Novel Myeloma-Specific Multiple Peptides Able to Generate Cytotoxic T Lymphocytes: Potential Therapeutic Application in Multiple Myeloma and Other Plasma Cell Disorders,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3990-3990
Author(s):  
Jooeun Bae ◽  
Ruben Carrasco ◽  
Ann-Hwee Lee ◽  
Rao Prabhala ◽  
Yu-Tzu Tai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Lymphocytes ◽  
Board Of Directors ◽  
Cytotoxic T Lymphocytes ◽  
Plasma Cell ◽  
Peptide Vaccine ◽  
Effector Memory ◽  
Therapeutic Application ◽  
Advisory Committees ◽  
Plasma Cell Disorders

Abstract Abstract 3990 Although single antigen targeted vaccination has been evaluated in multiple myeloma (MM), its efficacy has been limited. The major challenges in developing a MM-specific immunotherapy include heterogeneity of tumor associated antigens (TAA) expression, frequent mutations of specific TAA and variability of the human T-cell repertoire. We hypothesize that peptide vaccine efficacy may be enhanced by stimulating immune cells with multiple epitopes derived from different TAA. The goal of our study was to examine the effectiveness of a combination of four immunogenic HLA-A2-specific peptides derived from multiple MM-associated antigens to induce myeloma-specific cytotoxic T lymphocytes (CTL) ex vivo. The specific target antigens, XBP1, CD138 and CS1 play a significant role in MM pathogenesis. We have identified immunogenic HLA-A2-specific epitopes: heteroclitic XBP1 US184–192 (YISPWILAV), heteroclitic XBP1 SP367–375 (YLFPQLISV), native CD138260–268(GLVGLIFAV) and native CS1239–247 (SLFVLGLFL). In this study, first we evaluated each of the four epitopes in parallel and confirmed strong HLA-A2 binding affinity of the four individual peptides and demonstrated comparable phenotypes and overall functional activity of CTL generated with each peptide against HLA-A2+ MM cells. We next evaluated the multipeptide-specific CTL (MP-CTL) generated using a combination of all four peptides. The MP-CTL had an increased percentage of total CD8+ T cells, CCR7−CD45RO+(effector memory) and CD69+ (activated) cells. In addition, the MP-CTL demonstrated polyfunctional immune activities [higher IFN-g production, cell proliferation and cytotoxicity] against HLA-A2+ primary MM cells and MM cell lines, but not to HLA-A2− MM cells or HLA-A2+ breast cancer cells. Importantly, the MP-CTL demonstrated peptide-specific responses to all relevant epitopes including heteroclitic XBP1 US184–192 (YISPWILAV), heteroclitic XBP1 SP367–375 (YLFPQLISV), native CD138260–268(GLVGLIFAV) and native CS1239–247 (SLFVLGLFL), but not to an irrelevant CMV pp65 (NLVPMVATV) peptide in a various functional assays evaluated cytokine production and cytotoxicity. Moreover, the MP-CTL demonstrated similar or greater response against MM, compared to CTL generated using the individual peptides. Thus, targeting MM-associated antigens using a cocktail of specific peptides may provide an effective therapeutic application in patients with MM and related plasma cell disorders. Disclosures: Anderson: Celgene: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Munshi:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Tracking Daratumumab Clearance Using Mass Spectrometric Approaches: Implications on M Protein Monitoring and Reusing Daratumumab

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2707-2707
Author(s):  
Nadine Abdallah ◽  
David L Murray ◽  
Angela Dispenzieri ◽  
Prashant Kapoor ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Research Funding ◽  
Univariate Analysis ◽  
M Protein ◽  
Urine Protein ◽  
Advisory Committees ◽  
Plasma Cell Disorders

