Resistance to Lenalidomide in Multiple Myeloma Is Associated with a Switch in Gene Expression Profile

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1789-1789 ◽  
Author(s):  
Michael D. Amatangelo ◽  
Paola Neri ◽  
Maria Ortiz ◽  
Chad C. Bjorklund ◽  
Anita K. Gandhi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Research Funding ◽  
Gene Set Enrichment Analysis ◽  
Specific Gene ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Equity Ownership

Abstract Background: Cereblon (CRBN) is a substrate receptor of the Cullin 4 E3 ubiquitin ligase complex CRL4CRBN and is the molecular target of the IMiD® immunomodulatory drug lenalidomide. It has been shown that cereblon is required for the anti-proliferative activity of lenalidomide in multiple myeloma (MM) and that reduction of CRBN expression is associated with resistance to IMiD® compounds. Methods: RNA-seq analysis was performed on 12 paired MM patients samples of sorted CD138+ cells obtained prior to lenalidomide treatment initiation and after development of resistance. Transcriptome sequence data was generated on an Ion Torrent Proton sequencer with at least 70 million reads per sample. The STAR aligner was used to align raw reads to the Ensembl74 reference annotation. The HTseq and eXpress algorithms were used to quantify gene and transcript counts, respectively, and the Sailfish algorithm was used to validate eXpress transcript counts. The Deseq2 algorithm was used to determine differential expression at gene and transcript levels between paired samples. Results: Of 272 genes observed to change significantly in expression at relapse (FDR < 0.05), a majority (169) were up-regulated. Inter-pathway similarity analysis based on gene set enrichment analysis (GSEA; canonical pathways) suggested 4 distinct processes were down-regulated at relapse, including Notch Signaling, Interferon Signaling and G-coupled protein receptor signaling. Conversely, patients exhibited a single dominant up-regulated process associated with proliferation. Additional GSEA analysis on more specific gene categories revealed up-regulation of the Proliferation gene cluster described in the University of Arkansas for Medical Science (UAMS) classification for newly diagnosed MM (6 of 2599 gene sets tested; FDR<0.01), which is associated with poor prognosis. This suggests that specific gene expression profiles (GEPs) identified in newly diagnosed MM patients may be enriched in relapsed samples. Further analysis of differential gene expression was performed to assess correspondence against the 10 MM GEP subgroups identified by Broyl, et al. (Blood, 2010) from newly diagnosed multiple myeloma. The output revealed significant enrichment of the Proliferation and MMSET/FGFR3 subgroup classifications (FDR<0.01) and a corresponding decrease in the NFkB subgroup classification at relapse (FDR<0.01), indicating a switch in GEP enrichment in relapse samples. Significantly changed genes common between Proliferation-MMSET/FGFR3 and NFkB classifications and contributing to the switch in GEP included BUB1B (FDR<0.001), HMMR (FDR<0.001), TAGAP (FDR<0.001), SMC4 (FDR=0.002), RRM2 (FDR=0.005) and KLF6 (FDR=0.029). Examination of genes commonly associated with lenalidomide mechanism of action revealed that in this cohort CRBN RNA was down-regulated by more than 2-fold in one patient and an enrichment of CRBN transcript lacking exon 10 was observed in another patient. Interestingly, high levels of CRBN transcripts that retain introns 6, 7 and 8 and do not encode for protein were detected in both diagnostic and relapse samples, which might explain previously observed discordant expression between CRBN mRNA and protein. Furthermore, no significant changes in gene expression at relapse was observed for Aiolos, Ikaros, c-myc or IRF4, although there was a trend for c-myc up-regulation. Ikaros and Aiolos are known to undergo extensive splicing, however, we were unable to detect changes in Aiolos or Ikaros splicing in patients at relapse. Conclusions: Taken together, this data suggests that lenalidomide resistance in patients is associated with a switch in gene expression profile from NFkB to Proliferation and MMSET/FGFR3 subgroups identified by Broyl, et al (Blood 2012). Given these GEPs were obtained from newly diagnosed patients, this yields the hypothesis that lenalidomide treatment induces a reduction in MM cells with an NFkB gene expression profile and expansion of cells exhibiting a Proliferation and/or MMSET/FGFR3 associated GEP, which appear to be resistant to therapy. Future studies to understand how individual genes in the GEP subgroups identified contribute to lenalidomide sensitivity/resistance are on-going. Disclosures Amatangelo: Celgene Corporation: Employment, Equity Ownership. Neri:Celgene: Research Funding. Ortiz:Celgene Corporation: Employment. Bjorklund:Celgene Corporation: Employment, Equity Ownership. Gandhi:Celgene: Employment, Equity Ownership. Klippel:Celgene Corporation: Employment, Equity Ownership. Bahlis:Amgen: Consultancy; Johnson & Johnson: Consultancy; Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Daniel:Celgene Corporation: Employment, Equity Ownership. Chopra:Celgene Corporation: Employment, Equity Ownership. Trotter:Celgene Corporation: Employment. Thakurta:Celgene Corporation: Employment, Equity Ownership.

