A Phase IB, Multi-Center, Open-Label Dose-Escalation Study of Oral Panobinostat (LBH589) and I.V. Bortezomib in Patients with Relapsed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3852-3852 ◽  
Author(s):  
Jesús F. San-Miguel ◽  
Orhan Sezer ◽  
David Siegel ◽  
Andreas Guenther ◽  
Maria-Victoria Mateos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Clinical Investigation ◽  
Advisory Board ◽  
Protease Inhibition ◽  
Advisory Committees ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Synergistic Cytotoxicity

Abstract Abstract 3852 Poster Board III-788 Introduction Panobinostat (LBH589) is a highly potent pan-deacetylase inhibitor (pan-DACi), inclusive of HDAC6, which disrupts aggresome function, promotes accumulation of cytotoxic misfolded protein aggregates and triggers myeloma cell death. Combination of pan-DAC and protease inhibition by co-treatment with panobinostat (PAN) and bortezomib (BTZ) has demonstrated synergistic cytotoxicity in vitro and in vivo in multiple myeloma (MM) cell lines and may provide increased efficacy in patients with MM. The primary objective of this Phase Ib trial is to determine the maximum tolerated dose (MTD) of oral PAN when combined with BTZ in patients with relapsed or refractory MM. Safety, tolerability, PK/PD, and preliminary efficacy are the secondary objectives. Results A total of 29 patients have been enrolled into four completed dosing Cohorts: (I) 10 mg PAN (TIW) + 1 mg/m2 BTZ (i.v., Days 1, 4, 8, 11) during a 21-day cycle; (II) 20 mg PAN + 1 mg/m2 BTZ; (III) 20 mg PAN + 1.3 mg/m2 BTZ; (IV) 30 mg PAN + 1.3 mg/m2 BTZ. Enrollment into Cohort V is ongoing at 25 mg PAN + 1.3 mg/m2 BTZ with 6 patients accrued to date. In Cohorts I– IV, the median number of prior therapies was 3 (range 1–6); 25 patients had at least one prior auto-SCT. Of 16 BTZ pretreated patients, 11 were refractory to their last prior BTZ-based therapy (9 with PD, 2 with SD on BTZ). Median time on study has been 97 days (range 7–424). Overall, the combination of PAN and BTZ was safe and tolerated in Cohorts I - III with one dose-limiting toxicity (DLT) (Gr 4 afebrile neutropenia) in Cohort II. In Cohort IV, four DLTs were reported: two Gr 4 thrombocytopenias,(requiring platelet transfusions), Gr 3 pneumonia, and Gr 3 fatigue. In the subsequent Cohort V, PAN dose was de-escalated. Hematologic adverse events (AEs) have been frequent, including Gr 3/4 thrombocytopenia (25), neutropenia (18), and anemia (6). Non-hematologic AEs included: diarrhea (18), fever (15), nausea (14), fatigue (14), and asthenia (11). A total of 1,778 ECGs were centrally, reviewed with neither QTcF prolongation from baseline >60 msec nor absolute QTcF duration >480 msec noted. Gr 3/4 thrombocytopenia was manageable by dose modification and platelet transfusion; two patients only discontinued for this AE in Cohorts I – III and no hemorrhagic events were reported in association with thrombocytopenia. Encouraging clinical efficacy was observed in all four Cohorts, with 14 responders (partial response [PR] or better) in 28 evaluable patients (50%), including 4 with immunofixation (IF) negative complete response (CR). Four additional patients achieved minor responses, resulting in 64% overall response rate. Responses were also seen in the subset of patients refractory to prior BTZ, suggesting a strong clinical correlate for synergism of the PAN/BTZ combination: 6 of 10 (60%) BTZ-refractory evaluable pts responded, including 4 PR and 2 MR (see Table for details). Dexamethasone (DEX) was introduced at Cycle 2 (or 3) in 9 pts; 11 of 18 pts with a response did not receive DEX, including several pts refractory to BTZ. All 15 patients in Cohorts III and IV treated with the full registered dose of BTZ (1.3 mg/m2) in combination with PAN 20 mg experienced a clinical benefit; however, toxicity in Cohort IV was not acceptable. Conclusion The encouraging clinical anti-myeloma synergism of the PAN and BTZ combination in this trial warrants further clinical investigation in patients with refractory and relapsed MM. Given the frequency of thrombocytopenia and dose adjustments, the dosing schedule in subsequent Phase II/III studies will be modified to take the safety profile and dose-reduction/-interruption pattern into account. Disclosures: San-Miguel: Novartis: Advisory Board, Consultancy, Honoraria; J&J: Advisory Board, Consultancy, Honoraria; Millenium: Advisory Board, Consultancy, Honoraria; Celgene: Advisory Board, Consultancy, Honoraria. Sezer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Siegel:Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Speakers Bureau. Guenther:Novartis: Consultancy, Research Funding. Mateos:Ortho Biotech: Speakers Bureau; Novartis: Honoraria. Cavo:Novartis: Honoraria. Blade:Novartis: Honoraria; Janssen-Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Boccadoro:Celgene: Honoraria; Janssen Cilag: Honoraria. Bengoudifa:Novartis Pharma AG: Employment. Klebsattel:Novartis Pharma AG: Employment. Bourquelot:Novartis Pharma AG: Employment. Anderson:Millenium: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

A Phase I Study of Bendamustine Combined with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1856-1856 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Amy O’Sullivan ◽  
Silvana Lalo ◽  
Carrie Kruppa ◽  
Diane Gardner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Advisory Board ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1856 Poster Board I-882 Background: Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia. Conclusions: Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation. Disclosures: Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

A Phase I Study of Vorinostat, Lenalidomide, and Dexamethasone In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Excellent Tolerability and Promising Activity In a Heavily Pretreated Population

