HGF Measurement in AL Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1783-1783
Author(s):  
Julie Abraham ◽  
Estelle Desport ◽  
Benoit Marin ◽  
Sebastien Bender ◽  
Corinne Lacombe ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Roc Curve ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Renal Involvement ◽  
Threshold Value ◽  
Serum Levels ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis

Abstract Abstract 1783 Poster Board I-809 Purpose Hepatocyte Growth Factor (HGF) is a pro-angiogenic cytokine and a mitogenic, motogenic and morphogenic factor involved in tumor growth. Previous studies have shown that HGF is secreted by plasma cells in multiple myeloma and that HGF serum levels are higher in patients with multiple myeloma and correlate with disease activity. A previous study reported that serum HGF levels were significantly higher in patients with AL amyloidosis compared to patients with multiple myeloma (Iwasaki et al. Br J Haematol. 2002;116:796-802). A preliminary study of 18 AA and AL amyloidosis patients (Shikano et al, Intern Med. 2000;39:715-9) suggested that measurement of HGF might be useful for the diagnosis of amyloidosis. To determine whether HGF may be used as a relevant diagnosis marker and prognosis factor in AL amyloidosis, we have measured HGF serum levels in patients with AL amyloidosis and patients with plasma cell dyscrasia without amyloidosis. Patients and Methods Two groups of patients were included; patients with biopsy proven AL amyloidosis and patients with plasma cell dyscrasia (MGUS, multiple myeloma, POEMS) without amyloidosis as controls. Levels of HGF were measured by ELISA at diagnosis in the two groups, before any treatment (Quantikine® R&D Systems). Clinical features were recorded for AL patients. A Receiver Operating Characteristic curve (ROC) analysis was performed to assess the diagnostic accuracy of HGF for identification of amyloidosis cases among patients with monoclonal gammopathy. The area under the ROC curve (AUC) which can be interpreted as the probability that a randomly chosen amyloidosis patient has a test result greater than that of a randomly chosen non-amyloidosis patient, was calculated with its 95% confidence interval (95%CI). The ROC curve was also used to determine the best threshold for HGF. Using this threshold, sensitivity and specificity were calculated. Survival analyses were performed for patients suffering from AL amyloidosis. Baseline time was time from first HGF assessment to death or censoring date. Univariate analysis were done using Kaplan Meier and Cox proportional hazard models. Results Sixty-nine AL amyloidosis patients diagnosed between 2004 and 2008 and 76 controls (56 patients with MGUS, 17 with multiple myeloma, three with POEMS) were included. The median age was 61 (32-90) for AL patients and 60 (39-86) for controls. Median creatinine levels were respectively 86μmol/l (39-500) and 79μmol/l (44-317); 57 AL patients (82.6%) had renal involvement and 40 had (57.9%) cardiac disease. Monoclonal protein isotype was lambda in 69.6% of AL patients and kappa in 30.4%. HGF serum levels were significantly higher in patients with AL amyloidosis: 11.2ng/ml (0.5-200.4) compared with controls: 1.5ng/ml (0.8-8.2), p<0.0001 (healthy controls 0.9 ng/ml). HGF levels at diagnosis seemed to be discriminant with area under the ROC curve at 0.896 IC95% [0.834-0.94] p=0.0001. The threshold value of 2.4ng/ml conferred the best sensitivity : 82.6% IC95% [71.6-90.7] and specificity : 89.5% IC95% [80.3-95.3] for the diagnosis of AL amyloidosis. Patients were treated mainly by conventional chemotherapy (M-Dex), 65 % of AL patients were alive after a median follow up of 18 months. Univariate analysis showed a relative risk of mortality of 1.70 in AL patients with HGF levels upper than 11ng/ml, compared to those with HGF levels under 11 ng/l who showed a trend for better survival (p=0.22). Conclusion This study confirms that HGF levels are elevated in patients with AL amyloidosis, significantly higher than in patients with other plasma cell disorders. A threshold value of 2.4ng/ml confers a good sensitivity (80%) and specificity (90%) to suggest AL amyloidosis. HGF measurement may be used in patients with plasma cell dyscrasia to determine which patient should be considered for a biopsy. We found a trend towards reduced survival in patients with the highest levels of HGF. This, and the usefulness of HGF measurement in predicting clinical responses should be confirmed on larger studies. Disclosures No relevant conflicts of interest to declare.

