scholarly journals Identification of Dual PI3K/mTOR and BCL2 Inhibitors for the Treatment of High Risk Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 646-646
Author(s):  
Raija Silvennoinen ◽  
Muntasir Mamun Majumder ◽  
David Tamborero ◽  
Pekka Anttila ◽  
Samuli Eldfors ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Risk Stratification ◽  
Research Funding ◽  
Drug Sensitivity ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Treatment Options ◽  
Risk Markers ◽  
Nras Mutation

Abstract Introduction Multiple myeloma (MM) is an incurable malignant plasma cell disease with the highest incidence occurring at 65-70 years of age while 10% of patients are diagnosed below 55 years of age. The International Myeloma Working Group recently proposed new risk stratification standards for MM patients: high-risk (HR), standard (SR) and low-risk (LR) groups (Leukemia 2014, 28, 269−77). Although a median overall survival of LR patients is > 10 years from the diagnosis, new drugs and therapeutic innovations are urgently needed for HR patients (20%) who have a median overall survival of only two years. To identify new treatment options for MM patients, we compared ex vivo drug sensitivity data from primary CD138+ cells to standard risk stratification markers. Ex vivo responses indicated a number of investigational drugs as potential novel options for HR MM patients with links to risk markers. Methods Bone marrow aspirates were collected from newly diagnosed (n=14) and relapsed/refractory (n=21) MM patients. Cytogenetics were determined by fluorescence in situ hybridization (FISH) and the patients stratified based on the presence or absence of adverse FISH markers (t(4;14) and 17p del). Plasma cells (CD138+) were enriched from freshly isolated bone marrow samples and exome sequencing performed using DNA extracted from the CD138+ cells and matched skin biopsies. Ex vivo drug sensitivity was assessed by measuring the viability of the cells after 3-day incubation with 306 different oncology drugs in a 10,000-fold concentration range. Drug sensitivity scores were calculated based on the normalized area under the dose response curve (Scientific Reports 2014, 4, 5193) and select sensitivities determined by comparing results to healthy bone marrow cells. Based on drug sensitivities, the patients were classified in four different groups (sensitive, moderately sensitive, resistant and highly resistant). Results Of the 35 patients included in this study, 11 were classified as HR (31%) and 24 as SR/LR (69%). In the HR group 6/11 (55%) had t(4;14) and 5/11 patients (45%) had 17p13 del. In the SR/LR group common abnormalities included 13 monosomy/13q del (10/24), 1q gain (10/24) and K/NRAS mutation (11/24). Within the HR group, other co-occurring abnormalities included 1q gain (9/11), 13 monosomy/13q del (6/11), K/NRAS mutation (5/11), and TP53 mutation (2/11). Based on overall ex vivo drug sensitivity profiles of all patients, the majority of HR patients were classified as moderately sensitive (8/11; 73%) while SR/LR patients had diverse responses from sensitive to highly resistant. In the HR group, the highest select sensitivities were to BH3 mimetics and PI3K/mTOR inhibitors. While the t(4;14) is predicted to lead to upregulation and increased activity of the FGFR3, which could be targeted by FGFR inhibitors, none of the t(4;14) samples showed sensitivity to these drugs. However, with the exception of one t(4;14) sample, the rest all showed good sensitivity to dual PI3K/mTOR inhibitors, but not to rapalogs, suggesting that inhibition of PI3K and the mTORC1/2 complexes is required to inhibit t(4;14) cell growth rather than mTORC1 alone. Of the 17p del patients, 3/5 were classified as moderately sensitive, 1/5 sensitive and 1/5 highly resistant based on ex vivo drug response of CD138+ cells. All showed select sensitivity to BH3 mimetics/BCL2 inhibitors (navitoclax/ABT-263 and venetoclax/ABT-199/GDC-0199), while response to other drugs varied. Therefore, blocking cell survival signaling is likely essential for this group of HR MM patients. Conclusion By assessing the ex vivo sensitivity of primary plasma cells to a large collection of oncology drugs and comparing these data to standard risk stratification markers for MM, we have been able to identify potential new treatment options for high risk MM patients including dual PI3K/mTOR and BCL2- inhibitors. Although a larger cohort of patients is required to support the correlation between specific drug sensitivities and risk markers, these preliminary data indicate that currently used risk markers may be useful to predict the use of novel treatments. Disclosures Silvennoinen: Janssen-Cilag: Research Funding; Celgene: Research Funding; Janssen-Cilag: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding. Heckman:Celgene: Research Funding.

scholarly journals Prevalence of Smoldering Multiple Myeloma: Results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 151-151
Author(s):  
Sigrun Thorsteinsdottir ◽  
Gauti Kjartan Gislason ◽  
Thor Aspelund ◽  
Sæmundur Rögnvaldsson ◽  
Jon Thorir Thorir Oskarsson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Risk Stratification ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Population Based ◽  
M Protein ◽  
Screening Study