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1951-1951 ◽  
Author(s):  
Paul Richardson ◽  
Donna Weber ◽  
Constantine S. Mitsiades ◽  
Meletios A. Dimopoulos ◽  
Jean-Luc Harousseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase I Study ◽  
Response Rate ◽  
Advisory Board ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1951 Background: Although novel treatment combinations for multiple myeloma (MM) have improved outcomes, the disease remains incurable and new drug combinations are urgently needed. Vorinostat is an oral histone deacetylase inhibitor approved in the United States for treatment of patients (pts) with advanced cutaneous T-cell lymphoma who failed prior therapies. Vorinostat alters gene expression and protein activity, promoting MM cell death through multiple pathways, and has been shown in preclinical studies to synergistically enhance the anti-MM activity of bortezomib and immunomodulatory drugs, including lenalidomide, with or without dexamethasone. Aims: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) of vorinostat plus lenalidomide and dexamethasone in pts with relapsed or relapsed and refractory MM. Secondary objectives included overall safety, tolerability, response rate, duration of response, and time to progression (TTP). Methods: Pts in this Phase I multicenter open-label study were sequentially enrolled into 1 of 5 escalating doses of the combination regimen using a standard 3 + 3 design for ≤8 cycles. Pts who tolerated treatment and experienced clinical benefit were eligible for enrollment in an extension phase. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria (version 3.0). Response was assessed using the modified European Group for Blood and Marrow Transplantation criteria and International Myeloma Working Group Uniform Criteria. Safety and efficacy data were analyzed using summary statistics, except for TTP, which was estimated by the Kaplan-Meier method. Results: As of July 15, 2010, 31 pts were treated and evaluable for toxicity; 4 pts remain on study. Most pts had received prior thalidomide (n=22; 71%), bortezomib (n=20; 65%), or lenalidomide (n=14; 45%), with a median of 4 prior therapies (range, 1–10). The patient population contained both high-risk and low-risk pts, based on cytogenetic and/or fluorescence in situ hybridization analyses. Most adverse events (AEs) were mild or moderate in severity. The most common grade ≥3 treatment-related AEs, experienced by 19 (61%) pts, were neutropenia (26%), thrombocytopenia (16%), diarrhea (13%), anemia (10%), and fatigue (10%); 8 pts discontinued due to toxicity. One dose-limiting toxicity (grade 3 diarrhea lasting >48 h) was observed at the maximum assessed dose (level 5), but MTD was not reached (Table) and there were no treatment-related deaths. Among 30 pts evaluable for response, the median TTP was 32 weeks (5 mo), and 4 pts remain on study as of the data cutoff date; 26 of 30 pts (87%) have achieved at least stable disease (SD). Best single responses included 2 complete responses, 3 very good partial responses (VGPR), 11 partial responses (PR), and 5 minimal responses (MR), with 5 pts achieving SD and 4 developing progressive disease, resulting in an overall response rate (ORR; PR or better) of 53%. Of 13 evaluable pts who had previously received lenalidomide, a best single response of SD or better was observed in 9 (69%; 2 VGPR, 3 PR, 1 MR, 3 SD), resulting in a 38% ORR. Notably, SD or better (2 PR, 1 MR, 3 SD) was observed in 60% of 10 evaluable pts who were relapsed, refractory, or intolerant to previous lenalidomide-containing regimens. Conclusions: Preliminary data from this Phase I study suggest that vorinostat plus lenalidomide and dexamethasone is a convenient and generally well-tolerated regimen with promising activity for relapsed or relapsed and refractory MM. The MTD for this combination was not reached. Importantly, responses were observed in pts who had received prior lenalidomide, bortezomib, and thalidomide. Further evaluation of this regimen is planned in future trials. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Vorinostat, Lenalidomide, and Dexamethasone for treatment in Multiple Myeloma. Weber:Novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; Celgene- none for at least 2 years: Honoraria; Millenium-none for 2 years: Honoraria; Celgene, Millenium, Merck: Research Funding. Mitsiades:Millennium: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck & Co.: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centrocor: Consultancy, Honoraria; PharmaMar: Patents & Royalties; OSI Pharmaceuticals: Research Funding; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding. Dimopoulos:MSD: 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. Harousseau:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Houp:Merck Research Laboratories: Employment. Graef:Merck Research Laboratories: Employment. Gause:Merck Research Laboratories: Employment. Byrne:Celgene Corporation: Employment, Equity Ownership. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board.

Lin28B/Let-7 Axis Regulates Multiple Myeloma Proliferation By Enhancing c-Myc and Ras Survival Pathways

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 273-273
Author(s):  
Salomon Manier ◽  
John T Powers ◽  
Antonio Sacco ◽  
Michaela R Reagan ◽  
Michele Moschetta ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Advisory Board ◽  
Loss Of Function ◽  
Advisory Committees ◽  
Expression Levels ◽  
Gain And Loss