Secretome Analyses of Primary Bone Marrow Fibroblasts Isolated From MGUS and Multiple Myeloma Show a Stepwise Occurrence of Alterations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1801-1801
Author(s):  
Johannes Drach ◽  
Astrid Slany ◽  
Thomas Mohr ◽  
Johannes Griss ◽  
Christoph C Zielinski ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Growth Factor ◽  
Plasma Cell ◽  
Conflicts Of Interest ◽  
Cell Clone ◽  
Serum Levels ◽  
Plasma Cell Dyscrasia ◽  
Healthy Donors ◽  
Bone Marrow Fibroblasts

Abstract Abstract 1801 Poster Board I-827 The microenvironment of tumor cells in the bone marrow was demonstrated to contribute to tumor promotion and survival. The role of bone marrow fibroblasts (BMFs) in supporting the malignant plasma cell clone in multiple myeloma (MM) has been established, but it remains unclear to which extent the BM microenvironment in general and BMFs in particular are involved in the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. Therefore we performed proteomics studies on the secretome of BMFs isolated from healthy donors, patients suffering from MGUS and patients suffering from MM. Compared to normal background, BMFs derived from MGUS secreted elevated levels of proteins indicating mitogenic activity and moderate inflammation. These proteins included periostin, IL-6, CXCL5 and CSF-1. Insulin-like growth factor II, which is normally not expressed by normal BMFs, was secreted by BMF cells derived from MGUS as well as from MM. In addition to those and other proteins, BMF cells derived from MM were found to specifically secrete stem cell growth factor, MMP-28 and stanniocalcin-1. These data indicate a step-wise alteration of BMF secretion activity related to the stage of the underlying plasma cell dyscrasia. Therefore BMF might support the progression from MGUS to MM. In order to correlate the secretion performance of BMF with blood serum levels of candidate marker proteins, Luminex assays are employed. Based upon these results, it is our aim to identify serum biomarkers which allow to assess the functional state of BMF and thus the risk for the progression of MGUS to MM. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma

2018 ◽  
Vol 2 (20) ◽  
pp. 2607-2618 ◽  
Author(s):  
Tilmann Bochtler ◽  
Maximilian Merz ◽  
Thomas Hielscher ◽  
Martin Granzow ◽  
Korbinian Hoffmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cell ◽  
Clonal Evolution ◽  
Statistical Significance ◽  
Hematologic Malignancies ◽  
Absolute Difference ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis ◽  
Clone Size

Abstract Analysis of intraclonal heterogeneity has yielded insights into the clonal evolution of hematologic malignancies. We compared the clonal and subclonal compositions of the underlying plasma cell dyscrasia in 544 systemic light chain amyloidosis (PC-AL) patients with 519 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or symptomatic MM; ie, PC–non-AL patients). Using interphase fluorescence in situ hybridization, subclones were stringently defined as clone size below two thirds of the largest clone and an absolute difference of ≥30%. Subclones were found less frequently in the PC-AL group, at 199 (36.6%) of 544 as compared with 267 (51.4%) of 519 in the PC–non-AL group (P &lt; .001), and were not associated with the stage of plasma cell dyscrasia in either entity. In both groups, translocation t(11;14), other immunoglobulin heavy chain translocations, and hyperdiploidy were typically found as main clones, whereas gain of 1q21 and deletions of 8p21, 13q14, and 17p13 were frequently found as subclones. There were no shifts in the subclone/main clone ratio depending on the MGUS, SMM, or MM stage of plasma cell dyscrasia. In multivariate analysis, t(11;14) was associated with lower rates of subclone formation and hyperdiploidy with higher rates. PC-AL itself lost statistical significance, demonstrating that the lower subclone frequency in AL is a reflection of its exceptionally high t(11;14) frequency. In summary, the subclone patterns in PC-AL and PC–non-AL are closely related, implying that subclone formation depends on the main cytogenetic categories and is independent of disease entity and stage.

Localized AL Amyloidosis of the Breast: A Case Series.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4906-4906
Author(s):  
Marjory Charlot ◽  
David C. Seldin ◽  
Carl O'Hara ◽  
Martha Skinner ◽  
Vaishali Sanchorawala
Keyword(s):  
Plasma Cell ◽  
Congo Red ◽  
Conflicts Of Interest ◽  
Amorphous Material ◽  
Case Series ◽  
Screening Mammography ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis ◽  
Palpable Mass ◽  
Amyloid Deposits