Abstract Background Smoldering multiple myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM). Emerging data from clinical trials indicate that - compared to watchful monitoring - initiation of therapy at the SMM stage might be indicated. Currently, there is no established screening for SMM in the general population and therefore patients are identified incidentally. Here, we define for the first time, epidemiological and clinical characteristics of SMM in the general population based on a large (N>75,000) population-based screening study. Methods The iStopMM study (Iceland Screens Treats or Prevents Multiple Myeloma) is a nationwide screening study for MM precursors where all residents in Iceland over 40 years of age and older were invited to participate. Participants with a positive M-protein on serum protein electrophoresis (SPEP) or an abnormal free light chain (FLC) analysis entered a randomized controlled trial with three arms. Participants in arm 1 continued care in the Icelandic healthcare system as though they had never been screened. Arms 2 and 3 were evaluated at the study clinic with arm 2 receiving care according to current guidelines. In arm 3 bone marrow testing and whole-body low-dose CT (WBLDCT) was offered to all participants. SMM was defined as 10-60% bone marrow plasma cells on smear or trephine biopsy and/or M-protein in serum ≥3 g/dL, in the absence of myeloma defining events. Participants in arm 3 were used to estimate the prevalence of SMM as bone marrow biopsy was performed in all participants of that arm when possible. The age- and sex-specific prevalence was determined with a fitted function of age and sex, and interaction between those. Diagnosis at baseline evaluation of the individuals in the study was used to define the point prevalence of SMM. Results Of the 148,704 individuals over 40 years of age in Iceland, 75,422 (51%) were screened for M-protein and abnormal free light chain ratio. The 3,725 with abnormal screening were randomized to one of the three arms, and bone marrow sampling was performed in 1,503 individuals. A total of 180 patients were diagnosed with SMM, of which 109 (61%) were male and the median age was 70 years (range 44-92). Of those, a total of 157 (87%) patients had a detectable M-protein at the time of SMM diagnosis with a mean M-protein of 0.66 g/dL (range 0.01-3.5). The most common isotype was IgG in 101 (56%) of the patients, 44 (24%) had IgA, 2 (1%) had IgM, and 5 (3%) had biclonal M-proteins. A total of 24 (13%) patients had light-chain SMM. Four patients (2%) had a negative SPEP and normal FLC analysis at the time of SMM diagnosis despite abnormal results at screening. A total of 131 (73%) patients had 11-20% bone marrow plasma cells at SMM diagnosis, 32 (18%) had 21-30%, 9 (5%) had 31-40%, and 8 (4%) had 41-50%. Bone disease was excluded with imaging in 167 (93%) patients (MRI in 25 patients, WBLDCT in 113 patients, skeletal survey in 27 patients, FDG-PET/CT in 1 patient), 13 patients did not have bone imaging performed because of patient refusal, comorbidities, or death. According to the proposed 2/20/20 risk stratification model for SMM, 116 (64%) patients were low-risk, 47 (26%) intermediate-risk, and 17 (10%) high-risk. A total of 44 (24%) had immunoparesis at diagnosis. Using the PETHEMA SMM risk criteria on the 73 patients who underwent testing with flow cytometry of the bone marrow aspirates; 39 (53%) patients were low-risk, 21 (29%) patients were intermediate-risk, and 13 (18%) patients were high-risk. Out of the 1,279 patients randomized to arm 3, bone marrow sampling was performed in 970, and 105 were diagnosed with SMM (10.8%). The prevalence of SMM in the total population was estimated to be 0.53% (95% CI: 0.49-0.57%) in individuals 40 years of age or older. In men and women, the prevalence of SMM was 0.70% (95% CI: 0.64-0.75%) and 0.37% (95% CI: 0.32-0.41%), respectively, and it increased with age in both sexes (Figure). Summary and Conclusions Based on a large (N>75,000) population-based screening study we show, for the first time, that the prevalence of SMM is 0.5% in persons 40 years or older. According to current risk stratification models, approximately one third of patients have an intermediate or high risk of progression to MM. The high prevalence of SMM has implications for future treatment policies in MM as treatment initiation at the SMM stage is likely to be included in guidelines soon and underlines the necessity for accurate risk stratification in SMM. Figure 1 Figure 1. Disclosures Kampanis: The Binding Site: Current Employment. Hultcrantz: Daiichi Sankyo: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Intellisphere LLC: Consultancy. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Research Funding; Janssen: Other: IDMC; Celgene: Research Funding; Takeda: Other: IDMC; Janssen: Honoraria; Amgen: Honoraria; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

Development of a Cancer Pharmacopeia-Wide Ex-Vivo Drug Sensitivity and Resistance Testing (DSRT) Platform: Identification of MEK and mTOR As Patient-Specific Molecular Drivers of Adult AML and Potent Therapeutic Combinations with Dasatinib

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2487-2487
Author(s):  
Mika Kontro ◽  
Caroline Heckman ◽  
Evgeny Kulesskiy ◽  
Tea Pemovska ◽  
Maxim Bespalov ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Drug Response ◽  
Drug Sensitivity ◽  
Ex Vivo ◽  
Molecular Profiling ◽  
Resistance Testing ◽  
Patient Specific ◽  
Targeted Drugs ◽  
Response Profiles

