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 A Prospective Study and Identification of Genomewide Association Markers of Familial Predisposition to Plasma Cell Dyscrasias

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-8
Author(s):  
Adam S Sperling ◽  
Rebecca Georgakopoulou ◽  
Mehmet Kemal Samur ◽  
Christine Ivy Liacos ◽  
Brittany E Sandoval ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
B Cell ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Monoclonal Gammopathy ◽  
Research Funding ◽  
Advisory Committees ◽  
Familial Predisposition ◽  
Plasma Cell Dyscrasias ◽  
Second Degree

Introduction: An increased inherited risk for the development of plasma cell dyscrasias (PCDs) has long been suspected, however to date, only a limited number of potential genomic risk loci have been described. To characterize the inherited risk and facilitate identification of additional risk loci it is important to combine detailed pedigrees with extensive genetic analysis. To identify familial PCDs we initiated a prospective study with active recruitment of a large cohort of patients with PCDs and active screening of their relatives combined with tissue banking and subsequent genetic analysis. Methods: All patients in the Department of Clinical Therapeutics diagnosed with PCDs between January 2017 and January 2019, were offered enrollment in the study. Following informed consent, 1st and 2nd degree relatives over the age of 30 were eligible for screening. A detailed family pedigree was created for each index case with special focus on family history of PCDs, B-cell lymphomas, or other hematologic or solid malignancies. As a control, subjects' spouses were also screened. Screening included serum protein electrophoresis with immunofixation. In families where an additional member was identified with a PCD or B-cell malignancy, peripheral blood was collected from consenting family members over the age of 18 for further genetic analysis. Samples from affected individuals were profiled using whole genome sequencing (WGS) and unaffected individuals were genotyped using Axiom Arrays. Data were analyzed using Axion Array Suite and plink and GATK toolkit with BWA. Results: Of 1,084 patients screened for participation in the study; 752 had multiple myeloma (MM), 77 had smoldering MM, 81 a monoclonal gammopathy of undetermined significance, 93 Waldenström's Macroglobulinemia and 81 had AL amyloidosis. 176 (16.2%) patients refused to participate in the study, while 44 (4.1%) patients were ineligible for further screening due to the absence of a living first- or second-degree relative. The median number of screened first or second-degree relatives per index patient was 3 (range 1 to 10). The median age of index cases was 65 years, offspring was 37 years, second-degree relatives was 65 years, and spouses was 65 years. The incidence of a PCD among second-degree relatives was 4.5%, while it was 0.6% among offspring. As a control group, the incidence of PCDs among spouses was 2.6%. Overall at least one additional member (beyond the index patient) with a monoclonal gammopathy was detected in 98 families (11.3%). In 57 families (6.6%) there was a positive history of at least one additional first- or second-degree relative with a PCD or B-cell malignancy. In addition, 41 new cases of monoclonal gammopathy (4.7%) were identified through the screening process associated with this study. To identify genetic loci that could be associated with a predisposition to development of PCDs, genetic analysis was performed on the most heavily affected 18 families, those with at least three affected members or with early onset disease (i.e. PCD diagnosed before age 50). We have evaluated 838,750 SNPs from 103 samples from 18 families. 30 samples were from affected members and 73 from unaffected members. We found eight SNPs (rs13233413, rs11648113, rs59444635, rs148480125, rs113556240, rs11547122, rs671880, rs4726610) that are significantly enriched in affected members with a p-value below the suggestive cut-off of <1e-5. The top candidate was in the untranslated region (UTR) of TSPAN33, a marker of activated and malignant B-cells. We did not detect any significant enrichment in germline mutations in previously reported genes associated with familial PCD risk such as KDM1a, KRAS or DIS3. Functional annotation of the 8 SNPs identified here showed that rs148480125, located in the promoter region of the apoptosis regulator SIVA1, is predicted to impact the allele specific expression level. Further validation work is ongoing. Conclusions: Our active prospective screening approach to identify familial predisposition to PCDs revealed that 11.3% of patients had families with at least one additional affected member and some families had a substantially higher incidence of PCDs with earlier onset. Study of these high-risk families have identified genomewide association markers which in future may help us define familial predisposition to plasma cell dyscrasias. Disclosures Gavriatopoulou: Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:Amgen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria. Munshi:Janssen: Consultancy; OncoPep: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Consultancy; Legend: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; C4: Current equity holder in private company; Adaptive: Consultancy. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau.