Abstract Background MicroRNAs (miRNAs) play a pivotal role in tumorigenesis, due to their ability to target mRNAs involved in the regulation of cell proliferation, survival and differentiation. Lin28B is an RNA binding protein that regulates Let-7 miRNA maturation. Lin28B and Let-7 have been described to act as oncogenes or tumor suppressor genes, respectively, as demonstrated both in solid cancer and hematologic malignancies. However, the role of the Lin28B/Let-7 axis in Multiple Myeloma (MM) has not been studied. Method Lin28B level expression in MM patients was studied using previously published gene expression profiling (GEP) datasets. Let-7 expression levels were assessed in CD138+ primary MM cells and bone marrow stromal cells (BMSCs) by using PCR, as well as in circulating exosomes using miRNA array (Nanostring® Technology). Exosomes were collected from both normal and MM peripheral blood, using ultracentrifugation; and further studied by using electron microscopy and immunogold labeling for the detection of CD63 and CD81. The knockdown of Lin28B was performed on MM cell lines (U266, MM.1S, MOLP-8) by using a lentiviral Lin28B shRNA. Gain- and loss-of function studies for Let-7 were performed using Let-7 mimic and anti-Let-7 transfection in MM cell lines (MM1S, U266) and primary BMSCs. Cell proliferation has been evaluated by using thymidine assays. Effects of Let-7 and Lin28B on signaling cascades have been evaluated by western blot. Results Two independent GEP datasets (GSE16558; GSE2658) were analyzed for Lin28B expression, showing a significantly higher level in MM patients compared to healthy controls. In addition, high Lin28B levels correlated with a shorter overall survival (p = 0.0226). We next found that the Let-7 family members are significantly down-regulated in MM primary cells, particularly Let-7a and b (5 fold change, p < 0.05), as demonstrated by using qRT-PCR. Similarly, miRNA arrays showed a lower expression of Let-7-related miRNAs in circulating exosomes obtained from MM patients compared to healthy individuals. We further dissected the functional relevance of Lin28B in MM cells, by performing Lin28 knockdown (KD) in MM cell lines (U266, MOLP-8). This led to a significant decrease in MM cell proliferation associated with G1 phase cell cycle arrest. This was supported by up-regulation of Let-7 and down-regulation of c-Myc, Ras and Cyclin D1 in Lin28 KD MM cells. To further prove that Lin28B-dependent effects on MM cells are mediated by Let7, we next showed that let-7 gain- and loss-of-function studies regulate MM cell proliferation and Myc expression. Lin28B regulation in MM cells is dependent on Let-7, as demonstrated by an increase of both cell proliferation and c-Myc expression after anti-Let-7 transfection in the Lin28B KD cells. We therefore studied the regulation of Let-7 in MM cells through the interaction with BMSCs. Let-7 expression levels were significantly lower in BMSCs obtained from MM patients compared to healthy donors. Interestingly, the Let-7 expression level in MM cells was increased after co-culture with Let-7 over-expressing BMSCs, associated with a decrease of both cell proliferation and c-Myc expression. This suggests a potential transfer of Let-7 from BMSCs to MM cells. Conclusion This work describes a new signaling pathway involving Lin28B, Let-7, Myc and Ras in MM. Let-7 expression in MM cells is also regulated through the interaction of MM cells with BMSCs, leading to cell proliferation and Myc regulation in MM. Interference with this pathway might offer therapeutic perspectives. Disclosures: Leleu: CELGENE: Honoraria; JANSSEN: Honoraria. Daley:Johnson and Johnson: Consultancy, Membership on an entity’s Board of Directors or advisory committees; MPM Capital: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity’s Board of Directors or advisory committees; iPierian: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Solasia, KK: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Ghobrial:Onyx: Advisoryboard Other; BMS: Advisory board, Advisory board Other, Research Funding; Noxxon: Research Funding; Sanofi: Research Funding.

scholarly journals Spatiotemporal Assessment of Immunogenomic Heterogeneity in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-15 ◽  
Author(s):  
Maximilian Merz ◽  
Almuth Maria Anni Merz ◽  
Jie Wang ◽  
Lei Wei ◽  
Ahmed Belal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Advisory Board ◽  
Braf Inhibitors ◽  
Healthy Individuals ◽  
Advisory Committees ◽  
Site Specific

Introduction: Therapy and immune mediated processes are associated with clonal evolution in multiple myeloma (MM). In this study, we performed whole-exome sequencing (WES) and single cell RNA sequencing (scRNA-seq) on plasma cells (PC) from bone marrow aspirates of the iliac crest (BM) and corresponding osteolytic lesions (OL) to investigate spatial heterogeneity in patients with newly diagnosed (NDMM) and relapsed/refractory MM (RRMM). Next generation flow (NGF) and T-cell receptor sequencing (TCRseq) were performed to investigate the immunogenomic landscape surrounding malignant PC. Methods: In a prospective trial, 18 patients (NDMM: n=10; RRMM: n=8) consented to an imaging-guided biopsy of an OL in addition to the regular BM sampling. At inclusion, 37 different locations were biopsied. Follow-up samples were obtained from 5 patients in remission after therapy. After CD138+ selection, PC were subjected to WES and scRNA-seq (Chromium, 10x genomics). TCRseq was performed using multiplex PCR (ImmunoSEQ, Adaptive biotechnologies) on the CD138- fraction. For scRNA-seq data analyses, Cell Ranger (v3.1.0) and the Seurat R toolkit (v3.1) were used. TCRseq data were analyzed with immunoSEQ ANALYZER (v3.0) and the immunarch R toolkit (v0.6.6.). NGF was performed to study subsets of T-, B-, NK- and dendritic cells (DC). Results: Median PC infiltration was higher in OL compared to random BM (50.0% vs 12.5%, p=0.041). WES revealed more mutations in RRMM compared to NDMM (median; range: 189;120-523 vs 71;23-136, p&lt;0.001). Based on mutational profiles from WES, 4 of 18 patients showed a branching evolution in PC isolated from OL. Three of the 4 patients had RRMM and one patient with NDMM had a prior history of solitary plasmacytoma. PC were obtained from OL with adjacent extramedullary disease (EMD) in 3 of 4 patients with branching evolution. Among site-specific mutations, we found in one patient two distinct BRAF mutations: V600E in the BM and G469R in the OL. An additional NRAS mutation (G12D) was found in the OL. BRAF G469R and NRAS G12D cause resistance to BRAF inhibitors, although this patient was naïve to BRAF-inhibitors. Clonal evolution was also reflected by chromosomal aberrations, including site-specific chromothripsis of chromosome 1 in a patient with RRMM. Even in patients without spatially divergent clones as detected by WES, scRNA-seq of more than 150,000 PC from 10 patients and 21 different locations revealed multiple clones. Distinct PC clones were identified by differential expression of genes associated with homing to the BM (CXCR4), malignant transformation (Jun/Fos, CD27, CD79a), apoptosis (BCL-2) bone disease (DKK1) and LAMP-5. In a patient with NDMM in remission after induction therapy, scRNA-seq demonstrated the emergence of a PC clone characterized by the overexpression of Interferon-induced genes (ISG15, IFI27, IFI44L) compared to the initially predominant PC clones. Next, we investigated spatiotemporal differences of immune cells. Estimation of median TCR richness using an abundance-based estimator (Chao1) revealed significantly lower values in patients with RRMM (120444; 57706-212744) compared to NDMM (389341; 50318-525082, p&lt;0.001) and nine healthy individuals (460278; 138326-696419, p&lt;0.001). No significant differences were found for TCR clonality as indicated by Simpson's D. While longitudinal tracking of TCR clones at primary diagnosis showed no clonal expansion after treatment, induction therapy restored sample richness in patients with NDMM to levels of healthy individuals (p=0.61). Overlap analysis showed a high concordance of TCR repertoires from OL and random BM with Morisita indices ranging in 90% of patients from 0.80 to 0.95. Nevertheless, significant site-specific expansion of TCR clones was detected. In accordance with TCRseq, NGF showed in the BM of patients with RRMM more regulatory T-cells (p=0.048) and less myeloid DC (p=0.024), Th9 cells and CD8 effector memory T-cells compared to NDMM. Conclusion: We report the first prospective clinical trial to investigate spatiotemporal immunogenomic heterogeneity in multiple myeloma as assessed by WES and scRNA-seq of PC and NGF and TCRseq of the non-PC compartment. We demonstrate spatial evolution and reduced TCR diversity especially in patients with RRMM and/or EMD. ScRNA-seq adds another layer of complexity compared to WES and helps identifying how PC create an immune suppressive BM niche. Disclosures Merz: Amgen, BMS, Celgene, Takeda: Honoraria. Block:GlaxoSmithKline LLC: Current Employment. McCarthy:Karyopharm: Consultancy, Honoraria; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Genentech: Consultancy, Honoraria. Hillengass:Adaptive, Amgen, BMS, Celgene, GSK, Janssen, Oncotracker, Takeda: Honoraria.

