scholarly journals Myeloma Cell Associated Therapeutic Protein Discovery Using Single Cell RNA-Seq Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-5
Author(s):  
Lijun Yao ◽  
Reyka G Jayasinghe ◽  
Tianjiao Wang ◽  
Julie O'Neal ◽  
Ruiyang Liu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Surface ◽  
B Cell ◽  
Tumor Cells ◽  
Plasma Cell ◽  
Tissue Specificity ◽  
Plasma Cells ◽  
Expression Data ◽  
Intracellular Proteins

Multiple myeloma (MM) is a hematological cancer of the antibody-secreting plasma cells. Despite therapeutic advancements, MM remains incurable due to high incidence of drug-resistant relapse. In recent years, targeted immunotherapies, which take advantage of the immune system's cytotoxic defenses to specifically eliminate tumor cells expressing certain cell surface and intracellular proteins have shown promise in combating this and other B cell hematologic malignancies. A major limitation in the development of these therapies lies in the discovery of optimal candidate targets, which require both high expression in tumor cells as well as stringent tissue specificity. In an effort to identify potential myeloma-specific target antigens, we performed an unbiased search for genes with specific expression in plasma and/or B cells using single-cell RNA-sequencing (scRNAseq) of 53 bone marrow samples taken from 42 patients. By comparing >40K plasma cells to >97K immune cells across our cohort, we were able to identify a total of 181 plasma cell-associated genes, including 65 that encode cell-surface proteins and 116 encoding intracellular proteins. Of particular interest is that the plasma cells from each patient were shown to be transcriptionally distinct with unique sets of genes expressed defining each patient's malignant plasma cells. Using pathway enrichment analysis, we found significant overrepresentation of cellular processes related to B-Cell receptor (BCR) signaling, protein transport, and endoplasmic reticulum (ER) stress, involving genes such as DERL3, HERPUD1, PDIA4, PDIA6, RRBP1, SSR3, SSR4, TXNDC5, and UBE2J1. To note, our strategy successfully captured several of the most promising MM therapeutic targets currently under pre-clinical and clinical trials, including TNFRSF17(BCMA), SLAMF7, and SDC1 (CD138). Among these, TNFRSF17 showed very high plasma cell expression, with concomitant sharp exclusion of other immune cell types. To ascertain tissue specificity of candidate genes outside of the bone marrow, we analyzed gene and protein expression data from the Genotype-Tissue Expression (GTEx) portal and Human Protein Atlas (HPA). We found further support for several candidates (incl. TNFRSF17,SLAMF7, TNFRSF13B (TACI), and TNFRSF13C) as being both exclusively and highly expressed in lymphoid tissues. While several surface candidates were not found to be lymphocyte-restricted at the protein level, they remain relevant considerations as secondary targets for bi-specific immunotherapy approaches currently under development. To further investigate potential combinatorial targeting, we examine sample-level patterns of candidate co-expression and mutually-exclusive expression using correlation analysis. As the majority of our detected plasma cell-specific genes encode intracellular proteins, we investigated the potential utility of these epitopes as therapeutic targets via MHC presentation. Highly expressed candidates include MZB1, SEC11C, HLA-DOB, POU2AF1, and EAF2. We analyzed protein sequences using NetMHC and NETMHCII to predict high-affinity peptides for common class-I and class-II HLA alleles. To correlate MHC allelic preference with candidate expression in our cohort, we performed HLA-typing for 29 samples using Optitype. To support our scRNAseq-driven findings, we cross-referenced gene expression data with 907 bulk RNA-sequencing samples, including 15 from internal studies and 892 from the Multiple Myeloma Research Foundation (MMRF), as well as bulk global proteomics data from 4 MM cell lines (TIB.U266, RPMI8226, OPM2, MM1ST) and 4 patients. We see consistent trends across both cohorts, with high positive correlation (Pearson R ranging between 0.60 and 0.99) for a majority of genes when comparing scRNA and bulk RNA expression in the same samples. Our experimental design and analysis strategies enabled the efficient discovery of myeloma-associated therapeutic target candidates. In conclusion, this study identified a set of promising myeloma CAR-T targets, providing novel treatment options for myeloma patients. Disclosures Goldsmith: Wugen Inc.: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Variable Expression of Therapeutic Antibody Targets May Have Implications for Efficacy of Therapy in Myeloma and Waldenstrom Macroglobulinaemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3425-3425
Author(s):  
Ruth M de Tute ◽  
Jane Shingles ◽  
Andy C. Rawstron ◽  
Roger G Owen
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Surface Expression ◽  
Cell Populations ◽  
Expression Data ◽  
Expression Levels ◽  
Normal Bone ◽  
Cd38 Expression

