidomide alone. Longer follow up is required to determine how median PFS and OS will compare with those from lenalidomide monotherapy trials, and how SPM rates will continue to evolve. Table 1 Disclosures Thomas: X4 Pharma: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Xencor: Research Funding; Pharmacyclics: Other: Advisory Boards; Genentech: Research Funding. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Lee:Regeneron: Research Funding; Daiichi Sankyo: Research Funding; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy. Manasanch:JW Pharma: Research Funding; Merck: Research Funding; Quest Diagnostics: Research Funding; Takeda: Honoraria; BMS: Honoraria; Glaxo Smith Kline: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Research Funding; Sanofi: Honoraria, Research Funding. Patel:Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Cellectis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Nektar: Consultancy, Research Funding; Precision Biosciences: Research Funding; Poseida: Research Funding. Kaufman:Bristol Myers Squibb: Research Funding; Karyopharm: Honoraria; Janssen: Research Funding. Iyer:Trillium: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Merck: Research Funding; Rhizen: Research Funding; Seattle Genetics, Inc.: Research Funding; Target Oncology: Honoraria; Afffimed: Research Funding; CRISPR: Research Funding; Spectrum: Research Funding; Curio Biosciences: Honoraria. Qazilbash:Angiocrine: Research Funding; Bioclinica: Consultancy; Janssen: Research Funding; Bioline: Research Funding; Amgen: Research Funding. Bashir:Amgen: Other: Advisory Board; Purdue: Other: Advisory Board; Takeda: Other: Advisory Board, Research Funding; Acrotech: Research Funding; StemLine: Research Funding; Celgene: Research Funding; KITE: Other: Advisory Board. Orlowski:Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy. OffLabel Disclosure: Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against SLAM F7. It is FDA approved in combination with Lenalidomide and dexamethasone (DEX) for treatment of MM pts who have received 1-3 prior therapies. This is a phase 2 trial evaluating the efficacy and safety of adding ELO to LEN as maintenance therapy post-autologous stem cell transplant.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::9a788b72d8ca70fdbce5b4d1fafe7890Test
https://doi.org/10.1182/blood-2020-139934Test

6

Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of Griffin after 12 Months of Maintenance Therapy

المصدر: Blood. 136:45-46

مصطلحات موضوعية: Oncology, medicine.medical_specialty, business.industry, Bortezomib, Immunology, Daratumumab, Cell Biology, Hematology, Dara, medicine.disease, Biochemistry, Maintenance therapy, Internal medicine, medicine, In patient, business, Dexamethasone, Multiple myeloma, medicine.drug, Lenalidomide