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.

scholarly journals First Description of B Cell Maturation Antigen Expression in Light Chain Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5452-5452
Author(s):  
Susan Bal ◽  
Allison Sigler ◽  
Alexander Chan ◽  
David J. Chung ◽  
Ahmet Dogan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Staining Intensity ◽  
Advisory Committees ◽  
Light Chain Amyloidosis ◽  
B Cell Maturation

Background B-cell maturation antigen (BCMA) is a transmembrane protein belonging to the tumor necrosis factor (TNF) superfamily involved in the regulation of B cell proliferation and survival as well as maturation/differentiation into plasma cells. In multiple myeloma cells, overexpression of BCMA has been shown to activate mitogen activated protein kinase pathways (AKT, ERK1/2, and NF-κB) and upregulates anti-apoptotic proteins (MCL1, BCL2, BCL-xL) resulting in cellular proliferation. Immunotherapeutic strategies targeting BCMA are showing great promise in heavily pre-treated refractory multiple myeloma. Light Chain Amyloidosis (AL) is a multisystem disorder of clonal plasma cells that results in the production of an abnormal light chain which misfolds and deposits in the organs leading to disruption of tissue architecture, cellular stress, dysfunction and eventually, death. The smaller burden and lower proliferative potential of the offending clonal plasma cells in amyloidosis may potentially lend itself favorably to immunotherapeutic strategies targeting BCMA. Given the efficacy of this approach in MM, the evaluation of BCMA expression on the surface of amyloidogenic plasma cells is warranted. Methods All patients diagnosed with Light chain Amyloidosis at Memorial Sloan Kettering Cancer Center, NY between January 1, 2012, and December 31, 2018, who had unstained bone marrow samples were identified. These unstained BM biopsy samples were prospectively stained for BCMA expression using Immunohistochemistry (IHC). We utilized a clinical-grade assay (clone D6; catalog sc-390147; company Santa-Cruz; monoclonal antibody; dilution 1:400) in a CLIA compliant setting. We scored the biopsies for BCMA expression, intensity, and site of staining. We also obtained their demographic details, staging, and cytogenetic information for the patients with available samples. Results During the queried period, 28 unstained samples were available for testing from the time of disease diagnosis. The median age of the population was 63 years (range 41-73). 64% of patients were male and consistent with the literature; a majority of patients (75%) had lambda-typic clonal plasma cells. Cytogenetic abnormalities using fluorescence in situ hybridization (FISH) were reviewed, t(11;14) was seen in 36% patients, and chromosome 1q and del 13q were each seen in 32% of patients. No patient had t(4;14) or del 17p. The median clonal PC burden in BM at diagnosis was 10% (range2-80%) and 36% had > 10% plasma cells. In clonal PCs, the median BCMA expression was 80% (range 20-100%). Only one patient had a staining intensity under 50% (20%). Membranous staining was noted in 82% of patients and a Golgi pattern in 11%. The median staining intensity was 2 (range 1-3). Of the patients with baseline diagnostic samples available for testing, six patients had additional unstained bone marrow samples for staining at the time of relapse. The majority of patients (83%) who relapsed had >10% plasma cells with a higher median plasma cell burden of 35% (range 10-80). The median BCMA expression was 65% (range 50-80) with no patient having <50% expression. The staining pattern was membranous in 50%, Golgi in 17%, and Golgi-membranous in 33%. At the time of relapse, the median clonal PC burden was 13% (range 5-30). BCMA expression continued to be present at the time of relapse with a median 75% (range 50-100) with predominantly membranous staining (83%). The median staining intensity in both diagnostic and relapsed tissue within the six samples studied was 1. Conclusions Our study represents the first description of BCMA expression on the surface of amyloidogenic plasma cells to our knowledge. BCMA is uniformly expressed by pathologic PCs in AL amyloidosis both at the time of diagnosis and relapse. Given the efficacy of BCMA directed therapy in multiple myeloma, further investigation of these agents in light-chain amyloidosis are warranted and may provide an effective therapeutic strategy in this devastating disease. Figure Disclosures Dogan: Corvus Pharmaceuticals: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Roche: Consultancy, Research Funding. Giralt:Takeda: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Kite: Consultancy; Novartis: Consultancy; Actinium: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Miltenyi: Research Funding; Spectrum Pharmaceuticals: Consultancy. Hassoun:Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Landau:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1692-1700 ◽  
Author(s):  
Fenghuang Zhan ◽  
Bart Barlogie ◽  
Varant Arzoumanian ◽  
Yongsheng Huang ◽  
David R. Williams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Plasma Cell ◽  
Monoclonal Gammopathy ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Gene Expression Signature ◽  
Molecular Signature ◽  
Molecular Features ◽  
Major Cluster