Abstract Abstract 2487 Introduction: The molecular drivers of adult AML as well as the determinants of drug response are poorly understood. While AML genomes have recently been sequenced, many cases do not harbor druggable mutations. Treatment options are particularly limited for relapsed and refractory AML. Due to the molecular heterogeneity of the disease, optimal therapy would likely consist of individualized combinations of targeted and non-targeted drugs, which poses significant challenges for the conventional paradigm of clinical drug testing. In order to better understand the molecular driver signals, identify individual variability of drug response, and to discover clinically actionable therapeutic combinations and future opportunities with emerging drugs, we established a diagnostic ex-vivo drug sensitivity and resistance testing (DSRT) platform for adult AML covering the entire cancer pharmacopeia as well as many emerging anti-cancer compounds. Methods: DSRT was implemented for primary cells from adult AML patients, focusing on relapsed and refractory cases. Fresh mononuclear cells from bone marrow aspirates (>50% blast count) were screened in a robotic high-throughput screening system using 384-well plates. The primary screening panel consisted of a comprehensive collection of FDA/EMA-approved small molecule and conventional cytotoxic drugs (n=120), as well as emerging, investigational and pre-clinical oncology compounds (currently n=90), such as major kinase (e.g. RTKs, checkpoint and mitotic kinases, Raf, MEK, JAKs, mTOR, PI3K), and non-kinase inhibitors (e.g. HSP, Bcl, activin, HDAC, PARP, Hh). The drugs are tested over a 10,000-fold concentration range resulting in a dose-response curve for each compound and with combinations of effective drugs explored in follow-up screens. The same samples also undergo deep molecular profiling including exome- and transcriptome sequencing, as well as phosphoproteomic analysis. Results: DSRT data from 11 clinical AML samples and 2 normal bone marrow controls were bioinformatically processed and resulted in several exciting observations. First, overall drug response profiles of the AML samples and the controls were distinctly different suggesting multiple leukemia-selective inhibitory effects. Second, the MEK and mTOR signaling pathways emerged as potential key molecular drivers of AML cells when analyzing targets of leukemia-specific active drugs. Third, potent new ex-vivo combinations of approved targeted drugs were uncovered, such as mTOR pathway inhibitors with dasatinib. Fourth, data from ex-vivo DSRT profiles showed excellent agreement with clinical response when serial samples were analyzed from leukemia patients developing clinical resistance to targeted agents. Summary: The rapid and comprehensive DSRT platform covering the entire cancer pharmacopeia and many emerging agents has already generated powerful insights into the molecular events underlying adult AML, with significant potential to facilitate individually optimized combinatorial therapies, particularly for recurrent leukemias. DSRT will also serve as a powerful hypothesis-generator for clinical trials, particularly for emerging drugs and drug combinations. The ability to correlate response profiles of hundreds of drugs in clinical ex vivo samples with deep molecular profiling data will yield exciting new translational and pharmacogenomic opportunities for clinical hematology. Disclosures: Mustjoki: Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Porkka:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Kallioniemi:Abbot/Vysis: Patents & Royalties; Medisapiens: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer Schering Pharma: Research Funding; Roche: Research Funding.

High-Throughput Ex Vivo Drug Sensitivity and Resistance Testing (DSRT) Integrated with Deep Genomic and Molecular Profiling Reveal New Therapy Options with Targeted Drugs in Subgroups of Relapsed Chemorefractory AML

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 288-288
Author(s):  
Caroline A Heckman ◽  
Mika Kontro ◽  
Tea Pemovska ◽  
Samuli Eldfors ◽  
Henrik Edgren ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcriptome Sequencing ◽  
Research Funding ◽  
Drug Response ◽  
Drug Sensitivity ◽  
Ex Vivo ◽  
Molecular Profiling ◽  
Resistance Testing ◽  
Response Patterns ◽  
Serial Samples

Abstract Abstract 288 Introduction: Recent genomic analyses of acute myeloid leukemia (AML) patients have provided new information on mutations contributing to the disease onset and progression. However, the genomic changes are often complex and highly diverse from one patient to another and often not actionable in clinical care. To rapidly identify novel patient-specific therapies, we developed a high-throughput drug sensitivity and resistance testing (DSRT) platform to experimentally validate therapeutic options for individual patients with relapsed AML. By integrating the results with exome and transcriptome sequencing plus proteomic analysis, we were able to define specific drug-sensitive subgroups of patients and explore predictive biomarkers. Methods: Ex vivo DSRT was implemented for 29 samples from 16 adult AML patients at the time of relapse and chemoresistance and from 5 healthy donors. Fresh mononuclear cells from bone marrow aspirates (>50% blast count) were screened against a comprehensive collection of cytotoxic chemotherapy agents (n=103) and targeted preclinical and clinical drugs (n=100, later 170). The drugs were tested over a 10,000-fold concentration range resulting in a dose-response curve for each compound and each leukemia sample. A leukemia-specific drug sensitivity score (sDSS) was derived from the area under each dose response curve in relation to the total area, and comparing leukemia samples with normal bone marrow results. The turnaround time for the DSRT assay was 4 days. All samples also underwent deep exome (40–100×) and transcriptome sequencing to identify somatic mutations and fusion transcripts, as well as phosphoproteomic array analysis to uncover active cell signaling pathways. Results: The drug sensitivity profiles of AML patient samples differed markedly from healthy bone marrow controls, with leukemia-specific responses mostly observed for molecularly targeted drugs. Individual AML patient samples clustered into distinct subgroups based on their chemoresponse profiles, thus suggesting that the subgroups were driven by distinct signaling pathways. Similarly, compounds clustered based on the response across the samples revealing functional groups of compounds of both expected and unexpected composition. Furthermore, subsets of patient samples stood out as highly sensitive to different compounds. Specifically, dasatinib, rapalogs, MEK inhibitors, ruxolitinib, sunitinib, sorafenib, ponatinib, foretinib and quizartinib were found to be selectively active in 5 (31%), 5 (31%), 4 (25%), 4 (25%), 3 (19%), 3 (19%), 2 (13%), 2 (13%), and 1 (6%) of the AML patients ex vivo, respectively. DSRT assays of serial samples from the same patient at different stages of leukemia progression revealed patterns of resistance to the clinically applied drugs, in conjunction with evidence of dynamic changes in the clonal genomic architecture. Emergence of vulnerabilities to novel pathway inhibitors was seen at the time of drug resistance, suggesting potential combinatorial or successive cycles of drugs to achieve remissions in an increasingly chemorefractory disease. Genomic and molecular profiling of the same patient samples not only highlighted potential biomarkers reflecting the ex vivo DSRT response patterns, but also made it possible to follow in parallel the drug sensitivities and the clonal progression of the disease in serial samples from the same patients. Summary: The comprehensive analysis of drug responses by DSRT in samples from human chemorefractory AML patients revealed a complex pattern of sensitivities to distinct inhibitors. Thus, these results suggest tremendous heterogeneity in drug response patterns and underline the relevance of individual ex vivo drug testing in selecting optimal therapies for patients (personalized medicine). Together with genomic and molecular profiling, the DSRT analysis resulted in a comprehensive view of the drug response landscape and the underlying molecular changes in relapsed AML. These data can readily be translated into the clinic via biomarker-driven stratified clinical trials. Disclosures: Mustjoki: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria. Kallioniemi:Roche: Research Funding; Medisapiens: Membership on an entity's Board of Directors or advisory committees. Porkka:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

scholarly journals Phosphoproteomic Analysis of Primary Myeloma Patient Samples Identifies Distinct Phosphorylation Signatures Correlating with Chemo-Sensitivity Profiles in an Ex Vivo Drug Sensitivity Testing Platform

