Biomarkers of Cardiotoxicity Among Multiple Myeloma Patients Subsequently Treated with Proteasome Inhibitor Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4257-4257 ◽  
Author(s):  
Nikoletta Lendvai ◽  
Sean Devlin ◽  
Minal Patel ◽  
Kristina Marie Knapp ◽  
Daniel Ekman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Inhibitor Therapy ◽  
Matched Pair ◽  
P Value ◽  
High Dose ◽  
Underlying Mechanisms ◽  
Potential Biomarkers

Abstract BACKGROUND: Cardiovascular (CV) events are a known complication to proteasome inhibitor therapy in myeloma. Underlying mechanisms are unknown. We recently completed an investigator initiated, single institution Phase II study of high dose carfilzomib (56mg/m2) in patients with relapsed/refractory MM (NCT01351623). Among 42 response evaluable patients, 11 patients (25%) developed treatment-emergent heart failure of any grade, and 5 patients (11%) developed severe heart failure requiring mechanical ventilation. We undertook a study to identify potential biomarkers that may point to underlying mechanisms of CV events among multiple myeloma patients treated with carfilzomib therapy. METHODS: We performed a nested case-control study with 7 patients who experienced a CV event on our high dose carfilzomib study and had pre-treatment (baseline) plasma stored and 19 case matched controls treated on the same study who did not have a CV event. We screened for 90 proteins known to be associated with CV disease using O-linked glycosylation. We used the Proseek Multiplex CVD I 96x96 platform which is based on the Proximity Extension Assay (PEA) technique. PEA is a 96-plex immunoassay that allows high throughput detection of protein biomarkers in liquid samples. For each biomarker, a matched pair of antibodies linked to unique oligonucleotides (proximity probes) binds to the respective protein target. Upon binding, the unique proximity probes can hybridize to each other and subsequently be detected and quantified by real-time PCR. Mean biomarker levels were compared using a t-test. False discovery rate (FDR) was used for multiple comparisons adjustment. RESULTS: Using samples collected prior to initiation of carfilzomib therapy, in an agnostic statistical model we identified the following four proteins to have altered levels in myeloma patients who developed CV events (p=0.002-0.004, unadjusted; p=0.089, after FDR correction): matrix metalloproteinase-1 (MMP-1, heparin-binding EGF-like growth factor (HB-EGF), TNF-related apoptosis-inducing ligand (TRAIL), and myoglobin (MB). Myeloma patients who developed CV events had 37% lower MMP-1, 15% lower MB, and 4% lower HB-EGF, while TRAIL was 7% higher in patients who developed CV events. Matrix metalloproteinases are a family of proteolytic enzymes responsible, among other functions, for myocardial extracellular protein degradation. Interestingly, several MMP species, including MMP-1, have been identified within the human myocardium and are thought to be dysregulated in congestive heart failure. HB-EGF is a mitogenic and chemotactic glycoprotein that is essential for maintaining normal cardiac function and is known to play an important role in myocardial remodeling. CONCLUSIONS: We found that there was a trend towards lower MMP-1, HB-EGF, and MB levels and higher TRAIL levels in patients with CV events while receiving proteasome therapy. MMP-1 appears to be the most promising potential biomarker based on our data. Our study supports further investigation of these proteins as potential biomarkers for patients at risk of CV events when treated with carfilzomib. Table 1. CV event No CV event N=7 N=19 CKD Proteins1 Mean (SD) Mean(SD) Unadjusted P-value Adjusted P-value MMP_1 1.7 (0.5) 2.7 (0.9) 0.002 0.089 HB_EGF 6.9 (0.2) 7.2 (0.3) 0.004 0.089 TRAIL 8 (0.3) 7.5 (0.5) 0.004 0.089 MB 5 (0.5) 5.9 (0.8) 0.004 0.089 HSP_27 2.2 (0.3) 2.7 (0.8) 0.032 0.528 PDGF_subunit_B 4 (0.7) 5 (1.5) 0.036 0.528 CD40_L 3.4 (0.6) 4.2 (1.2) 0.042 0.533 EGF 3.7 (0.9) 4.7 (1.4) 0.053 0.592 CX3CL1 5.9 (0.2) 5.6 (0.6) 0.092 0.895 TRAIL_R2 4.2 (0.4) 4.6 (0.6) 0.101 0.895 1. Proteins are listed based on the p-value associated with the difference between patients who did and did not have CV events, with lowest p-value on the top. The top 10 biomarkers are shown. Disclosures Ekman: Olink Bioscience: Employment. Grundberg:Olink Bioscience: Employment. Hassoun:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Research Funding; Novartis: Consultancy. Lesokhin:Aduro: Consultancy; Efranat: Consultancy; Genentech: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Landau:Janssen: Consultancy; Prothena: Consultancy, Honoraria; Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria; Onyx: Honoraria, Research Funding; Takeda: Research Funding. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Landgren:Onyx: Honoraria; Celgene: Honoraria; BMJ Publishing: Consultancy; International Myeloma Foundation: Research Funding; Bristol-Myers Squibb: Honoraria; Onyx: Research Funding; Medscape: Consultancy; Medscape: Honoraria; BMJ Publishing: Honoraria; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy.