الوصف: Introduction: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for relapsed/refractory multiple myeloma and NDMM. In the primary analysis of the phase 2 GRIFFIN study (NCT02874742) in patients with transplant-eligible NDMM, DARA plus RVd (D-RVd) significantly improved rates of stringent complete response (sCR) by the end of post-transplant consolidation therapy versus RVd (Voorhees P, Blood 2020). Here, we present updated efficacy and safety results following 12 months of maintenance therapy with lenalidomide (R) or DARA plus R (D-R). Methods: Patients with NDMM eligible for high-dose therapy (HDT) and autologous stem cell transplant (ASCT) were randomized 1:1 to RVd ± DARA, stratified by ISS stage and creatinine clearance rate. Patients received 4 induction cycles, HDT, ASCT, 2 consolidation cycles, and maintenance with R ± DARA for 24 months. During induction and consolidation, patients received R 25 mg PO on Days 1-14; V 1.3 mg/m2 SC on Days 1, 4, 8, and 11; and d 40 mg QW every 21 days. DARA 16 mg/kg IV was given on Days 1, 8, and 15 of Cycles 1-4 and Day 1 of Cycles 5-6. During maintenance (Cycles 7-32), patients received R 10 mg (15 mg in Cycles 10+ if tolerated) on Days 1-21 every 28 days ± DARA 16 mg/kg IV Q8W (or Q4W per patient decision after Amendment 2). The primary endpoint was rate of sCR at the end of post-ASCT consolidation per IMWG criteria, evaluated by a validated computer algorithm. Key secondary endpoints included progression-free survival (PFS) and rate of minimal residual disease (MRD) negativity (10-5 threshold per IMWG criteria) assessed by next-generation sequencing (clonoSEQ; Adaptive Biotechnologies). The primary hypothesis was tested at a 1-sided alpha of 0.10. All secondary analyses were evaluated using a 2-sided P value (alpha 0.05) and were not adjusted for multiplicity. Results: In total, 207 patients were randomized (D-RVd, n=104; RVd, n=103). Baseline demographics and disease characteristics were well balanced between arms. At the end of post-transplant consolidation (median follow-up, 13.5 months) in the response-evaluable population, the sCR rate favored D-RVd versus RVd (42.4% [42/99] vs 32.0% [31/97]; 1-sided P=0.0680). With additional D-R or R maintenance therapy, responses continued to deepen and remained higher for the D-RVd group versus the RVd group. At the 12-months-of-maintenance therapy data cut (median follow-up, 26.7 months), the sCR rate still favored D-RVd versus RVd (63.6% [63/99] vs 47.4% [46/97], 2-sided P=0.0253; Figure). MRD-negativity (10‒5) rates in the ITT population favored D-RVd versus RVd (62.5% [65/104] vs 27.2% [28/103], P Conclusions: After 26.7 months of median follow-up, the addition of DARA to RVd induction and consolidation, followed by D-R maintenance in patients with transplant-eligible NDMM continued to demonstrate deep and improved responses, including higher sCR and MRD negativity rates, compared with lenalidomide alone. Maintenance therapy increased sCR and MRD negativity rates, compared to post-consolidation rates. No new safety concerns were observed with longer follow-up. Support: Alliance Foundation Trials; https://acknowledgments.alliancefound.orgTest; Janssen Oncology Disclosures Kaufman: Tecnopharma: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Sanofi/Genyzme: Consultancy, Honoraria; AbbVie: Consultancy; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Sborov:University of Utah: Current Employment; Celgene, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Reeves:Incyte: Honoraria; Takeda: Honoraria; Bristol Myers Squibb: Speakers Bureau. Rodriguez:BMS, Takeda, Amgen: Consultancy, Speakers Bureau. Chari:Janssen, Celgene, Novartis, Amgen, Bristol-Myers Squibb, Karyopharm, Sanofi, Genzyme, Seattle Genetics, Oncopeptides, Millennium/Takeda, Antengene, Glaxo Smith Kline, Secura Bio: Consultancy; Janssen, Celgene, Novartis, Amgen, Pharmacyclics, Seattle Genetics, Millennium/Takeda: Research Funding. Silbermann:Karyopharm: Consultancy; Janssen: Consultancy; Sanofi-Aventis: Consultancy, Research Funding. Costa:AbbVie: Consultancy; Sanofi: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genentech: Consultancy; BMS: Consultancy, Honoraria. Anderson:Amgen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Efebera:Pharmacyclics: Research Funding; Ohio State University: Current Employment; Celgene: Research Funding; Takeda: Honoraria, Speakers Bureau. Holstein:Sorrento: Consultancy; Adaptive Biotechnologies: Consultancy; Takeda: Consultancy; GSK: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding. Costello:Takeda, Celgene: Consultancy, Honoraria. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wildes:Seattle Genetics: Consultancy; Carevive Systems: Consultancy; Janssen: Research Funding. Orlowski:Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Shain:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; AbbVie: Research Funding; GlaxoSmithKline: Speakers Bureau; Adaptive: Consultancy, Honoraria; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Cowan:Nektar: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Bristol-Myer Squibb: Research Funding; Celgene: Consultancy, Research Funding; Cellectar: Consultancy; Sanofi-Aventis: Consultancy. Lutska:Janssen: Current Employment. Bobba:Janssen: Current Employment. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Lin:Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Voorhees:TeneoBio: Other: Advisory Board; Oncopeptides: Consultancy, Honoraria; Novartis: Consultancy; Janssen: Other: Advisory Board; GSK: Honoraria; BMS: Other: Advisory Board; Adaptive Biotechnologies: Other: Advisory Board. OffLabel Disclosure: The specific regimen combination is not yet approved, but individual components are.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::9fe9e2d6e52bd67066c03ba26e4971b8Test
https://doi.org/10.1182/blood-2020-137109Test

7

A Novel Therapeutic DNA Vaccine Elicits Reduction of Tumor Clones and Favorable Perturbations in the Immune Microenvironment in Patients (pts) with Untreated Smoldering Waldenström Macroglobulinemia (sWM)