scholarly journals Maintenance and Consolidation Regimens after a Second Autologous Transplant for Multiple Myeloma: A Decade of Experiences

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5700-5700
Author(s):  
Ghulam Rehman Mohyuddin ◽  
Maire Okoniewski ◽  
Osama Diab ◽  
Siddhartha Ganguly ◽  
Al-Ola Abdallah ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Standard Of Care ◽  
Advisory Board ◽  
Advisory Committees ◽  
Fda Approval ◽  
Novel Drugs ◽  
Significant Difference

Introduction: Autologous stem cell transplant (ASCT) followed by maintenance is the standard of care for eligible patients with multiple myeloma (MM). For patients that relapse, a second ASCT remains a viable option. However, the maintenance regimen to use for such patients remains an unanswered question, particularly in those with prior lenalidomide exposure. We retrospectively analyzed patients receiving two autologous transplants for a diagnosis of MM at our institution from 2008 to 2018 to determine maintenance strategies and outcomes upon completion of a second transplant. Methods: A total of 189 patients received two or more autologous transplants for MM at our institution from 2008 to 2018. Patients with planned tandem transplants, or those that proceeded directly to another transplant without interval progression were excluded. The remaining 135 patients were analyzed. Results: Patient characteristics are shown in Table 1. After first ASCT, 94 out of 135 patients (69.6 %) started maintenance therapy. The most commonly used maintenance regimen was lenalidomide in 63 patients, followed by bortezomib in 12 patients and thalidomide in 10 patients. Median time to initiation of maintenance from the date of transplant was 3.9 months. Overall median progression free survival (PFS) from transplant was 24.7 months with no significant difference between groups that received lenalidomide (median PFS: 21.2 months) or bortezomib (median PFS: 19.2 months, p:0.12). 10 (15.8%) patients discontinued lenalidomide due to toxicity, and 1 patient (8.3%) discontinued bortezomib due to toxicity. The median time from the onset of disease progression post first ASCT to time of second ASCT was 5.8 months. Strategies used post second ASCT includedconsolidation with triplet regimens followed by de-escalation (n=11) versus monotherapy (n=100). Table 2 highlights differing maintenance regimens used after the second ASCT. Median time from second ASCT to initiation of maintenance was 4.0 months. Median PFS post ASCT was 20.7 months. There was no statistically significant difference in PFS between the different regimens used (p=0.26), although there was a numerically higher discontinuation rate due to toxicity with older agents such as lenalidomide and bortezomib compared with newer agents such as daratumumab and pomalidomide. There was no statistically significant difference in the cytogenetic risk profile (p=0.21) or stage at diagnosis (p=0.36) between the groups that received different types of maintenance agents. However, patients receiving daratumumab as maintenance were more likely to have received more lines of therapy (median 5 for Daratumumab vs 3 for Lenalidomide, p=0.0001), and more likely to have previous exposure to daratumumab prior to second ASCT (92% vs 0% for other agents p=0.0001). Patients receiving daratumumab, carfilzomib or triple therapy were more likely to have been refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) (p=0.0001). Despite stratifying for use of newer novel drugs (FDA approval after 2010- pomalidomide, daratumumab, carfilzomib) vs older novel drugs (FDA approval before 2010- lenalidomide, bortezomib, thalidomide), there was no difference in PFS ( 21.2 months vs 20.4 months, p= 0.92), between these groups when used as part of a maintenance strategy. Conclusions: Our data show a variety of maintenance and consolidation regimens are used for patients with MM after their second ASCT. In this single-center, retrospective analysis, there was no clear superiority of a consolidative strategy using triplet over monotherapy, and no superiority of newer agents compared to older agents. This suggests that toxicity, prior therapies and their tolerance may be the more important patient-related factors for consideration when selecting an agent/agents. Randomized, prospective data will be important to ascertain the standard of care in this situation. Disclosures Ganguly: Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. McGuirk:Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation.