Mapping the Impact of Proteasome Inhibitor Therapy on the Immunopeptidome of Multiple Myeloma: Mass Spectrometry Identifies Robust Targets for T Cell Immunotherapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3001-3001
Author(s):  
Daniel Johannes Kowalewski ◽  
Simon D. Walz ◽  
Linus Backert ◽  
Heiko Schuster ◽  
Susanne M. Rittig ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
T Cell ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Inhibitor Therapy ◽  
Target Cells ◽  
Myeloma Cells ◽  
Hla Ligands ◽  
Support Research

Abstract Recent studies underscore that multiple myeloma is an immunogenic disease and suggest that it can be effectively treated by T cell based immunotherapy via immunomodulation. This strategy might be synergistically complemented by therapeutic vaccination, which may help induce and guide specific anti-cancer T cell responses. We have recently conducted a study which directly characterized the antigenic landscape of myeloma by mass spectrometric analysis of naturally presented HLA ligands and identified a panel of T cell epitopes characterized by exquisite myeloma-association (Walz, Stickel et. al., Blood 2015). As standard of care in myeloma includes proteasome inhibitor therapy and the proteasome plays a central role in the generation of MHC-presented peptides, it is of great importance to thoroughly characterize and take into account the effects of this treatment on the antigenic landscape of myeloma cells and implement only robustly presented targets for peptide vaccine design. This is even more important Here we present a mass spectrometry-based study, which longitudinally and semi-quantitatively maps the effects of treatment with the 2nd generation proteasome inhibitor carfilzomib in an in vitro model of multiple myeloma. We observed considerable plasticity of the HLA class I ligandome of MM.1S cells after treatment with carfilzomib with 17.9±1.1.% (mean of 3 biological replicates ± SD) of HLA ligands showing significant modulation (fold change ≥ 4, P ≤ 0.01) at t24h compared to mock-treated controls (down-modulated: 11.5±1.1%, up-modulated: 6.3±0.6%). We were able to longitudinally tracke the abundance of 28 previously defined myeloma antigens, confirming robust (16/28, 57.1%) or even increased presentation (8/28, 28.6%) under treatment for the majority of these peptides. However, - importantly - we observed highly distortive effects of carfilzomib treatment on the HLA allotype distribution of target cells, which manifested as a marked reduction of HLA ligands restricted by HLA-A*23:01 and A*24:02 (-62.5±1.8% and -57.0±0.6%, respectively, at t=24h after treatment). These findings indicate strong allotype-specific effects of carfilzomib on the antigenic landscape of myeloma cells, which we interpret to be a direct reflection of the mechanism of action of this drug. As a significant proportion of the U.S. population are carriers of the affected alleles (A*23:01: 8.2%; A*24:02: 22.6%), these findings could have broad implications for the design or implementation of antigen-specific therapies in patients under proteasome inhibitor treatment. Furthermore, these findings might indicate the possibility of altered cancer immunosurveillance as a consequence of proteasome inhibitor therapy. Disclosures Weisel: Amgen: Consultancy, Honoraria, Other: Travel Support; Onyx: Consultancy, Honoraria; Novartis: Other: Travel Support; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Noxxon: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support.