Abstract Background: MASS-FIX is a screening method for serum and urine monoclonal proteins in multiple myeloma and related plasma cell disorders, which uses immunoglobulin enrichment coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). In addition to superior sensitivity over conventional gel-based techniques, MASS-FIX can distinguish therapeutic monoclonal antibodies (MoAb) from patient's M protein. As the utilization of therapeutic MoAbs increases, it is essential to understand the persistence pattern of these therapeutic antibodies in the serum. We designed this study to evaluate the duration of daratumumab detection by MASS-FIX in the serum of treated patients. Methods: We used a prospectively maintained database at Mayo clinic to identify patients with multiple myeloma and related plasma cell disorders who were treated with a daratumumab-containing regimen anytime during their disease course and had serial MASS-FIX data available after discontinuation of daratumumab. A univariate analysis was performed to assess for factors that may impact the clearance of daratumumab. Results: We included 125 patients with plasma cell disorders who received daratumumab as first or subsequent line of treatment between March 15 th, 2016, and March 4 th, 2020. The median age was 60.2 years and 57% were male. The most common diagnoses were multiple myeloma (70%) and light chain amyloidosis (18%). Daratumumab-based treatments were initiated after a median of 28.8 (IQR: 6.4-76.3) months from initial diagnosis. The most common regimen used was daratumumab, bortezomib and dexamethasone (23%); 26% underwent transplant after daratumumab-based induction. The median duration of treatment with a daratumumab-based regimen was 208 (IQR: 99-479) days. The median follow-up from the time of daratumumab discontinuation was 457 (95% CI: 346-NR) days. By last follow up, daratumumab was not detected by MASS-FIX in 93 (74%) patients but remained detectable in 32 (26%) patients. The median time from daratumumab discontinuation to disappearance of daratumumab by MASS-FIX was 160 (IQR: 107-233) days. On univariate analysis, the presence of ≥0.5 grams of urine protein was associated with earlier disappearance of daratumumab on MASS-FIX [risk ratio (RR): 2.0, P=0.02). The median time from daratumumab discontinuation to disappearance of daratumumab on MASS-FIX was 116 (95%CI: 76-160) days in patients with urine protein ≥0.5 grams and 203 (95%CI: 162-216) days in patients with urine protein <0.5 grams (P=0.02). There was no association between the time to disappearance of daratumumab by MASS-FIX and old age ≥70 (RR: 0.9, P=0.81], male gender (RR: 0.9, P=0.60), eGFR <60 (RR: 1.0, P=0.98), daratumumab schedule (every 1/2 weeks vs >2weeks) (RR: 1.0, P=0.97), treatment duration (<200 days vs ≥200 days) ( RR: 1.0, P=0.95), or transplantation status (RR: 1.0, P=0.98). Conclusion: The therapeutic monoclonal antibody daratumumab remains detectable in the serum of treated patients by MASS-FIX for several months after discontinuation and the duration varies between individual patients. This data has implications for diagnostic and monitoring testing and may provide guidance for reuse of daratumumab in clinical trials and practice. Proteinuria is associated with earlier disappearance of daratumumab by MASS-FIX and may have implications in patients with amyloidosis and monoclonal immunoglobulin deposition disease (MIDD). Further studies are needed to identify additional factors associated with the timing of disappearance. Disclosures Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Tenebio: 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.

scholarly journals A Cross Sectional Epidemiological and Survival Analysis of All Patients with Plasma Cell Disorders Recorded between 2011- 2017 in the Social Insurance System of Turkey

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5847-5847
Author(s):  
Metin Dag ◽  
Meral Beksac
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Survival Analysis ◽  
Board Of Directors ◽  
Healthcare System ◽  
Plasma Cell ◽  
Real World ◽  
Real World Data ◽  
Advisory Committees ◽  
Plasma Cell Disorders