Patterns of Total Costs of Care for Newly Diagnosed Multiple Myeloma (MM) Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2656-2656
Author(s):  
Steven R. Arikian ◽  
Dejan Milentijevic ◽  
Gary Binder ◽  
Mara Silvia Monzini ◽  
X Henry Hu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Direct Costs ◽  
Drug Costs ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Monthly Total ◽  
Equity Ownership ◽  
The Cost ◽  
Over Time

Abstract Introduction: As clinical evidence has mounted in support of novel agents and longer treatment (Tx) durations for patients (pts) with newly diagnosed multiple myeloma (NDMM), questions have arisen regarding the economic impact of extending time to progression (TTP) in these pts, and the cost consequences once pts relapse and move to a second line of Tx. Previous analysis showed that relapsed myeloma pts incurred higher monthly costs once they advanced to later lines of Tx (Gaultney, 2013). There is limited information on the cost patterns of MM pts before and after their first relapse. A claims analysis was performed to evaluate the patterns of total direct costs of care, from Tx initiation until progression, for NDMM patients and for newly relapsed patients treated with novel agents, utilizing time to next therapy (TTNT) as a proxy measure for progression. Methods: A retrospective study was conducted using a large US medical and pharmacy claims database, covering > 25 million lives annually. NDMM patients were identified with at least 2 outpatient claims or 1 inpatient medical claim associated with a diagnosis of MM (ICD-9-CM] code 203.0X), with the first such claim used to define the index date. Inclusion criteria required a minimum of 12 months' pre-index enrollment and 6 months' post-index continuous enrollment between 2006 and 2012. Pts with claims for stem cell transplantation (SCT) were excluded, to avoid confounding results from various factors based on timing, costs, and site of care of SCT. The analysis focused on NDMM and relapsed MM pts receiving lenalidomide (LEN)- or bortezomib (BORT)- based Tx, where complete claim history was available from Tx onset to initiation of subsequent Tx. Using methods similar to those described by Gaultney, patients' average monthly costs were determined, including medical (inpatient, ambulatory, and emergency room) and pharmacy (index and other drugs) costs, and total cost patterns over quarterly time periods were calculated. Average Charlson comorbidity scores were determined to compare baseline measures between pt groups. Results: 897 NDMM pts and 280 relapsed MM pts were identified with complete data through initiation of subsequent Tx. Monthly total direct costs for NDMM pts were $15,400 in the first 3 months (mos) of Tx, and declined each quarter, reaching approximately $5,000/mo at 18+ mos. At relapse, monthly costs increased to over $12,000 for the first 3 mos and followed a quarterly pattern of reduction similar to that seen for NDMM pts (Fig 1). Quarterly cost reduction patterns were consistent for patients treated with LEN or BORT for both NDMM and relapsed pts. Pts' total monthly NDMM costs over the full TTNT period averaged $8,942 with LEN vs. $11,139 for BORT (due to 54% higher monthly medical costs for BORT), while monthly drug costs were nearly identical (Table 1). The baseline Charlson comorbidity index was similar between Tx groups in both lines of Tx. Figure 1: Direct monthly costs (medical and pharmacy) for LEN- and BORT-based treatments Figure 1:. Direct monthly costs (medical and pharmacy) for LEN- and BORT-based treatments Table 1: Direct monthly costs for NDMM pts Table 1 Table 1. Conclusions: For a population of NDMM pts receiving either LEN- or BORT-based Tx without SCT, followed until TTNT, total direct monthly costs per pt declined steadily over time, decreasing by 68% from the initial quarter to the period post 18 mos. Costs spiked when pts began 2nd-line therapy, then followed a similar pattern of decline over time. This pattern may suggest that further extending the TTP for NDMM pts may also yield economic benefits for each month extended before relapse. Patterns of cost decline were similar between the LEN and BORT groups, for NDMM and for relapsed patients, although mean monthly total costs were lower for NDMM pts receiving LEN-based Tx due to lower medical costs and similar drug costs. Disclosures Arikian: Genesis Research: Consultancy. Off Label Use: Lenalidomide in newly diagnosed multiple myeloma patients . Milentijevic:Celgene Corporation: Consultancy. Binder:Celgene Corporation: Employment, Equity Ownership. Monzini:Celgene Corporation: Employment, Equity Ownership. Hu:Celgene Corporation: Employment. Nagarwala:Celgene Corporation: Employment. Hussein:Celgene Corporation: Employment. Corvino:Genesis Research LLC: Consultancy. Surinach:Genesis Research LLC: Consultancy. Usmani:Celgene Corporation: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Array BioPharma: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding.

Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4229-4229
Author(s):  
Jatin J. Shah ◽  
Rafat Abonour ◽  
Mohit Narang ◽  
Jayesh Mehta ◽  
Howard R. Terebelo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Equity Ownership ◽  
Triplet Regimen

