scholarly journals Metformin Restores AMPK Alpha-Mediated Autophagy and Prevents Carfilzomib-Induced Cardiotoxicity In Vivo

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3214-3214
Author(s):  
Georgios Kremastiotis ◽  
Panagiotis Efentakis ◽  
Aimilia Varela ◽  
Constantinos H. Davos ◽  
Maria Tsoumani ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Board Of Directors ◽  
Molecular Mechanism ◽  
Research Funding ◽  
Steering Committee ◽  
Control Group ◽  
Advisory Committees ◽  
Pp2a Activity ◽  
Travel Grant

Abstract Introduction: Carfilzomib (Cfz) significantly prolongs progression-free survival in relapsed or refractory multiple myeloma patients, as highlighted in the ENDEAVOR trial. However, Cfz has high incidences of cardiotoxicity and heart failure, leading to treatment cessation. Thus, there is an imperative need for preventive therapies. The study aimed to i) establish an in vivo Cfz cardiotoxicity protocol, ii) investigate the molecular mechanism, identify molecular targets and iii) based on initial results, investigate the potential protective effect and mechanism of Metformin (Met). Methods: Male, C57BL/6 mice, were randomized in groups as following: Acute protocol (6 days): Control (n=7), Cfz (n=8); Sub-chronic protocol (14 days): Control (n=5), Cfz (n=8); Pharmacological intervention protocol (6 days): Control (n=8), Cfz (n=8), Cfz+Met (n=8), Met (n=4). Cfz (8 mg/kg, ip) was administered on alternate days and Met (140 mg/kg, po) daily. Glucose levels were monitored following Met administration. Mice underwent echocardiography on baseline and at the end of treatments. Blood and myocardial tissue samples were obtained for histology, proteasome activity, PP2A activity and signaling pathways focused on PI3K/Akt/eNOS axis, NO homeostasis and AMPKα-mTOR-mediated autophagy. Results: Following acute administration, echocardiography in Cfz group presented a significant reduction in fractional shortening (FS%) vs. Control group (39.87±0.47 vs. 43.03±0.50 respectively, p<0.001), combined with reduced thickness in the left ventricular (LV) posterior wall (LVPW diastole (mm): 0.69±0.01 vs. 0.76±0.01, p<0.01; LVPW systole (mm): 1.17±0.01 vs. 1.24±0.02, p<0.01). Sub-chronic Cfz administration resulted in moderate LV dilation (LV end-diastole diameter (mm): 3.24±0.03 vs. 3.04±0.04, p<0.01; LV end-systole diameter (mm): 1.88±0.02 vs. 1.71±0.02, p<0.01) and borderline FS% reduction (42.07±0.46 vs. 43.52±0.25, p<0.05). Following both protocols, Cfz did not cause major tissue lesions. Signaling pathways were studied in the acute protocol that demonstrated suppressed myocardial contractility. Cfz resulted in significant inhibition of proteasome in both myocardium (55.5% inhibition, p<0.05) and peripheral mononuclear blood cells (PBMCs) (90.6% inhibition, p<0.001) - inhibitory effect was comparable to clinical practice. Cfz, independently of PTEN expression, reduced phospho-PI3K (p<0.05), phospho-Akt (p<0.001) and phospho-eNOS (p<0.001), and increased iNOS expression (p<0.01). Cfz reduced phospho-AMPKα (p<0.001) and phospho-Raptor (p<0.05) leading to inhibition of autophagy, indicated by reduced LC3-II expression (p<0.01), without affecting phospho-mTOR or Beclin 1. Co-administration of Met prevented FS% reduction (Cfz group: 41.55±0.43 vs. 43.24±0.50 and 43.39±0.56, Control and Cfz+Met respectively, p<0.05), without exerting glucose lowering actions. Met did not interfere with Cfz-induced proteasome inhibition; Cfz and Cfz+Met groups had significantly reduced proteasomal activity vs. Control group in myocardium (p<0.05) and PBMCs (p<0.001 and p<0.01 respectively). Histology presented mild to moderate vascular congestion in Cfz+Met and Met vs. Control and Cfz groups (p<0.05), appearing to be non-specific finding that did not collocate with haemorrhage, vascular obstruction or tissue lesions. On a molecular level, Cfz+Met group presented increased phospho-Akt (p<0.01) vs. Cfz group, independently of PTEN, PI3K and eNOS/iNOS. Cfz+Met group restored phospho-AMPKα (p<0.05), phospho-Raptor (p<0.001) and LC3-II expression (p<0.05) vs. Cfz group, without inducing changes in mTOR and Beclin 1. Cfz inactivated Akt and AMPKα through increased PP2A activity (p<0.05), without altering PP2A expression; Met did not interfere with PP2A activity. Conclusions: Cfz exhibits decreased global LV function in vivo, without inducing tissue lesions. The molecular mechanism consists of increased PP2A activity leading to inactivation of AMPKα-mTOR and PI3K/Akt/eNOS pathways - combined with NO homeostasis deregulation. In an intervention approach, Met preserved cardiac function via restoring AMPKα-mediated autophagy. Met administration did not restore NO production and homeostasis; these pathways require further investigation. Met emerges to be a promising preventive therapy for Cfz-induced cardiotoxicity. Disclosures Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Genesis Pahrma: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Prothena: Consultancy, Honoraria. Dimopoulos:Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Terpos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; BMS: Consultancy; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding.

scholarly journals Functional Cure, Defined As PFS of More Than 7 Years, Is Achieved in 9% of Myeloma Patients in the Era of Conventional Chemotherapy and of First-Generation Novel Anti-Myeloma Agents; A Single-Center Experience over 20-Year Period

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1968-1968
Author(s):  
Evangelos Terpos ◽  
Maria Roussou ◽  
Ioannis Ntanasis-Stathopoulos ◽  
Nikolaos Kanellias ◽  
Despina Fotiou ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
First Generation ◽  
Steering Committee ◽  
First Line ◽  
Conventional Chemotherapy ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Line Therapy ◽  
Travel Grant