المؤلفون: Aaron Anderson, Sattva S. Neelapu, Zhe Wang, Donna M. Weber, Soung-chul Cha, Elisabet E. Manasanch, Sheeba K. Thomas, Lei Feng, Hans C. Lee, Szymon Jakub Szymura, Robert Z. Orlowski, Brandon N. Crumpton, Larry W. Kwak, Sheetal S Rao, Jasper B. Olsem, Sapna R. Parshottam, Krina K. Patel

المصدر: Blood. 136:6-7

مصطلحات موضوعية: Oncology, medicine.medical_specialty, business.industry, Immune microenvironment, Immunology, Waldenstrom macroglobulinemia, Cell Biology, Hematology, medicine.disease, Biochemistry, DNA vaccination, Vaccination, Kite Pharma, Clinical research, Internal medicine, medicine, In patient, Lost to follow-up, business

الوصف: Background: Idiotypic determinants of the surface immunoglobulin (Ig) associated with a given pt's B-cell lymphoma are unique to that tumor, and can thus serve as a tumor-specific marker. This study aims to use an idiotype DNA vaccine to lengthen the smoldering phase of WM without inducing cross-resistance to available therapies. Administered vaccine used recombinant plasmid DNA encoding a fusion protein, consisting of autologous lymphoma scFv (pt-specific idiotype) and human CCL20 (macrophage inflammatory protein-3 alpha - MIP-3α) chemokine. Targeted delivery of this fusion protein to antigen-presenting cells, and subsequent processing and presentation, is hypothesized to break tolerance and generate an immune response against the idiotype, promoting eradication of antigen-expressing B-cell lymphoma cells. Methods: Pts with sWM received 3 intradermal vaccinations of pt-specific DNA vaccine at 4-week (wk) intervals (wks 0, 4 and 8). Two dose levels (500 µg; 2500 µg) were evaluated in a 3+3 design. The primary objective was to evaluate the vaccine's safety and identify the maximum tolerated dose. Secondary objectives were to assess immunogenicity of the vaccine to generate tumor-specific cellular immune responses. Results: Between 1/2016 - 1/2019, 9 pts (7 men) were treated (500 µg: n = 3; 2500 µg: n = 6). Median age at enrollment was 67 yrs (range 56-78); median time from diagnosis to 1st vaccination was 26.5 mos (8.8-120.9). MYD88 L265P + (6 pts). CXCR4 WHIM + (1 pt). With median follow up of 38 months (range: 8.8-51), 8 pts are known alive; 1 has been lost to follow up. Six have maintained stable disease; 3 have progressed to symptomatic WM at 8, 25, and 28 months respectively, from 1st vaccination). All pts completed planned therapy. No DLTs or Grade 4 AEs occurred. Ten mos. after the 3rd vaccination, 1 pt had a grade 3 pleural effusion and leukopenia with an increase in rheumatoid factor (23.1 IU/mL [normal range 0.0-15.9]) and ANA titer of 1:80; all resolved within 2 mos. Grade 1-2 AEs observed in > 3pts include: leukopenia (6), nausea (5), anemia (4), increased creatinine (4), fatigue (4). Immune correlatives have now been completed in all 9 patients. Analysis is ongoing, and complete data will be presented at the meeting. Serial pre- and post- vaccine samples analyzed by single-cell RNA seq from 3 representative patients (LPL 005, LPL 007, LPL 008) treated at the 2500 mg dose are shown in the Figure. DNA vaccine treatment significantly reduced the number of clonal B-cells in the bone marrow compartment of the 2 patients who have maintained SD (LPL 007 and LPL 008). DNA vaccine treatment also induced increases in monocytes in the tumor microenvironment of these 2 patients. In addition, T-cell receptor (TCR) sequence analysis revealed clear increases in TCR clonal expansions, consistent with a vaccine effect. In contrast, LPL 005, who had the earliest progression to symptomatic phase WM, had an increase in tumor B cells on post vaccine samples, and TCR clonotypes showed no changes. Similar changes were observed with serial bone marrow samples from the remaining patients treated on the trial, correlating with clinical outcome. Conclusions: Idiotype (scFv-CCL20) DNA vaccine therapy appears to be safe in pts with sWM. Preliminary results of serial single cell RNAseq analysis suggest that the tumor immune microenvironment is favorably altered after chemokine-tumor antigen DNA vaccine treatment and these vaccine-induced changes may correlate with clinical outcome. The immunologic changes observed suggest response to this vaccine, and warrant further investigation in a Phase II trial, possibly in combination with immune checkpoint blockade. Disclosures Thomas: Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Research Funding; Pharmacyclics: Other: Advisory Boards; Xencor: Research Funding; X4 Pharma: Research Funding. Lee:GlaxoSmithKline: Consultancy, Research Funding; Regeneron: Research Funding; Daiichi Sankyo: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Genentech: Consultancy; Sanofi: Consultancy; Genentech: Consultancy. Manasanch:Adaptive Biotechnologies: Honoraria; Glaxo Smith Kline: Honoraria; BMS: Honoraria; Takeda: Honoraria; Quest Diagnostics: Research Funding; Merck: Research Funding; JW Pharma: Research Funding; Novartis: Research Funding; Sanofi: Honoraria, Research Funding. Patel:Nektar: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Celgene: Consultancy, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Oncopeptides: Consultancy. Orlowski:Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. Neelapu:Takeda Pharmaceuticals: Patents & Royalties; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; N/A: Other; Acerta: Research Funding; Karus Therapeutics: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Unum Therapeutics: Other, Research Funding; Calibr: Other; Adicet Bio: Other; Legend Biotech: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Precision Biosciences: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Pfizer: Other: personal fees. Kwak:CJ Healthcare: Consultancy; Sellas Life Sciences Grp: Consultancy; Enzychem Life Sciences: Membership on an entity's Board of Directors or advisory committees; Antigenics: Other: equity; InnoLifes, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pepromene Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xeme Biopharma/Theratest: Other: equity; Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Consultancy. OffLabel Disclosure: This study aims to use a novel idiotype DNA vaccine to lengthen the smoldering phase of WM without inducing cross-resistance to available therapies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::356d03a4795dceaa90dae80842583350Test
https://doi.org/10.1182/blood-2020-140007Test