Abstract Introduction: Triplet therapies are used for treatment (Tx) of both transplant-eligible and -ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Actual patterns and outcomes of Tx are not fully understood. Connect MM® is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize Tx patterns and outcomes for pts with NDMM. This analysis describes demographic and disease characteristics of pts who received triplet Tx as an induction regimen and for whom transplant was or was not intended. The analysis explores the relationship of these factors with overall survival (OS) and other efficacy endpoints. Patients and Methods: Pts aged ≥ 18 y with NDMM within 60 days of diagnosis were eligible for enrollment regardless of disease severity, medical history, or comorbidities. Data including transplant intent (yes/no) was collected at baseline; follow-up data was collected quarterly thereafter. Based on the initial intent, 2 groups were identified: patients with intent to transplant who received transplant (TT) and pts with no intent to transplant who did not receive a transplant (NT). Triplet Tx was defined as the combination of ≥ 3 concurrent therapeutic agents in the first course of Tx (within 56 days of study entry). KM analysis adjusted for age was conducted for OS. Because decisions on use of transplant and triplet therapy are influenced by multiple factors, a multivariable Cox regression analysis was performed to evaluate the contribution of the triplet therapy (yes/no) to OS and was adjusted for other variables, including age, comorbidities, and ISS staging. Results: Between September 2009 and December 2011, 1493 pts were enrolled. This analysis was on 1436 pts: 650 pts with transplant intent and 786 pts without transplant intent. The data cutoff date was November 30, 2014, and the median follow-up for overall survival (OS) was 33.8 mos. Of pts with transplant intent, 451 (69%) received transplant (TT) and 199 (31%) did not. Of pts without transplant intent, 62 (8%) received transplant and 724 (92%) did not (NT). The abstract focuses on TT and NT groups only. NT pts tended to be older and have more advanced ISS staging and higher β2-microglobulin levels than TT pts (Table). The most common triplet regimen given during the first course treatment (within 56 days) was lenalidomide, bortezomib, and dexamethasone (RVd). RVd was administered to 34% of the NT pts (76/225) and 59% of the TT pts (152/257). The most common non-triplet regimen was bortezomib and dexamethasone (Vd), which was given to 31% of NT pts (156/499) and 38% of TT pts (73/194). Within the NT group, pts given triplet Tx had a lower risk of death than those who did not receive triplet Tx (P = .0013). The multivariable analysis found triplet Tx to be associated with a 36% reduced risk of death (hazard ratio [HR] = 0.64 [95% CI, 0.50-0.82]; P = .001). ISS disease stage (HR = 1.43 [95% CI, 1.21-1.69]; P < .001) and history of diabetes (HR = 1.38 [95% CI, 1.08-1.78]; P = .012) were negative prognostic factors for OS. Within the TT group, pts who received triplet Tx did not attain an OS benefit (P = .8993), and no baseline characteristics were significantly associated with OS. These results may be limited by other factors not considered that may have influenced physicians' choice of treatment, including the use of maintenance therapy and a short follow-up period of 33.8 months. Conclusions: Triplet Tx as a first regimen is associated with longer OS in pts without transplant intent who did not receive a transplant. RVd and Vd were the most common first Tx regimens, respectively. Continued follow-up of these pts and enrollment of an additional cohort will provide additional data with mature follow-up. Table 1. Table 1. Disclosures Shah: Bristol-Myers Squibb: Research Funding; Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Research Funding, Speakers Bureau. Narang:Celgene: Speakers Bureau. Mehta:Celgene Corporation: Speakers Bureau. Terebelo:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacylics: 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, Speakers Bureau. Gasparetto:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Baseline and on-Treatment Bone Marrow Microenvironments Predict Myeloma Patient Outcomes and Inform Potential Intervention Strategies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1882-1882 ◽  
Author(s):  
Samuel A Danziger ◽  
Mark McConnell ◽  
Jake Gockley ◽  
Mary Young ◽  
Adam Rosenthal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Expression Profiles ◽  
Cell Types ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction The multiple myeloma (MM) tumor microenvironment (TME) strongly influences patient outcomes as evidenced by the success of immunomodulatory therapies. To develop precision immunotherapeutic approaches, it is essential to identify and enumerate TME cell types and understand their dynamics. Methods We estimated the population of immune and other non-tumor cell types during the course of MM treatment at a single institution using gene expression of paired CD138-selected bone marrow aspirates and whole bone marrow (WBM) core biopsies from 867 samples of 436 newly diagnosed MM patients collected at 5 time points: pre-treatment (N=354), post-induction (N=245), post-transplant (N=83), post-consolidation (N=51), and post-maintenance (N=134). Expression profiles from the aspirates were used to infer the transcriptome contribution of immune and stromal cells in the WBM array data. Unsupervised clustering of these non-tumor gene expression profiles across all time points was performed using the R package ConsensusClusterPlus with Bayesian Information Criterion (BIC) to select the number of clusters. Individual cell types in these TMEs were estimated using the DCQ algorithm and a gene expression signature matrix based on the published LM22 leukocyte matrix (Newman et al., 2015) augmented with 5 bone marrow- and myeloma-specific cell types. Results Our deconvolution approach accurately estimated percent tumor cells in the paired samples compared to estimates from microscopy and flow cytometry (PCC = 0.63, RMSE = 9.99%). TME clusters built on gene expression data from all 867 samples resulted in 5 unsupervised clusters covering 91% of samples. While the fraction of patients in each cluster changed during treatment, no new TME clusters emerged as treatment progressed. These clusters were associated with progression free survival (PFS) (p-Val = 0.020) and overall survival (OS) (p-Val = 0.067) when measured in pre-transplant samples. The most striking outcomes were represented by Cluster 5 (N = 106) characterized by a low innate to adaptive cell ratio and shortened patient survival (Figure 1, 2). This cluster had worse outcomes than others (estimated mean PFS = 58 months compared to 71+ months for other clusters, p-Val = 0.002; estimate mean OS = 105 months compared with 113+ months for other clusters, p-Val = 0.040). Compared to other immune clusters, the adaptive-skewed TME of Cluster 5 is characterized by low granulocyte populations and high antigen-presenting, CD8 T, and B cell populations. As might be expected, this cluster was also significantly enriched for ISS3 and GEP70 high risk patients, as well as Del1p, Del1q, t12;14, and t14:16. Importantly, this TME persisted even when the induction therapy significantly reduced the tumor load (Table 1). At post-induction, outcomes for the 69 / 245 patients in Cluster 5 remain significantly worse (estimate mean PFS = 56 months compared to 71+ months for other clusters, p-Val = 0.004; estimate mean OS = 100 months compared to 121+ months for other clusters, p-Val = 0.002). The analysis of on-treatment samples showed that the number of patients in Cluster 5 decreases from 30% before treatment to 12% after transplant, and of the 63 patients for whom we have both pre-treatment and post-transplant samples, 18/20 of the Cluster 5 patients moved into other immune clusters; 13 into Cluster 4. The non-5 clusters (with better PFS and OS overall) had higher amounts of granulocytes and lower amounts of CD8 T cells. Some clusters (1 and 4) had increased natural killer (NK) cells and decreased dendritic cells, while other clusters (2 and 3) had increased adipocytes and increases in M2 macrophages (Cluster 2) or NK cells (Cluster 3). Taken together, the gain of granulocytes and adipocytes was associated with improved outcome, while increases in the adaptive immune compartment was associated with poorer outcome. Conclusions We identified distinct clusters of patient TMEs from bulk transcriptome profiles by computationally estimating the CD138- fraction of TMEs. Our findings identified differential immune and stromal compositions in patient clusters with opposing clinical outcomes and tracked membership in those clusters during treatment. Adding this layer of TME to the analysis of myeloma patient baseline and on-treatment samples enables us to formulate biological hypotheses and may eventually guide therapeutic interventions to improve outcomes for patients. Disclosures Danziger: Celgene Corporation: Employment, Equity Ownership. McConnell:Celgene Corporation: Employment. Gockley:Celgene Corporation: Employment. Young:Celgene Corporation: Employment, Equity Ownership. Schmitz:Celgene Corporation: Employment, Equity Ownership. Reiss:Celgene Corporation: Employment, Equity Ownership. Davies:MMRF: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; TRM Oncology: Honoraria; Abbvie: Consultancy; ASH: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Copeland:Celgene Corporation: Employment, Equity Ownership. Fox:Celgene Corporation: Employment, Equity Ownership. Fitch:Celgene Corporation: Employment, Equity Ownership. Newhall:Celgene Corporation: Employment, Equity Ownership. Barlogie:Celgene: Consultancy, Research Funding; Dana Farber Cancer Institute: Other: travel stipend; Multiple Myeloma Research Foundation: Other: travel stipend; International Workshop on Waldenström's Macroglobulinemia: Other: travel stipend; Millenium: Consultancy, Research Funding; European School of Haematology- International Conference on Multiple Myeloma: Other: travel stipend; ComtecMed- World Congress on Controversies in Hematology: Other: travel stipend; Myeloma Health, LLC: Patents & Royalties: : Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC. Trotter:Celgene Research SL (Spain), part of Celgene Corporation: Employment, Equity Ownership. Hershberg:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Dervan:Celgene Corporation: Employment, Equity Ownership. Ratushny:Celgene Corporation: Employment, Equity Ownership. Morgan:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding.

