scholarly journals A Multicenter Phase II Single Arm Trial of Isatuximab in Patients with High Risk Smoldering Multiple Myeloma (HRSMM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3116-3116 ◽  
Author(s):  
Elisabet E. Manasanch ◽  
Sundar Jagannath ◽  
Hans C. Lee ◽  
Krina K. Patel ◽  
Connor Graham ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Infusion Reaction ◽  
Advisory Committees ◽  
Myeloma Cells ◽  
History Of ◽  
Smoldering Myeloma

Background High risk smoldering multiple myeloma (HRSMM), defined as having immunoparesis and at least 95% abnormal plasma cells/all plasma cells by advanced flow cytometry, has a risk of progression to multiple myeloma of about 75% after 5 years of diagnosis. These patient have no symptoms and current standard is to follow them without treatment. Isatuximab is an IgG1 monoclonal antibody that binds to CD38 highly expressed in myeloma cells. Isatuximab has activity as monotherapy (overall response rate (ORR) 35%), with lenalidomide/dexamethasone (ORR 56%) and pomalidomide/dexamethasone (ORR 62%) in relapsed MM. We designed a phase II study to test the efficacy of isatuximab in high risk smoldering myeloma. Our study is registered in clinicaltrials.gov as NCT02960555. Methods The primary endpoint of the study is the ORR of isatuximab 20 mg/kg IV days 1, 8, 15, 22 cycle 1; days 1, 15 cycles 2-6 and day 1 cycles 7-30 in high risk smoldering myeloma. 24 patients were accrued in the first stage (of maximum 61 patients). Secondary endpoints are PFS, OS, clinical benefit rate (CBR). Exploratory endpoints are quality of life analysis (QoL), MRD, molecular/immune characterization using DNA/RNA sequencing of myeloma cells and the microenvironment before and after treatment. Results 24 patients with HRSMM were accrued from 02/08/2017 until 12/21/2018 (Table 1). All patients are evaluable for response. Best responses: ORR (≥PR) 15(62.5%), CR MRD- flow at 10-5 1 (5%), VGPR 4 (17%), PR 10 (42%), minor response (MR) 4 (18%), stable disease 5 (21%); CBR (≥MR) 79%. Median number of cycles received were 11.5 (range 6-30). Five patients have stopped treatment (one has completed the study, one with heavy history of smoking was diagnosed with squamous cell cancer of the tongue, one could no longer travel to treatments due to relocation, two progressed to active multiple myeloma after 16 and 6 cycles of treatment, respectively). There have been no deaths. DNA/RNA seq is ongoing for biomarkers of response. There were 5 grade 3 severe treatment-related adverse events (RAE) which resolved to baseline: dyspnea -related to infusion reaction (n=2), headache (n=1), ANC decrease (n=1), urinary tract infection (n=1). Most common grade 1-2 related adverse events (n): nausea (7), vomit (5), WBC decrease (3), diarrhea (3), fatigue (6), headache (4), mucositis (4), myalgia (4) and infusion reaction (3). In patients with available QoL functional scores (n=9 at baseline and n=7 after 6 months of therapy), isatuximab was effective in reducing their anxiety and worry of progression to multiple myeloma. Isatuximab also improved general QoL scores by the end of cycle 6 of treatment which were now comparable to those in the general population (Figure 1). Conclusion Isatuximab is very well tolerated, results in high response rates in HRSMM and has the potential to change the natural history of this disease. In ongoing QoL analysis, initial data shows improvement in QoL and decreased cancer worry after isatuximab treatment. Immune-genomic analysis is ongoing and may identify patients that benefit the most from treatment. Disclosures Manasanch: celgene: Honoraria; merck: Research Funding; quest diagnostics: Research Funding; sanofi: Research Funding; BMS: Honoraria; Sanofi: Honoraria. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Merck: Consultancy. Lee:Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Patel:Poseida Therapeutics, Cellectis, Abbvie: Research Funding; Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding. Kaufman:Janssen: Other: travel/lodging, Research Funding. Thomas:Xencor: Research Funding; BMS: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Mailankody:Takeda Oncology: Research Funding; Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; CME activity by Physician Education Resource: Honoraria. Lendvai:Janssen: Employment. Neelapu:Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Merck: Consultancy, Research Funding; Allogene: Consultancy; Cellectis: Research Funding; Poseida: Research Funding; Karus: Research Funding; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Cell Medica: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Landgren:Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC. OffLabel Disclosure: Isatuximab for the treatment of smoldering myeloma

Targeting EZH2 in Multiple Myeloma Could be Promising for a Subgroup of MM Patients in Combination with IMiDs

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 311-311 ◽  
Author(s):  
Laurie Herviou ◽  
Alboukadel Kassambara ◽  
Stephanie Boireau ◽  
Nicolas Robert ◽  
Guilhem Requirand ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Myeloma Cells ◽  
Ezh2 Expression ◽  
Bone Marrow Plasma