Abstract Advances in the management of multiple myeloma (MM) led to a significant prolongation of overall survival (OS), mainly of the younger patients; almost 10% of them experience more than 10-year OS. Although long progression-free survival (PFS) correlates with extended OS, there is very limited information for the characteristics of patients who manage to be progression-free for a long period after first-line therapy. The aim of this analysis was to evaluate the characteristics of patients who achieved at least 7-year of PFS after frontline therapy and compare them with those of all other patients who were treated in a single center during the same time period. Between January 1994 and December 2010, 406 consecutive newly diagnosed MM patients received first line therapy in the Department of Clinical Therapeutics (Athens, Greece). All patients had symptomatic disease, based on the IMWG criteria of that period (at least one CRAB symptom to start anti-myeloma therapy). Thirty-six (8.8%; 23M/13F) patients achieved a PFS of at least 7 years (long PFS group) after frontline treatment. The median PFS of these 36 patients is 10 years, while the other patients had a median PFS of 22 months. Long PFS patients were younger (median age 56 vs 68 years; p<0.001), had bigger body surface area (median: 1.85 m2 vs. 1.76 m2; p=0.013) and lower ECOG performance status (score 0-1: 71% vs 52%; p=0.014) compared to all others. Long PFS patients had higher hemoglobin (11.4 g/dl vs 10.2 g/dl; p=0.001), higher platelet count (278 vs 224 x109/l; p<0.001) and higher creatinine clearance (CrCl, based on the MDRD formula: 88 vs 67 ml/min; p<0.001; no patient in the long PFS group presented with CrCl <45 ml/min at diagnosis). There was no difference between the two groups regarding percentage of patients with high LDH, presence of osteolysis, type of myeloma (IgG vs IgA vs others), levels of serum and/or urine M-protein, and percentage of plasma cell infiltration in the bone marrow. However, more patients in the long PFS group had ISS-1 or ISS-2 disease (86% vs 61%; p=0.002) and normal pattern of marrow infiltration in the MRI of the spine and pelvis (24% vs 15%; p=0.035). Regarding chromosome abnormalities at diagnosis, no patient in the long PFS group had high-risk cytogenetics (defined as presence of del17p, t(4;14) or t(14;16) vs 32% in all other patients. All patients received either conventional chemotherapy (CC) or first-generation novel anti-myeloma agent (bortezomib (B), thalidomide (T) or lenalidomide (R)-based regimens as frontline therapy. There was no difference between the two groups regarding CC versus novel agent-based induction treatment. Out of 36 long-term PFS patients, 11 (30%) received CC, 8 (22%) B-based, 8 (22%) RD, 6 (17%) T-based, and 3 (8%) VTD; 10 (28%) patients received first-line therapy participating in a clinical trial. Long PFS patients had received more often autologous stem cell transplantation (ASCT, 61% vs 23%; p=0.001) as part of first line therapy; therefore, more long PFS patients had also received consolidation and/or maintenance (50% vs 15%; p=0.001). Higher proportion of patients achieved at least VGPR (74% vs 41%) or at least CR (32% vs 18%) in the long PFS group. We performed next generation flow cytometry in 23 patients of the long PFS group to evaluate minimal residual disease (MRD) and 14 (61%) of them were MRD (-) at the level of the 10-6. The probability of achieving long PFS (≥7 years) for patients who managed to be progression-free at 2, 3 and 4 years was 11.6%, 13.2% and 15.3%, respectively. In the multivariate analysis, only younger age was associated with probability for long PFS (p<0.001). The median OS of the whole group of patients was 5 years; in the long-PFS group median OS has not been reached yet while in all other patients the median OS was 4.3 years. In conclusion, our study in an unselected group of patients, the majority of whom did not participate in clinical trials, showed that 9% of patients with newly diagnosed myeloma experience prolonged PFS of more than 7 years (median: 10 years) even in the era of CC or first-generation novel agents. These patients have low risk disease, mainly of ISS-1 or -2, no high-risk cytogenetics, no or mild renal impairment, and achieve deep responses after ASCT. These patients may be considered as "functionally" cured. The incorporation of novel treatment approaches may lead to a significant improvement in the probability of achievement of this "functionally" cured status. Disclosures Terpos: Novartis: Consultancy; BMS: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding. Kastritis:Prothena: 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; Takeda: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria.

scholarly journals Patients with Familial Thrombophilia of Unknown Origin Show Low APC Response to In Vivo Thrombin Formation in Stimulated Hemostasis Activity Pattern Evaluation (SHAPE)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3647-3647
Author(s):  
Heiko Rühl ◽  
Sara Reda ◽  
Franziska Isabelle Winterhagen ◽  
Christina Berens ◽  
Jens Müller ◽  
...  
Keyword(s):  
Risk Factor ◽  
Board Of Directors ◽  
Research Funding ◽  
Unknown Origin ◽  
Control Group ◽  
Advisory Committees ◽  
Mutation Carriers ◽  
D Dimer ◽  
Thrombin Formation

Background: In a large proportion of patients with unprovoked venous thromboembolism (VTE), no risk factors can be identified. Recently, we have shown that an increased activated protein C (APC) response to in vivo thrombin formation reduces the thrombotic risk of factor V Leiden (FVL) carriers but not of prothrombin G20210A mutation (PTM) carriers. In vivo thrombin formation was triggered by low-dose administration of recombinant activated factor VII (rFVIIa) followed by hemostasis biomarker monitoring. Aim of the present study was to extend this SHAPE approach to patients with thrombophilia of unknown origin. Methods: The study population consisted of 21 subjects with a positive self-history of unprovoked VTE (VTE+) as well as a positive family history, in whom no established thrombophilic risk factor was detectable (thrombophilia of unknown origin, TUO). A second cohort included 27 VTE+ patients tested positive for FVL (n=14) or PTM (n=13). None of the subjects was under anticoagulant treatment at the time of analysis. The control group consisted of 18 healthy volunteers. Blood samples were collected immediately before and during a period of 8 hours following injection of 15 µg/kg rFVIIa. Plasma levels of free thrombin and APC were quantified using oligonucleotide-based enzyme capture assays (OECAs). Prothrombin activation fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), and D-dimer were measured additionally. Results: Injections of rFVIIa were well-tolerated by all subjects and median D-dimer levels remained within the reference range in all three cohorts. Plasma levels of F1+2 increased after rFVIIa injection, showing no significant differences between the groups. A comparable increase of TAT was observed in both TUO patients and VTE+ mutation carriers, from a median of 21.3 to 51.1 pmol/L (P=.022), and from 21.3 to 43.9 pmol/L, respectively (Figure 1A). Median levels of TAT in the controls and median levels of free thrombin in all cohorts remained below their respective quantifiable limits after rFVIIa injection. APC increased from 0.80 to 3.84 pmol/L (P=.001) in TUO patients, from 1.14 to 5.82 pmol/L (P&lt;10-4) in VTE+ mutation carriers, and from 0.87 to 3.39 pmol/L (P=.001) in the control group. The APC increase was significantly smaller in the TUO cohort than in the VTE+ mutation carriers (P=.019) (Figure 1B). Conclusion: A low APC response to an increased in vivo thrombin formation is a frequent finding among patients with thrombophilia of unknown origin. This finding is in line with previous data suggesting that higher APC levels protect FVL carriers from thrombosis development. The results of the present study further suggest that a low APC response might be an independent risk factor of VTE. Further studies are warranted to identify the factors that modulate the APC response. Disclosures Rühl: Sanofi Genzyme: Honoraria; SOBI: Honoraria; Shire: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria; Grifols: Honoraria. Reda:Shire: Honoraria; Grifols: Honoraria. Winterhagen:SOBI: Honoraria. Berens:Pfizer: Honoraria; Shire: Honoraria; Biotest: Honoraria; CSL Behring: Honoraria; NovoNordisk: Honoraria; Baxter: Honoraria. Müller:Roche: Membership on an entity's Board of Directors or advisory committees; Siemens: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees. Oldenburg:Grifols: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Swedish Orphan Biovitrum: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Biotest: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Takeda (Shire): Consultancy, Research Funding, Speakers Bureau.