scholarly journals Gene Expression and Genomic Markers Identify a Subpopulation of Poor Prognosis t(4;14) Patients in Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 366-366
Author(s):  
Maria Ortiz ◽  
Fadi Towfic ◽  
Erin Flynt ◽  
Nicholas Stong ◽  
Sneh Lata ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
High Risk ◽  
Poor Prognosis ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Gene Set ◽  
Combining Data ◽  
Genomic Markers ◽  
Equity Ownership

Cytogenetics is an important prognostic marker in multiple myeloma (MM). Patients with t(4;14) (~15% of newly diagnosed MM patients) are known to have short progression free survival (PFS) and overall survival (OS). This feature, measured by FISH, is used in combination with ISS=3 as a selection marker for patients with high risk (HR) of progression. Only a subset of patients grouped by t(4;14) and ISS=3 display genuinely poor survival, however, with ~25% dying within 24 months after diagnosis (similar to the Double Hit subgroup defined by Walker et al1). To elucidate this observation, we created the largest dataset of MM t(4;14) patients to date by combining data from the Myeloma Genome Project (MGP, n=73) and data from TOUL (n=100, patients analyzed in routine practice) to identify transcriptomic and/or genomic markers associated with HR t(4;14). Gene expression (GE), copy number aberration (CNA), single nucleotide variant (SNV) and translocations were derived from RNAseq and WGS/WES profiling of biopsies from patients aged less than 75 years who received transplant, and integrated with clinical information (including Age, PFS and OS). Demographics: MGP median age=61; 30% female; median PFS (mPFS)=26.2months (m) and median OS (mOS) not reached. TOUL median age=60; 35% female, mPFS=23.7m and mOS = 86.1m. Our previous work (Ortiz ASH 2018, Ortiz EHA 2018) identified a molecularly-defined HR MM patient subgroup (MDMS8, mPFS&lt;20m, m0S&lt;35m) defined by GE patterns related to cell cycle dysregulation. In that analysis, 24% of t(4;14) patients were identified as MDMS8 (mPFS&lt;13m, mOS&lt;30m), the rest (76%) were grouped in other lower risk molecular segments (mPFS&lt;30m, mOS NR). A GE classifier for t(4;14) in MDMS8 vs the rest of t(4;14) patients was created on the MGP dataset and applied to identify similar patients in the TOUL data, obtaining a significant difference between MDMS8-like t(4;14) patients (20% prevalence, mPFS&lt;15m, mOS&lt;26m) in the TOUL dataset and non-HR t(4;14) (mPFS&lt;26m, mOS&lt;103m) in both PFS (p.value&lt;1e-3) and OS (p.value&lt;1e-5). Although there are some conventional t(4;14) gene expression surrogates, they do not identify the HR t(4:14) subgroup. Comparison of known t(4;14) gene expression markers MMSET and FGFR3 in HR t(4;14) (OS &lt; 24ms & not_alive, N=34) versus non-HR t(4;14) patients (N=94) across both datasets combined did not yield significant differential expression of either gene (p.value&gt;0.10). MMSET was over-expressed in all t(4;14) patients, while FGFR3 displayed a binomial distribution (two groups of patients with high (N=37, median value=10 log2CPM) and low (N=91, median value=2 log2CPM) FGFR3 expression) within t(4;14) patients (p.value&lt;0.05) without association with outcome (p.value&gt;0.10). GE analysis of HR t(4;14) vs non-HR t(4;14) patients aligned with MDMS8 biology, but identified new pathways also including DNA repair, MYC targets and Oxidative Phosphorylation being up-regulated in the HR t(4;14) group. A gene-set variation analysis based on the MSigDb C1 gene-set, wherein genes are grouped based on their genomic location, was performed to identify GE changes of potentially epigenomic origin. Results highlighted chr9q22, chr9q33, and chr13q13 as down-regulated in the HR t(4;14) group, while genes in 16q24 were significantly up-regulated. CNA analysis identified amplifications in chromosomes 3 and 19 and deletions in chr12p as significantly associated with the HR t(4;14) population (p.value &lt; 0.05); while deletions in chr14q (preceding the translocated region) occurred more frequently in the non-HR t(4;14) group. Our results provide new insights into identification of these patients and underlying biology that could drive poor prognosis in t(4;14) patients. Molecular identification of HR t(4;14) patients would enable proper risk classification for this MM patient group and understanding differences in HR t(4;14) biology could provide the basis for identification of a specific therapeutic target for this HR subpopulation. An ongoing aim of this work is development of a clinically applicable classifier that accurately identifies this subpopulation of MM patients and the biological drivers of their high-risk disease. Disclosures Ortiz: Celgene Corporation: Employment, Equity Ownership. Towfic:Celgene Corporation: Employment, Equity Ownership. Flynt:Celgene Corporation: Employment, Equity Ownership. Stong:Celgene Corporation: Employment, Equity Ownership. Lata:Celgene Corporation: Employment, Equity Ownership. Sampath:Celgene Corporation: Employment, Equity Ownership. Rozelle:Celgene Corporation: Other: Contractor for Celgene. Trotter:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership.