Abstract Abstract 4906 AL amyloidosis is characterized by widespread, progressive deposition of fibrillar amyloid protein derived from monoclonal immunoglobulin light chains, leading to organ failure and death. This disease is typically systemic, however, it can occur as a localized form. In localized amyloidosis, the deposits occur near the site of synthesis of the precursor protein and in some cases, plasma cells have been demonstrated histologically adjacent to the deposits. For unknown reasons, the tracheobronchial tree is the most common site for localized AL amyloidosis. Localized AL amyloidosis of the breast is a rare entity that has been described in the literature in isolated case reports. It can present as a palpable mass or as calcifications on routine screening mammography. We report here a case series of seven women (median age 63 years, range 46 to75) seen and evaluated at Boston University Medical Center from 1990-2008. We evaluated 1502 new patients with AL amyloidosis in this time period, making the incidence of localized AL amyloidosis of the breast to be 0.5% at a single referral center. All seven patients had abnormal screening mammography with calcifications, and biopsies that revealed Congo red positive amyloid deposits. Histologically, the amyloid deposits appeared as amorphous material in the stroma around the ducts and lobules in most patients; one patient had amyloid deposits in the ducts only, but not in the stroma. None of the patients had clinical or laboratory evidence of other organ involvement, all had negative Congo red staining of an abdominal fat pad aspirate, and all had a negative work up for a plasma cell dyscrasia or circulating paraprotein. The patients were treated with local excision of the regions of calcification or lumpectomy. Three out of seven patients underwent routine follow up within 6-12 months from the time of diagnosis with no evidence of disease recurrence or progression to systemic AL amyloidosis. One out of seven patients had bilateral and recurrent amyloidosis of the breasts and was found to have an associated stage I invasive ductal adenocarcinoma that was treated with lumpectomy and radiation. In summary, breast amyloidosis is rare, is not associated with a systemic plasma cell dyscrasia or amyloidosis in other organs, and can be treated surgically. Disclosures No relevant conflicts of interest to declare.

Serum C-Terminal Telopeptide Maintains Its Correlation with Bone Disease in Myeloma Patients Even Under Treatment with Bisphosphonates

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4003-4003
Author(s):  
Lara Pochintesta ◽  
Silvia Mangiacavalli ◽  
Federica Cocito ◽  
Cristiana Pascutto ◽  
Alessandra Pompa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Type I Collagen ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Positive Association ◽  
Disease Status ◽  
Serum Levels ◽  
Patient Specific ◽  
Type I

Abstract Abstract 4003 Skeletal related events (SREs) are a significant cause of morbidity and mortality in multiple myeloma (MM). Markers of bone turn-over, in particular serum C-terminal telopeptide of type I collagen (CTX), can be used for monitoring early signs of bone damage either in osteoporosis or in neoplasm such as Multiple Myeloma. Since serum CTX levels are significantly decreased during bisphosphonate treatments (Dennis, N Engl J Med 2008), it is not clear whether serum CTX monitoring still retain a role in predicting SREs once bisphosphonate treatments was started. Aim of this study was to test whether serum CTX monitoring significantly correlates with active bone disease in a population of MM patients irrespective of concomitant bisphosphonate treatment. An unselected cohort of 87 patients with multiple myeloma diagnosed at our Hematology Division with the following characteristics entered this study: the availability of a baseline determination of serum CTX prior to start bisphosphonate therapy, multiple sequential serum CTX determinations (≥2 performed with an interval of at least 4 weeks), a radiologic evaluation available at the time of any SREs. The study was approved by our local ethical committee and conducted according to Helsinki Declaration guidelines. Patients baseline characteristics were the following: M/F 59%/41%, median age 60 (range 37–86), Durie and Salmon stage I/II/III (11%/14%/75%). During the study period (median follow-up 2.8 year, range 0.4–21 years), 73 patients (83%) experienced at least one SRE. Development of SRE was evaluated by standard skeletal x-ray, CT or MRI scan. Serum CTX was measured by an enzyme chemiluminescence method. A total of 260 serum CTX determinations were available for statistical analysis (median number of determinations for each patient 3, range 2–9). Univariate analysis found a statistically significant association between serum CTX and bone disease status with higher values in patients with active lytic lesions when compared to patients without radiological evidence of bone disease (median value 0.411 vs 0.356, p<0.001). By contrast, we observed significantly lower serum CTX values in patients under bisphosphonates treatment (median value 0.160 vs 0.355, p=<0.001). Association between serum CTX values, bone disease status and active bisphosphonates treatment was analyzed with a time-series linear model, accounting for measurement being repeated sequentially on each patient (random-effects GLS regression). Bone disease status and bisphosphonates treatment resulted significantly and independently associated to serum CTX (regression coefficient 0.222, 95%CI: 0.107–0.338, p<0.001 and 0.208 95%,CI: 0.320–0.096, p<0.001 respectively for bone disease status and bisphosphonates, cfr Tab 1). In addition, variations of CTX serum levels correlated significantly with the presence of active bone disease even under treatment with bisphosphonates (p<0.001). In conclusion, this study confirmed a positive association between serum CTX and presence of active bone disease. In addition serum CTX levels show a significant decrease under treatment with bisphosphonates. Taking into account these observations, patient-specific variations rather than the absolute serum CTX value should be used for detecting the onset of new SREs during a concomitant bysphosphonates treatment. Tab 1: Levels of serum CTX according to bone disease status and bisphosphonates treatment. Bisphosphonates treatment Progression in bone disease Active None Yes 0.219 (0.03–1.79) 0.533 (0.02–4.14) No 0.139 (0.03–0.69) 0.345 (0.071–1.57) Disclosures: No relevant conflicts of interest to declare.