Results from Phase 1/2 Trial of Tagraxofusp in Combination with Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3145-3145 ◽  
Author(s):  
Paul G. Richardson ◽  
Myo Htut ◽  
Cristina Gasparetto ◽  
Jeffrey A. Zonder ◽  
Thomas G. Martin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: The bone marrow microenvironment of many multiple myeloma (MM) patients contains high levels of CD123-expressing plasmacytoid dendritic cells (pDCs). These pDCs have been shown to augment MM growth and contribute to drug resistance (Chauhan, et al., Cancer Cell, 2009). Tagraxofusp, a novel CD123 targeted therapy, has demonstrated high levels of anti-tumor activity in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive CD123+ malignancy of pDC origin. Tagraxofusp demonstrated potent in vitro and in vivo activity against MM cell lines and primary tumor samples via both a direct anti-MM effect and indirect pDC-targeting effect (Ray, et al., Leukemia, 2017), as well as demonstrating synergy in these systems when used in combination with traditional MM therapies including pomalidomide (POM). As such, targeting pDCs with tagraxofusp may offer a novel therapeutic approach in MM. Methods: This multicenter, single arm Phase 1/2 trial enrolled patients with relapsed or refractory (r/r) MM and tested two different doses of tagraxofusp (7 or 9 mcg/kg). Patients received tagraxofusp as a daily IV infusion for days 1-5 of a 28-day cycle as a single agent for the initial run-in cycle (cycle 0) and in combination with standard doses/administration of POM and dexamethasone (DEX) in cycles 1 and beyond. Objectives included evaluation of safety and tolerability, identification of the maximum tolerated or tested dose, and efficacy. Results: 9 patients with r/r MM received tagraxofusp (7 mcg/kg, n=7; 9 mcg/kg, n=2). 5 males, median age 65 years (range: 57-70), median 3 prior therapies (range 2-6). Median follow-up was 12 months (range: 7 - 19). The most common treatment-emergent AEs (TEAEs) were hypoalbuminemia 67% (6/9); chills, fatigue, insomnia, nausea and pyrexia each 56% (5/9); and dizziness, headache, hypophosphatemia, and thrombocytopenia each 44% (4/9). The most common grade 3 and 4 TEAEs were thrombocytopenia 44% (4/9) and neutropenia 33% (3/9). No grade 5 events reported. 5 patients treated with tagraxofusp and POM+DEX had a partial response (PR) after tumor evaluation. These patients demonstrated a rapid decrease in a set of myeloma-related laboratory values from pre-tagraxofusp treatment levels after the first combination cycle of tagraxofusp and POM+DEX. Additionally, these 5 patients demonstrated >50% decreases in peripheral blood pDC levels after both tagraxofusp monotherapy and combination therapy. Conclusions: Tagraxofusp was well-tolerated, with a predictable and manageable safety profile, when dosed in combination with POM+DEX in patients with r/r MM. Evidence of pDC suppression in peripheral blood and BM was observed in this patient population. 5 patients that received tagraxofusp and POM+DEX combination had PRs and decreases in pDC levels while on treatment with tagraxofusp. Given CD123 expression on pDCs in the tumor microenvironment and the potential synergy of tagraxofusp with certain MM agents including POM, tagraxofusp may offer a novel mechanism of action in MM. NCT02661022. Disclosures Richardson: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: 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, Research Funding; Bristol-Myers Squibb: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Zonder:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Rupprecht:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Chauhan:C4 Therapeutics.: Equity Ownership; Stemline Therapeutics: Consultancy. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder .

Vorinostat Combined with Bortezomib In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Update on the Vantage Study Program

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1952-1952 ◽  
Author(s):  
David S Siegel ◽  
Sundar Jagannath ◽  
Roman Hajek ◽  
Meletios A. Dimopoulos ◽  
Sung-Soo Yoon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Primary Objective ◽  
Advisory Board ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Ortho Biotech ◽  
Eortc Qlq