Abstract Background and Aim: The incidence and outcomes of patients with cancer diagnoses are reported annually as SEERs in few but not all countries. Clinical trials or myeloma group studies have documented the survival of patients with plasma cell disorders to improve with the approval of new drugs, early diagnosis and better follow-up. The outcome of patients included in clinical trials do not represent the real world data. There are two major pharma sponsored international prospective or retrospective analysis of real World data where patients from Turkey are also included (Mohty et al Clin Lymphoma Myeloma Leuk 2018 and Kumar et al. Leuk Lymphoma 2018). However the results do not confer to patients of any country in particular. According to the SGK's 2016 annual report, 98,6% of the population of Turkey is covered by the Healthcare Insurance System (SGK). Electronic data recording system (2007) and e- prescribing (2010) have been introduced to the healthcare system in Turkey. The aim of this study is to analyze and report the epidemiological features of patients who are recorded and received drugs approved and reimbursed by the Turkish Healthcare system . Patients and Methods: The study is performed following Ethical Committee approval by Ankara University and also by permission for publication from SGK. Patients recorded with the ICD of C90 between 2011-2017 and has received either of these medications: Melphalan, Thalidomide, Bortezomib, Lenalidomide, Bendamustine or high dose therapy with stem cell support(ASCT) were included in the analysis. This approach was taken to prevent false ICD entry or exclude patients with Monoclonal Gamopathy of Undetermined Significance or Smoldering Multiple Myeloma who are not being treated. Additionally patients who were privately insured or received drugs within clinical trials or compassionate/early access programs were also excluded. Patients registered earlier than 2011 were not included in the analysis to allow survival analysis. Statistical analysis were performed using the SQL, SPSS, MS Office software packages. Results: A total of 10146 patients were evaluated as eligible. Annual number of patients during the 2011-2017 period were as follows: 1168, 824, 2245, 1811, 1537, 1183, 1378. Males/females: 5655/4491, Median age of patients were constant with a minor increase from 63.8(2011) to 65.2(2017). ASCT (once or more)was received by 4060 (40%)patients. Overall survival (OS) of patients improved if diagnosed younger (Fig 1a), if they are female (Fig 1b) and received ASCT(Fig 1d). There was no OS benefit if ASCT was given more than once. Approval and reimbursement of novel drugs such as Bortezomib and Lenalidomide were achieved in 2005 and 2010 respectively. Both Carfilzomib and Pomalidomide are approved but only conditionally reimbursed since 2015 and 2016. Patients who started treatment during more recent years (after 2015)are able to survive longer than those who started earlier(Fig 1c). Conclusions: This is the first and most extensive epidemiological report for Multiple Myeloma from Turkey. It informs about annual incidence of patients eligible for treatment (approximately 1400), treatment success (OS: median 4 years) during a seven year period. Our results are supporting the survival advantage of ASCT (median 5 vs. 2 years, p=0.000) and younger age(p=0.000) plus female gender (p=.0.005). Patients who initiated treatment recently have better OS than patients starting earlier (p=0.001). More detailed survival and cost benefit analyses are aimed to be presented during the meeting. Disclosures Beksac: Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen,Janssen-Cilag,Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Oncogene Induced Senescence As a Potential Breakpoint Mechanism Against Malignant Transformation in Plasma Cell Disorders

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4474-4474
Author(s):  
Nicola Lehners ◽  
Elena Ellert ◽  
Jing Xu ◽  
Hartmut Goldschmidt ◽  
Mindaugas Andrulis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Malignant Transformation ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Healthy Controls ◽  
Advisory Committees ◽  
Expression Levels ◽  
Plasma Cell Disorders