Polyclonal Gamma Globulin Suppression and Risk Of MGUS Progression Into Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1875-1875 ◽  
Author(s):  
Jawad Z. Sheqwara ◽  
Mohammad Alhyari ◽  
Shannon Keating ◽  
Philip Kuriakose
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Plasma Cell ◽  
Total Protein ◽  
Gamma Globulin ◽  
Conflicts Of Interest ◽  
Significant Risk ◽  
M Protein ◽  
Plasma Cell Dyscrasia ◽  
Female Ratio

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is the most common form of plasma cell dyscrasia, with a prevalence of 3% in the general population above age of fifty. MGUS has a malignant evolution rate of 1% per year. Large longitudinal studies have suggested that virtually all patients diagnosed with multiple myeloma (MM) had a preceding MGUS, with 75 % having detectible Monoclonal (M) protein ≥8 years prior to diagnosis. It is important to identify the features at diagnosis that can predict neoplastic transformation to MM. Purpose We identified 239 patients at our institute in whom MGUS was diagnosed between 2000 and 2010. The presenting clinico-hematologic features were correlated with the frequency of evolution into MM to identify early predictors of evolution. The primary end point was progression to MM. Results The patients' mean age was 70.7 years. The Male/Female ratio was 0.7. The mean concentration of the M component (MC) was 0.7 g/dL. IgG was the most frequent MC (77%), followed by IgA (13%). The median ratio of MC protein to total protein was 0.5. Single or multiple background polyclonal (PC) suppression was noted in 36% of patients. PC suppression of 50% or more was noted in 20.1% of patients, 49.8% had < 50% and 30.1% had no suppression. Mean bone marrow plasma cell percentage was 4.5 percent and mean hemoglobin was 12.4 g/dL. Eighteen of the 239 patients with MGUS progressed into MM over ten years of follow up. Univariate comparisons of all variables between those who progressed and those who did not, showed that the initial concentration of the serum M protein, ratio of M protein to the total protein, number of PC gamma globulins suppressed, degree of PC suppression and IgM gamma globulin suppression were statistically significant risk factors that correlated with progression into MM. Fourteen out of eighteen patients with progressive disease had either PC suppression or background IgM suppression. Conclusions Monoclonal protein concentration, ratio of M protein to the total protein and abnormal serum free light chain ratio are simple variables that have been shown in multiple previous studies to predict the progression of MGUS into MM. In our study, we additionally found that number of PC suppressed, degree of suppression and IgM suppression are also key risk factors that can predict progression. We believe that these variables can be potentially applied into an approach that uses a detailed risk stratification system to predict which cases of MGUS will progress into MM and to provide more intensive monitoring for patients more likely to progress. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Safety and Tolerability of Cael-101 in Combination with Anti-Plasma Cell Dyscrasia Therapy in Patients with AL Amyloidosis: 1-Year Results from an Open-Label Phase 2 Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 468-468
Author(s):  
Jason Valent ◽  
Jeffrey A. Zonder ◽  
Michaela Liedtke ◽  
John Silowsky ◽  
Michael R. Kurman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Plasma Cell ◽  
Amyloid Fibrils ◽  
Renal Involvement ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis ◽  
Phase 2 ◽  
Open Label ◽  
Advisory Committees ◽  
Phase 2 Trial