scholarly journals Utilization of Autologous Stem Cell Transplantation in Older Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5701-5701
Author(s):  
Justin King ◽  
Mark A. Fiala ◽  
Scott R. Goldsmith ◽  
Keith E. Stockerl-Goldstein ◽  
Mark A. Schroeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Older Patients ◽  
Research Funding ◽  
Small Sample ◽  
Poor Performance Status ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Equity Ownership

Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

scholarly journals VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1835-1835 ◽  
Author(s):  
Katrina M Piedra ◽  
Hani Hassoun ◽  
Larry W. Buie ◽  
Sean M. Devlin ◽  
Jessica Flynn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cancer Trial ◽  
Oncology Research ◽  
Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: 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, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

scholarly journals Daratumumab, Pomalidomide, and Dexamethasone (DPd) for the Treatment of Relapsed/Refractory Multiple Myeloma: A Single Institution Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5642-5642 ◽  
Author(s):  
Al-Ola Abdallah ◽  
Neil Dunavin ◽  
Brian McClune ◽  
Leyla Shune ◽  
Ajoy L. Dias ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Median Number ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Duration Of Treatment ◽  
Effective Treatment Option ◽  
Refractory Multiple Myeloma ◽  
Overall Response

Abstract Background: Daratumumab triplet regimens containing dexamethasone and lenalidomide or bortezomib are an effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). Daratumumab was recently FDA-approved in combination with the second-generation immunomodulatory drug, pomalidomide, and dexamethasone based (DPd) on results of the EQUULEUS study where overall response rates (ORR) of 60% were seen. The goal of this retrospective study was to analyze clinical outcomes of the DPd triplet regimen in either a daratumumab and pomalidomide naïve or refractory population of heavily pretreated RRMM patients at our institution. Methods: Thirty-two patients with RRMM treated with DPd at the University of Kansas Health System between November 2015 and July 2018 were included in our analysis. DPd consisted of 28-day cycles of daratumumab 16 mg/kg intravenously (weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression); pomalidomide 4 mg orally (PO)on Days 1-21 and adjusted for cytopenia or toxicities; and dexamethasone 40 mg PO weekly adjusted based on tolerance. based on age. Responses were evaluated using IMWG criteria. Patient characteristics, disease course, and outcomes were summarized with descriptive statistics. Kaplan-Meier analyses were used to estimate progression-free (PFS) and overall survival (OS). Results:The median age was 64 years (range 44-83). Twenty-three patients (72%) had IgG isotype, 11 patients (34 %) had ISS stage III disease at diagnosis, 13 patients (41%) had high risk cytogenetics, and 13 patients (41%) had extramedullary disease. Median number of previous lines of therapy was 4 (1-9). Twenty-two patients (69%) received ≥3 prior therapies. Twenty-three patients (72%) were proteasome inhibitor refractory, 28 patients (88%) were immunomodulator refractory, 9 patients (28%) were daratumumab refractory, and 3 patients (15%) were double refractory to daratumumab and pomalidomide. Twenty-eight patients (88%) had received autologous stem cell transplant (ASCT) prior to DPd; 12 patients (38%) had ≥2 prior transplants. Median number of DPd cycles received was 6 (2-30) and the median duration of treatment was 5 months (2-30). At a median follow-up of 8.4 months (range: 2-29), the overall response rate (ORR) for all patients was 72% which compares favorably to the ORR of 60% in the EQUULEUS study. However, about half of the responses were partial responses (PR) (47%). The ORR rate for those who were refractory to either pomalidomide or daratumumab was 65%. The PFS was 8.3 months, while the median OS was not reached. Conclusion: DPd was recently approved for the treatment of RRMM. Our ORR compares favorably to the EQUULEUS study, however about half of responses were partial responses or better. Surprisingly, our analysis shows an impressive ORR in patients with previous exposure to proteasome inhibitor and immunomodulatory therapies in RRMM population, suggesting a benefit of DPd even in patients who received prior pomalidomide or daratumumab. Disclosures McGuirk: Astellas Pharma: Research Funding; Gamida Cell: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Pluristem Ltd: Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding. Ganguly:Daiichi Sankyo: Research Funding; Janssen: Consultancy; Amgen: Consultancy; Seattle Genetics: Speakers Bureau.