Abstract Multiple Myeloma is a B cell neoplasia characterized by the accumulation of clonal plasma cells within the bone marrow.Epigenetics is characterized by a wide range of changes that are reversible and orchestrate gene expression. Recent studies have shown that epigenetic modifications play a role in multiple myeloma (MM) by silencing various cancer-related genes. We investigated the epigenetic genes differentially expressed between normal bone marrow plasma cells (BMPC ; N=5) and MM plasma cells from patients (N=206). Using SAM (Significance Analysis of Microarrays) analysis, only 12 genes significantly differentially expressed between BMPC and MM cells (ratio > 2 and FDR (false discovery rate) < 5%) were identified, including the EZH2 histone methyltransferase. EZH2, the enzymatic subunit of Polycomb Repressive Complex 2, is a histone methyltransferases able to repress gene expression by catalyzing H3K27me3 histone mark. EZH2 overexpression has been associated with numerous hematological malignancies, including MM. We thus studied EZH2 role in MM physiopathology and drug resistance. EZH2 expression was analyzed in normal bone marrow plasma cells (BMPCs; N=5), primary myeloma cells from newly diagnosed patients (MMCs; N=206) and human myeloma cell lines (HMCLs; N=40) using Affymetrix microarrays. EZH2 gene is significantly overexpressed in MMCs of patients (median 574, range 105 - 4562) compared to normal BMPCs (median = 432; range: 314 - 563) (P < 0.01). The expression is even higher in HMCLs (median 4481, range 581 - 8455) compared to primary MMCs or BMPCs (P < 0.001). High EZH2 expression is associated with a poor prognosis in 3 independent cohorts of newly diagnosed patients (Heidelberg-Montpellier cohort - N=206, UAMS-TT2 cohort - N=345 and UAMS-TT3 cohort - N =158). Furthermore, GSEA analysis of patients with high EZH2 expression highlighted a significant enrichment of genes involved in cell cycle, downregulated in mature plasma cells vs plasmablasts, and EZH2 targets. Specific EZH2 inhibition by EPZ-6438 EZH2 inhibitor induced a significant decrease of global H3K27me3 in all the HMCLs tested (P < 0.01) and inhibited MM cell growth in 5 out of the 6 HMCLs tested. The inhibitory effect of EZH2 inhibitor on MM cell growth appeared at day 6 suggesting that it is mediated by epigenetic reprogramming. To confirm that EZH2 is also required for the survival of primary MMCs from patients, primary MM cells (n = 17 patients) co-cultured with their bone marrow microenvironment and recombinant IL-6 were treated with EPZ-6438. As identified in HMCLs, EZH2 inhibition significantly reduced the median number of viable myeloma cells by 35% (P = 0.004) from a subset of patients (n=9) while the other group (n=8) was resistant. Of interest, EPZ-6438 induced a significant global H3K27me3 decrease in both groups of patient. RNA sequencing of 6 HMCLs treated with EPZ-6438 combined with H3K27me3 ChIP analyses allowed us to create an EZ GEP-based score able to predict HMCLs and primary MM cells sensitivity to EZH2 inhibitors. We also observed a synergy between EPZ-6438 and Lenalidomide, a conventional drug used for MM treatment. More interestingly, pretreatment of myeloma cells with EPZ-6438 significantly re-sensitize drug-resistant MM cells to Lenalidomide. Investigating the effect of EPZ-6438/Lenalidomide combination in MMC, we identified that IKZF1, IRF4 and MYC protein levels were significantly more inhibited by the combination treatment (65.5%, 63.9% and 14.8% respectively) compared with Lenalidomide (51.5%, 43% and 2.2%) or EPZ-6438 (45.2%, 38.7% and 6.2%) alone. Clinical trials are ongoing with EZH2 inhibitors in lymphoma and could be promising for a subgroup of MM patients in combination with IMiDs. Furthermore, the EZ score enables identification of MM patients with an adverse prognosis and who could benefit from treatment with EZH2 inhibitors. Disclosures Goldschmidt: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Hose:EngMab: Research Funding; Takeda: Other: Travel grant; Sanofi: Research Funding.

scholarly journals Descriptive Analysis of Isatuximab Use Following Prior Daratumumab in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-21
Author(s):  
Melody R Becnel ◽  
Sandra B. Horowitz ◽  
Sheeba K. Thomas ◽  
Swami P. Iyer ◽  
Krina K. Patel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
North America ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Laboratory Research ◽  
Private Company ◽  
Advisory Committees ◽  
Advisory Boards