Abstract Recent advances in the treatment of myeloma have included the development of immunotherapies using monoclonal antibodies targeted against plasma cell specific antigens. Elotuzumab is a therapeutic antibody directed against the SLAM family member CS1, also known as CD319, SLAMF7 or CRACC. Expression of this antigen has been investigated extensively using immunohistochemistry and gene expression profiling and has been demonstrated on normal and malignant plasma cells. Clinical trials using Elotuzumab in myeloma have shown promising results, especially in combination with other therapeutic agents, such as lenalidomide and dexamethasone. Daratumumab, a humanised antibody to CD38, has also shown encouraging responses in a percentage of refractory patients in Phase I and II trials, both as a single agent and in combination with lenalidomide. Despite this progress a significant number of patients fail to respond to these therapies for reasons which remain unclear. Monoclonal antibody-based therapy in Waldenstrom macroglobulinemia (WM) has traditionally targeted the B cell component. We have previously demonstrated that WM plasma cells are not depleted with either rituximab or alemtuzumab resulting in delayed IgM responses. Plasma cell specific antibodies may be applicable to WM and may be particularly suited to those instances when the clinical features are a consequence of the M protein such as hyperviscosity and neuropathy. There are no published data correlating quantitative surface expression data with outcome and it is possible that variability in the surface expression levels of the targets could affect efficacy of these therapeutic antibodies. The aim of this study was to evaluate the expression of CD319 and CD38 in patients with a range of plasma cell dyscrasias using multi-parametric flow cytometry. Bone marrow aspirates from patients with myeloma, MGUS or WM along with normal staging bone marrows were analysed using 8-colour flow cytometry. Leucocytes were isolated using ammonium chloride lysis and cells were then incubated with a cocktail of surface antibodies containing CD319, CD19, CD38, CD138, CD45 and CD20. Following fixation and permeabilisation cells were then incubated with Kappa and Lambda. Plasma cells and B-cells were enumerated and monoclonal B-cell and plasma cell populations were assessed. Expression of CD319 was seen on all plasma cell populations and was absent from all B-cell populations (Median fluorescent intensity (MFI) 12088 vs 114, p<0.001). There was definite heterogeneity in both CD319 and CD38 expression on plasma cells (CD319 MFI range 1871-21865; CD38 MFI range 4393-156258) and this was as a result of differences between diagnostic groups. There were significantly lower levels of expression seen in the clonal plasma cells in myeloma cases compared to normal bone marrows (CD319 MFI 7743 (1871-13880) vs 11118 (8412-15685), p=0.188; CD38 MFI 10113 (4665-28627) vs 54650 (32078-91906), p=0.003). CD319 expression was below normal levels in 33% of myeloma cases and CD38 expression was below normal in all myeloma samples. Lower levels of expression were also seen in myeloma relative to WM cases (CD319 MFI 7743 (1871-13880) vs 14488 (7056-21865), p=0.079; CD38 MFI 10113 (4665-28627) vs 47695 (15174-156258), p=0.003). There was no significant difference in CD319 or CD38 expression for WM cases when compared to normal bone marrow samples. Although CD319 and CD38 expression was seen in all plasma cell populations, there were differences in expression levels between myeloma plasma cells and those from MGUS, WM or normal bone marrow samples. The heterogeneity in surface expression seen could potentially affect efficacy of antibody treatment and may offer some explanation for the non-responders that have been seen in early trials of Elotuzumab and Daratumumab. We have also shown that the clonal plasma cells in WM have higher levels of surface expression of both targets than those in myeloma. Following the encouraging results shown in the myeloma setting, this expression data suggests that Elotuzumab and Daratumumab may also be highly effective for eradication of the plasma cell component of WM. Prospective studies in both myeloma and WM correlating surface expression levels to outcome would be of interest. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Evidence for a bone marrow B cell transcribing malignant plasma cell VDJ joined to C mu sequence in immunoglobulin (IgG)- and IgA-secreting multiple myelomas.