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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3251-3251
Author(s):  
Chang-Ki Min ◽  
Sung-Soo Yoon ◽  
Wee Joo Chng ◽  
Shang-Yi Huang ◽  
Cheng-Shyong Chang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Zoledronic Acid ◽  
Research Funding ◽  
Acid Group ◽  
Newly Diagnosed ◽  
Primary Analysis ◽  
Employment Equity ◽  
Double Blind ◽  
Asian Patients ◽  
Equity Ownership

Abstract Introduction: Denosumab is a monoclonal antibody targeting receptor activator of nuclear factor-kappa B ligand (RANKL) that has been shown to reduce skeletal-related events (SREs) associated with bone lesions in patients with multiple myeloma. Results from the full primary analysis of an international, double-blind, double-dummy, randomized controlled phase 3 (20090482) study that assessed the efficacy and safety of denosumab vs zoledronic acid for preventing SREs in patients with multiple myeloma (MM) indicated that denosumab was non-inferior to zoledronic acid for time to SREs. Here we present a sub-analysis to evaluate efficacy and safety outcomes in a subgroup of Asian patients enrolled in the 20090482 study. Methods: Adult patients from Asian countries with newly diagnosed MM and ≥1 documented lytic bone lesion were included in this analysis. Patients received subcutaneous denosumab (120 mg) plus intravenous placebo or intravenous zoledronic acid (4 mg) plus subcutaneous placebo in 4-week cycles. The primary endpoint was time to first on-study SRE; the incidence of adverse events (AEs) by preferred term was also examined. Results: Overall, 196 Asian patients (denosumab, n=103; zoledronic acid, n=93) were included in this analysis. Patient demographics were generally well balanced between groups. Median (interquartile range [IQR]) number of months on study was 17.5 (9.8-30.2) for the denosumab group and 20.2 (13.1-29.2) for the zoledronic acid group. Median (IQR) cumulative drug exposure was 15.9 (8.5-24.0) months for denosumab and 17.4 (9.1-26.7) months for zoledronic acid. Fewer patients in the denosumab group developed first on-study SRE compared with the zoledronic acid group; the crude incidence of SREs at the primary analysis cutoff was 38.8% in the denosumab group and 50.5% in the zoledronic acid group. Median (95% CI) time in months to first on-study SRE was not reached (11.2-not reached) for the denosumab group and 12.3 (3.1-not reached) for the zoledronic acid group (hazard ratio [HR], 0.77; 95% CI, 0.48-1.26; Figure 1). Overall, all patients (100%) experienced ≥1 treatment-emergent AE; the AEs reported in ≥20% of patients in either treatment arm are presented in Table 1. The most common AEs reported in either subgroup (denosumab, zoledronic acid) were diarrhea (51.0%, 51.1%), nausea (42.2%, 46.7%), pyrexia (38.2%, 41.3%), upper respiratory tract infection (37.3%, 40.2%), and constipation (33.3%, 31.5%). Renal toxicity (preferred terms of blood creatinine increased, renal failure, urine output decreased, acute kidney injury, renal impairment, and blood urea decreased) occurred in 9 of 102 (8.8%) patients in the denosumab group and 20 of 92 (21.7%) patients in the zoledronic acid group. Adjudicated osteonecrosis of the jaw was reported in 7 (6.9%) patients in the denosumab group and 5 (5.4%) patients in the zoledronic acid group. Hypocalcemia was reported in 19 (18.6%) patients in the denosumab group and 17 (18.5%) patients in the zoledronic acid group. Conclusion: Results from this Asian subgroup analysis were comparable to those of the full analysis set. In addition, in this analysis there were numerically fewer patients in the denosumab arm that developed a first on-study SRE compared with those in the zoledronic acid arm, and the time to first on-study SRE had a trend favoring the denosumab-treated patients. The AE profiles for denosumab and zoledronic acid in the Asian subgroup were comparable to those observed in the full primary analysis, with renal toxicity similarly reported to be higher in the zoledronic acid group. Overall, this analysis supports that denosumab may be an additional treatment option for the standard of care for Asian patients with newly diagnosed MM with bone disease. Disclosures Chng: Merck: Research Funding; Aslan: Research Funding; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses. Chang:BMS: Consultancy, Speakers Bureau; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy; Takeda: Consultancy; Roche: Consultancy, Speakers Bureau; Novarits: Consultancy, Speakers Bureau. Wong:Amgen: Consultancy, Research Funding, Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Archigen: Research Funding; Baxalta: Research Funding; Pfizer: Research Funding; Apellis: Research Funding; Roche: Research Funding; Boehringer: Research Funding; Ingelheim: Research Funding; AbbVie: Research Funding; Alexion: Consultancy; Astellas: Speakers Bureau. Shimizu:Amgen Inc.: Other: Non-remunerative Position of Influence, Denosumab 20090482 Global Steering Committee Member; Fujimoto Pharmacuetical Corp: Consultancy; Daiichi-Sankyo, Co., Ltd: Consultancy. Gao:Amgen Asia Holding Limited: Employment, Equity Ownership. Glennane:Amgen: Employment, Equity Ownership. Guan:Amgen: Employment, Equity Ownership.