Background: Anti-CD38 monoclonal antibodies (mAb) like daratumumab (dara) have become integral in managing relapsed/refractory (RR) and newly diagnosed (ND) multiple myeloma (MM). Isatuximab (isa), a newer CD38 mAb, induces direct rather than indirect apoptosis of MM cells. However, little is known about whether the use of one prior CD38 mAb will alter the efficacy of another in subsequent lines of therapy. Methods: All patients (pts) with MM treated at MD Anderson with isa after receiving dara in prior lines of therapy were identified. We conducted a retrospective analysis with data points including patient and disease characteristics, responses to dara, response to isa, the presence of high risk features, and the presence of t(11,14). Results: 9 pts were identified, ages 56-72. 5 pts (55%) were male. 5 pts (55%) were alive at the time of data cutoff. 5 pts were Hispanic, 3 White, and 1 Black. 8 pts (89%) had high risk features as represented by the presence of del17p, t(4,14), t(14,16), t(14,20), p53 mutations, gain 1q, extramedullary disease (EMD), CNS disease, early relapse (within 1 year) after autologous transplant, or an increased (&gt;5%) peripheral blood plasma cells (PBPC). 2 (22%) had t(11,14). 4 (44%) had IgG MM. 2 (22%) with light chain disease, 2 (22%) with IgA MM, and 1 (11%) with IgD MM. Dara was initially used in lines 2-7. Dara combinations with pomalidomide (pom), bortezomib (bor), thalidomide (thal), lenalidomide (len), or carfilzomib (car); and pom combinations that also included elotuzumab (elo) or Cytoxan (cytox) are noted in table 1. Dara was discontinued (dc'd) in 8 pts due to progressive disease (PD) and in 1 pt due to toxicity. 8 pts (89%) experienced a best overall response (ORR) of partial response (PR) to dara; 1 pt had stable disease (SD). All pts received prior len and 8 pts received prior pom at some time during the treatment of MM. All pts received isa in combination with pom/dexamethasone (dex). Best ORR to isa/pom/dex: 5 pt (55%) had PR, 2 pt with minimal response (MR), 1 SD, 1 PD. Median treatment duration of isa/pom/dex was 5 weeks (2-14 weeks) at data cutoff. 3 pts dc'd isa/pom/dex due to infections, and 2 due to later progression. 2 pts remain on therapy. 1 pt chose to dc all MM therapy for quality of life purposes despite PR with isa/pom/dex. 1 pt died from cardiac disease unrelated to MM or treatment. Conclusions: Our current study of heavily pretreated pts with RRMM demonstrates that despite prior anti-CD38 therapy with dara, most patients (77%) experienced a response of MR or better with treatment with another anti-CD38 therapy isa. To our knowledge, this is the first report of outcomes to isa in patients with prior dara therapy. Further long term follow up will be needed to determine the length of response. Additional studies are planned to further evaluate this patient population. Table 1 Disclosures Thomas: Pharmacyclics: Other: Advisory Boards; BMS: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharma: Research Funding; Xencor: Research Funding; Genentech: Research Funding. Iyer:Rhizen: Research Funding; CRISPR: Research Funding; Spectrum: Research Funding; Merck: Research Funding; Curio Biosciences: Honoraria; Target Oncology: Honoraria; Afffimed: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Trillium: Research Funding; Seattle Genetics, Inc.: Research Funding. Patel:Celgene: Consultancy, Research Funding; Cellectis: Research Funding; Nektar: Consultancy, Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Manasanch:Adaptive Biotechnologies: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Takeda: Honoraria; Quest Diagnostics: Research Funding; Merck: Research Funding; JW Pharma: Research Funding; Novartis: Research Funding; Sanofi: Research Funding. Kaufman:Janssen: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Honoraria. Lee:Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy. Orlowski:Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding.

scholarly journals Identification of Novel Regulatory Pathway for Immunoglobulin Production Provides Rational Treatment for Bortezomib-Resistant Multiple Myeloma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-42
Author(s):  
Alexander Vdovin ◽  
Michal Durech ◽  
Tomas Jelinek ◽  
Tereza Sevcikova ◽  
Juli R. Bago ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Patient Survival ◽  
Advisory Committees ◽  
Myeloma Cells ◽  
Ubiquitinated Proteins ◽  
Ig Synthesis

Introduction Monoclonal immunoglobulin (Ig) is a valuable diagnostic marker in patients with multiple myeloma (MM). An inevitable consequence of extensive Ig synthesis is overload of misfolded proteins that saturate proteasome capacity making the myeloma cells highly sensitive to proteasome inhibitors (PI). Even though PI are regularly used in the clinic, resistance often emerges leaving clinicians with limited treatment options. Therefore, there is a need for a robust marker selecting MM patients for precise PI-based combination therapy. Methods We performed a multiple database search for genes associated with Ig production and MM patients' survival. Additionally, we compared gene expression profiles (RNAseq) of primary MM cells with low and high Ig levels. Next, we validated the identified hits by shRNA knockdown and overexpression studies using myeloma cell lines, primary MM samples, and mouse models. We also applied mass spectrometry-based proteomic analysis, advanced biochemical approaches, and genetic models to reveal the Ig production pathway components and function. Finally, we performed a limited rational drug screening to select suitable compounds for combination treatment. Results RNAseq and database mining revealed a strong association between the expression of plasma cell-specific deubiquitinase OTUD1, Ig production, and MM patient survival. Suppression of OTUD1 with shRNAs in RPMI8226 and MM1.S cell lines reduced Ig levels, increased proliferation, and induced bortezomib resistance. Conversely, inducible OTUD1 overexpression enhanced Ig production, slowed down proliferation, and increased bortezomib sensitivity. In the xenografts mouse models cells with high OTUD1 levels synthesized more Ig and developed smaller tumors. Intriguingly, the transcription of Ig genes was not influenced by OTUD1 expression suggesting that OTUD1 functions as a posttranslational regulator of Ig assembly. To gain mechanistic insight into the Ig pathway regulation by OTUD1, we utilized the biotin proximity labeling method (Turbo-ID) combined with mass spectrometry analysis. We found several novel OTUD1 interaction partners including the E3 ubiquitin ligase KEAP1 and endoplasmic reticulum (ER) redox protein PRDX4. We demonstrated that KEAP1 acts upstream of OTUD1 by regulating OTUD1 ubiquitination and stability. Consistently, survival analysis revealed that MM patients with high KEAP1 expression (low OTUD1) had a worse prognosis than patients with low levels of KEAP1 (high OTUD1). PRDX4 regulates disulfite bonds formation during protein folding and is uniquely expressed in fully differentiated plasma cells. Here, we revealed that OTUD1 specifically deubiquitinates and thus stabilizes PRDX4 inside the ER. Additionally, we performed rescue genetic experiments and found a direct link between the OTUD1-PRDX4 axis and Ig production. The increase in OTUD1 expression (high Ig) led to a dramatic increase in the total pool of ubiquitinated proteins formed mainly by misfolded Ig, while OTUD1 knockdown (low Ig) had an opposite effect. We showed that changes in the level of ubiquitinated proteins correlated with PI sensitivity. Of note, OTUD1 did not affect the expression of proteasome subunits, either their enzymatic activity. Our mechanistic findings prompted us to propose a novel therapeutic opportunity in PI resistant MM patients. We hypothesize that the resensitization of Ig low MM cells to PI could be achieved by enhancing ER stress leading to an increase in misfolded proteins that would ultimately saturate proteasomes. Indeed, from clinically relevant drugs tested so far, the HSP-90 inhibitor (17-AAG) reverted the PI resistance in OTUD1 low (Ig low) myeloma cells. An in vivo validation of the combination treatment and testing of Ig involvement in PI sensitivity and proliferation of MM cells is ongoing. Conclusion Here we present the discovery of a novel regulatory mechanism for Ig production in plasma cells. Based on our results and previously published studies, we conclude that Ig synthesis is a clinically significant factor related to PI response and MM patient survival. Our findings suggest that the intracellular Ig level is an important biomarker to identify patients benefiting the most from PI-based therapies. Finally, we provide a rational solution for selective, combination therapy to overcome PI resistance in MM patients with a decreased capacity to synthesize Ig. Figure Disclosures Hajek: Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; Oncopeptides: Consultancy.