Abstract Background: Cellular senescence has been recognized as a failsafe mechanism against hyperproliferation and might thus be induced by DNA replicative stress and oncogenic signaling, commonly termed oncogene-induced senescence (OIS). OIS has been described in several premalignant conditions such as colon adenomas and melanocytic nevi, with impaired OIS capabilities found in their malignant counterparts. Here, we analyze the possible impact of cellular senescence on malignant transformation in plasma cell disorders. Methods: Bone marrow and soft tissue biopsies from 125 patients with different stages of plasma cell disorders (16 monoclonal gammopathy of undetermined significance (MGUS), 32 smoldering multiple myeloma (SMM), 56 symptomatic multiple myeloma (MM), 21 extramedullary MM) as well as from 10 healthy donors were analyzed. Expression of OIS associated proteins p16INK4A, p21Cip1/Waf1, p27Kip1, phospho-Chk2, the DNA double-strand break marker γH2AX, as well as the proliferation marker Ki67 were assessed on plasma cells by immunohistochemistry. Additionally, double staining experiments for p21 and Ki67 were performed applying immunofluorescence confocal microscopy. Levels of protein expression were compared between different disease stages using the Kruskal-Wallis test. Results: A differential expression pattern was found for p21 in various stages of plasma cell disorders with peak expression of p21 in SMM compared to both healthy controls (p<0.001) and MGUS (p=0.02), as well as compared to symptomatic multiple myeloma (MM) (p=0.007) (see Figure 1a). Median p21 expression was 0.63% of plasma cells from healthy subjects, 6.67% in MGUS, 13.81% in SMM, 2.37% in MM, and 0% in EMM. Plasma cells of SMM patients expressing p21 were negative for Ki67 consistent with a potentially senescent phenotype. In contrast, p27 was highly expressed in healthy controls, MGUS and SMM but decreased significantly in MM patients (p=0.02) (see Figure 1b). p16 showed no nuclear expression in healthy controls, MGUS or SMM and was expressed only in few patients with MM. In addition, we found low expression of p21, p27 and phospho-Chk2 in extramedullary MM compared to medullary MM samples, accompanied by increased expression of γH2AX and high levels of proliferation (Ki67 58%). Conclusions: We found indication of induction of OIS in SMM compared to symptomatic MM, mainly mediated by increased expression of p21. Further disease progression to extramedullary MM was characterized by almost complete absence of OIS markers and increased signs of DNA damage and proliferation. These observations are consistent with the hypothesis of OIS as a breakpoint mechanism against malignant transformation in plasma cell disorders and should be further explored mechanistically and as a possible therapeutic target. Figure 1 Expression levels of p21 and p27in different stages of plasma cell disorders. Semiquantitative assessment of plasma cells positive for p21 (a) and p27 (b) is shown in healthy controls, MGUS, SMM, MM, and EMM patients. Significant differences in expression levels between cohorts are indicated by their respective p-values with * p-value < 0.05, ** < 0.01, *** < 0.001. Figure 1. Expression levels of p21 and p27in different stages of plasma cell disorders. Semiquantitative assessment of plasma cells positive for p21 (a) and p27 (b) is shown in healthy controls, MGUS, SMM, MM, and EMM patients. Significant differences in expression levels between cohorts are indicated by their respective p-values with * p-value < 0.05, ** < 0.01, *** < 0.001. Disclosures Goldschmidt: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Novartis: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy.

Induction of T Cell Immunity Using a Multipeptide Cocktail Containing XBP1, CD138 and CS1 Peptides in Smoldering Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5039-5039
Author(s):  
Jooeun Bae ◽  
Rao H. Prabhala ◽  
Weihua Song ◽  
Yu-Tzu Tai ◽  
Kenneth C. Anderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Board Of Directors ◽  
Advisory Committees ◽  
Smoldering Multiple Myeloma ◽  
Human T Cell ◽  
Cell Immunity ◽  
Equity Ownership

Abstract Abstract 5039 Smoldering multiple myeloma (SMM) patients are at high risk for progression to active multiple myeloma (MM), making them candidates for novel immunotherapeutic strategies to prevent or delay disease progression. Among potential strategies, the ability to induce cytotoxic T lymphocytes (CTL) against multiple immunogenic epitopes provides a framework for overcoming major therapeutic challenges including heterogeneity of tumor associated antigen expression, frequent mutations of specific antigens, and variability of the human T-cell repertoire among individuals. In this study, we provide evidence that a cocktail of four immunogenic HLA-A2 specific peptides, heteroclitic XBP1 US184–192, heteroclitic XBP1 SP367–375, native CD138260–268 and native CS1239–247, induces specific CTL response in T cells from SMM patients. Following repeated rounds of multipeptide stimulation, we induced development of CD8+ CTL from SMM patients' T cells. The multipeptide specific-CTL demonstrated polyfunctional immune activities including high levels of IFN-g production, cell proliferation and cytotoxicity against MM cells in an HLA-A2 restricted manner. The multipeptide-specific CTL displayed increased memory (CD45RO+) and activated (CD69+) CD3+CD8+ T lymphocytes, suggesting that a multipeptide vaccine has the potential to induce durable memory by generating specific memory CTL with characteristics of effector T cells against MM cells. In addition, the multipeptide-specific CTL demonstrated peptide-specific responses to each of the relevant epitopes including heteroclitic XBP1 US184–192, heteroclitic XBP1 SP367–375, native CD138260–268 and native CS1239–247, but not against an irrelevant HLA-A2-specific MAGE-3271–279 peptide in various functional assays including antigen-triggered CD137 (4-1BB) expression, IFN-g production and CD107a up-regulation. Therefore, these results suggest the potential of inducing a broad spectrum of immune responses against selected XBP1 unspliced, XBP1 spliced, CD138 and CS1 target antigens in SMM using multipeptide vaccination. In conclusion, these studies provide the framework for clinical trials of vaccination in patients with SMM to delay or prevent progression to active MM. Disclosures: Bae: Oncopep Inc. : Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Anderson:Oncopep Inc. : Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Munshi:Oncopep Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Outcomes of Autologous Transplants for Patients with Multiple Myeloma and Concurrent Multiple Plasmacytomas