scholarly journals Progression-Free Survival Subset Analysis - Denosumab Vs Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Double-Dummy, Randomized Controlled Phase 3 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1969-1969 ◽  
Author(s):  
Evangelos Terpos ◽  
Wolfgang Willenbacher ◽  
Kazuyuki Shimizu ◽  
Ramon García-Sanz ◽  
Anthony Glennane ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Board Of Directors ◽  
Research Funding ◽  
Steering Committee ◽  
First Line ◽  
Primary Analysis ◽  
Advisory Committees ◽  
First Line Therapy ◽  
Travel Grant ◽  
To Receive

Abstract Introduction: The full primary analysis of the international, double-blind, double-dummy, randomized controlled phase 3 study (20090482) that assessed the efficacy and safety of denosumab vs zoledronic acid for preventing skeletal-related events (SREs) in newly diagnosed patients with multiple myeloma (NDMM) met the primary noninferiority endpoint of time to first on-study SRE (Raje N, et al. Lancet Oncol. 2018). Overall survival, a secondary endpoint, was similar in both arms; however, this result was based on a limited number of events having occurred (denosumab 14.1% vs zoledronic acid 15.0%), which might have affected the ability to detect a difference and also may have been further diluted by multiple subsequent lines of therapy. In addition, results from an exploratory endpoint, progression-free survival (PFS), demonstrated a clinically meaningful 10.7 months median PFS benefit (hazard ratio [HR], 0.82; 95% CI, 0.68-0.99; descriptive P=0.036; Table 1) of denosumab versus zoledronic acid on top of standard of care first-line anti-myeloma treatment. This result provided suggestive clinical evidence of a potential anti-myeloma effect based on RANKL inhibition. Here we present further analysis of PFS according to prespecified subgroups of patients from the 20090482 study. Methods: Adult NDMM patients with ≥1 documented lytic bone lesion were included in this study. Patients received subcutaneous denosumab (120 mg) plus intravenous placebo or intravenous zoledronic acid (4 mg) plus subcutaneous placebo every 4 weeks. Both groups also received investigators' choice of first-line anti-myeloma therapy. The exploratory endpoint PFS (time from randomization to date of first overall disease progression or death due to any cause, investigator identified) was estimated using the Kaplan-Meier method and analyzed using a Cox proportional hazards model stratified by randomization stratification factors and adjusted for baseline covariates. PFS subgroup analyses were conducted according to the novel first-line therapy use (proteasome inhibitor [PI] use, immunomodulatory drug [IMiD] use, PI and IMiD use) and the intent to receive an autologous stem cell transplant (ASCT; yes, no). Results: Overall, 1718 patients (denosumab, n=859; zoledronic acid, n=859) were included in the primary analysis. By the time of the primary analysis cut-off, 219 patients (25.5%) in the denosumab group and 260 patients (30.3%) in the zoledronic acid group had a PFS event. The percentages of patients receiving novel first-line therapy were balanced between the two groups (see Table 1). For patients who had received first-line PI-based therapy, PFS favored denosumab vs zoledronic acid (median, 40.0 vs 35.4 months; HR, 0.74; 95% CI, 0.58-0.95; descriptive P=0.019; Table 1). For patients who had received first-line IMiD only-based therapy, median PFS was not reached with denosumab therapy and was 34.3 months with zoledronic acid therapy (HR, 0.85; 95% CI, 0.53-1.35; descriptive P=0.49). Median PFS was also not reached for either denosumab or zoledronic acid for patients who had received first-line PI plus IMiD therapy (HR, 0.95; 95% CI, 0.62-1.46; descriptive P=0.82). For patients with the intent at baseline to receive an ASCT (54% in each treatment group; Table 1), PFS favored denosumab vs zoledronic acid (median, 46.1 vs 35.7 months; HR, 0.65; 95% CI, 0.49-0.85; descriptive P=0.002). Conclusion: Overall results from this subanalysis indicated PFS impact and benefit of denosumab on top of anti-myeloma therapy, independent from first-line novel therapy which was balanced among treatment arms, mainly in the subgroup of patients receiving PI only-based first-line therapy. In addition, benefit was observed in patients with the intent to receive ASCT, described with an impressive HR of 0.65. Disclosures Terpos: Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; BMS: Consultancy; Novartis: Consultancy. Willenbacher:Amgen: Honoraria, Other: Steering board, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Roche: Honoraria, Research Funding; BMS: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Merck: Honoraria. Shimizu:Daiichi-Sankyo, Co., Ltd: Consultancy; Fujimoto Pharmacuetical Corp: Consultancy; Amgen Inc.: Other: Non-remunerative Position of Influence, Denosumab 20090482 Global Steering Committee Member. García-Sanz:Hospira: Research Funding; Pharmacyclics: Research Funding; Spanish Government: Research Funding; Gilead: Research Funding; Amgen Inc.: Research Funding; Incyte: Consultancy; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Glennane:Amgen: Employment, Equity Ownership. Guan:Amgen: Employment, Equity Ownership. Niepel:Amgen Inc.: Employment, Equity Ownership. Raje:BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy; AstraZeneca: Research Funding; Research to Practice: Honoraria; Medscape: Honoraria; Amgen Inc.: Consultancy.

scholarly journals Real-World Data on Incidence, Clinical Characteristics and Outcome of Patients with Macrofocal Multiple Myeloma (MFMM) in the Era of Novel Therapies: A Study of the Greco-Israeli Collaborative Myeloma Working Group

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3295-3295 ◽  
Author(s):  
Eirini Katodritou ◽  
Efstathios Kastritis ◽  
Moshe E. Gatt ◽  
Yael C Cohen ◽  
Irit Avivi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Steering Committee ◽  
Novel Therapies ◽  
Advisory Committees ◽  
Lytic Lesions ◽  
Travel Grant