Abstract Abstract 1952 Background: Initial clinical response rates have improved significantly with current treatments for multiple myeloma (MM). However, most patients eventually relapse or become refractory to approved agents, prompting the development of additional targeted agents and combination regimens. Vorinostat is a first-in-class oral histone deacetylase inhibitor that regulates the expression of genes and proteins involved in tumor growth and survival, and is approved in the United States for the treatment of patients with advanced cutaneous T-cell lymphoma in whom prior therapies have failed. Bortezomib, a reversible proteasome inhibitor, is approved for the treatment of patients with MM who have received at least 1 prior therapy. The synergistic effects of vorinostat and bortezomib have been shown in preclinical studies and confirmed in Phase I trials in patients with relapsed/refractory (RR) MM, producing objective response rates (ORRs; partial response or better) of up to 42% in all patients (including those with bortezomib-refractory disease) and overall clinical benefit of up to 90%. Methods: Vantage 088 is a global, Phase III, randomized, double-blind study to investigate the safety and efficacy of vorinostat vs placebo in combination with bortezomib in patients with relapsed MM and progressive disease after 1–3 prior antimyeloma regimens. The primary objective is to determine the duration of progression-free survival, with a planned enrollment of 742 patients. Overall survival, time to progression, ORR, tolerability, and patient-reported outcomes (PROs) will be included as secondary and exploratory outcomes. A distinctive aspect of this study design involves the evaluation of PROs using validated instruments, including quality-of-life (QoL) questionnaires for cancer patients (EORTC QLQ-C30) and myeloma patients (EORTC QLQ-MY20) and the EuroQoL-5D, presenting an opportunity to correlate PROs with efficacy and safety data. Interim analysis will take place when at least 126 events have occurred. Vantage 095 is a Phase IIB open-label study to investigate the efficacy and tolerability of vorinostat combined with bortezomib in patients with RR MM who had received ≥2 prior antimyeloma regimens; were refractory to bortezomib; and were relapsed, refractory to, intolerant of, or ineligible for other MM therapies, including immunomodulatory drugs (IMiDs). The primary objective is to determine the ORR, with a planned enrollment of 142 patients. In both studies, patients receive 21-day cycles of intravenous bortezomib (1.3 mg/m2; days 1, 4, 8, and 11) combined with oral vorinostat 400 mg (or matching placebo in Vantage 088) once daily on days 1–14. Efficacy is assessed using European Bone and Marrow Transplantation Group criteria. Adverse events (AEs; including clinical and laboratory events) are assessed and recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). Results: Vantage 088: As of June 11, 2010, 349 patients (range, 1–17 cycles) were randomized. Patients received a median of 2 prior regimens (range, 1–3 regimens; 25% prior bortezomib, 48% prior thalidomide, and 12% prior lenalidomide). Vantage 095: As of June 11, 2010, 108 patients were enrolled. Patients (median age, 62 y; 57% men; 67% with Eastern Cooperative Oncology Group performance status 1) were heavily pretreated (median prior regimens, 5 [range, 2–17]). Interim efficacy data were reviewed in January 2010 by an independent data monitoring committee (DMC) for the first 43 patients enrolled; the futility threshold was passed, and final results are expected to be available 2Q2011. Conclusion: 2 ongoing global, multicenter, investigational trials are evaluating the efficacy and safety of combined vorinostat and bortezomib in patients with RR MM and are rapidly accruing patients. The Vantage 088 trial has passed the initial safety evaluations by the DMC, while interim results from Vantage 095 suggest that combined vorinostat and bortezomib may have clinical activity in patients with RR MM who are refractory to bortezomib and IMiDs and ineligible for other regimens. Disclosures: Siegel: Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board, Consultancy. Off Label Use: Vorinostat Combined with Bortezomib for treatment in Multiple Myeloma. Jagannath:Celgene: Honoraria; Millenium: Honoraria; Ortho Biotech: Honoraria; Onyx Pharma: Honoraria; Merck: Honoraria; Proteolix: Honoraria; Imedex: Speakers Bureau; Medicom World Wide: Speakers Bureau; Optum Health Education: Speakers Bureau; PER Group: Speakers Bureau. Hajek:Janssen-Cilag: Honoraria; Celgene: Honoraria; Merck, Sharp, and Dohme: Honoraria. Dimopoulos:MSD: 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; Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Graef:Merck Research Laboratories: Employment. Pietrangelo:Merck Research Laboratories: Employment. Lupinacci:Merck Research Laboratories: Employment. Reiser:Merck Research Laboratories: Employment. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Clonal-Heterogeneity and Propensity for Bone Metastasis in Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3370-3370
Author(s):  
Yuji Mishima ◽  
Michele Moschetta ◽  
Jiantao Shi ◽  
Francois Mercier ◽  
Salomon Manier ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Gene Signature ◽  
Advisory Board ◽  
Clonal Heterogeneity ◽  
Advisory Committees ◽  
Primary Tumors ◽  
Synonymous Mutations ◽  
Bm Niche

Abstract Rationale Multiple Myeloma (MM) is characterized by the presence of multiple disease foci disseminated throughout the skeleton suggesting continuous circulation and metastasis of myeloma cells from one site of the bone marrow (BM) to another leading disease progression. However the metastatic process in MM has not been well characterized. In addition, the role of specific subclones that have the propensity for metastasis and tumor colonization in the BM niche has not been investigated. In this study, we developed a new BM metastasis xenograft model to examine clonal heterogeneity in tumor colonization of distant bone niches. We identified a set of genes that characterize potential driver genes for metastasis in MM by genomic and transcriptomic profiles of metastatic and primary tumor clones. Methods The model was developed by performing bilateral femur transplantation from donor SCID-bg mice to the dorsum of recipient mice of the same background. To study metastasis, the donor femurs were injected with MM cells (human MM1S, IM-9 and murine 5TGM1) and then implanted in the recipient mice. At the time of hind limb paralysis, the BM cells were flushed from the host or implanted femurs and analyzed by flow-cytometry. To investigate clonal heterogenity, IM-9 cells were transformed with four fluorescent proteins (FPs) simultaneously and sorted into fifteen subpopulations of all combinations of FPs. A mixture composed by equal proportion of all 15 FPs-labeled cells (rainbow mixture) was prepared and then used for in vivo experiment. At the time of sacrifice, clonal distribution of metastasized tumors were analyzed and the predominant clones (winner clones) were flow-sorted for genomic and transcriptomic studies. Library preparation and sequencing were performed according to manufacturer's protocols. Sequencing data was processed by bcbio_nextgen. Briefly for RNA-seq data, raw reads were aligned to reference human genome GRCh37, and gene-level read counts were calculated. Data normalization and differential expression were analyzed with DESeq2. For DNA-seq data, raw reads were aligned to GRCh37. Somatic single nucleotide variants and INDEL were called by MuTect and Indelocator, respectively. Results All myeloma cell lines studied were able to metastasize from the BM of transplanted femurs to the host BM and mice eventually developed paralysis after 6 to 11 weeks. Experiments using rainbow cells consistently showed that only a sub-clone of single color was able to invade and populate the host BM after metastasis, while all 15 color populations were developed in primary tumors. Interestingly, metastatic clones from different mice had similar expression profiles, although these were labeled by different colors. The studies were confirmed in a second MM cell line (MM1S) showing a similar metastasis gene signature (Fig. A). Differential expression analysis identified 238 genes significantly down regulated in both IM-9 and MM1S metastatic tumors compared to matched primary tumors (FDR < 1%). Pathway enrichment analysis indicated that AP-1, ATF2 and NFAT pathways were significantly over-represented (FDR < 5%) (Fig. A). Moreover, this metastatic signature was significantly repressed in relapsed MM patient samples compared to normal controls (FDR < 7%) using GSE6477 dataset (Fig. B). We also compared mutation fraction (MF) distributions in primary and metastatic tumors using DNA-seq data. There was only one peak in each primary tumor (MF around 0.1), while were two peaks for metastatic samples (MF at 0.1 and 0.4), strongly suggests that metastatic clones are derived from a single subclone (Fig. C). Similar results were observed with analysis of only the non-synonymous mutations (Fig. D). Out of all genes with non-synonymous mutations, we found 11 genes that are also functionally related to the metastatic signature using co-expression networks-based prioritization method. Two genes TET1 and PPP2R3A are indicated as examples (Fig. D). Conclusions Here we show a new model of bone metastasis that can be used to examine mechanisms of cell dissemination and colonization of the BM niche. Our studies demonstrate that specific winner subclones have a higher metastatic potential and are likely driver clones for tumor metastasis in MM. On the molecular level, a metastatic gene signature was found to be consistently down regulated in metastatic tumor samples, and 11 genes were identified as potential drivers. Figure 1 Figure 1. Disclosures Munshi: Janssen Research & Development: Membership on an entity's Board of Directors or advisory committees. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Acetylon: Scientific Founder Other; Oncopep: Scientific Founder Other. Scadden:Fate Therapeutics: Consultancy, Equity Ownership. Ghobrial:Sanofi: Research Funding; Noxxon: Research Funding; BMS: Advisory board, Advisory board Other, Research Funding; Onyx: Advisory board Other.