Abstract Background: AL amyloidosis, a rare, severe, progressive, systemic disorder caused by plasma cell dyscrasia (PCD), results in insoluble immunoglobulin light chain amyloid fibrils depositing in organs and causing significant dysfunction, morbidity, and mortality. Most patients receive anti-PCD therapy as standard of care (SOC) to suppress plasma cell proliferation and arrest the generation and deposition of new amyloid fibrils. At present, no approved therapies exist that target fibrils already deposited. CAEL-101, a monoclonal antibody, binds to amyloid light chain fibrils and promotes removal from tissues. In this Phase 2 trial, patients were treated with doses up to 1000 mg/m 2, combined with SOC, demonstrating this dose was well tolerated and appropriate for Phase 3. Aim: Evaluate long-term safety and tolerability of CAEL-101, administered with SOC in AL amyloidosis. Methods: Adult patients with confirmed AL amyloidosis diagnosis (Mayo Stages I, II, IIIa), 6-month minimum life expectancy, and measurable hematologic disease were eligible for this ongoing, open-label, phase 2 study (NCT04304144). Patients with other forms of amyloidosis, multiple myeloma, supine systolic blood pressure &lt;90 mm Hg, or symptomatic orthostatic hypotension were excluded. All patients received CAEL-101 1000mg/m 2 every other week with SOC anti-PCD therapy until investigator decided anti-PCD was no longer needed (Figure). Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory tests, electrocardiograms, vital signs, and physical examinations. Pharmacokinetic endpoints included maximum serum concentration (C max) and minimum serum concentration of CAEL-101 prior to next dose (C trough). Exploratory endpoints included biomarkers for cardiac function (cardiac troponin T [cTnT] and N-terminal pro-brain natriuretic peptide [NT-proBNP]), and renal function (estimated glomerular filtration rate and proteinuria). Results: The 25 patients averaged 65.2 years (range 47 to 80), with the majority male (72.0%). Mayo Stages I (8.0%), II (76.0%), and IIIa (16.0%) reflected the wide range of disease severity in enrolled patients ; 19 (76.0%) presented with cardiac involvement, 8 (32.0%) with renal involvement, and 20 (80.0%) had received prior anti-PCD therapy. Twenty-four (96.0%) patients experienced TEAEs, but only 6 (24.0%) experienced a possibly treatment related TEAE (Table). Eight (32.0%) patients experienced at least 1 Grade ≥3 TEAE and 7 (28.0%) experienced at least 1 serious adverse event. There were 3 (12.0%) discontinuations; 1 death due to septic pneumonia (investigator determined not related to CAEL-101), one heart transplant, and one patient who withdrew consent. Most common TEAEs included nausea (9 [36.0%]], constipation (8 [32.0%]), and diarrhea, fatigue, or rash (7 [28.0%] each). Addition of daratumumab (n = 12) to the anti-PCD combination treatment of cyclophosphamide-bortezomib-dexamethasone (CyBorD) did not alter the pharmacokinetic or tolerability profile of CAEL-101. Of the 19 current cardiac evaluable patients (baseline NT-proBNP ≥332 ng/L and ≥1 post-first-dose NT-proBNP value), 15 (78.9%) have responded (≥ 30% NT-proBNP decrease from baseline) or are stable on CAEL-101 therapy. Renal evaluable patients, as determined by Investigator at a single site, showed a similar proteinuria response. Discussion: This ongoing trial is evaluating the long-term safety and tolerability of CAEL-101 administered with anti-PCD SOC as a treatment to reduce amyloid burden in patients with cardiac AL amyloidosis. CAEL-101 was well tolerated when administered with anti-PCD therapy. Most TEAEs observed were mild to moderate in severity and did not require intervention. There were no meaningful differences in tolerability or exposure to CAEL-101 when daratumumab was added to the anti-PCD regimen. Improvements in cardiac and renal response biomarkers were observed in most patients presenting with cardiac or renal involvement, respectively, at study entry. Conclusion: After approximately 1-year, CAEL-101, as part of an AL amyloidosis treatment strategy, demonstrates to be well tolerated. This updated report confirms previous findings for the use of CAEL-101 in combination with anti-PCD. A Phase 3 clinical program is ongoing to further elucidate the efficacy and safety of CAEL-101. Figure 1 Figure 1. Disclosures Valent: Takeda Pharmaceuticals: Speakers Bureau; Amgen: Speakers Bureau; Caelum Biosciences: Other: Clinical Trial Funding; Celgene Corporation: Speakers Bureau. Zonder: Caelum Biosciences: Consultancy; Regeneron: Consultancy; Intellia: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy; BMS: Consultancy, Research Funding. Liedtke: Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees. Silowsky: Caelum Biosciences: Current Employment. Kurman: Caelum Biosciences: Other: Medical Monitor. Daniel: Caelum Biosciences: Current Employment. Jobes: Caelum Biosciences: Current Employment. Harnett: Caelum Biosciences: Current Employment. Raviwong: Caelum Biosciences: Current Employment. Spector: Caelum Biosciences: Current Employment. Sobolov: Caelum Biosciences: Current Employment.

scholarly journals Improved Outcomes of Autologous Hematopoietic Cell Transplantation (AHCT) for Light Chain (AL) Amyloidosis: A Center for International Blood and Marrow Transplant Registry (CIBMTR) Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 193-193 ◽  
Author(s):  
Anita D'Souza ◽  
Baldeep Wirk ◽  
Mei-Jie Zhang ◽  
Jiaxing Huang ◽  
Amrita Krishnan ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Plasma Cell ◽  
Light Chain ◽  
Conflicts Of Interest ◽  
Renal Involvement ◽  
Organ Involvement ◽  
High Dose ◽  
Al Amyloidosis ◽  
Karnofsky Performance Score ◽  
Renal Response