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2666-2666
Author(s):  
Katie Dunphy ◽  
Paul Dowling ◽  
Juho J. Miettinen ◽  
Caroline A. Heckman ◽  
Paula Meleady ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Research Funding ◽  
Drug Sensitivity ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Resistance Mechanisms ◽  
Group Iv ◽  
Group I ◽  
Resistant Group ◽  
Sensitive Group

Abstract Introduction: Multiple myeloma (MM) is characterized by the clonal expansion of plasma cells in the bone marrow resulting in end-organ damage. Despite an extensive increase in the five-year survival rate in recent years, MM is still considered an incurable disease as patients will repeatedly relapse and develop resistance to current chemotherapies. A key focus for the personalization of myeloma therapy is understanding the biological mechanisms of drug resistance and identifying clinically useful biomarkers of therapeutic response. Highly efficient techniques for the enrichment of phosphorylated peptides followed by high resolution mass spectrometry facilitates the quantitation of thousands of site-specific phosphorylation events. Here, we have performed a phosphoproteomic analysis on MM cell lysates stratified based on their ex vivo drug response profiles to advance our understanding of drug resistance mechanisms. Materials and Methods: CD138 + plasma cells were isolated from 20 adult MM patient bone marrow aspirates at diagnosis (n=7) or relapse (n=13). Samples were grouped based on ex vivo drug sensitivity and resistance testing (DSRT) as follows: highly sensitive (Group I), sensitive (Group II), resistant (Group III), highly resistant (Group IV) [1]. For the phosphoproteomic analysis, peptides were generated and purified using the filter aided sample preparation (FASP) protocol. Peptide tandem mass tag (TMT) labelling, Fe 3+ immobilized metal ion affinity chromatography (IMAC), synchronous precursor selection (SPS), and triple stage tandem mass spectrometry (MS3) was performed. Nonenriched peptides were used for proteomic analysis. Resulting data was analysed using MaxQuant, followed by normalization of phosphosite intensities using the internal reference scale (IRS) method, and statistical analysis using Perseus. Functional enrichment and kinase enrichment analyses were performed on significant phosphoproteins using g:profiler and KEA2, respectively. Results: Our quantitative MS-based phosphoproteomic analysis identified 2,945 phosphorylation sites on 2,232 phosphopeptides from 690 phosphoproteins. Of these phosphorylation sites, 176 were significantly changed between all four DSRT groups and 267 were significantly changed between Group I and Group IV (False Discovery Rate (FDR) < 0.05). Hierarchical clustering was performed to highlight the distinct phosphoproteomic profiles associated with each DSRT group, of which the very sensitive (Group I) and very resistant (Group IV) subgroups demonstrated a well-defined separation (Fig. 1A, 1B). KEGG pathway analysis and gene ontology (GO) analysis of significantly increased phosphorylated proteins in Group IV compared to Group I MM patients demonstrated an increased phosphorylation of proteins associated with tight junctions, the Rap1 signalling pathway and the phosphatidylinositol signalling system; indicating an upregulation of cell adhesion associated processes in drug resistant MM. Phosphoproteins increased in abundance in Group I compared to Group IV MM patients revealed an increased phosphorylation of proteins involved in translation and RNA processing including the spliceosome, RNA transport and RNA binding pathways (Fig. 1C). We identified filamin A serine 2152, RAS guanyl-releasing protein 2 serine 576 and proto-oncogene tyrosine-protein kinase Src serine 17 as increased in Group IV MM, and nuclease-sensitive element-binding protein 1 (YBX1) serine 165, CD44 serine 697 and Bcl2-associated agonist of cell death (BAD) serine 99 as increased in Group I MM. KEA of the upregulated phosphoproteome in Group IV revealed an enrichment of cyclin dependent kinase 1 (CDK1) and ribosomal s6 kinases (RPS6K) whereas casein kinase 2 (CK2) and the glycolysis-associated kinases were enriched in Group I (Fig. 1D). Conclusion: Our study has generated a phosphoproteomic dataset demonstrating distinct phosphorylation signatures associated with drug sensitivity in clinical MM plasma cells. The identification of phosphorylation events associated with drug resistance provides a basis for further exploration of these events and associated signalling pathways to further understand drug resistance mechanisms in MM and identify potential biomarkers of therapeutic response and targets for drug re-sensitization in MM. References: [1] M. M. Majumder et al., Oncotarget 8(34), 56338 (2017) Figure 1 Figure 1. Disclosures Heckman: Novartis: Research Funding; Orion Pharma: Research Funding; Celgene/BMS: Research Funding; Oncopeptides: Consultancy, Research Funding; Kronos Bio, Inc.: Research Funding.

scholarly journals Combining Next Generation Proteomics Platforms with Drug Sensitivity Resistance Testing Allows Identification of Physiologically Distinct Sub-Clones That Can Inform Therapeutic and Drug Development Strategies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1901-1901
Author(s):  
Despina Bazou ◽  
Muntasir M Majumder ◽  
Ciara Tierney ◽  
Sinead O'Rourke ◽  
Pekka Anttila ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Board Of Directors ◽  
Research Funding ◽  
Drug Sensitivity ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Resistance Testing ◽  
Proteomics Analysis ◽  
Advisory Committees ◽  
Group I