8

Prognostic Impact of Beta 2 Microglobulin in Patients with Immunoglobulin Light-Chain Amyloidosis Undergoing Autologous Hematopoietic Stem Cell Transplantation

المؤلفون: Uday R. Popat, Donna M. Weber, Partow Kebriaei, Elisabet E. Manasanch, Qaiser Bashir, Gregory P. Kaufman, Neeraj Saini, Richard E. Champlin, Aimaz Afrough, Robert Z. Orlowski, Chitra Hosing, Samer A. Srour, Muzaffar H. Qazilbash, Regan Murphy, Ruby Delgado, Krina K. Patel, Sheeba K. Thomas, Elizabeth J. Shpall, Hans C. Lee

المصدر: Blood. 136:20-21

مصطلحات موضوعية: Immunoglobulin Light-chain Amyloidosis, Beta-2 microglobulin, business.industry, medicine.medical_treatment, Immunology, Cancer research, Medicine, In patient, Cell Biology, Hematology, Hematopoietic stem cell transplantation, business, Biochemistry

الوصف: Background: Risk stratification for Immunoglobulin light chain amyloidosis (AL) has been refined with advances in the understanding of disease biology. Although nonspecific, beta 2 microglobulin (β2M) levels correlate with disease burden and are considered a prognostic marker in several hematologic malignancies. Recently, we and others have shown the association of β2M levels with survival in AL. In this study, we evaluated the role of β2M as a predictor of outcome for high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) in patients with AL. Methods: We identified 175 consecutive patients with AL who received auto-HCT between 2009 and 2019 at our institution. A β2M≥3.5 mg/L, regardless of renal function status was used as a cutoff value. Hematologic and organ responses were evaluated according to the Consensus Guidelines for AL. Revised Mayo staging system was utilized for Cardiac staging. Results: The median age at auto-HCT was 60 years (range, 27 to 77). Of 175 patients, 153 (87%) had a β2M value available, of whom 57 (37%) had a β2M ≥ 3.5 mg/L. There were no significant differences in baseline characteristics between the 2 groups, except for the higher level of LDH, worse renal function, and more patients with renal involvement in the β2M ≥ 3.5 group, and more patients with lambda light chain type in the β2M The 3-year progression-free survival (PFS) was 66%, and 74% in patients with β2M≥3.5, and β2M Conclusion: In this single-center retrospective analysis, we showed that high serum β2M is associated with shorter OS. β2M may be incorporated as a prognostic marker for AL if these findings are confirmed in larger studies. Disclosures Bashir: Acrotech: Research Funding; StemLine: Research Funding; Celgene: Research Funding; Takeda: Other: Advisory Board, Research Funding; KITE: Other: Advisory Board; Amgen: Other: Advisory Board; Purdue: Other: Advisory Board. Hosing:NKARTA Inc.: Consultancy. Popat:Bayer: Research Funding; Novartis: Research Funding. Kebriaei:Novartis: Other: Served on advisory board; Jazz: Consultancy; Ziopharm: Other: Research Support; Kite: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Amgen: Other: Research Support. Shpall:Takeda: Other: Licensing Agreement; Magenta: 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; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees. Manasanch:Sanofi: Research Funding; Adaptive Biotechnologies: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Takeda: Honoraria; Quest Diagnostics: Research Funding; Merck: Research Funding; JW Pharma: Research Funding; Novartis: Research Funding. Lee:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy. Kaufman:Janssen: Research Funding; Karyopharm: Honoraria; Bristol Myers Squibb: Research Funding. Patel:Cellectis: Research Funding; Nektar: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding. Thomas:BMS: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharma: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Pharmacyclics: Other: Advisory Boards. Orlowski:STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Champlin:Genzyme: Speakers Bureau; Johnson and Johnson: Consultancy; Actinium: Consultancy; Cytonus: Consultancy; Omeros: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents & Royalties. Qazilbash:Angiocrine: Research Funding; Bioline: Research Funding; Amgen: Research Funding; Bioclinica: Consultancy; Janssen: Research Funding.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::98f719283865049dc4d54d7e84a41be5Test
https://doi.org/10.1182/blood-2020-141360Test

9

Dose- and Schedule-Dependent Immunomodulatory Effects of the Novel Celmod Agent CC-92480 in Patients with Relapsed/Refractory Multiple Myeloma

المصدر: Blood. 136:47-48

مصطلحات موضوعية: Oncology, Schedule, medicine.medical_specialty, business.industry, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Internal medicine, Relapsed refractory, medicine, In patient, business, health care economics and organizations, Multiple myeloma