Abstract Macrofocal Multiple Myeloma (MFMM) has been described as a distinct entity of Multiple Myeloma (MM) characterized by young age, lytic lesions and limited bone marrow infiltration by clonal plasma cells (BMPCs), in the absence of other features of symptomatic MM (i.e. anemia, renal insufficiency and hypercalcemia). Few case studies have indicated a possible favorable prognosis of MFMM patients compared to patients with typical symptomatic MM. Our aim was to investigate the incidence, characteristics and outcome of patients with MFMM, under the light of modern therapeutic approach of MM. MFMM definition required: clonal BMPCs <20%, multiple lytic lesions, absence of anemia, renal insufficiency and hypercalcemia and among 4650 MM patients (3%) registered in the MM databases of Greek and Israeli centers during 2001-2017, we identified 140 patients with MFMM (M/F: 93/47, median age: 61, range: 26-89, IgG: 86, IgA: 12, light chain: 21, IgD: 4, non-secretory: 16, IgM: 1). Most of patients with MFMM (60%) were <65 years; 68% had performance status 0-2 according to Eastern Cooperative group (ECOG) scale; 70% had advanced bone disease (>3 lytic lesions). In 20/140 (14%) patients bone plasmacytomas preceded MM diagnosis. In 95/140 (68%) patients bone, soft tissue or mixed plasmacytomas in multiple locations, were present at diagnosis or during MFMM course and this was significantly more frequent compared with standard MM. Median BMPCs infiltration was 14% (range 0-19%); immunoparesis was less common in MFMM (55% vs. 90% in standard MM). Elevated lactate dehydrogenase (LDH) and β2 microglobulin (β2Μ) ≥ 3.5mg/L were found in 9% and 20% of patients, respectively. Cytogenetics by fluorescence in situ hybridization (FISH) were available in 60% of patients and high-risk features were found in 11%; overall, adverse prognostic parameters (i.e. high LDH, advanced age, high β2Μ, high risk cytogenetics) were less common in patients with MFMM compared with others (p<0.05). According to the International staging system (ISS) patients were stratified as follows: ISS1:71%, ISS2: 25% and ISS3: 4%. Per Revised ISS the distribution was R-ISS1: 54%, RISS2: 46%, no R-ISS3). Induction therapy included novel agents in 90% of patients (bortezomib-based: 61%, thalidomide-based: 14%, bortezomib-lenalidomide-dexamethasone: 4%, lenalidomide-based: 11%); 47% underwent autologous transplantation (ASCT) upfront and 13% at 1st relapse. An objective response (ORR) was achieved in 90%: 70% had at least very good partial response (vgPR), 21% partial response, 6% stable disease and 3% had progressive disease; ORR and achievement of ≥vgPR were significantly higher compared with typical MM (p<0.05). After a median follow up of 52 months (95% CI: 40-64), 33 patients have died (MM progression: 19, lung infection: 8, other causes: 6). Early deaths (<12 months) observed in 5% of patients; 53 patients received 2nd line therapy (proteasome inhibitor-based or lenalidomide-dexamethasone: 79%) and 5 patients received only radiotherapy for plasmacytomas; early relapse (<12 months) was less common in MFMM compared with standard MM (p<0.05). Progression-free survival (PFS) and overall survival (OS) were 46 months (95% CI: 40-52) and 129 months (95% CI: 79-178) respectively, both significantly longer compared with typical MM treated during the same period (p<0.001). In the univariate analysis age <65, early stage disease (ISS1, R-ISS1), 1st line treatment with proteasome inhibitor (PI)-based regimens, ASCT, and standard risk cytogenetics predicted positively for OS in MFMM patients; treatment with PI-based therapies was the only independent predictor for OS in the multivariate analysis (HR: 3.9; p<0.001). In conclusion, MFMM is a rare entity of MM characterized by limited bone marrow infiltration, extended bone lesions and frequent presence of plasmacytomas, prior or during the diagnosis or the course of the disease. MFMM patients are younger have less often adverse prognostic features compared with standard MM and achieve high quality responses when treated with novel therapies. Treatment with PI-based regimens was the strongest predictor for OS in MFMM indicating that it is probably the best therapeutic option for these patients. Disclosures Kastritis: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cohen:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Aviv:ABBVIE: Consultancy; ROCHE: Research Funding. Terpos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; BMS: Consultancy; Novartis: Consultancy. Dimopoulos:Amgen: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

scholarly journals Carfilzomib-Associated Renal Toxicity Is Common and Unpredictable: An Analysis of 114 Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1966-1966 ◽  
Author(s):  
Efstathios Kastritis ◽  
Maria Roussou ◽  
Charikleia Gakiopoulou ◽  
Erasmia Psimenou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Renal Toxicity ◽  
Steering Committee ◽  
Light Chains ◽  
Advisory Committees ◽  
Renal Complications ◽  
History Of ◽  
Travel Grant