1993 ◽  
Vol 178 (3) ◽  
pp. 1091-1096 ◽  
Author(s):  
P Corradini ◽  
M Boccadoro ◽  
C Voena ◽  
A Pileri
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Indirect Evidence ◽  
Specific Marker

Multiple myeloma is a B cell malignancy characterized by the expansion of plasma cells producing monoclonal immunoglobulins (Ig). It has been regarded as a tumor arising at the B, pre-B lymphocyte, or even stem cell level. Precursor cells are presumed to proliferate and differentiate giving rise to the plasma cell clonal expansion. Antigenic features and specific Ig gene rearrangement shared by B lymphocytes and myeloma cells have supported this hypothesis. However, the existence of such a precursor is based upon indirect evidence and is still an open question. During differentiation, B cells rearrange variable (V) regions of Ig heavy chain genes, providing a specific marker of clonality. Using an anchor polymerase chain reaction assay, these rearranged regions from five patients with multiple myeloma were cloned and sequenced. The switch of the Ig constant (C) region was used to define the B cell differentiation stage: V regions are linked to C mu genes in pre-B and B lymphocytes (pre-switch B cells), but to C gamma or C alpha in post-switch B lymphocytes and plasma cells (post-switch B cells). Analysis of bone marrow cells at diagnosis revealed the presence of pre-switch B cells bearing plasma cell V regions still joined to the C mu gene. These cells were not identified in peripheral blood, where tumor post-switch B cells were detected. These pre-switch B cells may be regarded as potential myeloma cell precursors.

scholarly journals A novel membrane antigen selectively expressed on terminally differentiated human B cells

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 1922-1930 ◽  
Author(s):  
T Goto ◽  
SJ Kennel ◽  
M Abe ◽  
M Takishita ◽  
M Kosaka ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Affinity Constant ◽  
Target Antigen ◽  
Specific Marker

Abstract A monoclonal antibody (MoAb) that defines a novel terminal B-cell- restricted antigen, termed HM1.24, was developed against a human plasma cell line. The MoAb, designated anti-HM1.24, reacted with five different human myeloma cell lines, as well as with monoclonal neoplastic plasma cells obtained from the bone marrow or peripheral blood of patients with multiple myeloma or Waldenstrom's macroglobulinemia. The HM1.24 antigen was also expressed by mature Ig- secreting B cells (plasma cells and lymphoplasmacytoid cells) but not by other cells contained in the peripheral blood, bone marrow, liver, spleen, kidney, or heart of normal individuals or patients with non- plasma-cell-related malignancies. The anti-HM1.24 MoAb bound to human myeloma RPMI 8226 cells with an affinity constant of 9.2 x 10(8) M-1, indicating approximately 84,000 sites/cell. By immunoprecipitation assay under reducing conditions, this MoAb identified a membrane glycoprotein that had a molecular weight of 29 to 33 kD. Our studies indicate that the HM1.24-related protein represents a specific marker of late-stage B-cell maturation and potentially serves as a target antigen for the immunotherapy of multiple myeloma and related plasma cell dyscrasias.

scholarly journals A novel membrane antigen selectively expressed on terminally differentiated human B cells

Blood ◽  
1994 ◽  
Vol 84 (6) ◽  
pp. 1922-1930 ◽  
Author(s):  
T Goto ◽  
SJ Kennel ◽  
M Abe ◽  
M Takishita ◽  
M Kosaka ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Affinity Constant ◽  
Target Antigen ◽  
Specific Marker

A monoclonal antibody (MoAb) that defines a novel terminal B-cell- restricted antigen, termed HM1.24, was developed against a human plasma cell line. The MoAb, designated anti-HM1.24, reacted with five different human myeloma cell lines, as well as with monoclonal neoplastic plasma cells obtained from the bone marrow or peripheral blood of patients with multiple myeloma or Waldenstrom's macroglobulinemia. The HM1.24 antigen was also expressed by mature Ig- secreting B cells (plasma cells and lymphoplasmacytoid cells) but not by other cells contained in the peripheral blood, bone marrow, liver, spleen, kidney, or heart of normal individuals or patients with non- plasma-cell-related malignancies. The anti-HM1.24 MoAb bound to human myeloma RPMI 8226 cells with an affinity constant of 9.2 x 10(8) M-1, indicating approximately 84,000 sites/cell. By immunoprecipitation assay under reducing conditions, this MoAb identified a membrane glycoprotein that had a molecular weight of 29 to 33 kD. Our studies indicate that the HM1.24-related protein represents a specific marker of late-stage B-cell maturation and potentially serves as a target antigen for the immunotherapy of multiple myeloma and related plasma cell dyscrasias.