Safety and Efficacy of Daratumumab with Lenalidomide and Dexamethasone in Relapsed or Relapsed, Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 84-84 ◽  
Author(s):  
Torben Plesner ◽  
Hendrik-Tobias Arkenau ◽  
Henk M. Lokhorst ◽  
Peter Gimsing ◽  
Jakub Krejcik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
M Protein ◽  
Open Label ◽  
Advisory Committees ◽  
Dose Escalation Study ◽  
Human Dose

Abstract Background: Daratumumab (DARA) (HuMax™-CD38), a human IgG1κ monoclonal antibody effectively mediates destruction of CD38-expressing malignant plasma cells. In the first-in-human dose-escalation study, 42% of heavily pretreated patients with relapsed, or relapsed, refractory (RR) multiple myeloma (MM) treated with DARA alone (≥4mg/kg) achieved partial response (PR) and 25% had minimal response (MR) (modified IMWG guidelines) (1). In preclinical studies, DARA + lenalidomide (LEN) enhanced killing of MM cells in vitro (2). We evaluated safety, pharmacokinetics (PK) and efficacy of DARA + LEN + low-dose dexamethasone (DEX) in patients with relapsed or RR MM. Methods: This ongoing phase I/II open-label multicenter study consisted of 2 parts: Part1 was dose-escalation study in which patients (≥ 18 years old) with life expectancy ≥3 months and ECOG status 0, 1 or 2 received DARA+LEN+DEX (DARA [2-16 mg/kg] per week [8 weeks], twice a month [16 weeks], then, once monthly until disease progression, unmanageable toxicity or 24 months in total; LEN [25 mg PO day 1 through 21 of 28-days cycles]; DEX [40 mg] once weekly). Part 2 was cohort expansion study which explored the testing of maximum tolerated DARA dose (MTD) (16 mg/kg) determined in part 1 along with LEN (25 mg mg PO day 1 through 21 of 28-days cycles) and DEX (40 mg) once weekly. Results: Data from 22 patients (13 patients [fully enrolled] from part 1 and 9 patients from part 2, [ongoing enrollment]) were presented at ASCO earlier this year (3). These results demonstrated that the most frequent (>30% patients) adverse events (AEs) were neutropenia and diarrhea; no dose limiting toxicities (DLTs) were reported. Infusion reactions (grade 1 and 2) were reported in 4 patients. 8 serious AEs were reported, all assessed as unrelated to DARA. MTD was not reached. DARA+LEN+DEX PK-profile was similar to DARA alone suggesting LEN and DEX do not affect the DARA PK-profile. Available preliminary efficacy data from 20 patients demonstrated marked decrease in M-protein in all patients; 15/20 patients achieved PR or better, 3/20 with CR, 6/20 with VGPR. Median time to response was 4.3 weeks (range: 2.1-11.3). Overall response rate (ORR) was 75% (15/20) combining all patients in part 1 and 2 and 92.3% (12/13) for part 1 patients, who had at least 2 months of follow-up or discontinued earlier. Conclusions: DARA+LEN+DEX has favorable safety profile with manageable toxicities in relapsed and RR MM. Encouraging early activity is seen with marked reduction in M-protein and majority of the patients (~75%) achieved PR or better. Results of approximately 30 patients from part 2 with at least 2 months of treatment exposure and 10 patients (out of 30 patients) with shortened duration of infusion will be presented. References Lokhorst et. al., EHA 2013 abstract #8512 van der Veer et. al., Haematologica 2011;96(2):284-90 Plesner et. al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8533). Disclosures Plesner: Genmab: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees. Lokhorst:Celgene: Research Funding; J&J: Research Funding; Genmab: Research Funding. Minnema:Janssen: Consultancy, Honoraria. Laubach:Onyx: Research Funding; Novartis: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Ahmadi:Janssen: Employment. Yeh:Janssen: Employment. Guckert:Janssen: Employment. Feng:Janssen: Employment. Brun:Genmab: Employment. Lisby:Genmab: Employment. Basse:Genmab: Employment. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Richardson: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; Millennium: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding.