Abstract Background: Light chain (AL) amyloidosis is a rare plasma cell neoplasm associated with systemic amyloid deposition leading to organ dysfunction and death without treatment. The use of AHCT in AL amyloidosis remains controversial as a prospective randomized control trial suggested inferior outcomes when compared with standard chemotherapy, driven primarily by high peri-transplant mortality (TRM) up to 24%. Improved patient selection criteria, supportive care and risk-adapted therapy have reduced TRM in recent single center studies. We analyzed trends and prognostic factors associated with AHCT outcomes in AL amyloidosis patients. Methods: We identified 1532 AL amyloidosis patients who underwent AHCT following high dose melphalan (MEL) within 24 months of diagnosis between 1995 and 2012 from the CIBMTR database. A subset of patients with more complete level of research data reported between 2001 and 2012 was analyzed for multivariate analysis (n=354). The primary endpoints were day30 and day100 mortality, hematologic progression free survival (PFS), hematologic relapse/progression and overall survival (OS). Data regarding cardiac, renal, hepatic and neurologic amyloid involvement was collected. Hematologic and organ response and progression were defined based on the 2004 uniform consensus criteria. Results: The median age at transplant was 57 years, with 61% males. AHCT was performed within 6 months of diagnosis in 66% patients. Karnofsky performance score (KPS) was <80 in 14%, HCT-CI was ≥ 3 in 20% and 69% had a lambda isotype. Organ involvement included renal, cardiac, hepatic and autonomic nervous system involvement in 74%, 38%, 16% and 11% respectively. Coexistent myeloma (>10% bone marrow plasma cells) was seen in 14%. Progressively higher numbers of patients received AHCT from 1995-2000 (n=140) to 2001-2006 (n=595) and 2007-2012 (n=800). The majority were untreated pre-transplant (77%) while 8% received melphalan, 6% thalidomide and 4% each received lenalidomide and bortezomib based pre-AHCT therapy. The median CD34 cell dose infused was 4.4 X 106/kg cells (IQR 3.3-6.2). MEL dose reduction was common (60% received < MEL 180 mg/m2 and 38% < MEL 140 mg/m2). The median length of hospital stay was 17 days (IQR 13-23). The median follow-up of patients from the time of transplant was 61 months (range 3-145). Day100 response included hematologic complete response, CR (12%), partial response, PR (26%), stable disease, SD (23%), and renal response (12%) with an ultimate best response of hematologic CR (33%), PR (28%), SD (19%) and renal response in 31%. Table 1 shows day30 and day100 mortality and OS at 1, 3 and 5 years showing steady declines in mortality rates and improvements in survival in successive time cohorts. Figure 1 shows the 5 year OS in each of the time cohorts. On multivariate analysis, albumin ≥ 3 g/dl at diagnosis, KPS ≥80, pre-transplant anti-plasma cell therapy and MEL ≥180 mg/m2 were associated with lower hematologic relapse/progression. KPS ≥80 and predominant renal involvement were associated with superior hematologic PFS while KPS ≥80 and < 2 organ involvement correlated with OS. Table 1 Outcomes of AHCT in AL amyloidosis. Values are expressed as probabilities with 95% confidence intervals. 1995-2000 N=140 2001-2006 N=595 2007-2012 N=800 Day 30 mortality 11 (7-17) 5 (4-7) 3 (2-4) Day 100 mortality 20 (14-27) 11 (8-13) 5 (4-7) 1 year survival 75 (67-82) 85 (81-87) 90 (88-92) 3 year survival 64 (56-72) 72 (68-75) 83 (80-86) 5 year survival 55 (46-63) 61 (57-65) 77 (72-82) Conclusions: There has been a significant improvement in survival of AL patients after AHCT driven primarily by a reduction in early peri-transplant mortality. Limited organ involvement, higher KPS, use of pre-transplant therapy and higher dose melphalan conditioning contributed to superior outcomes. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Hyperdiploidy Is Rare in Patients with AL Amyloidosis – Identification of Major Cytogenetic Groups in Early Monoclonal Plasma Cell Disorders.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2823-2823 ◽  
Author(s):  
Tilmann Bochtler ◽  
Ute Hegenbart ◽  
Christiane Heiss ◽  
Axel Benner ◽  
Stephanie Pschowski-Zuck ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Multiple Testing ◽  
Conflicts Of Interest ◽  
Cell Clone ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis ◽  
Inverse Association ◽  
Chromosome 11 ◽  
Tree Model ◽  
Cytogenetic Aberrations