The Proteasome Inhibitor Bortezomib Stimulates Osteoblastic Differentiation of Human Osteoblast Precursor Cells Via Upregulation of Vitamin D Receptor Signaling

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1899-1899
Author(s):  
Martin Kaiser ◽  
Maren Mieth ◽  
Orhan Sezer ◽  
Ulrike Heider
Keyword(s):  
Multiple Myeloma ◽  
Vitamin D ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Fold Increase ◽  
Osteoblastic Differentiation ◽  
Luciferase Reporter ◽  
Human Osteoblast ◽  
Myeloma Cells ◽  
Osteoblast Precursors

Abstract Abstract 1899 Introduction In multiple myeloma (MM), interactions of the malignant plasma cell clone with the bone marrow microenvironment lead to an enhanced osteoclast recruitment and impaired osteoblast activity. The proteasome inhibitor bortezomib has been shown to suppress osteoclast activity, and there is recent evidence that bortezomib enhances osteoblast differentiation. The aim of this study was to investigate the effects of bortezomib on human osteoblast precursors, focusing on vitamin D (VD) dependent osteoblastic differentiation. Since vitamin D receptor (VDR) is degraded by the proteasome, we hypothesized that bortezomib could influence its signaling and hence vitamin D induced osteoblastic differentiation. This might be of clinical importance, since an increased rate of vitamin D deficiency has recently been reported in patients with MM. Methods Primary human mesenchymal stem cells (hMSC) and primary human osteoblasts (hOB) were isolated from bone marrow aspirates or from bone fragments of healthy donors undergoing orthopedic surgery, respectively. Ascorbic acid and β-glycerolphosphate were used for osteoblastic stimulation (OS), either in combination with or without vitamin D. In order to analyze the effects of proteasome inhibition on osteoblastic differentiation and activity, hMSC and hOB were incubated with bortezomib at subapoptotic doses (1 - 5 nM). In addition, coculture experiments of hMSC, hOB and myeloma cells were performed. Expression of osteocalcin and osteopontin (OPN) were quantified by real-time PCR as markers of osteoblastic lineage differentiation. Expression of VDR was analyzed by western blot in subcellular fractions and VDR signaling was investigated using luciferase reporter assays. Results In coculture experiments, myeloma cells inhibited the vitamin D dependent differentiation and activity of osteoblast precursors, e.g. coculture of hMSC with the myeloma cell line LP-1 for 4 days decreased their osteocalcin expression by 58%. Treatment with bortezomib led to an increased osteoblastic differentiation of hMSC and hOB by OS, represented by an enhanced expression of osteoblast markers osteocalcin and OPN. Importantly, this effect could be further increased, when vitamin D was added. In hMSC stimulated with OS only, addition of 5 nM bortezomib led to an 18.3 fold increase in OPN mRNA expression. In comparison, hMSC stimulated with OS + vitamin D showed a 27.5 fold increase in OPN mRNA with the addition of bortezomib. Osteocalcin expression was increased 1.9 fold by bortezomib in the presence of OS and vitamin D, but not with OS alone. Similar results were obtained with osteoblasts: Incubation with bortezomib slightly increased osteocalcin and OPN mRNA expression in cells stimulated with OS only (1.3 fold and 2.4 fold, respectively). In comparison, in cells stimulated with OS and vitamin D, bortezomib elevated osteocalcin and OPN expression 2.9 fold and 5.5 fold, respectively. Bortezomib led to an increase in nuclear VDR levels in hMSC in western blot analyses. Primary hMSC transfected with a VDR luciferase reporter construct showed a 3.7 fold increase in VDR signaling with bortezomib. Conclusion Our data show that bortezomib stimulates osteoblastic differentiation of hMSCs and hOBs and acts, at least in part, through VDR signaling. Substitution of vitamin D in multiple myeloma patients treated with bortezomib may be beneficial for bone turnover and needs clinical evaluation. Disclosures: Kaiser: Johnson & Johnson: Research Funding. Mieth:Johnson & Johnson: Research Funding. Sezer:Johnson & Johnson: Research Funding. Heider:Johnson & Johnson: Research Funding.