Abstract Introduction: A hallmark of Multiple Myeloma (MM) is the sequel development of drug resistant phenotypes, which may be present initially or emerge during the course of treatment. These drug resistant phenotypes reflect the intra-tumor and inter-patient heterogeneity of this cancer. Most MM cells are sensitive to proteasome inhibitors (PIs), which have become the standard of care in the treatment of newly diagnosed and relapsed MM. However, resistance develops (intrinsic/acquired). Although several novel drugs have recently been approved or are in development for MM, there are few molecular indicators to guide treatment selection. To address this limitation we have combined mass spectrometry-based proteomics analysis together with ex vivo drug response profiles and clinical outcome to elucidate a best possible accurate phenotype of the resistant sub-clones, thus yielding a theranostic profile that will inform therapeutic and drug development strategies. Methods: We performed mass spectrometry-based proteomics analysis on plasma cells isolated from 38 adult MM patient bone marrow aspirates (CD138+). Samples were obtained at diagnosis or prior to commencing therapy. The participating subjects gave written informed consent in accordance with the Declaration of Helsinki that was approved by local ethics committees. For the proteomics analysis, peptides were purified using the filtered aided sample preparation (FASP) method. Subsequently, samples were prepared for label-free liquid chromatography mass spectrometry (LC-MS/MS) using a Thermo Scientific Q-Exactive MS mass spectrometer. Proteins were analysed using the MaxQuant and Perseus software for mass-spectrometry (MS)-based proteomics data analysis, UniProtKB-Swiss Prot database and KEGG Pathway database. In parallel, we undertook a comprehensive functional strategy to directly determine the drug dependency of myeloma plasma cells based on ex vivo drug sensitivity and resistance testing (DSRT)as previously described (1). Results: Our initial proteomic analysis was generated by examining MM patient plasma cells, grouped based on DSRT to 142 anticancer drugs including standard of care and investigational drugs. Each of the 142 drugs was tested over a 10,000-fold concentration range, allowing for the establishment of accurate dose-response curves for each drug in each patient. MM patients were stratified into four distinct subgroups as follows: highly sensitive (Group I), sensitive (Group II), resistant (Group III) or highly resistant (Group IV) to the panel of drugs tested. We then performed blinded analysis on the 4 groups of CD138+ plasma cells divided based on the ex vivo sensitivity profile, identifying a highly significant differential proteomic signature between the 4-chemosensitivity profiles, with Cell Adhesion Mediated-Drug Resistance (CAM-DR) related proteins (e.g. integrins αIIb and β3) significantly elevated in the highly resistant phenotype (Group IV). In addition our results showed that Group I patients displayed significant upregulation of cell proliferation proteins including: MCM2, FEN1, PCNA and RRM2. Furthermore, Group I patients have shorter Progression Free Survival (PFS) as well as Overall Survival (OS) compared to the other subgroups. Figure 1 shows the Heatmap summarizing the expression of proteins (log2 fold change) in the four distinct MM patient subgroups. Conclusions:Our findings suggest that combining a proteomics based study together with drug sensitivity and resistance testing allows for an iterative adjustment of therapies for patients with MM, one patient at a time, thus providing a theranostic approach. Our results suggest that the disease driving mechanisms in the patient subgroups are distinct, with highly resistant patients exhibiting cell adhesion mediated cytoprotection, while highly sensitive patients show an increased cell proliferation protein profile with shorter PFS and OS. Our study aims to guide treatment decisions for individual cancer patients coupled with monitoring of subsequent responses in patients to measure and understand the efficacy and mechanism of action of the drugs. Future work will include the establishment of flow cytometry-based screening assays to identify the different resistant phenotypes at diagnosis/relapse. References: (1) M. M. Majumder et al., Oncotarget 8(34), 56338 (2017) Disclosures Anttila: Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Silvennoinen:Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Heckman:Orion Pharma: Research Funding; Celgene: Research Funding; Novartis: Research Funding.

ON 01910.Na Suppresses Cyclin D1 Accumulation in trisomy 8 Myelodysplastic Syndromes Patients While Decreasing Bone Marrow CD34+ Blast Counts and Aneuploid Clone Size.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 120-120
Author(s):  
Elaine M Sloand ◽  
Matthew J. Olnes ◽  
Naomi Galili ◽  
Aarthi Shenoy ◽  
Loretta Pfannes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Cyclin D1 ◽  
Research Funding ◽  
Treatment Options ◽  
Cell Cycle Control ◽  
Trisomy 8 ◽  
Clone Size ◽  
Monosomy 7

Abstract Abstract 120 Patients with high risk MDS can be successfully treated with 5-azacytidine, or with lenalidomide but non-responding patients have few treatment options. Chemotherapy produces significant morbidity and very short remissions and most patients are too old for bone marrow transplantation. We previously demonstrated up-regulation of c-myc, survivin, and cyclin D1 in CD34+ cells in patients with trisomy 8 (and selected patients with monosomy 7). siRNA-mediated knockdown of survivin or c-myc decreased trisomy 8 cell growth in vitro (Sloand et al, Blood 2007, 110: 822). We postulated that increased cyclin D1 causes upregulation of survivin, resulting in resistance of these cells to apoptosis. The styryl sulfone, ON 01910.Na, decreases cyclin D1 accumulation in cultured bone marrow from patients with high risk trisomy 8 MDS and in some monosomy 7 patients (who also show upregulation of cyclin D1), while selectively decreasing blasts and aneuploidy with this cytogenetic abnormality (ASH Abstracts Nov 2008; 112: 1651). Here we examine the clinical response to ON1910 in an ongoing phase I/II clinical trial in which 13 evaluable patients with intermediate-1(int-1) to high risk MDS and treatment-refractory trisomy 8 AML were enrolled. Patients were treated with escalating doses of ON 01910.Na at 800 mg/m2 × 2 days every 3/4 weeks, 800 mg/m2 × 3 days every 2 weeks, 800 mg/m2 × 5 days every 2 weeks, and 1500 mg/m2 × 2 days every 3/4 weeks at two institutions. No significant toxicity could be ascribed to the drug. Patients with trisomy 8 and monosomy 7 demonstrated significant declines in aneuploidy measured by florescence in situ hybridization (FISH) (mean aneuploidy; 50% before and 24% after 1 cycle of treatment; p=0.02 :Fig below). Rather than becoming cytopenic, many patients showed substantial improvements of blood counts and one patient (01-02; graphic shown below) became red cell transfusion-independent and maintains his remission 14 months after stopping therapy. Cyclin D1 measurement by flow cytometry showed decreases of this protein in both CD34 and CD33 cells during infusion of ON 1910 infusion (example shown in Fig below). Results from individual evaluable patients are shown in table 1. These results indicate that modulation of cell cycle control by cyclin D1 may represent a novel targeted approach for trisomy 8 and monosomy 7 MDS. Disclosures: Sloand: Onconova: Research Funding. Olnes:Onconova: Research Funding. Galili:Onconova: Research Funding. Wilhelm:Onconova: Employment. Groopman:Onconova: Membership on an entity's Board of Directors or advisory committees. Raza:Onconova: Research Funding.