Abstract Abstract 2823 Poster Board II-799 AL amyloidosis (AL) is characterized by the deposition of amyloid fibrils in diverse tissues due to an underlying monoclonal plasma cell dyscrasia. In a previous study (Bochtler et al, Blood 2008) we have demonstrated that in AL cytogenetic aberrations were detectable in about 90% of patients (pts). Translocation t(11;14) proved to be the most frequent aberration in AL found in 45% of the pts. In this study we evaluated whether the concept of hyperdiploidy and non-hyperdiploidy as major pathogenetic pathways in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is also applicable to AL. Our study was based on the largest patient group tested for cytogenetics in AL thus far including 184 pts with AL - among them 21 pts with concomitant MM I. They were assessed for their ploidy status by interphase fluorescence in situ hybridization (FISH). 179 MGUS and MM I pts not requiring therapy served as controls. We used a well established score (Wuilleme et al, Leukemia 2005), which requires extra copies for at least two out of the three probes 5p15/5q35, 9q34 and 15q22 as criterion for hyperdiploidy. The hyperdiploidy frequency was very low in AL with 14% as compared to 32% in MGUS / MM I (p<0.001). Among AL pts those with a concomitant MM I displayed a higher hyperdiploidy frequency than those without (43% versus 10%, p<0.001) suggesting that chromosomal gains reflect progression of the monoclonal plasma cell clone. Addressing hyperdiploidy probes in detail, we could show that both in the 184 pts. with AL and 179 pts. with MGUS / MM I gains of 11q23, 17p13 and 19q13.3 closely clustered with the three hyperdiploidy defining probes 5p15/5q35, 9q34 and 15q22 (p'0.01 for all probes after adjusting for multiple testing). However, gain of 11q23 was also frequently detected in association with t(11;14). The group with gain of 11q23 subdivides into a t(11;14) positive and a hyperdiploidy positive subgroup in both the AL (p<0.001) and the MGUS / MM I (p<0.001) entities. As revealed by additional probes for 11p15 and 11cen, gain of 11q23 in hyperdiploid pts reflected a gain of the whole chromosome 11 in all tested pts (10 AL and 31 MGUS / MM I). On the contrary, gain of 11q23 in t(11;14) positive pts was merely due to the translocation involving chromosome 11 (with 25 out of 26 AL and 5 out of 7 MGUS / MM I pts displaying a normal diploid status for 11p15 and 11cen). Therefore, gain of 11q23 is a poor indicator of hyperdiploidy in AL, where t(11;14) frequencies are particularly high and hyperdiploidy frequencies are particularly low. Addressing the cytogenetic clustering of hyperdiploidy with other cytogenetic aberrations we observed a strong inverse association of hyperdiploidy with t(11;14) in both AL and MGUS / MM I (p<0.001 in both entities). Accordingly, both aberrations were allocated to branches separating from each other already at the root in the oncogenetic tree model (see figure 1). Del13q14/t(4;14) and IgH translocations with an unknown partner also separated as distinct branches early from the root. These similar clustering patterns of both AL and MGUS / MM I with 4 major cytogenetic groups suggests common pathogenetic mechanisms in both entities despite their differing hyperdiploidy and t(11;14) frequencies. Disclosures: No relevant conflicts of interest to declare.

CD81: A Novel, Specific and Highly Sensitive Marker in Flow Cytometric Diagnosis of Plasma Cell Dyscrasia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2880-2880
Author(s):  
Prashant Ramesh Tembhare ◽  
Constance Yuan ◽  
Neha Korde ◽  
Irina Maric ◽  
Katherine Calvo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Antigen Expression ◽  
Plasma Cell Dyscrasia ◽  
Fluorescent Intensity ◽  
Reliable Marker ◽  
Sensitive Marker