الوصف: Introduction: CC-92480 is an oral novel cereblon (CRBN) E3 ligase modulator (CELMoD) agent currently in phase 1/2 development in patients with relapsed/refractory multiple myeloma (RRMM). CC-92480 induces rapid degradation of the transcription factors Ikaros and Aiolos, leading to apoptosis of myeloma cells and immune-stimulatory effects. The innovative CC-92480-MM-001 phase 1 study design investigated the effects of a broad range of CC-92480 doses and schedules. The pharmacodynamic effects will be discussed in this analysis with a focus on modulation of immune cell subsets. Methods: An adaptive Bayesian dose-escalation design was used in the CC-92480-MM-001 study (NCT03374085) that allowed for evaluation of several dosing schedules. The continuous schedules included 10 days on followed by 4 days off × 2, and 21 days on followed by 7 days off in a 28-day cycle. The intensive schedules included 3 days on followed by 11 days off × 2, and 7 days on followed by 7 days off × 2. An intensive biomarker sampling program was included in the study to allow for characterization of pharmacodynamic changes. Peripheral blood and bone marrow aspirates (BMA) were obtained from patients enrolled in part 1 of the dose-escalation study for biomarker analysis. Samples were taken pre-dose and during treatment at multiple time points. Biomarker analyses included Ikaros and Aiolos levels in peripheral blood mononuclear cells by flow cytometry; CRBN, Aiolos, Ikaros, and ZFP91 expression by immunohistochemistry (IHC) in BMA; weekly levels of serum free light chain (sFLC) and soluble B-cell maturation antigen (sBCMA), and effects on immune cells in peripheral blood. CC-92480 plasma exposures were collected at several time points in Cycle 1. Results: CC-92480 1.0 mg, 21/28-days was selected as the recommended phase 2 dose (RP2D) based on tolerability, efficacy, and pharmacodynamic effects. Degradation of Ikaros and Aiolos was evident at all dose levels in bone marrow plasma cells independent of baseline CRBN staining intensity and prior treatment. In these heavily pretreated patients with RRMM, CC-92480 induced rapid and sustained decreases in sFLC (median 94%) and sBCMA (median 78%) in Cycle 1 at the RP2D. Ikaros and Aiolos degradation in peripheral blood T cells was dose-dependent and reached > 80% degradation at 0.6 mg and above. Substrate recovery occurred during drug holidays, with faster recovery at lower doses, and reached full recovery with ≥ 7-day breaks. Focusing on the immunomodulatory effects, dynamic and dose- and schedule-dependent changes were demonstrated in immune cell subtypes. B cells decreased with increasing dose and reached > 90% at 0.8 mg and above in the continuous schedules. Recovery was evident during drug holidays, especially at lower doses. T-cell proliferation by Ki-67 staining increased between 30% and 350% during treatment and returned toward baseline during drug holidays at lower doses and with longer breaks. NK-cell proliferation by Ki-67 staining was evident at all doses and peaked at approximately 1 week post dose regardless of schedule. T cells demonstrated a shift from naïve to effector phenotype at all doses and schedules, and showed an increase in activation markers, HLA-DR, CD38, and ICOS. Regulatory T cells increased by 90% and 130% at 0.8 mg and 1.0 mg, respectively. At the 1.0 mg dose (RP2D) and more continuous schedules (10/14 days × 2 and 21/28 days), higher percentages of proliferating CD3+CD4+ and CD3+CD8+ T cells associated with a clinical response. Conclusions: The novel study design and biomarker sampling have allowed us to understand how depth, duration, and recovery of Ikaros and Aiolos degradation lead to specific immune changes. CC-92480 pharmacodynamic activity was dose-dependent