Abstract Monoclonal gammopathy of undetermined significance (MGUS) can progress to multiple myeloma (MM). Although these diseases share many of the same genetic features, it is still unclear whether global gene-expression profiling might identify prior genomic signatures that distinguish them. Through significance analysis of microarrays, 52 genes involved in important pathways related to cancer were differentially expressed in the plasma cells of healthy subjects (normal plasma-cell [NPC]; n = 22) and patients with stringently defined MGUS/smoldering MM (n = 24) and symptomatic MM (n = 351) (P < .001). Unsupervised hierarchical clustering of 351 patients with MM, 44 with MGUS (24 + 20), and 16 with MM from MGUS created 2 major cluster branches, one containing 82% of the MGUS patients and the other containing 28% of the MM patients, termed MGUS-like MM (MGUS-L MM). Using the same clustering approach on an independent cohort of 214 patients with MM, 27% were found to be MGUS-L. This molecular signature, despite its association with a lower incidence of complete remission (P = .006), was associated with low-risk clinical and molecular features and superior survival (P < .01). The MGUS-L signature was also seen in plasma cells from 15 of 20 patients surviving more than 10 years after autotransplantation. These data provide insight into the molecular mechanisms of plasma-cell dyscrasias.

scholarly journals Difference in Involved and Uninvolved Free Light Chain (dFLC) of Less Than 1mg/DL Early Post Risk Adapted Melphalan and Autologous Stem Cell Transplantation (RA-ASCT) Predicts Renal Response at 1 Year in Light Chain (AL) Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4577-4577
Author(s):  
Sneha Purvey ◽  
Kenneth Seier ◽  
Sean M. Devlin ◽  
Josel D Ruiz ◽  
Molly A. Maloy ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Cardiac Involvement ◽  
Plasma Cells ◽  
Al Amyloidosis ◽  
Organ Function ◽  
Advisory Committees ◽  
Renal Response ◽  
Hematologic Response