scholarly journals Normal Plasma Cell Biology: Natural Achilles Heels as Targets in Myeloma

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-7-SCI-7
Author(s):  
Katia Georgopoulos
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Gene Family ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Biology ◽  
Plasma Cells ◽  
B Cell Differentiation ◽  
High Affinity ◽  
Bone Marrow Plasma

Abstract Normal Plasma Cell Biology: Natural Achilles Heels as Targets in MyelomaÊ Primary exposure to antigen leads to affinity maturation, selection and terminal differentiation of mature B cells to antibody-secreting plasma cells. Long-lived high-affinity plasma cells and their immediate precursors reside in the bone marrow and are responsible for rapid recall reactions and a life-time production of high affinity antibodies. Members of the IKAROS gene family have been specifically implicated in the generation of long-lived plasma cells. Mice deficient for Aiolos, the B cell specific member of the IKAROS gene family fail to produce high affinity plasma cells in the bone marrow and to sustain serum antibody titers after both primary or secondary immunization with a range of hapten concentrations. Chimera reconstitutions have demonstrated that the bone marrow plasma cell defect is B cell intrinsic. However, lack of AIOLOS does not alter expression of any of the previously described factors required for B cell differentiation into the plasma cell stage. No defect in somatic hyper-mutation, the generation of memory B cells, or short-lived high affinity plasma cells in the spleen is observed upon challenge or re-challenge. Thus this IKAROS family member is critically required for high-affinity bone plasma cells possibly by regulating their interaction with the bone marrow microenvironment, a process that is likely critical for long-term survival. High-affinity bone marrow plasma cells are the normal counterpart of the devastating B cell malignancy multiple myeloma. Multiple myeloma is treatable with immune modulatory drugs (IMiD) such as lenalidomide. Recent studies have shown that IMiD alter the specificity of the CRL4-CEREBLON (CRL4CRBN) E3 ubiquitin ligase complex. Among the new targets for the CRL4CRBN complex are two of the IKAROS family members, AIOLOS and IKAROS, whose degradation adversely affects the cellular fitness of multiple myeloma cells. Recent studies in B cell precursors have implicated the IKAROS gene family in the regulation of bone marrow stromal interactions. IKAROS and AIOLOS activities balance self-renewal, survival, and pre-B cell differentiation by engaging epigenetic and transcriptional machineries through discrete lineage-specific superenhancers. Such AIOLOS and IKAROS-dependent regulatory pathways engaged in early B cell precursors may also be involved in controlling bone marrow stromal interactions with high affinity plasma cells and their malignant counterparts thereby contributing to long-term growth and survival. Further exploitation of IKAROS family-targeted pathways in bone marrow plasma cells and multiple myeloma is warranted. Disclosures No relevant conflicts of interest to declare.

Targeting the UPR-Transcription Factor XBP1 to Overcome Drug-Resistance in Ph+ ALL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 872-872
Author(s):  
Behzad Kharabi Masouleh ◽  
Christian Hurtz ◽  
Huimin Geng ◽  
Parham Ramezani-Rad ◽  
Laurie H. Glimcher ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Death ◽  
Transcription Factor ◽  
B Cell ◽  
Cell Survival ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Leukemia Cells