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1973-1973
Author(s):  
Seema Naik ◽  
Paul J. Shaughnessy ◽  
Behyar Zoghi ◽  
Jose C Cruz ◽  
Carlos Bachier
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Light Chain ◽  
Disease Recurrence ◽  
Solitary Plasmacytoma ◽  
Advisory Committees ◽  
Autologous Transplants ◽  
Lytic Lesions ◽  
Drug Regimens

Abstract Introduction: Outcomes of Multiple myeloma (MM) have improved in the recent years with combination of novel agents, autologous transplants followed by maintenance therapies. One of the current challenges is to optimize transplant strategies for MM patients with extramedullary plasmacytomas (EMP). Patients and Methods: We retrospectively analyzed outcomes of 237 consecutive MM patients (M132:F105) who underwent ASCT at Texas Transplant Institute, between December 2011 and June 2014. The study was approved by Institutional Review Board. The median length of follow-up was 44.8 months (10 - 86.8 months) in all patients. Censoring date was the last clinic visit prior to December 2014. Results: A total of 237 MM patients were evaluated for presence of plasmacytomas. Patients presented either with multiple intraosseous lytic lesions (MM-IOL) without EMP (n=105; 44%); MM without lytic lesions or EMP in (n=80; 34%) and remaining MM-EMP (n=52; 22%) presented with EMP without multiple lytic lesions. Disease subtype was nonsecretory (5%; n=13), IGA (15%; n=35), IGG (56%; n=133), kappa light chain (16%; n=38) and lambda light chain (8%; n=18) for all 237 patients. (Table 1). Cytogenetics was available in 216 patients (91%) and statistically different among the 3 groups (p=0.05). The sites of EMP included the abdomen, pelvis, chest wall; liver, soft tissue, with sizes ranging from 1.8 cm 10 cm. EMP patients developed recurrent EMP after autologous transplant in 20% (10/52) cases. Fifty percent of patients with recurrent EMP (5/10) died of EMP progression. A total of 140 (59%) patients received triple drug regimens either CyBorD (n=51; 22%) or VRD (n=89; 38%) prior to transplant. Radiation therapy was given to 42 % (n=22/52) patients with EMP and only 4% patients without EMP (n=8 /185). There was no difference in OS and PFS for patients treated with 2 drugs (VD/RD) compared to 3 drug regimens (CyBorD/VRD) for either OS or PFS. Prior solitary plasmacytoma were seen more frequently in 19% patients (n=10/52) who had EMP manifestations prior to transplant. Prior MGUS /smoldering myelomas were seen in 13 % MM-IOL patients. Disease characterisitics (p=0.0515), plasma cell percentage (p=0.0119) and disease recurrence (p=<0.0001) were statistically different for OS for all 237 patients. Disease characteristics (p=0.0751) and recurrence (p=<0.0001) were prognostic for PFS. 3 year probability of OS was 82% (95% CI, 64%- 92%), 84.7% (95% CI, 72%- 92%) and 71.6% (95% CI, 53%- 84%) for patients MM without EMP, MM-IOL and MM-EMP, respectively. Conclusion: Novel therapeutic approaches including proteasome inhibitors and immunomodulatory agents followed by transplant can overcome poor prognosis of MM-EMP patients. Those that do relapse do extremely poorly suggesting need for alternative new therapies. Table 1. Patient Characteristics Variable All patients MM withoutIOL/EMP MM-IOL MM-EMP (M132:F105) (n=237)(100%) (n=80)(34%) (n=105)(44%) (n=52)(22%) Median age P=0.5038 63 (37-79) 62 (40-76) 63 (37-79) 63 (39-77) MM subtype P=0.9589 IGG subtype 133 (56%) 45(56%) 61(58%) 28(23%) IGG kappa 91 (38%) 31(39%) 42(40%) 18(4%) IGG lambda 42 (18%) 14(18%) 19(18%) 9(17%) IGA Subtype 35 (14.7%) 13(16%) 16(15.2%) 6(12%) Kappa LCD 38 (16%) 14(18%) 16(16%) 8 (15%) Lambda LCD 18 (8%) 4(5%) 8(8%) 6(12%) Nonsecretory 13 (6%) 4(5%) 4(4%) 5(10%) Prior Plasma Cell Disorder* P=0.0001 Smoldering MM* 7 (3%) 3(4%) 4(4%) 0(0%) Plasmacytoma* 13 (6%) 1(1%) 2(2%) 10(19%) MGUS* 26 (11%) 13(16%) 9(9%) 4(8%) Cytogenetics P=0.0586 Normal Cytogenetics 84(34%) 41(51%) 25(26%) 27(54%) Mono 13/13 del 22(13%) 10(13%) 20(19%) 6(12%) 17 del 4(2%) 1(1%) 3(3%) 1(2%) Trisomy 11/t(11:14) 8(3%) 6(8%) 3(3%) 6(12%) T(4:14) 5(2%) 2(2.5%) 4(4%) 2(4%) Hyperdiploidy 22(9%) 6(8%) 11(10%) 2(4%) Prior Treatments P=0.1122 CyBorD 51(22%) 19 (24%) 26(25%) 6(12%) VRD/VTD 89(38%) 27(34%) 43(41%) 18(34%) VD/RD/TD 91(38%) 30(38%) 36(34%) 24(46%) Other 6(2.5%) 3(4%) 0(0%) 3(6%) 3 yr OS (p=0.462) 86.1% (65%-95%) 91.3% (81%-96%) 83.4% (65%-93%) 3 yr PFS (p=0.1302) 82.8% (64%-92%) 84.7% (72%-92%) 71.6% (53%-84%) Disclosures Shaughnessy: pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; sonofi/genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Anti-Tumor Activities of XBP1 Antigen-Specific Cytotoxic T Lymphocytes Are Enhanced By HDAC6 Inhibitor ACY241