A Comparison of Chemotherapy + G-CSF Versus Plerixafor (Mozobil®) + G-CSF for Stem Cell Mobilization In Patients with Multiple Myeloma Treated with Lenalidomide

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2258-2258
Author(s):  
Tomer M Mark ◽  
Adriana C Rossi ◽  
Roger N Pearse ◽  
Morton Coleman ◽  
David Bernstein ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Yield ◽  
High Dose ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Stem Cell Collection

Abstract Abstract 2258 Background: Prior use of lenalidomide beyond 6 cycles of therapy in the treatment of multiple myeloma (MM) has been shown to negatively impact stem cell yield, but this phenomenon can be overcome with the addition of high-dose cyclophosphamide to standard G-CSF mobilization. We hypothesized that the use of plerixafor (Mozobil®) would compare similarly to chemotherapy in rescuing the ability to collect stem cells in lenalidomide-treated myeloma. Methods: We performed a retrospective study comparing the efficacy of plerixafor + G-CSF mobilization (PG) to chemotherapy + G-CSF (CG) (either high-dose cyclophosphamide at 3g/m2 or DCEP [4-day infusional dexamethasone/ cyclophosphamide/ etoposide/cisplatin]) in 49 consecutive stem cell collection attempts in patients with MM exposed to prior lenalidomide. The primary endpoint was the ability to collect sufficient stem cells for at least two transplants (minimum 5×106 CD34+ cells/kg), comparing results in terms of total exposure to lenalidomide and time elapsed from lenalidomide exposure until the mobilization attempt. The secondary endpoint was number of apheresis days required to meet collection goal. Resilts: Twenty-four patients underwent PG mobilization and twenty-five with CG (21 with G-CSF + cyclophosphamide, 4 with G-CSF+DCEP). The two groups did not differ in terms of total amount of lenalidomide exposure: median number of lenalidomide cycles for patients mobilized with PG was 6.5 (range 1.2–86.6), vs. 6 (range 2–21.6), for patients mobilized with CG (P = 0.663). The median time between mobilization and last lenalidomide dose was also similar between the two groups: 57.5 (range 12–462) days for PG vs. 154 (range 27–805) days for CG (P = 0.101). There was an equivalent rate of successful collection of 100% for PG and 96% for CG, P = 0.322. One patient failed collection in the CG group due to emergent hospitalization for septic shock during a period of neutropenia; no patient collected with PG had a serious adverse event that interrupted the collection process. Stem cell yield did not differ between the two arms (13.9 vs. 18.8 × 106 million CD34+ cells/kg for PG vs. CG respectively, P = 0.083). Average time to collection goal was also equal, with a median of time of 1 day required in both groups, (range 1–2 days for PG, 1–5 days for CG, P = 0.073). There was no relationship between amount of lenalidomide exposure and stem cell yield with either PG (P = 0.243) or CG (P = 0.867). Conclusion: A plerixafor + G-CSF mobilization schedule is equivalent in efficacy to chemotherapy + G-CSF in obtaining adequate numbers of stem cells for two autologous stem cell transplants in patients with MM exposed to lenalidomide; however, PG may be a less toxic approach than chemomobilization. Number of lenalidomide cycles has no impact on chances of stem cell collection success using either method. Disclosures: Mark: Celgene Corp: Speakers Bureau; Millenium Corp: Speakers Bureau. Zafar: Celgene Corp: Speakers Bureau. Niesvizky: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding.

Investigational Agent MLN2238/MLN9708, a Specific, Orally Available, Small Molecule Proteasome Inhibitor, Shows Promising In Vitro Activity Against Multiple Myeloma Cell Lines

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3014-3014
Author(s):  
Giada Bianchi ◽  
Vijay G. Ramakrishnan ◽  
Teresa Kimlinger ◽  
Jessica Haug ◽  
S. Vincent Rajkumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Er Stress ◽  
Cell Lines ◽  
Small Molecule ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Proteasome Inhibitors ◽  
Biologically Active ◽  
Investigational Agent