Abstract Abstract 872 Background: The unfolded protein response (UPR) is a cellular machinery required to salvage of ER stress and to promote cell survival. The pathway consists of three different components, namely inositol-requiring enzyme 1a (IRE-1), PKR-like ER kinase (PERK) and activating transcription factor 6 (ATF6) and converges at the level of its effector molecule X-box binding protein 1 (XBP1). Previous work identified Xbp1 as a central requirement of plasma cell development and as critical mediator of cell survival in plasma cell-derived multiple myeloma. RESULTS: While the role of Xbp1 in plasma cells and plasma cell malignancies is well established, we report here the unexpected finding of a central role of Xbp1 in the survival of pre-B cell-derived Ph+ ALL cells. Surprisingly, patient-derived Ph+ ALL cells express Xbp1 (and related molecules in the IRE1 pathway) at significantly higher levels than normal bone marrow pre-B cells. In addition, we found that high expression levels of Xbp1 at diagnosis predict poor poor overall survival (OS), relapse-free survival (RFS) of leukemia patients in two clinical trials for patients with high risk acute lymphoblastic leukemia (n=207; COG P9906 trial; p=1.12e-4 and ECOG E2993; n=215; p=2.48e-5). In addition, high levels of XBP1 correlated with positive minimal residual disease (MRD) status at day 29 after onset of chemotherapy. To study the function of Xbp1 in Ph+ ALL in a genetic experiment, we developed a Ph+ ALL leukemia model based on bone marrow progenitor cells from mice carring loxP-flanked allele of Xbp1 (Xbp1fl/fl). On the basis of this model, bone marrow B cell precursors were transformed by BCR-ABL1 in the presence of IL7. Inducible Cre-mediated deletion of Xbp1 was achieved by transduction of leukemia cells with tamoxifen (4-OHT)-inducible Cre. Interestingly, 4-OHT-induced deletion of Xbp1 in Ph+ ALL-like leukemia cells caused rapid cell death within two days of induction. Xbp1-deletion resulted in extensive apoptosis, cellular senescence and cell cycle arrest owing to increased levels of p53, p21 and Arf. Interestingly, similar observations were made in an in vivo setting where Xbp1-deletion resulted in prolonged survival of NOD-SCID transplant recipient mice (n=7; p=0.007). Mechanistically, deletion of Xbp1 leads to increased expression of the pro-apoptotic molecule CHOP as in plasma cells/multiple myeloma and phosphorylation of the stress MAP kinases p38 and JNK. CLINICAL RELEVANCE: To test the potential clinical relevance of these findings, we used a recently identified small-molecule inhibitor STF-083010 (Papandreou et al., 2011), which blocks the endonuclease activity of upstream molecule IRE-1, essential for the splicing of the active form of Xbp1. STF-083010 indeed inhibited splicing of XBP1 and overall mimicked findings in genetic experiments. Importantly, targeting of Xbp1 by STF-083010 also induced cell death in three patient-derived cases of Ph+ ALL carrying the T315I mutations, which confers far-reaching TKI-resistance. CONCLUSIONS: These findings identify Xbp1 as a fundamentally novel target for the therapy of TKI-resistant Ph+ ALL. Like plasma cells and tumor cells in multiple myeloma, Ph+ ALL cells are selectively sensitive to ER stress and critically dependent on Xbp1 and likely other factors of the UPR pathway. Clinical validation of this concept could lead to improved treatment options for patients with TKI-resistant Ph+ ALL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Single Arm, Prospective, Open-Label Phase II Trial to Evaluate the Efficacy of Isatuximab in Patients with Monoclonal Gammopathy of Renal Significance

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3161-3161 ◽  
Author(s):  
Vikram Premkumar ◽  
Suzanne Lentzsch ◽  
Divaya Bhutani
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Plasma Cell ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Cell Clone ◽  
Advisory Committees ◽  
Renal Response ◽  
Hematologic Response ◽  
Stable Renal Function