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 Global Expression Changes of Malignant Plasma Cells over Time Reveals the Evolutionary Development of Signatures of Aggressive Clinical Behavior

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4457-4457
Author(s):  
Eileen M Boyle ◽  
Adam Rosenthal ◽  
Yan Wang ◽  
Phil Farmer ◽  
Michael W Rutherford ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Adverse Outcome ◽  
Patient Specific ◽  
Advisory Committees ◽  
Over Time

Abstract Introduction: Clustering of gene expression signatures at diagnosis has identified a number of distinct disease groups that correlate with outcome in multiple myeloma (MM). Some of these are defined by an etiologic genetic event whereas others, such as the proliferation cluster (PR) and GEP70 risk relate to acquired clinical behaviors regardless of the underlying background. The PR cluster has a number of important features, including markers of proliferation, and has been associated with an adverse outcome. This logic led us to study how gene expression patterns change over time with the aim of gaining insight into acquired features that could be targeted therapeutically or be used to predict outcome. Methods: We followed 784 newly diagnosed MM patients from the Total Therapy trials over a median of 9.5 years for whom repeated GEP of CD138+ plasma cells using Affymetrix U133 Plus 2.0 plus arrays were obtained. Raw data were MAS5 normalized and GEP70-based high-risk (HR) scores, translocation classification (TC) and molecular cluster classification were derived, as previously reported. Results: At diagnosis, 85.9% percent of patients (666/784) were identified as low-risk (LR). Among them, 23.1% (154/666) went on to develop HR status (defined by a GEP70 score > 0.66) at least once after initial diagnosis. Among the non-PR cases, 28.5% (193/677) were seen to develop a PR phenotype at some point during follow-up. Similarly, among the PR patients (n=107), we observed that 43.1% (25/58) identified as LR by GEP70 at presentation eventually develop HR status at least once during follow-up. We further analyzed 147 patients with paired diagnosis and relapse samples. Seventeen percent of patients (25/147) were PR at diagnosis. Most patients were from favorable TC prognostic groups [80% D1-D2, 8% t(11;14), 8% t(4;14) and 4% t(14;20)]. Seventy-six percent of PR patients remained PR at relapse (19/25) whereas 23% switched cluster in accordance to their translocation group. Fifteen percent of patients (22/147) became PR at relapse. They originated from four clusters and three TC groups [77% from the D1-D2, 14% t(4;14) and 9% from the t(11;14)]. Overall-survival from the time of relapse was inferior for patients categorized as PR at relapse compared to other subgroups (p< 0.0001); among PR patients at relapse, there was no difference in outcome between patients classified as PR or non-PR at diagnosis (p= 0.74). When looking at GEP70 defined risk scores, the incidence of HR status rose from 23% to 39% between diagnosis and relapse with a significant increase in mean GEP70 scores using paired t-test (p<0.0001). Patients identified as HR by GEP70 at relapse had an inferior post-relapse outcome compared to patients identified as LR (p< 0.0001); there was no difference in the outcome of patients identified as HR at relapse depending on their risk status at diagnosis (p = 0.10). Discussion: Following the introduction of therapeutic regimens aimed at maximizing response, long term survival in MM has improved. This also led to an apparent increase in the development of more aggressive disease patterns at relapse including extra-medullary disease and plasma cell leukemia. Here we show, that HR features both in terms of PR and GEP70 risk status, develop as a variable over time. At relapse, most acquired HR cases originate from standard-risk presentation cases, suggesting selective pressure for HR features. Moreover, we show that the detection of such behaviors is associated with an adverse outcome from the time of relapse. These data also suggest that repeating GEP during follow-up adds precision to better comprehend individual risk and may help identify patient specific therapeutic strategies. Indeed, understanding how these patterns develop, which genes are implicated, and their impact on the immune microenvironment should allow us to effectively utilize a wide array of treatment approaches ranging from immune-therapies to novel cell-cycle targeting agents to specifically address this type of aggressive behavior. Conclusion: The acquisition of high risk patterns captured by GEP70 risk and PR status is an ongoing process from initial diagnosis. Such high risk prognostic features have an adverse outcome from the time of development. Repeating GEP during follow-up may therefore help better predict outcome and identify patient specific therapeutic strategies. Disclosures Boyle: Janssen: Honoraria, Other: travel grants; Takeda: Consultancy, Honoraria; Gilead: Honoraria, Other: travel grants; Abbvie: Honoraria; Celgene: Honoraria, Other: travel grants; La Fondation de Frace: Research Funding; Amgen: Honoraria, Other: travel grants. Dumontet:Janssen: Honoraria; Roche: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Facon:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Barlogie:Celgene: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Other: travel stipend; European School of Haematology- International Conference on Multiple Myeloma: Other: travel stipend; Dana Farber Cancer Institute: Other: travel stipend; Millenium: Consultancy, Research Funding; 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; International Workshop on Waldenström's Macroglobulinemia: Other: travel stipend. Davies:TRM Oncology: Honoraria; Janssen: Consultancy, Honoraria; ASH: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria.