Abstract Abstract 3014 Background: Proteasome inhibitors have proven particularly effective in treatment of multiple myeloma, the second most frequent hematologic malignancy in the western world. Bortezomib, the first in class proteasome inhibitor in clinical use, was first approved in 2003 via fast FDA track, given the remarkable activity shown during phase II clinical trials. Nevertheless, more than 50% of multiple myeloma patients did not respond to single agent bortezomib when administered as second line agent. Moreover, bortezomib is only available for intravenous administration, representing a cumbersome therapy for patients, and its use is limited by significant toxicities (especially peripheral neuropathy). MLN9708 (Millennium Pharmaceuticals, Inc.), an investigational orally available, small molecule, is a potent, specific and reversible inhibitor of the 20S proteasome. It is currently under clinical investigation for the treatment of hematologic and non-hematologic malignancies. Upon exposure to aqueous solutions or plasma, MLN9708 rapidly hydrolyzes to MLN2238, the biologically active form, and MLN2238 was used for all of the preclinical studies reported here. In vitro biochemistry studies have shown that MLN2238 has a faster dissociation rate from the proteasome compared to bortezomib, and in vivo studies of MLN2238 have shown antitumor activity in a broader range of tumor xenografts when compared to bortezomib. Given these encouraging preclinical results, we set to investigate the anti-myeloma activity of MLN2238 in vitro. Results: MLN2238 proved to have anti-proliferative and pro-apoptotic activity against a broad range of MM cell lines with EC50 at 24 hours ranging between 10 and 50 nM, even in relatively resistant MM cell lines (OPM2, DOX6, RPMI, etc.). In MM.1S cells, induction of apoptosis was time and dose dependent and related to activation of both caspase 8 and 9. When compared to MM.1S treated for 24 hours with EC50 dose of bortezomib, treatment with EC50 dose of MLN2238 resulted in the same extent of caspases cleavage occurring at an earlier time point (8-12 hours), possibly suggesting more rapid onset and/or irreversibility of apoptosis in cells treated with MLN2238. Treatment with MLN2238 was associated with early, but persistent induction of endoplasmic reticulum (ER) stress with BiP being induced 2–4 hours after treatment with EC50 dose and gradually increasing over time. While bortezomib has been associated with early induction and late decrease in proteins involved in ER stress, MLN2238 appears to induce a persistent rise in these factors, suggesting either more sustained proteasome blockade with stabilization of proteasome substrates or de-novo induction of unfolded protein response (UPR) genes. MLN2238 also proved effective in reducing phosphorylation of ERK1-2 with no overall alteration in the total ERK level, thus accounting for the observed reduction in proliferation upon treatment. Preliminary data indicate potential for additive and synergistic combination with widely used drugs, including doxorubicin and dexamethasone. Conclusion: While further clinical data are needed to establish the effectiveness of MLN2238 in the treatment of multiple myeloma, these preliminary nonclinical data, together with the favorable biochemical and pharmacokinetic properties, including oral bioavailability, make the investigational agent MLN9708 an appealing candidate for treatment of multiple myeloma. Further in vitro data could help establish whether a difference in the apoptotic mechanisms exist between MLN2238 and other proteasome inhibitors, primarily bortezomib, and could also help inform combination treatment approaches aimed at increasing effectiveness, overcoming bortezomib resistance and decreasing toxicity. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Components of Global Quality of Life In Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4735-4735
Author(s):  
Catherine D Williams ◽  
Irina Proskorovsky ◽  
Philip Lewis ◽  
K. Jack Ishak ◽  
Krista A Payne ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Multiple Myeloma ◽  
Body Image ◽  
Research Funding ◽  
Multiple Regression Model ◽  
Future Perspective ◽  
P Value ◽  
Disease Symptoms ◽  
The Mean