Abstract Carfilzomib (CFZ) is a non-reversible proteasome inhibitor approved for the treatment of patients with relapsed or refractory myeloma (RRMM), either in combination with dexamethasone (Kd) or with lenalidomide and dexamethasone (KRd). CFZ has been associated with a risk of cardiovascular toxicity but although a signal of clinically significant renal complications has also been identified, renal toxicity is less extensively investigated. Thus, we analyzed the data of 114 consecutive patients who received CFZ for RRMM in our center (Department of Clinical Therapeutics, Athens, Greece) for renal outcomes and complications. Detailed baseline characteristics and medical history (demographics, history of renal and cardiovascular diseases, diabetes, medication use) and detailed data on myeloma status, proteinuria and urine electrophoresis, serum free light chains (sFLC), serum creatinine and cardiovascular complications were available in all patients for the duration of CFZ therapy. Median age was 70 years (range 36-86, 25% were ≥75) and 60.5% were men. Median number of prior therapies was 2 (range 1-7): 78% had prior bortezomib, 73% prior IMiDs, 27% prior anthracyclines and 46.5% prior ASCT. CFZ dose was 20/27 in 30%, 20/36 in 11% and 20/56 in 59%; 75% received Kd, 14% received KRd and 11% other CFZ-based combinations. Median follow up from start of CFZ is 27 months, median duration of CFZ therapy is 5.5 months (IQR 3.2 to 11.5) and 28 (24.5%) patients continue on CFZ therapy at the time of analysis. During CFZ therapy, 19 (17%) patients developed renal complications, not related to MM progression: 6 (5%) developed thrombotic microangiopathy (TMA), 7 (6%) developed albuminuria > 1gr/day (in all with very low amounts of light chains or with negative urine immunofixation) and 6 (5%) developed acute kidney injury/ acute renal failure (AKI/ARF) at least grade 3, which was not otherwise explained. Median time to development of renal complications was 62 days (~2 months) (IQR 35 to 272) and in 15/19 patients CFZ was discontinued due to renal complications. Median time from CFZ start to TMA was 3 months (0.3-19.5). At diagnosis of TMA, median platelet counts were 20x109/L (range 11-30), median hemoglobin 8 gr/dl, median LDH 449 IU/L (ULN<225, range 371-619) and median blood schistocytes were 2.5% (range 2%-6.5%). All received plasmapheresis: 5 recovered renal function and platelet counts while one died of sepsis. In 2 patients in whom ADAMTS13 was measured, no deficiency was found. No patient was re-exposed to CFZ after TMA. Median time to proteinuria >1 gr/d was 6 months (range 2-59 months), median proteinuria was 3.7 gr/d (range 1 - 4.5) and in all cases >90% of urine protein was albumin; all patients were in disease remission (VGPR or CR); median eGFR was 53 ml/min/1.73 m2 (range 41-92). Only one patient had proteinuria before CFZ which was mainly Bence Jones proteinuria. Following interruption of CFZ, proteinuria decreased in 2/7 patients and in one patient CFZ was resumed at a reduced dose. A renal biopsy was performed in 5/6 patients with albuminuria and one with AKI: none had immunoglobulin mediated pathology (cast nephropathy, MIDD or amyloidosis) or pathology related to the alternative complement activation pathway. The most constant finding (in all patients with albuminuria), was a pattern of focal segmental glomerulosclerosis (FSGS) of various subtypes. Coexistent with the previous lesions, a pattern of TMA with intraglomerular and/or arteriolar fibrin microthrombi and/or mucoid degeneration of arteriolar/arterial wall and/or reduplication of glomerular basement membranes with endothelial cells' swelling, was seen in 4 biopsies. We found no association between CFZ dose with renal complications or of baseline proteinuria (immunoglobulin or albumin), sFLC or myeloma type, age, prior history of cardiovascular disease or hypertension or baseline eGFR. Among 33 patients with baseline eGFR < 60 ml/min, 18 (54.5%) patients improved their eGFR to >60 ml/minafter CFZ therapy. We conclude that renal complications during CFZ therapy are common, occur mostly early and are essentially unpredictable. Albuminuria associated with FSGS and TMA developed in 6% and 5% of our patients respectively and warrant further investigation. A potential effect of CFZ on the renal endothelium could be implicated in the pathogenesis of these complications and may also share common pathophysiology with cardiovascular effects of CFZ. Figure. Figure. Disclosures Kastritis: Amgen: 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: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; BMS: Consultancy; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Novartis: Consultancy. Dimopoulos:Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria.

scholarly journals Carfilzomib Induces Acute Endothelial Dysfunction Which Correlates with the Occurrence of Cardiovascular Events

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3247-3247
Author(s):  
Efstathios Kastritis ◽  
Aggeliki Laina ◽  
Maria Gavriatopoulou ◽  
Georgios Georgiopoulos ◽  
Evangelos Eleutherakis-Papaiakovou ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Board Of Directors ◽  
Recovery Rate ◽  
Vascular Function ◽  
Research Funding ◽  
Steering Committee ◽  
Proteasome Activity ◽  
Advisory Committees ◽  
Travel Grant

Abstract Carfilzomib (CFZ) is a proteasome inhibitor associated with cardiovascular (CV) adverse events (AEs) mainly hypertension (HTN) and cardiac dysfunction. Endothelial dysfunction is a major mediating mechanism in cardiovascular diseases and endothelial function may be adversely affected by proteasome inhibition. However, CFZ effects on endothelial and vascular function and associations with inhibition of proteasome activity have not been explored in humans. We prospectively evaluated CFZ effects on endothelial function and underlying mechanisms as well as baseline vascular function and its response to treatment as potential predictors of CFZ-associated CV toxicity. In this prospective study (NCT03543579), 48 relapsed/refractory myeloma patients (median 1 (1-3) lines of therapy, median age: 67.5, 67% men) received Kd [CFZ 20/56 mg/m2 and dexamethasone] in routine practice. A detailed medical history and evaluation of risk factors for cardiotoxicity [age≥65 years, obesity, smoking, HTN, hypercholesterolemia, diabetes mellitus, previous anthracyclin use, chest or mediastinum radiotherapy and current myocardial disease] were recorded. Before CFZ start and at prespecified timepoints cardiac echo, hemodynamic parameters and vascular function that reflect pivotal mechanisms involved in development of HTN and CV events were non-invasively assessed [aortic blood pressure and arterial wave reflections, aortic stiffness and endothelial function using flow-mediated dilatation of the brachial artery (FMD)] along with 24h ambulatory blood pressure monitoring. Proteasome activity (PrA) was measured in peripheral blood mononuclear cells (PBMC) before and 2 hours post CFZ infusion on days 1 (FMDbaseD1 and FMDpostCFZD1) and 2 (FMDbaseD2 and FMDpostCFZD2) of cycle 1 and at prespecified time points concurrently with vascular function assessment. CV AEs were recorded and rated according to CTCAE v4.03. The prevalence of risk factors for cardiotoxicity was high (median 3 factors, IQR 2-4). After first CFZ dose, FMD decreased acutely at 2 hours (FMDbaseD1: 5.2%, IQR: 3.2-7.4 vs FMDpostCFZD1: 3.6%, IQR: 1.5-4.7, p=0.008), which partially recovered before and after second CFZ infusion (FMDbaseD2: 4.1% and FMDpostCFZD2: 4%, as compared to FMDbaseD1) (Figure1A). However, FMD decrease was more pronounced among patients who subsequently had lower recovery rate of PBMC PrA 24 hours after first CFZ administration (FMDbaseD1: 5.1%, vs FMDpostCFZD1: 3%, p=0.002) while FMD was not decreased significantly in those who had higher recovery rates of PrA (FMDbaseD1: 5.3%, vs FMDpost CFZD1: 4.5%, p=0.197, Figure 1B), suggesting that the ability to recover PrA is implicated in CFZ induced endothelial dysfunction. At the time of analysis, enrolment has completed; 35 patients are still receiving therapy, 13 have discontinued Kd and median follow up is 4.73 months. CV AEs were recorded in 17 (35.4%) patients [HTN(Gr3): 20.8%, Gr3 Left Ventricular dysfunction : 8.3%, Gr3 acute coronary syndrome: 4.2%, Gr3 pulmonary embolism: 2.1%] and generally occurred early (median time to CV event 2.9 months). Kd was discontinued in 2 patients (4.2%) due to cardiotoxicity and in 2 patients (4.2%) CFZ dose was reduced due to cardiotoxicity; no CFZ dose reduction or discontinuation was needed for HTN. Among clinical and hemodynamic parameters assessed at baseline, patients with higher aortic SBP (i.e at higher quartile) had a higher risk of HTN even after adjustment for age, gender and baseline HTN (HR=8, 95%CI 2.4-26, p=0.001 and HR=4.9, 95%CI 1.5-15, p=0.007 respectively). Lower PrA recovery rate was associated with increased risk of developing Gr3 HTN (log-rank test p=0.01). Higher post-CFZ reduction of FMD was associated with HTN in patients not receiving statins but not in those receiving statins (a drug class strongly affecting FMD), indicating that statin treatment may exert protective effects against CFZ-related CV toxicity. In conclusion, CFZ causes acute endothelial dysfunction; however, higher recovery of proteasome activity is associated with ameliorated depression of endothelial function. Given that poor proteasome recovery rate and acute deterioration of endothelial function are both associated with development of HTN, these findings may improve our understanding of CFZ-related CV toxicity and its prevention. The study is ongoing and more data will be presented at the meeting. Disclosures Kastritis: Takeda: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: 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. Terpos:Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; BMS: Consultancy; Novartis: Consultancy. Dimopoulos:Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