Abstract Abstract 2880 Background: The percent abnormal plasma cells (aPC) as determined by flow cytometry (FC) has been shown to be an independent risk factor for progression from myeloma precursor disease (monoclonal gammopathy of uncertain significance, MGUS; smoldering multiple myeloma, SMM) to multiple myeloma (MM). However, differentiation of aPCs from normal PCs (nPCs) in these patients is challenging. MM cell lines are know to underexpress the tetraspanin proteins (e.g. CD81, CD82) in comparison to nPCs. Although CD81, a nonglycosylated tetraspanin, is robustly expressed on the surface of nPCs, little information is available regarding its expression in the aPCs of MM, SMM and MGUS. In this study we evaluate the expression of CD81 in conjunction with CD19, CD45 and CD56 in bone marrow aPCs and nPCs from patients with MM, SMM and MGUS. Methods: Bone marrow aspirates from 41 patients (9 MGUS, 22 SMM, 7 MM, 3 non-neoplastic with clinical suspicion of MGUS) were analyzed with 8-color multiparametric FC using a panel of antibodies (CD138, CD38, CD19, CD20, CD27, CD28, CD45, CD56, CD81, CD13, CD14, CD16, CD3, CD34 and intracellular kappa & lambda light chains). The pattern of surface antigen and intracellular light chain expression was utilized to determine the percent aPC (defined as monoclonal with aberrant antigen expression) and percent nPC (defined as polyclonal with normal antigen expression). In all cases the pattern of antigen expression was evaluated in the aPCs; additionally, in cases with greater than 5% nPCs (19/41 patients: 8 MGUS, 8 SMM and 3 non-neoplastic) the pattern of antigen expression was evaluated in the nPCs. The ability to detect clonal aPC by evaluation of FC pattern of antigen expression was determined and compared for CD19, CD45, CD56 and CD81. We also examined the sensitivity and specificity of the CD19 and CD81 combination verses the conventional combination of CD19, CD56 and CD45 (Perez-Persona et al, Blood 2007) for the detection of clonal aPC. Results: CD81 was strongly expressed by nPC (average mean fluorescent intensity (MFI): 11500, standard deviation (SD): 5061, range: 5347–21657) in contrast to aPC with abnormally weak expression (average MFI: 1487, SD: 887, range: 647–4311). CD81 was a highly reliable marker for the detection of clonal PC; with 90% sensitivity and 100% specificity. It was the most specific and second most sensitive marker in our study (Table 1). CD81 was equally sensitive in detection of aPCs in MGUS, SMM and MM. Evaluation of the combined pattern of expression of CD19 and CD81 resulted in 100% sensitivity and 100% specificity for detection of aPC, which is greater than the conventional combination of CD19, CD56 and CD45, yielding 100% sensitivity but 90% specificity, for diagnostic evaluation of aPC. Conclusions: CD81 is a highly reliable marker in the detection of abnormal plasma cells in MM, SMM and MGUS. The combined approach of CD19 and CD81 is superior to other conventional marker combinations (i.e. CD19, CD45, and CD56) in terms of detection of clonal plasma cells and may replace their use in the clinical evaluation of bone marrow aspirates for plasma cell processes. Furthermore, it should help widening the applicability of minimal residual disease testing in MM. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact Of Comorbidity In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5340-5340 ◽  
Author(s):  
Rafael Ríos Tamayo ◽  
Joaquín Martínez López ◽  
Manuel Jurado ◽  
María Esther Clavero Sánchez ◽  
Fátima López Jiménez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
Liver Disease ◽  
Plasma Cell ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Prognostic Impact ◽  
Alcoholic Fatty Liver

Abstract Multiple myeloma (MM) is a heterogeneous disease. Evaluation of prognostic factors and risk stratification at diagnosis is necessary to compare outcome. Attempts have been made to apply a comorbidity score in the clinical sitting, but a standardized general approach is still lacking. We hypothesized that a comprehensive examination of every associated disease in a large cohort of patients could better highlight the prognostic impact of comorbidity in MM. All consecutive patients diagnosed in our institution, from 1993 to 2013, with symptomatic MM according to IMWG criteria were included in our population-based MM registry. Patients with plasma cell leukemia or with palliative management were excluded. Clinical variables analyzed were: age, sex, Durie-Salmon, International Scoring System (ISS), percentage of plasma cell in bone marrow by morphology (PC), serum creatinine (Cr) and estimated glomerular filtration rate according with Modification of Diet in Renal Disease (eGFR-MDRD). The following comorbodities were analysed: hypertension (HTA), diabetes (DM), obesity (OB) (body mass index > 30 Kg/m2), hyperlipaemia (HL), prior malignancy (PM), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), peptic ulcer (PU), thromboembolism (TE), renal transplant (RT), splenectomy (S), cutaneous disease (CD), amyloidosis (AM), heart disease (HD) (arrhythmia, congestive heart failure, coronary artery disease, other), lung disease (LD) (chronic obstructive pulmonary disease, asthma, other), liver disease (HE) (cirrhosis, non-alcoholic fatty liver disease, other), neurological disorder (ND), psychiatric disorder (PD) and rheumatologic disorder (RD). Kaplan-Meier method was used to estimate OS curves. Cox regression was used to determine the prognostic impact of each comorbidity in a univariate and multivariate model. 311 patients were eligible. Median age was 66 years (12-91), 148 men (47.6 %) and 163 women. Percentage of comorbidities was: HTA 45; OB 32.5; DM 20.4; HD 20.4; LD 15.2; PU 10; HL 9.7; ND 8; PM 7.8; PD 6.5; HBV 3.9; HE 3.9; TE 3.6; RD 3,5; AM 2.3; HCV 1.9; CD 1.6; S 1; RT 0.6; HIV 0.3. 63 patients (20.4 %) showed no comorbidities. Univariate analysis (table 1) demonstrated that AM (P=0.022), HCV (0.038), HIV (0.022), PD (0.015) and ND (0.05) were significantly associated with shorter OS. The variables associated with mortality in the multivariate analysis were age (p=0.002), ISS (III vs I: p=0.01), PC (p=0.05) and Cr (p=0.02). Results will be validated in another MM series and presented during the meeting. The overall prognosis of MM depends on a variety of host and disease-related characteristics. We confirm age, ISS, PC and Cr as robust and independent prognostic factors. Adjusting for these factors, no isolated comorbidity reach statistical significance; however, comorbidity seems to have a role in MM prognosis. More studies are warranted to define the prognostic impact of comorbidities in MM. Disclosures: No relevant conflicts of interest to declare.

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