Background: Monoclonal gammopathy of renal significance (MGRS) is a monoclonal B cell disorder, not meeting the definition of lymphoma or myeloma, that produces monoclonal proteins which deposit in the kidneys. Permanent renal damage can occur either as a consequence of direct deposition of toxic proteins or by an induced inflammatory response. Due to the low burden of the plasma cell clone, patients do not otherwise qualify for potentially toxic anti-plasma cell treatments and treatment is generally based on consensus opinion. To date there are no clinical trials exploring treatment options. Isatuximab is a chimeric mouse/human IgG1k monoclonal antibody which targets CD38 on both malignant and normal plasma cells and exhibits it antitumor effects primarily by antibody-dependent cellular toxicity. Isatuximab has recently been shown to be an active drug in the treatment of multiple myeloma, with improvements seen in hematologic and renal markers, and has been shown to have manageable toxicity. Given the efficacy of isatuximab in multiple myeloma, we propose a trial evaluating isatuximab monotherapy to treat the small plasma cell clone in MGRS with the hopes of maximizing response and minimizing toxicity. Study Design and Methods: The primary objective of this study is to evaluate efficacy of isatuximab monotherapy in patients with MGRS in order to establish a standard of care treatment for patients with this disease. Adult patients with proteinuria of at least 1 gram in 24 hours and a histopathological diagnosis of MGRS on renal biopsy in the last 24 months will be eligible for the trial. Patients will be excluded if their estimated GFR is below 30 mL/min, they have multiple myeloma, high risk smoldering myeloma, other B cell neoplasm meeting criteria for treatment, concurrent diabetic nephropathy, or require dialysis. Patients will be screened for B cell disorders with bone marrow biopsy and aspirate, serum protein electrophoresis (SPEP) with immunofixation (IFE), 24-hour urine protein electrophoresis (UPEP), free light chain (FLC) testing and screening PET/CT at time of enrollment. Enrolled patients will be administered isatuximab 20 mg/kg IV weekly for 4 weeks and then will receive the same dose every 2 weeks thereafter for a total of 6 months. Patients may be continued on treatment following completion of the 6 months at the discretion of the provider. To reduce the risk of infusion related reactions, patients will receive premedications with corticosteroids, diphenhydramine, H2 blockade and acetaminophen at least 60 minutes prior to infusion. Patients will have repeat SPEP + IFE, 24-hour UPEP + IFE and FLC testing every 4 weeks. There will be an optional repeat kidney biopsy 9-12 months following treatment initiation to assess pathologic response in the kidneys. Statistical Methods: The study will be comprised of 20 patients being treated with isatuximab over a span of 24-30 months. Ten patients will be initiated on the therapy for a period of 6 months. Interim analysis will be done after these patients have completed all the treatment cycles. If 4 out of 10 patients show response in form of improved/stable renal function, the study will proceed to include next 10 patients. If >50% of the first group of 10 patients show doubling of creatinine while on therapy, that would be considered as an indication to discontinue the therapy and the study due to drug toxicity. Endpoints: The primary endpoint will be efficacy as measured by renal response and hematologic response. Renal response will be measured by assessing the amount of proteinuria in a 24 hour urine sample. A sustained reduction in proteinuria by 30% from the patient's baseline amount of proteinuria with stable renal function (serum eGFR within 20% of baseline) will be considered a positive renal response. Hematologic response will be quantified per the 2016 International Myeloma Working Group (IMWG) uniform response criteria for multiple myeloma. An important secondary endpoint will be safety and will be analyzed from all patients who receive any study drug. Adverse events will be characterized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Other endpoints include time to dialysis and rate of minimal residual disease (MRD) negativity. Disclosures Lentzsch: Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy; Takeda: Consultancy; BMS: Consultancy; Proclara: Consultancy; Abbvie: Consultancy; Clinical Care Options: Speakers Bureau; Sanofi: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Honoraria; International Myeloma Foundation: Honoraria; Karyopharm: Research Funding; Columbia University: Patents & Royalties: 11-1F4mAb as anti-amyloid strategy. Bhutani:Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Our trial will be evaluating the efficacy of targeting CD38 on plasma cells with isatuximab in patients with monoclonal gammopathy of renal significance (MGRS). We will evaluate the effects of this drug on 24 hour proteinuria and hematologic response.

scholarly journals Multiple myeloma: circulating lymphocytes that express plasma cell antigens

Blood ◽  
1984 ◽  
Vol 64 (2) ◽  
pp. 352-356
Author(s):  
GJ Ruiz-Arguelles ◽  
JA Katzmann ◽  
PR Greipp ◽  
NJ Gonchoroff ◽  
JP Garton ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Peripheral Blood Lymphocytes ◽  
Tumor Burden ◽  
B Cell Differentiation ◽  
Blood Lymphocytes ◽  
Bone Marrow Plasma

The bone marrow and peripheral blood of 14 patients with multiple myeloma were studied with murine monoclonal antibodies that identify antigens on plasma cells (R1–3 and OKT10). Peripheral blood lymphocytes expressing plasma cell antigens were found in six cases. Five of these cases expressed the same antigens that were present on the plasma cells in the bone marrow. Patients that showed such peripheral blood involvement were found to have a larger tumor burden and higher bone marrow plasma cell proliferative activity. In some patients, antigens normally found at earlier stages of B cell differentiation (B1, B2, and J5) were expressed by peripheral blood lymphocytes and/or bone marrow plasma cells.