scholarly journals Defining the Differentiation States of Multiple Myeloma at Single Cell Resolution Reveals Opportunities for Immunotherapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3091-3091
Author(s):  
Julia Frede ◽  
Praveen Anand ◽  
Andrew J. Yee ◽  
Tushara Vijaykumar ◽  
Monica S. Nair ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Advisory Board ◽  
Therapeutic Resistance ◽  
Cellular Plasticity ◽  
Advisory Committees ◽  
Myeloma Cells

Introduction: Despite recent advances in the treatment of multiple myeloma, responses may be short-lived and therapeutic resistance develops almost invariably. Non-genetic cellular plasticity and dedifferentiation have recently emerged as a basis for therapeutic resistance in cancer as cells acquire transcriptional states which no longer depend on the drug target. Therefore, a better understanding of plasticity and adaptive state changes in myeloma cells is critical to develop effective therapeutic approaches that can overcome drug resistance. Here we show that cellular plasticity, though frequently invoked as a basis for therapeutic resistance in cancer, can also lead to new therapeutic opportunities. Methods: To define transcriptional states in myeloma at a single cell level, we performed fluorescence activated cell sorting and full-length single-cell RNA sequencing. We assayed a total 6000 CD38+CD138+ plasma cells and CD45+ immune cells from the bone marrow of 8 patients with relapsed and refractory multiple myeloma (RRMM) before and after immuno-modulatory treatment on a clinical trial with elotuzumab, pomalidomide, bortezomib and dexamethasone (Elo-PVD; NCT02718833) and 2 healthy donors. Surface expression of selected markers was validated by flow cytometry. Results: Assessing pre-treatment samples, we discovered that the transcriptional states of single myeloma cells are highly distinct between individual patients, despite the presence of the same established genomic classifiers, such as t(11;14). Furthermore, distinct transcriptional states co-exist within individual patients, indicating there is substantial inter- and intra-individual heterogeneity. Transcriptional states diverge from normal plasma cells towards more immature cells, of the B lymphoid lineage, suggesting a substantial cellular plasticity. Notably, we detected co-expression of myeloid and lymphoid developmental programs in the same single cells. Interestingly, these altered differentiation states were associated with up-regulation of potential immunotherapeutic targets, such as CD20, CD19, and CD33, indicating that this plasticity may result in novel therapeutic vulnerabilities. To define gene-regulatory relationships, we identified a shared core regulatory network present in malignant and normal plasma cells with the active transcription factors XBP1, ATF4, and CREB3, suggesting that myeloma cells retain lineage-specific regulons. However, we further identified patient-specific regulons not detected in any of the mature immune cell populations assayed, such as TEAD4, ELF3 and SNAI1, illustrating an aberrant and promiscuous activation of transcriptional regulators in myeloma cells. Consistent with this finding, we observed an increased number of expressed genes in myeloma cells compared to normal plasma cells as well as an increase in single cell transcriptional entropy, measures that have been linked to cell potency in normal development and cancer. Comparison of pre- and post-treatment samples interestingly revealed a further increase in transcriptional diversity and signatures associated with stemness and developmental potential following treatment. Conclusions: In conclusion, we find that higher transcriptional diversity and activation of alternate gene regulatory programs facilitate the emergence of altered transcriptional states. Interestingly, these altered states are associated with up-regulation of putative immune-therapeutic targets in myeloma cells, thus providing novel therapeutic vulnerabilities. Disclosures Lipe: amgen: Research Funding; Celgene: Consultancy; amgen: Consultancy. O'Donnell:Celgene: Consultancy; Takeda: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Amgen: Consultancy. Munshi:Celgene: Consultancy; Amgen: Consultancy; Oncopep: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Adaptive: Consultancy; Oncopep: Consultancy; Takeda: Consultancy. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder . Lohr:T2 Biosystems: Honoraria; Celgene: Research Funding. OffLabel Disclosure: Samples for ancillary research were obtained in the context of a phase II clinical trial evaluating Elotuzumab, pomalidomide, bortezomib, dexamethasone The combination of elo-PVD is off label.