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2143-2143
Author(s):  
Jooeun Bae ◽  
Matthew Ho ◽  
Brandon Nguyen ◽  
Arghya Ray ◽  
Dharminder Chauhan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Lymphocytes ◽  
Board Of Directors ◽  
Cytotoxic T Lymphocytes ◽  
Cytokine Production ◽  
Suppressor Cells ◽  
Advisory Committees ◽  
Hdac6 Inhibitor ◽  
Equity Ownership

Abstract The effects of histone deacetylase (HDAC) inhibition on immune effector cells may have significant clinical implications; however, this has not yet been elucidated. The goal of this study was to investigate the immunomodulatory potential of the selective HDAC6 inhibitor ACY241 in combination with a cancer vaccine to enhance the efficacy of antigen-specific cytotoxic T lymphocytes (CTL) and the specific activities against tumor cells. Here, we report the effects of ACY241 treatment on antigen expression, immune activation, proliferation, and functional activities of XBP1 antigen-specific cytotoxic T lymphocytes (XBP1-CTL). The antigen-specific CTL were generated in vitro by repeated stimulation with novel immunogenic heteroclitic HLA-A2 XBP1 peptides (YISPWILAV, YLFPQLISV), as described previously by our group (Bae et al. Leukemia 2011; Bae et al. Oncoimmunology 2014l; Bae et al. Leukemia 2016). We found that treatment with ACY241 up-regulated key co-stimulatory (CD28, CD40L) and activation (CD38, CD69, CD137) molecules on XBP1-CTL, without inducing expression of co-inhibitory checkpoints (PD1, LAG3, CTLA4, VISTA). In addition, ACY241 increased the frequency of memory CTL subsets and enhanced their anti-tumor activities (cytotoxic activity, Th1-type cytokine production, CTL proliferation) against HLA-A2+ and XBP1+ multiple myeloma, breast cancer, and colon cancer cells. The XBP1-CTL responses were dramatically increased in combination with ACY241, including higher levels of tumor-specific CD107a up-regulation, perforin release, IFN-g/IL-2/TNF-a cytokine production and proliferation of the CD3+CD8+ T cells expressing CD28/CD38 in response to the specific XBP1 peptides. ACY241 also enhanced the expression of various tumor-associated antigens (XBP1, CD138, CS1, BCMA, CD44), MHC class I/II molecules, along with co-stimulatory B7 molecules (CD80, CD86) on HLA-A2+ myeloma (U266), breast cancer (MDA-MB231) and colon cancer (SW480) cell lines. Furthermore, in vitro ACY241 treatment consistently decreased the frequency of immune suppressor cells including myeloid-derived suppressor cells (CD14- CD15+/CD11b+ CD33+/HLA-DRlow) and regulatory T cells (CD25+ FOXP3+/CD3+ CD4+) in peripheral blood or bone marrow mononuclear cells from multiple myeloma patients in a dose-dependent manner. In conclusion, our data demonstrates the immunomodulatory effects of selective HDAC6 inhibition by ACY241 and supports its potential role for improving tumor-specific CTL function and tumor cell recognition when used in combination with antigen-specific cancer vaccine. Disclosures Bae: OncoPep Inc.: Consultancy, Equity Ownership. Chauhan:Stemline Therapeutics: Consultancy. Hideshima:Acetylon: Consultancy; C4 Therapeutics: Equity Ownership. Munshi:OncoPep Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Anderson:OncoPep Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Chromatin Accessibility Profiling Reveals Cis-Regulatory Heterogeneity and Novel Transcription Factor Dependencies in Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1313-1313
Author(s):  
Christopher J. Ott ◽  
Raphael Szalat ◽  
Matthew Lawlor ◽  
Mehmet Kemal Samur ◽  
Yan Xu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Therapeutic Target ◽  
Chromatin Accessibility ◽  