Towards CD38-Targeted Immunochemotherapy of Multiple Myeloma: Significant Improvement of Anti-Myeloma Effects of Lenalidomide, Bortezomib and Dexamethason by CD38-Specific Antibody Daratumumab, Even in Chemotherapy Resistant/Intolerant Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4988-4988
Author(s):  
Inger S. Nijhof ◽  
Jeroen Lammerts van Bueren ◽  
Berris van Kessel ◽  
Michel de Weers ◽  
Joost M Bakker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Research Funding ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Human Antibody ◽  
Synergistic Activity ◽  
Effector Cells ◽  
Complement Dependent Cytotoxicity

Abstract Abstract 4988 To date, multiple myeloma (MM) remains an incurable malignancy of antibody-producing clonal plasma cells. The introduction of a new generation of immunomodulatory agents, such as lenalidomide (LEN), and the potent proteasome inhibitor bortezomib (BORT), used alone or in combination with steroids (dexamethasone; DEX or prednisone; PRED) has significantly improved the overall survival of MM patients. Nonetheless, all chemotherapy strategies are eventually hampered by the development of drug-resistance. Towards a novel and effective targeted immunotherapy for MM, we have developed daratumumab (DARA), a CD38 human antibody with broad-spectrum killing activity. In vitro, DARA induces substantial anti-MM effects mainly via ADCC (antibody dependent cellular cytotoxicity) and CDC (complement dependent cytotoxicity). In ex vivo assays, which allowed us to address killing of MM cells in bone marrow aspirates isolated from MM patients, enhanced or even synergistic MM cell killing was observed when DARA was combined with LEN, or with cocktails of LEN/BORT/DEX and melphalan/BORT/DEX. We now extended these ex vivo analyses to evaluate whether DARA in combination with LEN, BORT and DEX could improve the lysis of MM cells in bone marrow aspirates derived from 22 patients of whom 9 became refractory for LEN and 6 for LEN and BORT. DARA significantly enhanced the lysis of MM cells when combined with LEN or BORT in virtually all patients, including the LEN- and LEN/BORT-refractory patients. The combination of DARA+BORT and DARA+DEX induced additive killing, suggestive of lysis by independent mechanisms. When combined with LEN, DARA improved the lysis of MM cells in a synergistic manner in both non-refractory and LEN-refractory patients. This is suggestive of killing by at least partly complementary mechanisms. Synergistic activity of LEN and DARA was attributable to LEN-induced activation of effector cells that were involved in DARA-mediated ADCC. In addition, enhanced/synergistic direct killing of MM cells was observed. Experiments are under way to further investigate the mechanism underlying synergistic activity of DARA and LEN. In conclusion, our results provide a rationale for clinical evaluation of DARA in combination with LEN, BORT and DEX including in patients refractory to these drugs. Disclosures: van Bueren: genmab: Employment. de Weers:genmab: Employment. Bakker:genmab: Employment. Parren:genmab: Employment. Lokhorst:genmab: Consultancy, Research Funding. Mutis:genmab: Research Funding.

The Prognostic Significance of Polyclonal Bone Marrow Plasma Cells in Patients with Actively Relapsing Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1194-1194
Author(s):  
Toshi Ghosh ◽  
Wilson I Gonsalves ◽  
Dragan Jevremovic ◽  
S. Vincent Rajkumar ◽  
Michael M. Timm ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
High Risk ◽  
Research Funding ◽  
Plasma Cells ◽  
Labeling Index ◽  
Light Chains ◽  
Fish Cytogenetics ◽  
Kaplan Meier