Selective Inhibition of HDAC6 with a New Prototype Inhibitor (ACY-1215) Overcomes Bortezomib Resistance In Multiple Myeloma (MM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2997-2997
Author(s):  
Loredana Santo ◽  
Teru Hideshima ◽  
Andrew L. Kung ◽  
Matthew Jarpe ◽  
Diana Cirstea ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Hdac Inhibitors ◽  
Group Versus ◽  
Control Group ◽  
Advisory Committees ◽  
Dose Dependent

Abstract Abstract 2997 HDAC enzymes, whose activity has been linked to the transcription of DNA in several cancers including multiple myeloma (MM), are being studied as novel therapeutic targets. Four classes of HDAC enzymes have been identified and several non-specific pan-HDAC and class I HDAC inhibitors have been evaluated in clinical studies. HDAC6, a class II HDAC, has recently been linked to the activity of aggresomes that degrade unfolded and misfolded ubiquitinated proteins. Importantly, targeting both proteasomal and aggresomal protein degradation systems with proteasome inhibitors and HDAC inhibitors respectively, induces accumulation of polyubiquitinated proteins, followed by activation of apoptotic cascades and synergistic cytotoxocity. Here we investigated the preclinical activity of an HDAC6 selective inhibitor ACY-1215 in MM, either alone or in combination with bortezomib. In vitro enzyme assays showed that ACY-1215 has potent inhibitory activity against HDAC6 (IC50 0.0054 μ M) compared to the other HDACs, including Class I HDACs. Maximal cytotoxicity of ACY-1215 against MM cell lines was observed at 48h, with IC50 values ranging from 2–8 μ M. ACY-1215 was also effective against patient MM cells, including bortezomib resistant MM cells, without significant cytotoxicity in normal peripheral blood mononuclear cells (PBMCs). Moreover, ACY-1215 in a dose-dependent manner inhibited DNA synthesis of MM cells at 48h triggered either by binding to bone marrow stromal cells (BMSCs) or by exogenous IL6 and IGF-1, confirming its ability to overcome the proliferative advantage conferred by BMSCs and cytokines. We next studied whether the highly selective HDAC6 inhibitor ACY-1215 could achieve the same efficacy as a pan-HDAC inhibitor such as SAHA, but with less toxicity. Compared to SAHA, ACY-1215 was not toxic to PHA stimulated PBMCs. Importantly, both ACY-1215 and SAHA induced dose-dependent acetylation of α-tubulin in MM.1S cells, but ACY-1215 induced less potent acetylation of lysine on histone H3 and histone H4 than SAHA, further confirming its specific inhibitory effect on HDAC6 activity. We next combined low doses of ACY-1215 to inhibit aggressomal with bortezomib to inhibit proteasomal protein degradation, and showed synergistic anti MM activity (Combination Index < 0.9), resulting in apoptosis via the activation of caspase-8,-9,-3 and poly (ADP) ribosome polymerase. Annexin V+PI+ staining after 24h treatment confirmed increased cells in early and late apoptosis after combined therapy (83.6%) compared to ACY-1215 1μ M (10.2%) or bortezomib 5 nM (36.6%) treatment alone. Since NF-kB pathway plays a crucial role in MM cell survival and bortezomib triggers NF-κB activity in some MM cell lines, we next investigated the effect of combined therapy on NF-κB activity. MM.1S cells were co-cultured with BMSCs and then treated with bortezomib 5nM, ACY-1215 1μ M, or the combination. Interestingly, bortezomib treatment significantly enhanced NF-κB activity in MM.1S cells co-cultured with BMSCs, whereas ACY-1215 treatment resulted in only a modest increase in NF-κB activity. Importantly, combined therapy was associated with partial abrogation of bortezomib-induced NF-κb activity. Ongoing studies are determining whether this effect on NF-κB activity contributes to the cytotoxic effect of ACY-1215/bortezomib combination therapy. Finally, we confirmed the synergistic anti-MM activity of ACY-1215 and bortezomib in vivo using two different xenograft mouse models: human MM injected subcutaneously (plasmacytoma model); and luciferase-expressing human MM injected intravenously (disseminated MM model). In the, plasmacytoma model, daily (5×/week) dosing of ACY-1215 (IP: 50 mg/kg) and bortezomib (IV: 0.5 mg/kg) given twice weekly significantly inhibited tumor growth (p<0.0001) and prolonged survival (34 days in the combined treatment group versus 22 days in the control group, p<0.0011). In the disseminated MM model, daily (5x/week) dosing of ACY-1215 (IP: 75 mg/kg) and bortezomib (IP: 1.5mg/kg) once weekly significantly inhibited tumor growth (p<0.0001) and prolonged survival (40 days in the combined treatment group versus 17 days in the control group, p<0.0001). Importantly, no significant adverse effects were noted in either in vivo model. These results therefore provide the preclinical rationale for clinical trials of ACY-1215 together with bortezomib in the treatment of MM. Disclosures: Jarpe: Acetylon: Employment. Anderson:MILLENNIUM: Consultancy; CELGENE: Consultancy; NOVARTIS: Consultancy; ONYX: Consultancy; MERCK: Consultancy; BMS: Consultancy; Acetylon: Membership on an entity's Board of Directors or advisory committees. Jones:Acetylon: Employment. Raje:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Astra Zeneca: Research Funding; Acetylon: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Consolidation with a Short Course of Daratumumab Improves Complete Response Rates in Patients with AL Amyloidosis or Lcdd

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3246-3246
Author(s):  
Efstathios Kastritis ◽  
Maria Gavriatopoulou ◽  
Fotiou Despina ◽  
Ioanna Dialoupi ◽  
Dimitrios C. Ziogas ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Steering Committee ◽  
High Dose ◽  
Al Amyloidosis ◽  
Primary Therapy ◽  
Advisory Committees ◽  
Hematologic Response ◽  
Short Course ◽  
Travel Grant