Abstract Abstract 4735 Introduction: Symptoms of multiple myeloma (MM) and the adverse events (AEs) associated with MM treatment can be debilitating on many levels. A better understanding of the extent to which patients are affected and how this in turn impacts global health-related quality of life (HRQOL) can improve management of patients. Methods: A survey in 11 centers in the United Kingdom and Germany gathered, among other items, data on HRQOL, measured by the European Organization for Research and Treatment of Cancer's (EORTC) generic cancer and MM modules (QLQ-C30 and QLQ-MY20 scales), from a cross-section of patients with multiple myeloma at various phases of the disease. The QLQ-C30 is comprised of a global QOL domain, 5 functional and 3 symptom domains, and 6 AE items; the QLQ-MY20 includes scales for disease symptoms, treatment side-effects, future perspective and body image. This analysis aimed to explore the association between individual QOL scales (from QLQ-C30 and QLQ-MY20) and global QOL. Values for each scale range from 0 to 100; higher values indicate better HRQOL for the global, functional, future perspective and body image scales, and worse HRQOL for the AE items, symptom domains, disease symptoms and side-effects scales. Scoring of the QLQ-C30 and MY-20 scales was described previously by Fayers et al. [i] and Cocks et al. [ii] respectively. The distribution and correlations (Spearman) between the various scales was explored. Moreover, a multiple linear regression analysis was carried out to assess the association between individual scales and global QOL (from QLQ-C30) with the aim to identify those that independently impact global QOL. Each scale was first considered alone as a predictor of global QOL; those with a statistically significant association at a p-value ≤ 0.10 were included in a multiple regression model. This was then trimmed to exclude scales that became non-significant (p-value > 0.10). Results: The survey included 154 patients: 63.0% were male and the mean age was 66.4 (SD: 10.0). Mean time since diagnosis was 3.7 years (SD: 3.7), 51.9% were currently on treatment, and 42.9% had at least one prior line of MM therapy. The mean global QOL score was 60.1 (SD: 25.5), with the middle two quartiles of patients scoring between 41.7 and 83.3. Cognitive and emotional functioning scores had means near or above 80, suggesting that these aspects of HRQOL were less affected than role (62.9 (IQR: 33.3–100)), social (63.9(IQR: 33.3–100)) and physical functioning (68.7(IQR:53.3-93.3)). While body image scores were generally high (77.9 (IQR:66.7-100)), future perspective appeared to be relatively more affected (59.9 (33.3-77.8)). Patients’ HRQOL is most affected by pain and fatigue (based on symptom and AE scales of the QLQ-C30), with means above 30, followed by insomnia and dyspnoea with means above 20, while diarrhea and nausea/vomiting scales had the lowest mean scores (below 10). The Disease Symptom (23.3 (IQR:0-38.9)) and Side Effect scale scores (19.5 (IQR:7.4-29.6)) from the QLQ-MY20 were consistent with the AE and symptom scales from the QLQ-C30. All of the domains except diarrhea and nausea/vomiting individually showed at least moderate correlations with global QOL (Spearman correlations above 0.25 in absolute value), but also exhibited strong correlations between themselves. The final multiple regression model retained physical and social functioning, fatigue, disease symptoms (QLQ-MY20) and future perspective scales (QLQ-MY20), all of which had relatively similar strength of association with global QOL. Conclusion: This study demonstrates that the impact of MM and treatment AEs can be seen on various dimensions of patients’ HRQOL, particularly reduced physical and social functioning, future perspective and various disease symptoms such as bone pain (as captured by the disease symptoms scale of the QLQ-MY20) and fatigue. Fayers P, Aaronson N, Bjordal K, Groenvold M, Curran D, Bottomley A: The EORTC QLQ-C30 Scoring Manual. 3 Edition EORTC Quality of Life Group, Brussels 2001. [ii]Cocks K, Cohen D, Wisloff F, et al. An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma. Eur J Cancer 2007;43:1670-1678. Disclosures: Williams: Celgene: Honoraria; Jansen Cilag: Consultancy, Honoraria. Off Label Use: Some of the patients in the study received Thalidomide for the treatment of relapsed or refractory multiple myeloma. Proskorovsky:United BioSource Corporation: Consultancy, Research Funding. Lewis:Celgene International SARL: Employment. Ishak:United BioSource Corporation: Consultancy, Research Funding. Payne:United BioSource Corporation: Consultancy, Research Funding. Lordan:United BioSource Corporation: Consultancy, Research Funding. Davies:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Peters:Celgene: Consultancy.