Background: Deep and durable hematologic remissions following RA-ASCT are associated with improved organ function and extended overall survival (OS) in AL amyloidosis. Achieving at least a very good partial response (VGPR) defined by a dFLC <4mg/dL is an accepted goal of therapy based on favorable outcomes, including improved renal survival (REF: Palladini JCO 2012, Palladini Blood 2014). Recently more profound clonal suppression as indicated by no evidence of minimal residual plasma cell disease (MRD) in bone marrow (BM) (Muchtar Blood 2017) and achieving dFLC <1mg/dL (Manwani Blood 2018) have shown additional benefit. While depth of hematologic response by standard criteria are important, this study assessed additional factors that influence renal response and time to renal response. Methods: All patients (pts) with AL and renal involvement (biopsy proven renal tissue diagnosis and/or 24hr proteinuria >500mg/day) undergoing RA-ASCT at Memorial Sloan Kettering Cancer Center between January 1, 2007 to December 31, 2016 were included. Pts with follow up less than 12 months post RA-ASCT, hemodialysis prior to RA-ASCT and Waldenstrom macroglobulinemia were excluded. Melphalan dose was assigned based on age, cardiac involvement and renal compromise (Landau Leukemia 2013). Hematologic response was assessed at 3 and 12 months (mos) post RA-ASCT (Palladini JCO 2012) and those with less than complete response (CR) were offered consolidation therapy with bortezomib and dexamethasone (BD). All pts underwent serial organ function assessment (Palladini Blood 2014). Logistic regression models were used to assess association with renal response by 12 mos. Covariates for adjustment in multivariate models were chosen based on univariate analyses and clinical relevance. Results: Sixty-four patients with renal AL meeting the inclusion criteria were identified; 3 pts died within a year post RA-ASCT were excluded. Median age (range) was 61 years (44-73), M:F 49%:51%, white 90% and 34% had cardiac involvement. Median (IQR) 24 hr proteinuria pre RA-ASCT was 5014 mg/day (2632-7514) and eGFR 68 ml/min/1.73 m2 (44-91). Renal amyloid stage I:II:III was 33%:52%:15%. Mayo cardiac stage (2004) I:II:III was 28%:61%:11% and revised Mayo stage (2012) I:II:III:IV was 13%:57%:21%:8%. Median BM plasma cells pre RA-ASCT was 9% (IQR 2-14%). 46% pts received treatment prior to ASCT. Melphalan dose (mg/m2) 200:140:100 was 44%:43%:11%. 46% pts received BD consolidation. Hematologic response at 3 mos post RA-ASCT was CR 44%, VGPR 29%, partial response (PR) 20% and stable disease (SD) 7%. MRD in BM by 10-color flow cytometry was assessed in 33 pts and 13 (39%) were MRD negative. dFLC <1mg/dL was achieved in 63% of pts. Renal response by 12 mos following RA-ASCT was achieved in 32 pts (53%). Median (IQR) time to renal response in these pts was 5.8 mos (5.1 - 11.3). Amongst renal responders, 50% were in CR, 53% had MRD negative BM (of 15 pts) and 78% with dFLC <1mg/dL early post RA-ASCT. In pts who achieved dFLC <1mg/dL early post RA-ASCT, 66% had renal response. By univariate analysis (Table 1) OR (95% CI) Mayo cardiac Stage (2004) II and III 0.23 (0.07-0.83, p=0.025), early post RA-ASCT dFLC <1mg/dL 3.00 ( 1.01-8.93, p=0.048), VGPR early post RA-ASCT 7.80 (1.69-36.06, p=0.009), dFLC <1mg/dL at 12 mos 7.20 (2.14-24.21, p=0.001) and CR at 12 mos 10.27 (1.14-92.26, p=0.038) were significantly associated with renal response. Neither renal stage, Mayo stage (2012), MRD negativity, melphalan dose nor consolidation was associated with renal response. By multivariate analysis (Table 2), early post RA-ASCT dFLC <1mg/dL continued to be the most significant factor predicting renal response, OR (95% CI) 4.52 (1.26-16.24, p=0.021), when adjusted for renal amyloid stage and Mayo cardiac stage (2004). Conclusion: In this single center study, we report that RA-ASCT results in renal response in more than half (53%) of the patients at 1 year. Achieving dFLC <1mg/dL early post ASCT is significantly associated with renal response. Renal response is independent of baseline proteinuria and BM plasma cells or MRD status post ASCT. Our study supports that pathologic entity in organ damage is not the plasma cells but rather light chains. Further studies using dFLC <1mg/dL should be evaluated in organ response. Mass spectrometric light chain monitoring may even be more sensitive and could potentially serve as a non-invasive way to measure disease burden. Disclosures Shah: Janssen: Research Funding; Amgen: Research Funding. Hassoun:Janssen: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Giralt:Celgene: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Landau:Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Oncogene Induced Senescence As a Potential Breakpoint Mechanism Against Malignant Transformation in Plasma Cell Disorders

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4474-4474
Author(s):  
Nicola Lehners ◽  
Elena Ellert ◽  
Jing Xu ◽  
Hartmut Goldschmidt ◽  
Mindaugas Andrulis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Malignant Transformation ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Healthy Controls ◽  
Advisory Committees ◽  
Expression Levels ◽  
Plasma Cell Disorders