Abstract A deep hematologic response (i.e at least a very good partial hematologic response - hemVGPR or a complete hematologic response- hemCR) is associated with the highest probability of organ function and survival improvement in patients with AL amyloidosis. Bortezomib-based therapy is the mainstay of anti-clonal therapy for patients with AL amyloidosis and 70-80% of patients with previously untreated AL may achieve a hematologic response, however, hemVGPR or better is expected in less than 50%. Given that clones in AL are often small and indolent, further improvement of hematologic response may be achieved by consolidation strategies which may include high dose melphalan with autologous stem cell transplantation (HDM-ASCT); however, toxicity is significant and only a minority of patients is eligible for HDM-ASCT. New targets may provide new opportunities to eliminate the residual clonal plasma cells. Anti-CD38 targeting monoclonal antibody daratumumab has shown activity in myeloma and in AL amyloidosis with minimal toxicity. Specifically in AL, recent data indicate that even a short course of daratumumab was able to induce hematologic responses in several patients with relapsed or refractory AL. Thus, daratumumab may be a unique treatment to improve the outcomes of patients with AL amyloidosis. The endpoint was improvement of response 1 month In order to evaluate the feasibility and activity of a short course of daratumumab as a consolidation strategy, we administered 4 weekly infusions of daratumumab in consecutively treated patients at the Department of Clinical Therapeutics, Athens, Greece with AL or LCDD which had achieved either PR or VGPR after completing their primary therapy. Patients that had not achieved a response to primary therapy were excluded and received full dose salvage therapy. All patients received consolidation with 4 weekly infusions of daratumumab 16 mg/kg with dexamethasone 20 mg. Pre-emptive therapy for IRR was given starting two days before the first infusion of daratumumab that included low dose steroids (equivalent of 16 mg of methylprednisolone), H1 & H2 inhibitors and montelukast. So far 17 patients (15 AL and 2 LCDD) have received daratumumab consolidation. Among patients with AL amyloidosis, median age is 67 (range and 73% were males, kidneys and heart were involved in 80% and in 73% respectively, baseline Mayo stage was 20%, 67% and 13% for stage 1,2 & 3 respectively. Baseline immunofixation in serum or urine was positive in all patients (13/15 of AL patients were lambda). Median time from start of first line therapy to daratumumab consolidation was 9 months and all patients had completed the planned therapy of bortezomib-based treatment. At the time of initiation of daratumumab, 16 patients were in VGPR and one in PR and the median level of dFLC was 12 mg/L, all had positive serum or urine immunofixation and in all patients next generation flow (NGF) according to Euroflow protocol was positive for the presence of MRD. Except for one patient, all the others received the planned 4 daratumumab infusion; the single patient that did not receive the planned therapy did so because of a severe infection that occurred 1 day after the first daratumumab infusion and was not considered daratumumab related. IRRs occurred in 3 patients and were mild (grade 1 in 2 and grade 2 in one patient); no IRRs occurred after the first infusion. One month after completion of consolidation with daratumumab, median dFLC dropped to 5 mg/L and 41% of the patients improved their response: 37.5% from VGPR to hemCR and the one patients with PR to VGPR. Notably, small IgGkappa bands were found in 4 patients at one month post daratumumab. Among those that achieved a CR after daratumumab, 50% became MRD negative by NGF; however, further follow up is needed for the evaluation of organ responses after consolidation. We conclude that consolidation with a short course of daratumumab can improve the depth of response in patients with AL or LCDD that have not achieved a hemCR after primary therapy. In addition, some patients may even achieve MRD negative disease status. We will further explore this strategy in a formal clinical trial with a longer duration of daratumumab therapy so that CR and MRD negative rates may improve further. Disclosures Kastritis: Prothena: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Terpos:BMS: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of steering committee, Research Funding; Genesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: member of DMC, Research Funding; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, steering committee member, Research Funding; Novartis: Consultancy. Dimopoulos:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

scholarly journals Carfilzomib-Induced Cardiotoxicity in an In Vivo Model of Aging

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-18
Author(s):  
Panagiotis Efentakis ◽  
Garyfallia Psarrakou ◽  
Panagiota-Efstathia Nikolaou ◽  
Michael Chatzistefanou ◽  
Eleni-Dimitra Papanagnou ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
The Elderly ◽  
In Vivo Model ◽  
Control Group ◽  
Myocardial Tissue ◽  
Advisory Committees ◽  
Aged Mice ◽  
Young Mice

Introduction: Carfilzomib (Cfz) is an approved irreversible proteasome inhibitor for the treatment of patients with relapsed/refractory multiple myeloma (R/R MM). Despite remarkable efficacy in R/R MM, Cfz clinical use is hampered by the incidence of cardiotoxicity. Age is recognized as an independent factor for the manifestation of cardiac failure and cardiovascular events. We have previously established a translational in vivo model of Cfz-induced cardiotoxicity, in which metformin (Met) had a potent prophylactic therapy, as it restored AMP-activated kinase α (AMPKα)-dependent autophagy in the myocardium of young mice, which had been inhibited by carfilzomib treatment (Efentakis P et al. Blood. 2019;133(7):710-723). Taking into consideration that MM is primarily a disease of the elderly, we sought to investigate whether our previous findings in young mice could be recapitulated in an aging in vivo model. Methods: Ten young C57Bl/6 mice (12-14 weeks of age) and thirty aged C57Bl/6 mice (15-17 months of age) were randomly assigned as follows: (i) Control group [Normal Saline (N/S) 0.9%, n=6]; (ii) Cfz group (8 mg/kg, n=6); (iii) Met group (140mg/kg, n=6); (iv) Cfz+Met group (8 mg/kg and 140 mg/kg respectively, n=6). N/S and Cfz were administered intraperitoneally on alternate days, while Met was administered per os daily for 7 days. At baseline and at the end of the experiments, mice were anesthetized with isoflurane (2% in 100% O2) and underwent echocardiography in order to investigate cardiac contractility markers (fractional shortening, FS%) and carotid plasticity markers (pulsatility index, PI% and resistance index, RI%). Subsequently mice were sacrificed for blood and myocardial tissue collection. Peripheral blood mononuclear cell (PBMCs), isolated from the whole blood, as well as myocardial tissue underwent proteasome activity assessment. Snap-frozen myocardial tissue underwent molecular immunoblotting analysis for the investigation of the molecular signaling. Results: Aged mice did not show any decreased proteasomal activity neither in the PBMCs or in the myocardium versus young C57Bl/6 mice. Cfz decreased proteasomal activity both in the PBMCs and the myocardium independently of Met administration. Aged mice presented a significant reduction of the FS% compared to the young mice at baseline, which represents an already established cardiac dysfunction in the elderly mice (mean FS%±SD: 37.40±1.6 vs. 45.62±0.8, respectively, p&lt;0.005). In compliance with our previous findings in young C57Bl/6 mice, Cfz deteriorated the already present cardiac dysfunction in aged mice versus controls (mean FS%±SD: 28.2±1.8 vs. 37.8±1.8, respectively, p&lt;0.05). Cfz+Met co-administration in elderly mice showed a marginal increase in terms of FS% compared to Cfz only treated mice (mean FS%±SD: 32.60±2.1 vs. 28.2±1.8, respectively), while FS% in the Cfz+Met group continued to be lower compared to control group (32.60±2.1 vs. 37.8±1.8). Assessment of the carotid stiffness revealed that Cfz sub-acute treatment led to a decrease in PI% compared to controls (p&lt;0.05), while no changes in RI% were observed among groups, indicating a Cfz-induced vascular hypo-contraction in the elderly mice. Molecular analysis of the myocardial tissues showed that Cfz led to a decreased AMPKα and Protein Kinase B (Akt) phosphorylation, while Met restored AMPKα phosphorylation and increased endothelial nitric oxide synthase (eNOS) and Akt expression in the Cfz+Met co-administration group. Conclusion: Cfz induced cardiotoxicity in this aged murine model, in accordance with our previous findings in the young mice. Additionally, sub-acute Cfz treatment leads to a decrease in pulsatility capacity of the vessels, possible leading to vascular hypo-contraction in vivo. Co-administration with metformin exerts cardioprotection, even in the elderly mice, in an AMPKα-dependent manner. The latter is of great clinical significance as it further supports the translational value of metformin as a potent prophylactic therapy against Cfz-induced cardiotoxicity. Disclosures Efentakis: Amgen: Research Funding. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Andreadou:Amgen: Research Funding. Terpos:Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding.