Abstract Background: Prior studies suggest that the presence of >5% polyclonal plasma cells (pPCs) among total plasma cells (PCs) within the bone marrow (BM) is associated with a longer progression-free survival, higher response rates, and lower frequency of high-risk cytogenetic abnormalities in patients with newly diagnosed multiple myeloma (MM). However, the incidence and prognostic utility of this factor in patients with relapsed and/or refractory MM has not been previously evaluated. Thus, we evaluated the prognostic value of quantifying the percentage of pPCs among the total PCs in the BM of patients with actively relapsing MM. Methods: We evaluated all MM patients with actively relapsing disease (biochemical and/or symptomatic) seen at the Mayo Clinic, Rochester, from 2012 to 2013, who had BM samples evaluated by seven-color multiparametric flow cytometry. All patients had at least 24 months of follow-up from the date of flow evaluation. Cell surface antigens were assessed by direct immunofluorescence antibodies for CD45, CD19, CD38, CD138, cytoplasmic Kappa and Lambda Ig light chains, and DAPI nuclear stain. The flow cytometry data was collected using the Becton Dickinson FACSCanto II instruments that analyzed 150,000 events (cells); this data was then analyzed by multi-parameter analysis using the BD FACS DIVA Software. PCs were selectively analyzed through combinatorial gating using light scatter properties and CD38, CD138, CD19, and CD45. Clonal PCs were separated from pPCs based on the differential expression of CD45, CD19, DAPI (in non-diploid cases), and immunoglobulin light chains. The percentage of pPCs was calculated in total PCs detected. Survival analysis was performed by the Kaplan-Meier method and differences were assessed using the log rank test. Results: There were 180 consecutive patients with actively relapsing MM who had BM biopsies analyzed via flow cytometry as part of their routine clinical evaluation. The median age of this group was 65 years (range: 40 - 87); 52% were male. At the time of this analysis, 104 patients had died, and the 2-year overall survival (OS) rate for the cohort was 58%. The median number of therapies received was 4 (range: 1 - 15). Of these patients, 61% received a prior ASCT, and almost all (99%) received prior regimens containing either immunomodulators or proteasome inhibitors. There were 55 (30%) patients with >5% pPCs among the total PCs in their BM. The median percentage of pPCs among total PCs in these 55 patients was 33% (range: 5 - 99). The median OS for those with >5% pPCs was not reached compared with 22 months for those with <5% pPCs (P = 0.028; Figure 1). Patients with <5% pPCs PCs had a higher likelihood of high-risk FISH cytogenetics compared with the rest of the patients. In a univariate analysis, increasing number of pPCs was associated with an improved OS, while higher labeling index, number of prior therapies, and the presence of high-risk FISH cytogenetics were associated with a worse OS. In a multivariate analysis, only the increasing number of pPCs (P = 0.006), higher labeling index (P = 0.0002) and number of prior therapies (P = 0.003) retained statistical significance. Conclusion: Quantitative estimation of the percentage of pPCs among the total PCs in the BM of patients with actively relapsing MM was determined to be a predictor of worse OS. As such, this parameter is able to identify a group of patients with MM with actively relapsing disease who have a particularly poor outcome. Further studies evaluating its biological significance are warranted. Figure 1 Kaplan-Meier curve comparing OS between patients with ≥5% pPCs and <5% pPCs among the total PCs in their BM. Figure 1. Kaplan-Meier curve comparing OS between patients with ≥5% pPCs and <5% pPCs among the total PCs in their BM. Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Gertz:Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Ionis: Research Funding; Annexon Biosciences: Research Funding. Kumar:AbbVie: Research Funding; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy; BMS: Consultancy.

Stratification of Multiple Myeloma Patients Based on Ex Vivo Drug Sensitivity and Identification of New Treatments for Patients with High-Risk Relapsed/Refractory Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3006-3006
Author(s):  
Muntasir Mamun Majumder ◽  
Raija Silvennoinen ◽  
Pekka Anttila ◽  
David Tamborero ◽  
Samuli Eldfors ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Drug Testing ◽  
Drug Response ◽  
Drug Sensitivity ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Resistant Group ◽  
Sensitive Group

Abstract Introduction Response to treatment for multiple myeloma (MM) patients is variable and often unpredictable, which may be attributed to the heterogeneous genomic landscape of the disease. However, the effect of recurrent molecular alterations on drug response is unclear. To address this, we systematically profiled 50 samples from 43 patients to assess ex vivo sensitivity to 308 anti-cancer drugs including standard of care and investigational drugs, with results correlated to genomic alterations. Our results reveal novel insights about patient stratification, therapies for high-risk (HR) patients, signaling pathway aberrations and ex-vivo-in-vivo correlation. Methods Bone marrow (BM) aspirates (n=50) were collected from MM patients (newly diagnosed n=17; relapsed/refractory n=33) and healthy individuals (n=8). CD138+ plasma cells were enriched by Ficoll separation followed by immunomagnetic bead selection. Cells were screened against 308 oncology drugs tested in a 10,000-fold concentration range. Drug sensitivity scores were calculated based on the normalized area under the dose response curve (Yadav et al, Sci Reports, 2014). MM selective responses were determined by comparing data from MM patients with those of healthy BM cells. Clustering of drug sensitivity profiles was performed using unsupervised hierarchical ward-linkage clustering with Spearman and Manhattan distance measures of drug and sample profiles. Somatic alterations were identified by exome sequencing of DNA from CD138+ cells and skin biopsies from each patient, while cytogenetics were determined by fluorescence in situ hybridization. Results Comparison of the ex vivo chemosensitive profiles of plasma cells resulted in stratification of patients into four distinct subgroups that were highly sensitive (Group I), sensitive (Group II), resistant (Group III) or highly resistant (Group IV) to the panel of drugs tested. Many of the drug responses were specific for CD138+ cells with little effect on CD138- cells from the same patient or healthy BM controls. We generated a drug activity profile for the individual drugs correlating sensitivity to recurrent alterations including mutations to KRAS, DIS3, NRAS, TP53, FAM46C, and cytogenetic alterations del(17p), t(4;14), t(14;16), t(11;14), t(14;20), +1q and -13. Cells from HR patients with del(17p) exhibited the most resistant profiles (enriched in Groups III and IV), but were sensitive to some drugs including HDAC and BCL2 inhibitors. Samples from patients with t(4;14) were primarily in Group II and very sensitive to IMiDs, proteasome inhibitors and several targeted drugs. Along with known recurrently mutated genes in myeloma, somatic mutations were identified in genes involved in several critical signaling pathways including DNA damage response, IGF1R-PI3K-AKT, MAPK, glucocorticoid receptor signaling and NF-κB signaling pathways. The predicted impact of these mutations on the activity of the pathways often corresponded to the drug response. For example, all samples bearing NF1 (DSS=21±7.9) and 67% with NRAS (DSS=15±4.35) mutations showed higher sensitivity to MEK inhibitors compared to healthy controls (DSS=5±.21). However, sensitivity was less predictable for KRAS mutants with modest response only in 47% samples (DSS=7±2.14) . One sample bearing the activating V600E mutation to BRAF showed no sensitivity to vemurafenib, which otherwise has good activity towards V600E mutated melanoma and hairy-cell leukemia. Comparison of the chemosensitive subgroups with survival showed patients in Groups I and IV had high relapse rate and poor overall survival. The ex vivo drug sensitivity results were used to decide treatment for three HR patients with results showing good ex vivo -in vivo correlation. Summary Our initial results suggest that ex vivo drug testing and molecular profiling of MM patients aids stratification. Grouping of patients based on their ex vivo chemosensitive profile proved extremely informative to predict clinical phenotype and identify responders from non-responders. While some molecular markers could be used to predict drug response, others were less predictive. Nevertheless, ex vivo drug testing identified active drugs, particularly for HR and relapsed/refractory patients, and is a powerful method to determine treatment for this group of patients. Disclosures Silvennoinen: Genzyme: Honoraria; Sanofi: Honoraria; Janssen: Research Funding; Celgene: Research Funding; Research Committee of the Kuopio University Hospital Catchment Area for State Research Funding, project 5101424, Kuopio, Finland: Research Funding; Amgen: Consultancy, Honoraria. Porkka:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Heckman:Celgene: Honoraria, Research Funding.