Abstract Background: Cellular senescence has been recognized as a failsafe mechanism against hyperproliferation and might thus be induced by DNA replicative stress and oncogenic signaling, commonly termed oncogene-induced senescence (OIS). OIS has been described in several premalignant conditions such as colon adenomas and melanocytic nevi, with impaired OIS capabilities found in their malignant counterparts. Here, we analyze the possible impact of cellular senescence on malignant transformation in plasma cell disorders. Methods: Bone marrow and soft tissue biopsies from 125 patients with different stages of plasma cell disorders (16 monoclonal gammopathy of undetermined significance (MGUS), 32 smoldering multiple myeloma (SMM), 56 symptomatic multiple myeloma (MM), 21 extramedullary MM) as well as from 10 healthy donors were analyzed. Expression of OIS associated proteins p16INK4A, p21Cip1/Waf1, p27Kip1, phospho-Chk2, the DNA double-strand break marker γH2AX, as well as the proliferation marker Ki67 were assessed on plasma cells by immunohistochemistry. Additionally, double staining experiments for p21 and Ki67 were performed applying immunofluorescence confocal microscopy. Levels of protein expression were compared between different disease stages using the Kruskal-Wallis test. Results: A differential expression pattern was found for p21 in various stages of plasma cell disorders with peak expression of p21 in SMM compared to both healthy controls (p<0.001) and MGUS (p=0.02), as well as compared to symptomatic multiple myeloma (MM) (p=0.007) (see Figure 1a). Median p21 expression was 0.63% of plasma cells from healthy subjects, 6.67% in MGUS, 13.81% in SMM, 2.37% in MM, and 0% in EMM. Plasma cells of SMM patients expressing p21 were negative for Ki67 consistent with a potentially senescent phenotype. In contrast, p27 was highly expressed in healthy controls, MGUS and SMM but decreased significantly in MM patients (p=0.02) (see Figure 1b). p16 showed no nuclear expression in healthy controls, MGUS or SMM and was expressed only in few patients with MM. In addition, we found low expression of p21, p27 and phospho-Chk2 in extramedullary MM compared to medullary MM samples, accompanied by increased expression of γH2AX and high levels of proliferation (Ki67 58%). Conclusions: We found indication of induction of OIS in SMM compared to symptomatic MM, mainly mediated by increased expression of p21. Further disease progression to extramedullary MM was characterized by almost complete absence of OIS markers and increased signs of DNA damage and proliferation. These observations are consistent with the hypothesis of OIS as a breakpoint mechanism against malignant transformation in plasma cell disorders and should be further explored mechanistically and as a possible therapeutic target. Figure 1 Expression levels of p21 and p27in different stages of plasma cell disorders. Semiquantitative assessment of plasma cells positive for p21 (a) and p27 (b) is shown in healthy controls, MGUS, SMM, MM, and EMM patients. Significant differences in expression levels between cohorts are indicated by their respective p-values with * p-value < 0.05, ** < 0.01, *** < 0.001. Figure 1. Expression levels of p21 and p27in different stages of plasma cell disorders. Semiquantitative assessment of plasma cells positive for p21 (a) and p27 (b) is shown in healthy controls, MGUS, SMM, MM, and EMM patients. Significant differences in expression levels between cohorts are indicated by their respective p-values with * p-value < 0.05, ** < 0.01, *** < 0.001. Disclosures Goldschmidt: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; 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, Research Funding; Millennium: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Novartis: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy.