scholarly journals A Phase II Study of Daratumumab in Patients with High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1649-1649
Author(s):  
Omar Nadeem ◽  
Robert A. Redd ◽  
Michael Z. Koontz ◽  
Jeffrey V. Matous ◽  
Andrew J. Yee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Low Risk ◽  
M Protein ◽  
Advisory Committees ◽  
Bone Marrow Plasma

Abstract Introduction : Daratumumab (Dara) is an anti-CD38 monoclonal antibody that is approved for use in patients with newly diagnosed and relapsed multiple myeloma (MM). We hypothesized that early therapeutic intervention with Dara in patients with high-risk MGUS (HR-MGUS) or low-risk SMM (LR-SMM) would lead to eradication of the tumor clone by achieving deep responses, resulting in prevention of progression to MM. We present results of our phase II, single arm study of Dara in HR-MGUS and LR-SMM. Methods : Patients enrolled on this study met eligibility for either HR-MGUS or LR-SMM. HR-MGUS is defined as &lt;10% bone marrow plasma cells and &lt;3g/dL M protein and at least 2 of the following 3 high-risk criteria: Abnormal serum free light chain ratio (SFLC) of &lt;0.26 or &gt;1.65, M protein ≥ 1.5g/dL or non-IgG M protein. LR-SMM is defined by one of the following 3 criteria: M protein ≥3g/dL, ≥10% bone marrow plasma cells, SFLC ratio &lt;0.125 or &gt;8. Dara (16mg/kg) was administered intravenously on a weekly schedule for cycles 1-2, every other week cycles 3-6, and monthly during cycles 7-20. The primary objective of this study was to determine the proportion of patients who achieve very good partial response (VGPR) or greater after 20 cycles of Dara. Secondary objectives included duration of response, safety, and rates of minimal residual disease (MRD)-negativity in VGPR or greater patients. Correlative studies included assessing changes in immune microenvironment, evaluating clonal heterogeneity using deep sequencing, and determining association of genomic aberrations correlating with either response to therapy or progression of disease. Results : At the time of data cutoff, a total of 42 patients were enrolled on this study from 2018 to 2020 with participation of 5 sites. The median age for all patients at enrolment was 60 years (range 38 to 76), with 22 males (52.4%) and 20 females (47.6%). Majority of patients enrolled were classified as LR-SMM (n = 37, 88.1%) and the remaining 5 patients had HR-MGUS (11.9%). 41 patients have started treatment and are included in toxicity assessment, and 40 patients have at least completed 16 cycles (range 6-20). Grade 3 toxicities were rare and only experienced in 5/41 patients including diarrhea (n =1/41; 2%), flu like symptoms (n = 1/41; 2%), headache (n=1/41; 2%), and hypertension (n=2/41; 5%). Most common toxicities of any grade included fatigue (n = 24/41, 51%), cough (n = 19/41, 46%), nasal congestion (n = 18/41, 44%), headache (n = 14/41, 34%), hypertension (n = 11/41, 27%), nausea (n = 13/41, 32%), and leukopenia (n = 13/41, 32%). No patients have discontinued therapy due to toxicity. Minimal response or better was observed in 82.9% of patients (34/41) and PR or better was observed in 51.2% of patients (21/41). This included overall CR (n = 4, 9.8%), VGPR (n = 1, 2.4%), PR (n = 16, 39.0%), MR (n = 13, 31.7%), and SD (n = 7, 17.1%). In the 40 patients who completed at least 16 cycles, response rates were as follows: MR or better 85% (34/40), PR or better 52.5% (21/40) and VGPR or better 12.5% (5/40). Median time to VGPR was 7 months. Median overall survival and progression-free survival have not been reached and no patients have progressed to overt multiple myeloma while on study. Conclusion : Dara is very well tolerated among patients with HR-MGUS and LR-SMM with minimal toxicities. Responses are seen in majority of patients. Early therapeutic intervention in this precursor patient population appears promising but longer follow up is required to define the role of single agent Dara in preventing progression to MM, therefore avoiding more toxic interventions in this low-risk patient population. Disclosures Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Yee: GSK: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Zonder: Caelum Biosciences: Consultancy; Amgen: Consultancy; BMS: Consultancy, Research Funding; Intellia: Consultancy; Alnylam: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy. Rosenblatt: Attivare Therapeutics: Consultancy; Imaging Endpoints: Consultancy; Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Wolters Kluwer Health: Consultancy, Patents & Royalties. Mo: AbbVIE: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sperling: Adaptive: Consultancy. Richardson: Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

scholarly journals B-PRISM (Precision Intervention Smoldering Myeloma): A Phase II Trial of Combination of Daratumumab, Bortezomib, Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4782-4782
Author(s):  
Omar Nadeem ◽  
Robert A. Redd ◽  
Julia Prescott ◽  
Amada Metivier ◽  
Kelsey Tague ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Plasma Cells ◽  
M Protein ◽  
Focal Lesion ◽  
Advisory Committees