from 0.1 mg to 1.0 mg and recovery was dose- and schedule-dependent. These changes were also demonstrated in immune cell subsets. Dynamic changes of immune cell subsets in peripheral blood occurred in concert with Ikaros and Aiolos degradation and recovery, suggesting that immune profiles may be modified and optimized by dose and schedule. This new insight may be utilized to provide the rationale for dose and schedule for specific immune effects when combining with other immunotherapies, such as bispecific antibodies and CAR T cells. Disclosures Wong: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Lamba:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. Jiménez Nuñez:CITRE, a Bristol-Myers Squibb Company, Spain: Current Employment. Bauer:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Bahlis:Sanofi: Consultancy, Honoraria; BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Genentech: Consultancy, Honoraria. Ramasamy:Takeda: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Trudel:Pfizer: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Takeda, Karyopharm, AstraZeneca, Sanofi: Honoraria; Janssen: Honoraria, Research Funding; Amgen: Consultancy, Research Funding. Martínez-Lopez:Altum, Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Vivia Biotech: Honoraria; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding. Mateos:EDOMundipharma: Consultancy; Adaptive: Consultancy; Pharmamar: Consultancy; GlaxoSmithKline: Consultancy; AbbVie: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Rodriguez-Otero:Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Lonial:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Merck: Consultancy, Honoraria, Other: Personal fees; GSK: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; Takeda: Consultancy, Other: Personal fees, Research Funding; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; JUNO Therapeutics: Consultancy; Millennium: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Personal fees; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria. Popat:AbbVie: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Oriol:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Orlowski:Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; STATinMED Research: Consultancy; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Berdeja:Amgen: Consultancy, Research Funding; Abbvie: Research Funding; Bluebird: Research Funding; Servier: Consultancy; Takeda: Consultancy, Research Funding; Vivolux: Research Funding; Kesios: Research Funding; Karyopharm: Consultancy; Glenmark: Research Funding; Genentech, Inc.: Research Funding; EMD Sorono: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; CURIS: Research Funding; Poseida: Research Funding; Prothena: Consultancy; Kite Pharma: Consultancy; Legend: Consultancy; Lilly: Research Funding; Novartis: Research Funding; Teva: Research Funding; Acetylon: Research Funding; Bioclinica: Consultancy; BMS: Consultancy, Research Funding. Pourdehnad:Celgene: Ended employment in the past 24 months, Patents & Royalties: Various CC-122 patents; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Various CC-122 patents. Pierce:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::32cf97c657bd4c810035a672634af292Test
https://doi.org/10.1182/blood-2020-137161Test

10

Outcome of Patients with Immunoglobulin Light-Chain Amyloidosis with t(11;14) Undergoing Autologous Hematopoietic Stem Cell Transplantation

المصدر: Blood. 136:18-19

مصطلحات موضوعية: medicine.medical_specialty, business.industry, Immunology, Cell Biology, Hematology, Biochemistry, Kite Pharma, Baseline characteristics, Family medicine, Overall survival, Medicine, In patient, business, Laboratory research, Bristol-Myers, Staging system, Complete response