scholarly journals Genomic and Immunologic Analysis of Cmaf and Hypermutated Multiple Myeloma: Implications for Immunologic Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3093-3093
Author(s):  
Hearn Jay Cho ◽  
Deepak Perumal ◽  
Adeeb H Rahman ◽  
Donald Jackson ◽  
Michael Robbins ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Clonal Evolution ◽  
Control Group ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Mutation Burden ◽  
Equity Ownership

The advent of therapeutic monoclonal antibodies (elotuzumab, daratumumab) for multiple myeloma (MM) heralded a new era of immunologic therapy for this disease. Laboratory and clinical data suggest that immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis are a promising novel strategy, as PD-L1 is commonly expressed on MM cells and a phase 2 clinical trial demonstrated encouraging responses to pembrolizumab (anti-PD-1) in combination with pomalidomide and dexamethasone. However, two late stage MM clinical trials of ICI combined with either lenalidomide or pomalidomide were halted due to safety concerns and lack of efficacy, although subgroup analysis suggested that the overall response rate in subjects with immune related adverse events was higher in subjects who received pembrolizumab + pomalidomide and dexamethasone vs the control group. As a result, further investigation of ICI in MM has largely discontinued. This discrepancy with the positive findings in the early phase trial suggests that genetic or immunologic features of the tumors or immune microenvironment of the patients may influence outcome to ICI, but these factors are as yet undefined. In solid tumors, high mutation burden as assessed by microsatellite sequence instability-high (MSI-high) or mismatch repair genes deficiency (dMMR) was correlated to response to anti-PD-1 ICI, and is now an indication for these agents. Newly diagnosed MM is considered an intermediate-low mutation burden disease (<10 muts/Mb), but a subset of newly diagnosed subjects, often characterized by overexpression of cMAF, have two-to-ten-fold higher average mutation burden. In addition, clonal evolution, characterized by accumulation of somatic mutations, is a common feature of MM and increases the mutation burden through its natural history. We hypothesized that cMAF/hyper-mutated (HM) MM patients may be more likely to have a tumor microenvironment (TME) that is amenable to ICI therapy, analogous to MSI-high/dMMR solid tumor patients. To investigate this, we identified cMAF/HM (n=25) and standard mutation burden (n=20) subjects from the CoMMPass database of newly-diagnosed MM patients. We performed bulk RNA sequencing and mass cytometry (CyTOF) analysis of CD138- bone marrow mononuclear cells, representing the TME, and proteomic (O-link) and grand serology (ELISA-based) analysis of peripheral blood plasma. CyTOF analysis of the TME demonstrated that cMAF/HM subjects had relatively decreased cycling myeloid cells and increased CD4+, CD73low T cells compared to standard. cMAF/HM subjects had significantly higher frequencies of antibody titers against the MM-associated autologous antigens SOX2 and NY-ESO-1. These results suggest that cMAF/HM patients are more likely to feature immune activation in the TME and generate adaptive immune responses to MM-associated antigens, but these responses are not sufficient to control the disease, possibly due to inhibition by checkpoint ligands such as PD-L1. These results support further investigation of ICI-based combination therapies in cMAF/HM MM patients. Disclosures Cho: The Multiple Myeloma Research Foundation: Employment; Celgene: Honoraria, Research Funding; Takeda: Research Funding; Agenus: Research Funding; Genentech: Honoraria, Research Funding; BMS: Consultancy; GSK: Consultancy. Jackson:Bristol-Myers Squibb: Employment, Equity Ownership. Robbins:Bristol-Myers Squibb: Employment, Equity Ownership. Parekh:Karyopharm Inc.: Research Funding; Foundation Medicine Inc.: Consultancy; Celgene Corporation: Research Funding.