Abstract Background: Early therapeutic intervention with lenalidomide and dexamethasone in patients with high-risk smoldering multiple myeloma (HR-SMM) has shown to be effective by delaying time to progression to overt myeloma (Lonial J Clin Oncol 2020 Apr 10;38(11):1126-1137). Triplet and quadruplet combination therapies utilizing a proteasome inhibitor, immunomodulatory agent and a CD38 monoclonal antibody are used extensively in patients with multiple myeloma due to far greater efficacy compared to lenalidomide and dexamethasone alone. These combinations have been studied in HR-SMM, demonstrating encouraging activity, including ixazomib, lenalidomide and dexamethasone and elotuzumab, lenalidomide and dexamethasone. There are also current ongoing studies with curative intent utilizing more potent therapy in HR-SMM, including carfilzomib, lenalidomide and dexamethasone with autologous stem cell transplantation (Mateos EHA 2019, abstract S871) and daratumumab, carfilzomib, lenalidomide and dexamethasone (NCT03289299). Daratumumab, bortezomib, lenalidomide and dexamethasone (D-RVD) combination is highly effective and well-tolerated in newly diagnosed multiple myeloma at achieving high response rates as well as minimal residual disease (MRD) negativity based on results from the phase II GRIFFIN trial (Voorhees Blood 2020 Aug 20;136(8):936-945). Thus, we propose to examine the activity and safety of D-RVD in patients with HR-SMM. Study Design and Methods: This is a phase II single center, single-arm, open label study evaluating the combination of D-RVD in HR-SMM. Primary objective of this study is to determine the proportion of HR-SMM patients who are MRD negative at 2 years after receiving D-RVD. Secondary objectives include MRD negativity rate at 6 months, 12 months, 24 months and 36 months, progression-free survival, response rates and safety. Exploratory objectives include assessment of mass spectrometry quantification of M protein, examination of molecular evolution of tumor cells and to determine role of immune cells in progression of SMM. Patients must meet criteria for HR-SMM based on bone marrow clonal plasma cells ≥10% and any one or more of the following: Serum M protein ≥3.0 gm/dL, immunoparesis with reduction of two uninvolved immunoglobulin isotypes, serum involved/uninvolved free light chain ratio ≥8 (but less than 100), progressive increase in M protein level (evolving type of SMM), bone marrow clonal plasma cells 50-60%, abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells are clonal) and reduction of one or more uninvolved immunoglobulin isotypes, high risk FISH defined as any one or several of the following: t(4;14), t(14;16), t(14;20), del 17p or 1q gain, MRI with diffuse abnormalities or 1 focal lesion (≥5mm), PET-CT with one focal lesion (≥5mm) with increased uptake without underlying osteolytic bone destruction. Patients that meet high risk definition by the new Mayo/IMWG 2018 "20-2-20" criteria are also eligible if they have 2 out of the following 3 criteria: Bone marrow plasmacytosis ≥20% , ≥2g/dl M protein, ≥20 involved: uninvolved serum free light chain ratio. Treatment duration with D-RVD is for 2 years (24 cycles). Daratumumab is administered at a dose of 1800mg subcutaneously (SQ) weekly for cycles 1-2, biweekly for cycles 3-6 and monthly until completion of cycle 24. Bortezomib is given at a dose of 1.3mg/m2 SQ on days 1, 8, 15 for cycles 1-6 and then biweekly until completion of cycle 24. Lenalidomide is administered on days 1-21 at a dose of 25mg for cycles 1-6 and 15mg for cycles 7-24. Dexamethasone is administered weekly at 20mg cycles 1-6 and biweekly during cycles 7-24. All eligible patients will undergo stem cell collection after cycle 6 of therapy. A single-stage design will be employed with 30 eligible patients entered. If 12 or more of the 30 eligible patients are MRD negative at 2 years (observed rate of &gt;=40%), we will conclude that this treatment warrants further study. The probability of concluding that the treatment is effective if the true rate is 25% is 0.051 and is 0.90 if the true rate is 50%. Figure 1 Figure 1. Disclosures Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy. Sperling: Adaptive: Consultancy. Richardson: Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Janssen: Consultancy; Secura Bio: Consultancy; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

scholarly journals Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 804-804 ◽  
Author(s):  
Mark Bustoros ◽  
Chia-jen Liu ◽  
Kaitlen Reyes ◽  
Kalvis Hornburg ◽  
Kathleen Guimond ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Disease Progression ◽  
Board Of Directors ◽  
Rna Sequencing ◽  
Research Funding ◽  
Response Rate ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background. This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods. Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al., Blood 2014. The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and Dexamethasone at days 1, 8, 15, and 22. This induction phase is followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle is defined as 28 consecutive days, and therapy is administered for a total of 24 cycles total. Bone marrow samples from all patients were obtained before starting therapy for baseline assessment, whole exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle to isolate cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Stem cell collection is planned for all eligible patients. Results. In total, 26 of the planned 56 patients were enrolled in this study from February 2017 to April 2018. The median age of the patients enrolled was 63 years (range, 41 to 73) with 12 males (46.2%). Interphase fluorescence in situ hybridization (iFISH) was successful in 18 patients. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 11 patients (61.1%). The median number of cycles completed was 8 cycles (3-15). The most common toxicities were fatigue (69.6%), followed by rash (56.5%), and neutropenia (56.5%). The most common grade 3 adverse events were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). One patient had grade 4 neutropenia during treatment. Additionally, grade 4 hyperglycemia occurred in another patient. As of this abstract date, the overall response rate (partial response or better) in participants who had at least 3 cycles of treatment was 89% (23/26), with 5 Complete Responses (CR, 19.2%), 9 very good partial responses (VGPR, 34.6%), 9 partial responses (34.6%), and 3 Minimal Responses (MR, 11.5%). None of the patients have shown progression to overt MM to date. Correlative studies including WES of plasma cells and single-cell RNA sequencing of the bone microenvironment cells are ongoing to identify the genomic and transcriptomic predictors for the differential response to therapy as well as for disease evolution. Furthermore, we are analyzing the cfDNA and CTCs of the patients at different time points to investigate their use in monitoring minimal residual disease and disease progression. Conclusion. The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma. The high response rate, convenient schedule with minimal toxicity observed to date are promising in this patient population at high risk of progression to symptomatic disease. Further studies and longer follow up for disease progression are warranted. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy.