Secondary Primary Malignancies in Patients with Multiple Myeloma Treated with High-Dose Chemotherapy and Autologous Blood Stem Cell Transplantation,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4087-4087 ◽  
Author(s):  
Roland Fenk ◽  
Florian Neubauer ◽  
Ingmar Bruns ◽  
Christian Saure ◽  
Thomas Schroeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Blood Stem Cell ◽  
Novel Agents ◽  
High Dose ◽  
Blood Stem Cell Transplantation

Abstract Abstract 4087 Introduction: Secondary primary malignancies (SPM) are an emerging issue in patients with multiple myeloma (MM) since the French IFM 99–02 trial has been closed as a consequence of a higher incidence of SPM in patients who had received lenalidomide as maintenance treatment compared to the patients in the placebo arm. Methods: To evaluate the incidence of SPM in the group of patients, who were treated with high-dose therapy (HDT) followed by autologous peripheral blood stem cell transplantation (PBSCT), we retrospectively looked at a homogeneous group of 313 consecutive patients, who were diagnosed with MM and had received HDT and autologous PBSCT at our hospital between December 1994 and January 2009. Induction treatment consisted of conventional chemotherapy without novel agents in 95% of patients and maintenance treatment was given with interferon or thalidomide in 37% und 35% of patients, respectively. Results: Within 313 patients with a median age of 55 (range: 31–74) years at diagnosis, we observed 18 (5.8%) patients who developed a SPM at various time points during the course of their disease. The number of patients who developed a solid neoplasm or a hematologic malignancy was identical. While the types of solid tumor observed varied greatly, we noted 8 patients with MDS/AML and only one patient with Hodgkins Disease. The median time from diagnosis of MM to the occurrence of SPM was 56 months (range: 14–127). The cumulative incidence of SPM was 19.7% with a rate of 0.7%, 5.8% and 15.7% at 2, 5 and 10 years after diagnosis without statistical differences between the group of patients with solid tumors (0.3%, 4.4%, 7.5%) and those with hematologic malignancies (0.4%, 1.8%, 9.3%). OS from the time of diagnosis in our group of 18 patients with SPM was not significantly different from that of patients without SPM with in median 70 and 83 months (p=0.7, HR 0.9 (0.5–1.7)), respectively. The same was true, when a landmark analysis was performed for patients alive after 2, 5 and 8 years with hazard ratios of 0.9 (95%CI 0.5–1.7, p=0.8), 0.6 (95%CI 0.3–1.4, p=0.2) and 1.0 (95%CI 0.2–4.3, p=1.0), respectively. In line with this finding, we found that survival time of more than 5 years from the time of diagnosis was the only prognostic parameter indicating a greater risk for the development of SPM (HR 4.7 (95%CI 1.1–19.8), p=0.04). In particular, we did not find any relationship to the incidence of SPM and the treatment with novel agents. The incidence rate of 206 patients, who were exposed to thalidomide was 6% (n=13, HR1.4 (95%CI 0.5–4.0), p=0.5), while of the 123 patients exposed to bortezomib 5 developed a SPM (4%, HR 0.4 (95%CI 0.1–1.1), p=0.1). There were two cases of SPM among the 71 patients following lenalidomide treatment (3%, HR 0.4 (95%CI 0.1–1.5), p=0.2). Having a closer look at the maintenance setting, which is associated with a longer duration of drug exposure, we did not find a higher incidence of SPM in patients treated with thalidomide maintenance after HDT in comparison to patients who had received interferon or no maintenance therapy (HR 1.0, 95%CI 0.3 – 3.2, p=1.0). Conclusions: In conclusion, the incidence of SPM in patients with MM treated with HDT is increased, especially for patients with a prolonged life span. SPM were not related to various treatment modalities including maintenance treatment with thalidomide. As a consequence on the available data, physicians should be aware of the risk of SPM and diagnostic measures to detect SPM should be included in the daily clinical workup of patients with MM. Disclosures: Fenk: Celgene: Consultancy, Research Funding; Ortho Biotec: Consultancy. Germing:Celgene: Consultancy, Research Funding. Gattermann:Celgene: Consultancy, Research Funding. Kobbe:Celgene: Consultancy, Research Funding; Ortho Biotec: Consultancy.

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