Open Chromatin ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Multiple myeloma (MM) is a plasma cell malignancy characterized by clinical and genomic heterogeneity. Recurrent IgH translocations, copy number abnormalities and somatic mutations have been reported to participate in myelomagenesis; however no universal driver of the disease has been identified. Here, we hypothesize that transcriptional deregulation is critical for MM pathogenesis and the maintenance of the MM cell state. In order to capture signatures of transcription factor engagement with the myeloma epigenome, we performed the assay for transposase-accessible chromatin sequencing (ATAC sequencing), deep RNA sequencing in 23 primary myeloma samples and 5 normal plasma cell samples (NPC) from healthy donors along with whole genome sequencing and H3K27ac ChIP-seq in a cohort of these primary MM samples. We identified 22,603 variable accessible loci between MM and NPC and correlated impact of these on expression of associated genes using RNA-seq data. Together with robust differential analysis of open chromatin regions and nuclease-accessibility footprints to identify discrete transcription factor binding events, we have discerned the myeloma-specific open chromatin landscape, identified transcription factor dependencies and potential new myeloma drivers. In our dataset we observe a vast number of loci with heterogeneous chromatin states across the sample cohort, and the majority of the open chromatin sites identified are unique to a single sample. However, distinct variable chromatin accessibility signatures indicative of the MM chromatin state when compared to normal plasma cells were observed. Remarkably, we observed more frequent recurrent loss of variable accessible loci compared to gains. In addition, specific open chromatin profiles evident in hyperdiploid and non-hyperdiploid MM were also identified. Accessibility footprinting revealed MM-specific enrichment for transcription factors known to be essential for MM cell survival including Interferon Regulatory Factors (IRFs), Nuclear Factor Kappa B (NFkB), Ikaros, and Sp1. Interestingly, we also identify the myocyte enhancer factor 2 (MEF2) family of transcription factors as being specifically enriched in open chromatin regions in MM cells. Using a CRISPR-Cas9 knockout system, we identify the MEF2 family member MEF2C as essential for MM cell proliferation and survival. MEF2C is significantly overexpressed at the RNA level in our study as well as in several independent cohorts and is a central enhancer-localized transcription factor in MM core regulatory circuitry as determined by H3K27ac ChIP-sequencing profiles of primary MM samples. In order to evaluate MEF2C as a therapeutic target, we used small molecule inhibitors targeting MEF2C activity via inhibition of MEF2C phosphorylation using inhibitors of salt-induced kinases (SIK) and microtubule-associated protein/microtubule affinity regulating kinases (MARK). SIK/MARK have been described to specifically activate MEF2C. SIK and MARK inhibition resulted in both dose- and time-dependent inhibition of MM cell growth and survival in a panel of 12 MM cell lines with various genotypic and phenotypic characteristics, revealing a potential approach to targeting the dysregulated gene regulatory state of myeloma. To conclude, here we identify here an altered chromatin accessibility landscape in multiple myeloma that likely contributes to oncogenic transcription states through the activity of transcription factors such as MEF2C, representing a new MM dependency and potential therapeutic target. Disclosures Anderson: Millennium Takeda: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; Bristol Myers Squibb: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; OncoPep: Equity Ownership, Other: Scientific founder. Young:Camp4 Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Omega Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Munshi:OncoPep: Other: Board of director.