Plasma Cell Disorders

2015 ◽  
Author(s):  
Morie A. Gertz
Keyword(s):  
Multiple Myeloma ◽  
Black Women ◽  
Plasma Cell ◽  
Bone Disease ◽  
Monoclonal Gammopathy ◽  
White Women ◽  
Plasma Cells ◽  
The United States ◽  
Lytic Lesion ◽  
Undetermined Significance

Multiple myeloma represents 1.4% of all new patients with cancer and will result in an estimated 11,090 deaths in 2014. It is twice as common in black men as in white men and 2.5 times more common in black women than in white women. Myeloma is the 14th most common cause of cancer in the United States, with a median age at diagnosis of 69 years. Multiple myeloma is defined by the presence of a clonal growth of plasma cells, usually in the bone marrow, but patients may also present with extramedullary disease. Anemia and bone disease are common in patients with multiple myeloma. Multiple myeloma cells display multiple genetic abnormalities, with no one specific genetic lesion common to a majority of patients. This module describes the immunologic profile of multiple myeloma and its diagnosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, plasmacytoma, plasma cell leukemia, the clinical presentation of multiple myeloma bone disease, anemia, renal impairment, hypercalcemia, and neurologic symptoms associated with multiple myeloma. Therapy for transplantation-eligible and non–transplantation-eligible patients, maintenance treatment for multiple myeloma, Waldenström macroglobulinemia, and amyloidosis are also discussed. Tables outline the risk of monoclonal gammopathy of undetermined significance evolution, the myeloma staging system, recommended diagnostic testing and uniform response criteria for myeloma, and commonly used regimens in the treatment of myeloma. Figures include a magnetic resonance image showing multiple plasmacytomas, tibial lytic lesion from myeloma, calvarial lytic lesions, a positron emission tomographic scan in a myeloma patient, and hyperviscosity causing retinal hemorrhages. This review contains 5 highly rendered figures, 5 tables, and 149 references.

scholarly journals Gene-expression profiling of Waldenström macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2755-2763 ◽  
Author(s):  
Wee J. Chng ◽  
Roelandt F. Schop ◽  
Tammy Price-Troska ◽  
Irene Ghobrial ◽  
Neil Kay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Clone ◽  
Expression Profiles ◽  
Mapk Signaling ◽  
Lymphocytic Leukemia

Abstract Waldenström macroglobulinemia (WM) is a B-cell malignancy characterized by the ability of the B-cell clone to differentiate into plasma cells. Although the clinical syndrome and the pathologic characteristics are well defined, little is known about its biology and controversy still exists regarding its cell of origin. In this gene-expression study, we compared the transcription profiles of WM with those of other malignant B cells including (chronic lymphocytic leukemia [CLL] and multiple myeloma [MM]) as well as normal cells (peripheral-blood B cells and bone marrow plasma cells). We found that WM has a homogenous gene expression regardless of 6q deletion status and clusters with CLL and normal B cells on unsupervised clustering with very similar expression profiles. Only a small gene set has expression profiles unique to WM compared to CLL and MM. The most significantly up-regulated gene is IL6 and the most significantly associated pathway for this set of genes is MAPK signaling. Thus, IL6 and its downstream signaling may be of biologic importance in WM. Further elucidation of the role of IL-6 in WM is warranted as this may offer a potential therapeutic avenue.

scholarly journals Monoclonal gammopathy of undetermined significance

Blood ◽  
2019 ◽  
Vol 133 (23) ◽  
pp. 2484-2494 ◽  
Author(s):  
Tarek H. Mouhieddine ◽  
Lachelle D. Weeks ◽  
Irene M. Ghobrial
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Monoclonal Gammopathy ◽  
Cell Clone ◽  
Plasma Cell Dyscrasia ◽  
Bone Marrow Niche ◽  
Immunologic Factors ◽  
Risk Of Progression ◽  
Undetermined Significance

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell dyscrasia that consistently precedes multiple myeloma (MM) with a 1% risk of progression per year. Recent advances have improved understanding of the complex genetic and immunologic factors that permit progression from the aberrant plasma cell clone to MGUS and overt MM. Additional evidence supports bidirectional interaction of MGUS cells with surrounding cells in the bone marrow niche that regulates malignant transformation. However, there are no robust prognostic biomarkers. Herein we review the current body of literature on the biology of MGUS and provide a rationale for the improved identification of high-risk MGUS patients who may be appropriate for novel clinical interventions to prevent progression or eradicate premalignant clones prior to the development of overt MM.

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.

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