الوصف: Background- In patients with light chain amyloidosis (AL), t(11;14) detected by fluorescence in situ hybridization (FISH) is the most common cytogenetic aberration. Several studies have shown that t(11;14) is associated with inferior outcomes in newly diagnosed AL patients [1, 2]. In contrast, at least one study in patients with t(11;14) who underwent high-dose therapy and autologous hematopoietic stem cell transplantation (auto-HCT) showed improved complete response (CR) rate and prolonged hematologic event-free survival[3]. In this single-center, retrospective analysis, we evaluated the outcome of patients with AL and t(11;14) who underwent auto-HCT at our institution. Method- We identified 122 consecutive patients with AL with cardiac or renal involvement who received an auto-HCT between 2011 and 2019. Baseline FISH data were available for 92 patients, 15 (16 %) of whom had t(11;14). Seventy-seven (84%) patients without t(11;14) were included as control . Hematologic and organ responses were evaluated according to the Consensus Guidelines for AL [4]. Revised Mayo staging system was utilized for Cardiac staging [5]. Result- The median age at auto-HCT was 60 years (range, 27 to 77). There were no significant differences in baseline characteristics between the two groups (Table 1). The median follow-up from auto-HCT was 28 months (range, 1 to 100). Overall, 40%, and 42% of patients with or without t(11;14), respectively (p=0.573), received post-auto-HCT maintenance therapy. One-year non-relapse mortality (NRM) was 2%. The 1-year NRM was 0 and 2.6% (n=2) in patients with or without t(11;14) (p=0.366). Hematologic CR after auto-HCT was seen in 7 (47%) and 33 (42%) patients with or without t(11;14), respectively (p=0.78). Organ response (OR) after auto-HCT was seen in 10 (71%) and 50 (67%) patients with or without t(11;14), respectively (p=0.586). The 2-year hematologic disease-free survival (Heme DFS) was 93% and 87% with or without t(11;14), respectively (p=0.422). The 2-year progression-free survival (PFS) was 92%, and 87% in patients with or without t(11;14) (p=0.6) (Figure 1A).The 2-year overall survival was 100%, ad 87% in patients with or without t(11;14) (p=0.2) (Figure 1B). Cardiac involvement with AL was associated with a shorter OS (p=0.012). Conclusion- In this single-center retrospective analysis, we showed that auto-HCT is safe and feasible in selected patients with AL and t(11;14), and these patients have comparable outcomes to patients without t(11;14). Disclosures Bashir: Celgene: Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Takeda: Other: Advisory Board, Research Funding; KITE: Other: Advisory Board; Purdue: Other: Advisory Board; Amgen: Other: Advisory Board. Hosing:NKARTA Inc.: Consultancy. Popat:Bayer: Research Funding; Novartis: Research Funding. Kebriaei:Amgen: Other: Research Support; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Novartis: Other: Served on advisory board; Ziopharm: Other: Research Support; Jazz: Consultancy. Shpall:Takeda: Other: Licensing Agreement; Magenta: 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; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees. Manasanch:Adaptive Biotechnologies: Honoraria; Sanofi: Research Funding; Novartis: Research Funding; JW Pharma: Research Funding; Merck: Research Funding; Quest Diagnostics: Research Funding; Takeda: Honoraria; BMS: Honoraria; Sanofi: Honoraria; GSK: Honoraria. Lee:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy. Kaufman:Janssen: Research Funding; Karyopharm: Honoraria; Bristol Myers Squibb: Research Funding. Patel:Oncopeptides: Consultancy; Celgene: Consultancy, Research Funding; Cellectis: Research Funding; Janssen: Consultancy, Research Funding; Nektar: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Poseida: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Thomas:Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharma: Research Funding; Xencor: Research Funding; Pharmacyclics: Other: Advisory Boards; Genentech: Research Funding; BMS: Research Funding. Orlowski:STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Champlin:Actinium: Consultancy; Omeros: Consultancy; Takeda: Patents & Royalties; Cytonus: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Genzyme: Speakers Bureau; Johnson and Johnson: Consultancy. Qazilbash:Janssen: Research Funding; Bioline: Research Funding; Angiocrine: Research Funding; Amgen: Research Funding; Bioclinica: Consultancy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::b339a5de179a2b21007eca9706591a75Test
https://doi.org/10.1182/blood-2020-141307Test

تنقيح النتائج