Investigational Agent MLN9708 Target Tumor Suppressor MicroRNA-33b in Multiple Myeloma Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 136-136
Author(s):  
Ze Tian ◽  
Jian-Jun Zhao ◽  
Jianhong Lin ◽  
Dharminder Chauhan ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Tumor Suppressor ◽  
Board Of Directors ◽  
Expression Profiling ◽  
Research Funding ◽  
Advisory Committees ◽  
Myeloma Cells ◽  
Investigational Agent ◽  
Reporter Activity

Abstract Abstract 136 Investigational Agent MLN9708 Target Tumor Suppressor MicroRNA-33b in Multiple Myeloma Cells Ze Tian, Jianjun Zhao, Jianhong Lin, Dharminder Chauhan, Kenneth C. Anderson Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115 MicroRNAs (miRNAs) are 19–25 nucleotide-long noncoding RNA molecules that regulate gene expression both at the level of messenger RNA degradation and translation. Emerging evidence shows that miRNAs play a critical role in tumor pathogenesis by functioning as either oncogene or tumor suppressor genes. The role of miRNA and their regulation in response to proteasome inhibitors treatment in Multiple Myeloma (MM) is unclear. Here, we utilized MLN9708, a selective orally bio-available proteasome inhibitor to examine its effects on miRNA alterations in MM.1S MM cells. Upon exposure to aqueous solutions or plasma, MLN9708 rapidly hydrolyzes to its biologically active form MLN2238. Our previous study using both in vitro and in vivo models showed that MLN2238 inhibits tumor growth and triggers apoptosis via activation of caspases. Moreover, MLN2238 triggered apoptosis in bortezomib-resistant MM cells, and induced synergistic anti-MM activity when combined with HDAC inhibitor SAHA, dexamethasone, and lenalidomide. In the current study, we treated MM.1S cells with MLN2238 (12 nM) for 3 hours and harvested; total RNA was subjected to miRNA profiling using TaqMan® Array Human miRNA A-Card Set v3.0 and the data was analyzed using dChip analysis. Results showed that MLN2238 modulates miRNA expression with a total of 36 miRNA changing their expression profiling (δδCT>1.5 or δδCT <-1.5; 19 were upregulated and 17 showed a downregulation). Among all miRNA, miR-33b was highly (δδCT>7) upregulated in response to MLN2238 treatment. We therefore hypothesized that miR-33b may play a role in MM pathogenesis as well as during MLN2238-induced proteasome inhibition in MM cells. We first utilized quantitative polymerase chain reaction (q-PCR) to validate the changes in miRNA expression profiling. Results confirmed that MLN2238 treatment triggers significant increase in the miR-33b expression in MM.1S cells (2.1 and 2.2 folds at 3h and 6h, respectively; P<0.001). Examination of normal PBMCs and plasma cells showed higher expression of miR-33b than patient MM cells (P<0.001). We further investigated the functional role of miR-33b in MM cells at baseline and during MLN2238 treatment. Drug sensitivity, cell viability, apoptosis, colony formation, and migration assays were performed using cell TilTer-Glo, Annexin V-FITC/PI staining, MTT staining, and Transwell assays, respectively. Signaling pathways modulated post miR-33b overexpression were evaluated by q-PCR, immunoblot, and reporter assays. Our findings show that overexpression of miR-33b significantly decreased cell viability, cell migration, colony formation, as well as increased apoptosis and sensitivity of MM cells to MLN2238 treatment. Targetscan analysis predicted pim-1 as a putative downstream target of miR-33b. Overexpression of miR-33b downregulated pim-1 mRNA and protein expression. To further corroborate these data, we co-tranfected miR-33b and Pim-1-wt or Pim-1-mt in 293T and MM.1S cell lines. In concert with our earlier findings, miR-33b decreases pim-1-wt, but not pim-1-mt reporter activity in both cell lines. Reflecting the overexpression study results, MLN2238 treatment also decreases pim-1-wt, but not pim1-mt reporter activity. Moreover, a biochemical inhibitor of pim1/2 triggered apoptosis in MM cells. Finally, overexpression of miR-33b inhibits tumor growth (P<0.001) and prolongs survival (P<0.001) in both subcutaneous and disseminated human MM xenograft models. In summary, our study suggests that miR-33b is a tumor suppressor, which plays a role during MLN2238-induced apoptotic signaling in MM cells, and provide the basis for novel therapeutic strategies targeting miR-33b in MM. Disclosures: Anderson: Millennium: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership.

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