scholarly journals Safety and Efficacy of the Combination of Selinexor, Lenalidomide and Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3165-3165 ◽  
Author(s):  
Darrell J White ◽  
Suzanne Lentzsch ◽  
Cristina Gasparetto ◽  
Nizar Bahlis ◽  
Christine I Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Introduction: The nuclear export protein Exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma. Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks XPO1, forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was recently approved based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Lenalidomide in combination with dexamethasone has been approved for the treatment of relapsed/refractory multiple myeloma with an ORR of 60-76%. The STOMP study assessed the efficacy and safety of the all oral combination of selinexor, lenalidomide and dexamethasone (SRd) in patients with relapsed/refractory and newly diagnosed multiple myeloma. We previously reported the recommended phase 2 dose (RP2D) of once weekly selinexor 60 mg, lenalidomide 25 mg and dexamethasone achieved an ORR of 92% in patients with RRMM who were lenalidomide naive. Here we evaluated once weekly selinexor in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma. Methods: STOMP is a multicenter, open-label study with a dose escalation (phase 1) and expansion (phase 2) to assess the maximum tolerated dose, RP2D, efficacy and safety of SRd in patients with newly diagnosed multiple myeloma. Patients with newly diagnosed multiple myeloma were eligible if they had symptomatic myeloma per the International Myeloma Working Group (IMWG) guidelines with either hypercalcemia, renal failure, anemia, bone lesions (CRAB) criteria or myeloma defining events needing systemic therapy. Enrollment in this arm is ongoing. Results: As of July 01 2019, 8 patients (4 males and 4 females ) with newly diagnosed multiple myeloma were enrolled at the starting dose level of selinexor 60 mg on days 1, 8, 15, and 22; lenalidomide 25 mg daily 1-21and dexamethasone 40 mg weekly on a 28 day cycle. The median age was 74 years (range: 51-86 years). No dose limiting toxicities (DLT) were observed in 5 DLT evaluable patients, 3 patients were not DLT evaluable because 1 patient did not finish cycle 1 due to social reasons and 2 patients missed doses due to serious adverse events (SAEs) unrelated to study drugs.. Common treatment related hematologic AEs (Grades 1/2, ≥3) were neutropenia (0%, 75%), anemia (0%, 25%), and thrombocytopenia (0%, 25%). Common non-hematologic AEs were diarrhea (63%, 0%), nausea (50%, 0%), fatigue (0%, 38%) decreased weight (38%, 0%), constipation (25%, 0%), hypokalemia (25%, 0%), and hypomagnesemia (25%, 0%). Among 7 efficacy evaluable patients, 6 patients achieved a response (ORR of 86%) including 1 complete response, 1 very good partial responses, 4 partial responses (2 unconfirmed), and 1 patient achieved a minimal response. With a median follow-up of 6.1 months, median progression-free survival was not reached. Conclusions: The all oral combination of SRd has promising activity with 6 of 7 efficacy evaluable patients achieving an objective response in patients with newly diagnosed multiple myeloma and no new or unexpected safety signals. Disclosures White: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Lentzsch:Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. 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 . Bahlis:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Chen:Janssen: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Schiller:Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Sangamo Therapeutics: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Onconova: Research Funding; Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding. Tuchman:Karyopharm: Honoraria; Prothena: Research Funding; Roche: Research Funding; Alnylam: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Kotb:Karyopharm: Equity Ownership; Janssen: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Leblanc:Janssen: 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Sebag:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Venner:Sanofi: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria; J&J: Research Funding; Takeda: Honoraria; Celgene: Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Sheehan:Karyopharm Therapeutics: Employment, Equity Ownership. Chai:Karyopharm Therapeutics: Employment, Equity Ownership. Kai:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baljevic:Karyopharm: Other: Internal Review Committee participant; Cardinal Health Specialty Solutions: Consultancy; Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Crowdsourced High-Risk Classifiers for Multiple Myeloma Patients Commonly Identify PHF19 As a Robust Progression Biomarker

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4370-4370
Author(s):  
Michael J Mason ◽  
Carolina D. Schinke ◽  
Christine Eng ◽  
Fadi Towfic ◽  
Fred Gruber ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
High Risk ◽  
Disease Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Multiple myeloma (MM) is a hematological malignancy of terminally differentiated plasma cells residing within the bone marrow with 25,000-30,000 patients diagnosed in the United States each year. The disease's clinical course depends on a complex interplay chromosomal abnormalities and mutations within plasma cells and patient socio-demographic factors. Novel treatments extended the time to disease progression and overall survival for the majority of patients. However, a subset of 15%-20% of MM patients exhibit an aggressive disease course with rapid disease progression and poor overall survival regardless of treatment. Accurately predicting which patients are at high-risk is critical to designing studies with a better understanding of myeloma progression and enabling the discovery of novel therapeutics that extend the progression free period of these patients. To date, most MM risk models use patient demographic data, clinical laboratory results and cytogenetic assays to predict clinical outcome. High-risk associated cytogenetic alterations include deletion of 17p or gain of 1q as well as t(14;16), t(14;20), and most commonly t(4,14), which leads to juxtaposition of MMSET with the immunoglobulin heavy chain locus promoter, resulting in overexpression of the MMSET oncogene. While cytogenetic assays, in particular fluorescence in situ hybridization (FISH), are widely available, their risk prediction is sub-optimal and recently developed gene expression based classifiers predict more accurately rapid progression. To investigate possible improvements to models of myeloma risk, we organized the Multiple Myeloma DREAM Challenge, focusing on predicting high-risk, defined as disease progression or death prior to 18 months from diagnosis. This effort combined 4 discovery datasets providing participants with clinical, cytogenetic, demographic and gene expression data to facilitate model development while retaining 4 additional datasets, whose clinical outcome was not publicly available, in order to benchmark submitted models. This crowd-sourced effort resulted in the unbiased assessment of 171 predictive algorithms on the validation dataset (N = 823 unique patient samples). Analysis of top performing methods identified high expression of PHF19, a histone methyltransferase, as the gene most strongly associated with disease progression, showing greater predictive power than the expression level of the putative high-risk gene MMSET. We show that a simple 4 feature model composed of age, stage and the gene expression of PHF19 and MMSET is as accurate as much larger published models composed of over 50 genes combined with ISS and age. Results from this work suggest that combination of gene expression and clinical data increases accuracy of high risk models which would improve patient selection in the clinic. Disclosures Towfic: Celgene Corporation: Employment, Equity Ownership. Dalton:MILLENNIUM PHARMACEUTICALS, INC.: Honoraria. Goldschmidt:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; John-Hopkins University: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Research Funding; Amgen: Consultancy, Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; MSD: Research Funding; Sanofi: Honoraria, 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; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; John-Hopkins University: Research Funding. Avet-Loiseau:takeda: Consultancy, Other: travel fees, lecture fees, Research Funding; celgene: Consultancy, Other: travel fees, lecture fees, Research Funding. Ortiz:Celgene Corporation: Employment, Equity Ownership. Trotter:Celgene Corporation: Employment, Equity Ownership. Dervan:Celgene: Employment. Flynt:Celgene Corporation: Employment, Equity Ownership. Dai:M2Gen: Employment. Bassett:Celgene: Employment, Equity Ownership. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Shain:Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy. Munshi:Abbvie: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Celgene: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Celgene Corporation, Janssen: Research Funding; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses. Walker:Celgene: Research Funding. Thakurta:Celgene: Employment, Equity Ownership.