scholarly journals Comparing the Efficacy of Aspirin or Low Molecular Weight Heparin or Vitamin K Antagonists in the Risk of Thromboembolic Events in Patients with Multiple Myeloma Treated with Lenalidomide-Based Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1121-1121
Author(s):  
Martha L Louzada ◽  
Maria-Victoria Mateos ◽  
Lenicio Siqueira ◽  
Jose-Maria B Bermejo ◽  
Enrique M Ocio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Expert Opinion ◽  
Research Funding ◽  
Low Dose ◽  
Vitamin K Antagonists ◽  
Advisory Board ◽  
Low Molecular Weight ◽  
Advisory Committees ◽  
Increased Risk

Abstract Background Malignancy is a well-recognized risk factor for venous thromboembolism (VTE). In multiple myeloma the incidence of VTE varies between 3% and 10%. Immunomodulatory drugs (IMiDs) play a crucial role in the treatment of myeloma and are known to be associated with an increased risk of arterial and venous thromboembolic events (TE). It appears that patients with newly diagnosed multiple myeloma (NDMM) are at higher risk for TE compared to patients with relapsed or refractory myeloma (RRMM) at the start of IMiD therapy. Lenalidomide is a second-generation IMiD which in combination to dexamethasone has shown to be an effective and well-tolerated therapy for patients with NDMM or RRMM. However, studies have consistently demonstrated the need for TE prophylaxis in patients receiving the combination lenalidomide-dexamethasone which leads to a 4.4-fold increased risk for VTE compared to dexamethasone alone in the absence of prophylactic anticoagulants. Panel consensus from the International Myeloma Work Group has agreed that the choice of thromboprophylaxis depends on the individual risk of TE, as determined by patient and treatment-related factors, such as obesity, prior VTE, central venous catheter, immobilization, recent surgery, comorbidities, use of erythropoietin stimulating agents and myeloma therapy. Aspirin (ASA) is recommended for patients with one or no risk factors, and LMWH for those with more than one risk factor. However, the optimal approach to thromboprophylaxis has not yet been established. In this study we sought to compare the efficacy of ASA or low molecular weight heparin (LMWH) or vitamin K Antagonists (VKA) in the prevention of VTE or arterial thromboembolism (ATE) in patients with myeloma using lenalidomide-based therapy. Methods We performed a retrospective chart review in 2 centres (London, Canada; and Salamanca, Spain) on patients with NDMM or RRMM multiple myeloma receiving lenalidomide-based therapy. We collected data from january 2010 to December2014. We included adult patients diagnosed with NDMM or RRMM receiving lenalidomide-based therapy. We did not include who received lenalidomide but refused or had contra-indication to thromboprophylaxis; or used single agent lenalidomide. Results We included 168 patients with multiple myeloma receiving lenalidomide-based therapy. 14 (8%) were NDMM and 154 (92%) had RRMM. Median age was 68 (31-89) and 106 (63%) were males. On average patients with RRMM had 1.6 previous treatments (range:1-11). 104 (62%) patients were low risk and 64 (38%) were high risk for TE. 140 (83%) patients received prophylaxis with ASA, 32 (19%) LMWH and 6 (4%) VKA. 10 patients started with prophylactic LMWH for an average of 2 months then were empirically switched over to ASA. In total, there were 18 (10.7%) TE of which, 16 (9.5%) were VTE: 3 PE, 12 DVT, 1 both. The relative risk for TE was the same regardless of risk stratification [RR=1.27 (95%CI 0.524 - 3.059; p=0.599)]. At TE diagnosis, 16 patients were on ASA, 1 on LMWH and 1 on VKA. The relative risk of TE was significantly higher for patients on ASA compared to LMWH or VKA [RR= 2.17 (0.522 - 9.03; p= 0.286). After the TE, all patients changed anticoagulation strategy: 15 of 16 (94%) patients with VTE switched to therapeutic LMWH and 1 who was on VKA had ASA added. In the 2 patients with ATE, 1 started on full dose LMWH and the other one continued on ASA. 16 of 18 patients with a TE continued on lenalidomide-based therapy. There was no recurrent arterial or venous TE within the first 6 months of anticoagulation after the TE. Univariate analysis suggested that BMI, use of ASA and sex could be potential predictors of TE; but the logistic regression was not statistically significant (Table). Conclusions In patients with multiple myeloma on lenalidomide-based therapy the preferred TE prophylactic approach is low dose ASA irrespective of patients' risk assessment for thromboembolism. However, VTE risk in these patients is not negligible (9.5%) and low dose ASA may not be the best prophylactic strategy for them. It appears that patients on ASA, obese and males are at higher risk for TE. Future studies are needed to confirm these assumpations. Table 1. Multivariate Analysis of the TE risk for patients with myeloma on lenalidomide-based therapy Odds Ratio Variable Point Estimate 95% CI p -value Sex 2.316 0.854 6.278 0.0989 BMI 1.705 0.501 5.804 0.3935 ASA 3.870 0.486 30.796 0.2010 Disclosures Louzada: Celegene: Consultancy, Other: advisory board and expert opinion; pfizer: Consultancy, Other: advisory board and expert opinion; janssen: Consultancy, Other: advisory board and expert opinion. Mateos:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ocio:Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Mundipharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MSD: Research Funding; Pharmamar: Consultancy, Research Funding; Janssen: Honoraria. Porras:Celgene: Consultancy, Honoraria.

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