scholarly journals Complement receptors regulate differentiation of bone marrow plasma cell precursors expressing transcription factors Blimp-1 and XBP-1

2005 ◽  
Vol 201 (6) ◽  
pp. 993-1005 ◽  
Author(s):  
Dominique Gatto ◽  
Thomas Pfister ◽  
Andrea Jegerlehner ◽  
Stephen W. Martin ◽  
Manfred Kopf ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Antibody Responses ◽  
Complement Receptors ◽  
Essentially Normal ◽  
Bone Marrow Plasma

Humoral immune responses are thought to be enhanced by complement-mediated recruitment of the CD21–CD19–CD81 coreceptor complex into the B cell antigen receptor (BCR) complex, which lowers the threshold of B cell activation and increases the survival and proliferative capacity of responding B cells. To investigate the role of the CD21–CD35 complement receptors in the generation of B cell memory, we analyzed the response against viral particles derived from the bacteriophage Qβ in mice deficient in CD21–CD35 (Cr2−/−). Despite highly efficient induction of early antibody responses and germinal center (GC) reactions to immunization with Qβ, Cr2−/− mice exhibited impaired antibody persistence paralleled by a strongly reduced development of bone marrow plasma cells. Surprisingly, antigen-specific memory B cells were essentially normal in these mice. In the absence of CD21-mediated costimulation, Qβ-specific post-GC B cells failed to induce the transcriptional regulators Blimp-1 and XBP-1 driving plasma cell differentiation, and the antiapoptotic protein Bcl-2, which resulted in failure to generate the precursor population of long-lived plasma cells residing in the bone marrow. These results suggest that complement receptors maintain antibody responses by delivery of differentiation and survival signals to precursors of bone marrow plasma cells.

scholarly journals Primary tumor cells of myeloma patients induce interleukin-6 secretion in long-term bone marrow cultures

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2269-2277 ◽  
Author(s):  
HM Lokhorst ◽  
T Lamme ◽  
M de Smet ◽  
S Klein ◽  
RA de Weger ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Cells ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Adherent Cells ◽  
Myeloma Cells ◽  
Bone Marrow Cultures ◽  
Marrow Cultures

Abstract Long-term bone marrow cultures (LTBMC) from patients with multiple myeloma (MM) and normal donors were analyzed for immunophenotype and cytokine production. Both LTBMC adherent cells from myeloma and normal donor origin expressed CD10, CD13, the adhesion molecules CD44, CD54, vascular cell adhesion molecule 1, very late antigen 2 (VLA-2), and VLA- 5, and were positive for extracellular matrix components fibronectin, laminin, and collagen types 3 and 4. LTBMC from myeloma patients and normal donors spontaneously secreted interleukin-6 (IL-6). However, levels of IL-6 correlated with the stage of disease; highest levels of IL-6 were found in LTBMC from patients with active myeloma. To identify the origin of IL-6 production, LTBMC from MM patients and normal donors were cocultured with BM-derived myeloma cells and cells from myeloma cell lines. IL-6 was induced by plasma cell lines that adhered to LTBMC such as ARH-77 and RPMI-8226, but not by nonadhering cell lines U266 and FRAVEL. Myeloma cells strongly stimulated IL-6 secretion in cocultures with LTBMC adherent cells from normal donors and myeloma patients. When direct cellular contact between LTBMC and plasma cells was prevented by tissue-culture inserts, no IL-6 production was induced. This implies that intimate cell-cell contact is a prerequisite for IL-6 induction. Binding of purified myeloma cells to LTBMC adherent cells was partly inhibited by monoclonal antibodies against adhesion molecules VLA-4, CD44, and lymphocyte function-associated antigen 1 (LFA-1) present on the plasma cell. Antibodies against VLA-4, CD29, and LFA-1 also inhibited the induced IL-6 secretion in plasma cell-LTBMC cocultures. In situ hybridization studies performed before and after coculture with plasma cells indicated that LTBMC adherent cells produce the IL-6. These results suggest that the high levels of IL-6 found in LTBMC of MM patients with active disease are a reflection of their previous contact with tumor cells in vivo. These results provide a new perspective on tumor growth in MM and emphasize the importance of plasma cell-LTBMC interaction in the pathophysiology of MM.

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