scholarly journals Characteristics and Prognosis of AML Patients with or without a History of Clonal Hematopoiesis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 224-224
Author(s):  
Felicitas Thol ◽  
Larissa Köhler ◽  
Sabrina Klesse ◽  
Razif Gabdoulline ◽  
Arnold Kloos ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Intensive Therapy ◽  
Control Group ◽  
Advisory Committees ◽  
Clonal Hematopoiesis ◽  
Travel Grant

Abstract Background: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the detection of mutations in genes like DNA methyltransferase 3A (DNMT3A) and has recently been described to occur in healthy people and to predispose them to myeloid malignancies. DNMT3A is frequently mutated in acute myeloid leukemia (AML) and mutations have been detected in CD3 positive T-cells of some AML patients. In these patients DNMT3A mutations are early events that are likely to arise from CHIP. It is unknown how a history (hx) of CHIP influences the characteristics of AML patients and their response to therapy. We studied this question on the basis of a large cohort of DNMT3A mutated AML patients. Patients and Methods: 171 DNMT3A mutated AML patients (aged 18-87 years) were included in our study. 127 patients were treated intensively in trials of the AMLSHG and AMLSG. 34 patients received non-intensive therapy and for 10 patients the therapy is unknown. 148 patients carried a mutation at arginine R882. At the time of diagnosis and relapse samples were further sequenced for 54 genes involved in leukemia with next generation sequencing (NGS) on the Illumina platform. Library preparation of diagnostic samples was performed with the TruSight Myeloid sequencing panel (Illumina). T-cells (CD3+ CD11b- CD14- CD33-) were purified by flow cytometry from AML samples at the time of diagnosis. DNMT3A mutational analysis of T-cell samples and of mononuclear cells during remission or at relapse was performed also with ultra-deep sequencing using customized DNMT3A NGS primers. Presence of a DNMT3A mutation in sorted T cell populations was used as an indicator of a hx of CHIP. Results: A total of 40 patients (23%) were found to have the DNMT3A mutation in mononuclear cells and T-cells (hx of CHIP), while 131 patients (77%) had a DNMT3A mutation in mononuclear cells, but not T-cells (control cohort). Comparing these two patient cohorts revealed that significantly more patients in the hx of CHIP cohort had secondary AML (p=0.009), were older (p=0.005) and less likely to receive intensive treatment (p=0.047) while other clinical parameters did not significantly differ. Analysing the mutational profile of 54 genes revealed that the number of mutations per patient between these 2 groups was similar (median 5 vs 4 mutations, p=0.39). Patients with a hx of CHIP were significantly more likely to harbour mutations in TET2 (p=0.006), RUNX1 (p=0.004), SF3B1 (p=0.049), U2AF1 (p=0.015) but less likely to be NPM1 mutated (p=0.005). There was no significant difference in the allelic burden of DNMT3A in the CHIP hx (mean 43.6) vs control group (mean 44.5). The mean variant allele frequencies of DNMT3A, RUNX1 and NPM1 were highest (44, 45 and 43 respectively) as compared to other mutated genes like IDH1, IDH2 and FLT3 (32, 37 and 34). In relapse samples (n=11), the identical DNMT3A mutation could always be identified. However, patients with a hx of CHIP (n=2) had comparable allelic frequencies compared to diagnosis of mutated DNMT3A (<10% difference), but not NPM1 (> 10% difference), while 7 out of 9 patients in the control group had a change in the allelic frequency at the time of relapse (mostly reduction). In all remission samples DNMT3A mutations could be identified with ultra-deep NGS but with variable allelic frequencies (0.13-50.01% in the control group, 0.25-70.14% in the hx of CHIP group). In the cohort of patients with intensive therapy there was no difference in CR rates between hx of CHIP and control groups (82 vs 90%, p=0.31). Overall survival (OS) was not influenced by a hx of CHIP (whole cohort: HR 1.09; 95%CI 0.67-1.79; P=.73; intensively treated cohort: HR 0.72; 95%CI 0.34-1.51; P=.38). Relapse-free survival (RFS) was also not different in the hx of CHIP vs the control group (HR 1.06; 95%CI 0.58-1.93; P=.85; intensively treated cohort only HR 0.91; 95%CI 0.46-1.78; P=.78). However, when looking at the influence of allogeneic stem cell transplantations (HSCT) on outcome in intensively treated patients, patients with a hx of CHIP showed abenefit from HSCT (HR 0.082; 95%CI 0.009-0.75; P= 0.027 Figure 1A) as compared to the control group (HR 0.68; 95%CI 0.39-1.21; P= 0.19, Figure 1B). Conclusion: AML patients with a hx of CHIP, as defined by mutated DNMT3A in T-cells, show a distinct clinical and molecular profile and may benefit from HSCT. Figure 1A. Figure 1A. Figure 1B. Figure 1B. Disclosures Bug: TEVA Oncology, Astellas: Other: Travel Grant; NordMedica, Boehringer Ingelheim, Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene, Novartis: Research Funding. Fiedler:Pfizer, Amgen, Kolltan: Research Funding; Teva, Amgen, Astellas: Other: Travel Grant; Karyopharm: Research Funding. Schlenk:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding.

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