scholarly journals BMT CTN 1803: Haploidentical Natural Killer Cells (K-NK002) to Prevent Post-Transplant Relapse in AML and MDS (NK-REALM)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-41
Author(s):  
Sumithra Vasu ◽  
Nelli Bejanyan ◽  
Steven M Devine ◽  
Elizabeth O. Hexner ◽  
Brent Logan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Nk Cells ◽  
Natural Killer ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Ex Vivo ◽  
Advisory Committees ◽  
Free Survival

Background and Rationale: Relapse remains the leading cause of treatment failure for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic bone marrow transplantation (BMT). Although the risk depends on parameters such as age and conditioning intensity, relapse is experienced by 30-50% of patients after conventional BMT in high-risk AML/MDS. Initial safety and post-BMT relapse risk reduction results were reported from a phase I study of haploidentical (haplo) donor-derived natural killer (NK) cells expanded ex vivo on feeder cells expressing IL-21 and 4-1BBL (FC21-NK) in conjunction with haploBMT. Of 13 patients with high-risk myeloid malignancies treated with FC21-NK cells, no infusion reactions or dose-limiting toxicities occurred and only 1 patient, treated at the lowest dose of 1×105 cells/kg, relapsed (Ciurea, Blood, 2017). This experience supports investigation of K-NK002, a product derived from haploidentical donor NK cells and expanded ex vivo in a feeder cell-free system using plasma membrane (PM21) particles bearing membrane-bound IL-21 and 4-1BBL. We used contemporary data from the Center for International Blood and Marrow Transplant Research registry to determine baseline relapse rates that informed the statistical design. K-NK002 will be given in the peri-transplant period to test the hypothesis that haploidentical NK cells can mediate an effective anti-leukemia response. Trial Design and Methods: BMT CTN 1803 is a phase II, single-arm, open-label, multicenter trial designed to investigate the safety and efficacy of K-NK002 for the treatment of patients with high-risk AML or MDS undergoing haploBMT (NCT04395092). An initial 6 patient safety run-in phase will precede enrollment into the full study of approximately 60 patients. Major inclusion criteria of patients and donors are listed in Table 1. Production of the haploidentical donor NK-cells is completed prior to the planned haploBMT. BMT conditioning will consist of 140 mg/m2 (100 mg/m2 for patients ≥60 years old) melphalan on Day -7; 40 mg/m2 fludarabine on Days -7, -6, -5, and -4; and 2 Gy of total body irradiation on Day -3. Donor bone marrow will be harvested and given on Day 0. Three doses of K-NK002 (1×108 NK cells/kg) will be administered IV on Days -2, +7, and +28, relative to the haploBMT. Graft-versus-host disease (GVHD) prophylaxis consists of post-transplantation cyclophosphamide with tacrolimus and mycophenolate mofetil. The primary endpoint is cumulative incidence of relapse at 1 year post haploBMT in patients receiving at least 1 infusion of K-NK002. Secondary endpoints are safety and tolerability of K-NK002; overall survival; non-relapse mortality; relapse-free survival; GVHD-free survival; cumulative incidence of acute GVHD and chronic GVHD; hematologic recovery; donor-cell engraftment; primary and secondary graft failure; overall incidence of toxicity; and cumulative incidence of infections including cytomegalovirus re-activation and symptomatic BK virus hemorrhagic cystitis. Exploratory endpoints are systemic immunosuppression-free survival; immune reconstitution at Days 28, 100, and 365 post haploBMT; proportion of patients with detectable minimal residual disease at Days 28 and 100 post haploBMT; feasibility of administering the planned K-NK002 doses; and impact of NK-cell alloreactivity on relapse and survival. Disclosures Bejanyan: Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees. Devine:Magenta Therapeutics: Consultancy. Luznik:WindMil Therapeutics: Patents & Royalties: Patent holder; Genentech: Research Funding; Merck: Research Funding, Speakers Bureau; AbbVie: Consultancy. Sandler:Kiadis Pharma: Current Employment. Krakow:HighPass Bio: Research Funding. Fitzgerald:Kiadis Pharma: Current Employment. Tracey:Kiadis Pharma: Current Employment. Champlin:DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents & Royalties; Actinium: Consultancy; Johnson and Johnson: Consultancy; Cytonus: Consultancy; Omeros: Consultancy; Genzyme: Speakers Bureau.

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