scholarly journals Preliminary Results from a Phase I Study of Isatuximab (ISA) in Combination with Bortezomib, Lenalidomide, Dexamethasone (VRd), and in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Non-Eligible for Transplant

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 595-595 ◽  
Author(s):  
Enrique M. Ocio ◽  
Paula Rodriguez Otero ◽  
Sara Bringhen ◽  
Stefania Oliva ◽  
Axel Nogai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Induction Phase ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: Isatuximab (ISA) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells via direct tumor targeting and immune cell engagement. ISA, combined with bortezomib, has demonstrated strong potentiation in a multiple myeloma (MM) xenograft model (Clin Cancer Res 2014:20:4754). This supported evaluation of ISA with bortezomib combinations in pts with newly diagnosed multiple myeloma (NDMM) ineligible for transplant. In the initial cohort, ISA combined with bortezomib, cyclophosphamide, and dexamethasone (dex) was well tolerated with 73% of pts achieving very good partial response (VGPR) or better and 40% with complete response (CR) (Blood 2017; 130: 3160). The combination of bortezomib, lenalidomide, and dex (VRd) is also effective in NDMM (Lancet 2017:389:519-27). Here, we report initial data from a Phase Ib study of ISA plus VRd in pts with NDMM (NCT02513186). Methods: Pts with NDMM ineligible for transplantation were treated in 2 phases: induction and maintenance. Induction phase (four 6-week cycles [C]): ISA (10 mg/kg) on Day (D) 1, 8, 15, 22, 29 (C1), followed by D1, 15, 29 (C2-4); bortezomib (1.3 mg/m2) on D1, 4, 8, 11, 22, 25, 29, 32 (C1-4); lenalidomide (25 mg/day): D1-14 and D22-35 (C1-4); dex (20 mg/day): D1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, 33. Maintenance phase (4-week cycles): ISA (10 mg/kg) on D1, 15 (all cycles); lenalidomide (25 mg/day): D1-21 (all cycles); dex (40 mg): D1, 8, 15, 22 (all cycles), unless the pt was >75 years of age, then the dose was 20 mg. The primary objective was to evaluate safety and preliminary efficacy (overall response rate [ORR] and CR rate, [IMWG criteria]) of ISA plus VRd. Minimal residual disease (MRD) was evaluated using next generation sequencing (NGS) and flow cytometry (NGF) at a sensitivity of 10-6 in pts achieving VGPR or above. Here, we report results from a protocol-planned interim analysis. Results: All 22 pts were included in the safety analysis (pts who received ≥1 dose of ISA) and 14 were eligible for preliminary efficacy analyses (first 14 pts who completed the 4 induction cycles). Median age was 71 (range 63-77) years. At study entry, 6, 12, and 1 pt were International Staging System Stage I, II, and III, respectively. One pt had extramedullary plasmacytoma at baseline. At data cut-off (Mar 22, 2018), the median number of cycles was 5.5 (1-9). Three pts discontinued treatment (2 VGPR, 1 not efficacy-evaluable): 2 pts due to adverse event (AE); Grade (Gr) 3 infusion reaction (IR) (ISA-related; Gr 3 dyspnea, Gr 2 glottic edema, Gr 2 nasal edema, and Gr 2 generalized rash), and Gr 5 bacteremia (lenalidomide- and dex-related); and 1 pt withdrew consent; 19 (86%) pts are continuing treatment. Dose reduction of bortezomib, lenalidomide, and dex was required in 6 (29%), 4 (16%), and 5 (28%) pts, respectively. TEAEs occurred in 19 (86%) pts. Most frequent TEAEs (any Gr; excluding laboratory abnormalities) were constipation (10 pts [46%]), IRs and peripheral edema (9 pts [41%] each), asthenia, diarrhea, and peripheral sensory neuropathy (8 pts [36%] each), hypotension (7 pts [32%]), fatigue and respiratory tract infection (6 pts [27%] each), cough and dyspnea (5 pts [23%] each). Gr ≥3 AEs were reported in 10 (46%) and serious AEs (SAEs) in 4 (18%) pts. Treatment-related SAEs occurred in 2 (9%) pts (IR and pancreatitis). IRs were Gr 1/2 in all but 1 (5%) pt (Gr 3). Gr 3/4 laboratory hematologic abnormalities: lymphopenia (8/22), neutropenia (4/22), thrombocytopenia (4/22)VGPR, 1 partial response (PR) and 1 pt with stable diseaseMedian time to first response was 1.4 months (end of C1) and, with a median follow-up of 7.49 months (at cut-off date), no pt has progressed, with all except 3 pts continuing on therapy. Five (38.5%) of 13 pts achieved MRD-negative status (by NGF and NGS, or NGS only). Conclusion: These data suggest that ISA plus VRd followed by ISA plus Rd is well tolerated with a high ORR of 93%. All responders had VGPR or CR except 1 pt with PR. Quality of CR may have been underestimated due to ISA interference which could be resolved with an interference assay. Funding: Sanofi Disclosures Ocio: Janssen: Consultancy, Honoraria; AbbVie: Consultancy; BMS: Consultancy; Pharmamar: Consultancy; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Rodriguez Otero:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Janssen: Consultancy, Honoraria; Clínica Universidad de Navarra: Employment; Bristol Myers Squibb: Research Funding. Bringhen:Amgen: Honoraria, Other: Advisory Board; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy. Oliva:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Attal:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janseen: Consultancy, Research Funding; Sanofi: Consultancy. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kanagavel:Sanofi: Employment, Equity Ownership. Fitzmaurice:Sanofi: Employment, Equity Ownership. Wu:Sanofi: Employment, Equity Ownership. Martinez Lopez:Janssen: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau.

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