scholarly journals Plasma Cell Proliferative Index Is an Independent Predictor of Progression in Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3160-3160
Author(s):  
Mohammed A Aljama ◽  
M Hasib Sidiqi ◽  
Arjun Lakshman ◽  
Angela Dispenzieri ◽  
Dragan Jevremovic ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Confidence Interval ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Research Funding ◽  
Independent Predictor ◽  
Time To Progression ◽  
Proliferative Index ◽  
Advisory Committees

Abstract The plasma cell proliferative index (PCPI) provides an insight into plasma cell biology in plasma cell disorders. It recognizes cells that are actively synthesizing DNA and gives an indication of the proliferative rate of the malignant plasma cells.The PCPI has been shown to be a prognostic tool in patients with multiple myeloma and amyloidosis. We conducted a retrospective review analyzing the prognostic impact of PCPI in 306 patients with smoldering multiple myeloma (SMM). The median age was 66 (56-73) years and 61% (n=186) were males. The median follow-up for the entire cohort was 10.2 years (95% confidence interval: 9.0-10.9). One-hundred sixty-nine (55%) patients were alive at the time of study analysis while 118 (39%) had progressive disease. The median time to progression was 5.9 years (95% confidence interval: 4.8-8.2). Symptomatic events at the time of progression included anemia in 41% (n=48), bone complications in 37% (n=44), renal complications in 9% (n=11), hypercalcemia in 2% (n=2) and development of amyloidosis in 2% (n=2). Seventeen patients (14%) were categorized as having progression due to rapid progressive elevation in the serum free light chains (sFLC) and/or progressive increase in the size of their M-spike. The median time between the diagnosis and PCPI date was 0 months (interquartile range 0-1). An elevated PCPI was defined as a level >0.5%. Seventy-nine (26%) patients had an elevated PCPI. Patients with an elevated PCPI were significantly older (median age: 69 years for elevated PCPI vs 64 years for low PCPI (p= 0.008) and predictably had more proliferative disease with a higher rate of patients with bone marrow plasma cells >20% (48% for elevated PCPI vs 34% for low PCPI, p=0.03). An elevated PCPI predicted a shorter time to progression (TTP); median 3.0 years versus 7.1 years for those with a low PCPI (p= 0.0004). Within 24 months, the progression rate was significantly higher for patients with an elevated PCPI; 49% versus 20% (p<0.0001). We constructed two multivariable models using the conventional and recently proposed Mayo risk stratification tools. In both models, an elevated PCPI was an independent predictor of to multiple myeloma. PCPI is a valuable tool in risk stratifying patients with SMM and identifies patients with earlier progression who may benefit from closer follow up and consideration of early intervention trials. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Research to Practice: Consultancy; spectrum: Consultancy, Honoraria; Abbvie: Consultancy; Amgen: Consultancy; janssen: Consultancy; Physicians Education Resource: Consultancy; Teva: Consultancy; celgene: Consultancy; annexon: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; Medscape: Consultancy; Apellis: Consultancy; Ionis: Honoraria. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document