Clustering of Prognostically Important Cytogenetic Aberrations in Multiple Myeloma with Translocation t(11;14)) (q13;q32)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3961-3961
Author(s):  
Luba Trakhtenbrot ◽  
Anfisa Stanevsky ◽  
Ilya Novikov ◽  
Merav Leiba ◽  
Arnon Nagler ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cluster Analysis ◽  
Odds Ratio ◽  
Strong Association ◽  
P Value ◽  
Kappa Statistics ◽  
Exact Tests ◽  
Cytogenetic Aberrations ◽  
Number Of Patients ◽  
1Q Gain

Abstract Abstract 3961 The prognostic value of the translocation t(11;14)(q13;q32) in patients (pts) with Multiple Myeloma (MM) is not fully resolved. Using FISH, t(11;14) can be identified in 15–20% of patients with MM and in 15–30% of cases with MGUS. The clustering of prognostically established cytogenetic aberrations (CAs), namely gains of 1q and deletions of 13q,17p, 1p, 16q, as well as deletions of IGH segments, was analyzed by combined morphology and FISH techniques in 94 MM and 8 MGUS pts carrying the t(11;14)(q13;q32) translocation. We used commercially available LSI CCND1, LSI IGH/CCND1, LSI IGH, LSI IGH/MAF and LSI 13 (RB1) probes (Vysis, Downers, Grove, IL)and p53 deletion and CKS1B/CDKN2C amplification/deletion probes (Cytocell Ltd., Cambridge, UK). CAs were not found in MGUS patients and in 37/94 MM patients (39.4%). In 57 MM patients one to five CAs were found: one in 14, two in 21, three in 13, four in 5 and five in 4 patients. The association between different CAs within the group with t(11;14) translocation were studied using the kappa statistics, Odds Ratio and Fisher exact tests. We did cluster analysis of the binary variables (presence/absence) of each of CAs using median linkage with Yule measure of similarity. The Yule measure Y for two aberrations is defined as (ad-bc)/(ad+bc), where “a” is the number of patients with both aberrations, “d” is the number of patients with no one of the two aberrations, and “b” and “c” are the numbers of persons with only one of the aberrations. All calculations were done with STATA 12 SE software. A strong association was found between four CAs: del(13q), del (IGH), del(17p) and del(16q). A high correlation was also found between 1q gain and 1p loss, while correlation of these CAs with the other four CAs was not detected (Tab.1). Cluster analysis led to the identification of a cluster including del(13q), del (IGH), del(17p) and del(16q), while 1p loss and 1q gain were identified as a separate cluster. The apparently close connection between CAs from the same cluster raises the question whether these aberrations occur concurrently as the result of a single oncogenic event. It is possible to suggest that in the oncogenesis of MM with t(11;14) the formation of these clusters is not related and results from different oncogenic events. In conclusion we were able to demonstrate the strong association between del(13q), del (IGH), del(17p) in MM with translocation t(11;14) using a combination of morphology and FISH analyses, that was overlooked in previous investigations. The study of association between CAs additional to t(11;14) in MM patients is important for evaluating the prognostic significance of the combination of CAs and can provide insights into the biology of MM. Table 1. Chi-square exact tests and odds ratio (OR) test for the analysis of coexistence of different CAs Number in pairs* Fisher' P-value CA #1 CA#2 −/− +/− −/+ +/+ Kappa/p-value OR(95%CI) del(13q) del (IGH) 58 7 2 35 0.8145 (<0.0001) 145 (28.5–737.5) <0.001 del(13q) del(17p) 59 35 1 7 0.1797/0.0028 11.8 (1.39–99.95) 0.008 del(13q) loss 1p 55 40 5 2 −0.0408/0.7587 0.55 (0.102–2.98) 0.697 del(13q) gain 1q 51 29 9 13 0.1718/0.0269 2.54 (0.87–7.56) 0.085 del(13q) del(16q) 55 26 5 16 0.3218/0.0879 6.77 (2.04–25.7) <0.001 del (IGH) del(17p) 63 31 2 6 0.1581/0.0088 6.1 (1.16–31.97) 0.025 del (IGH) loss 1p 62 33 3 4 0.0751/0.1170 2.5 (0.53–11.87) 0.252 del (IGH) gain 1q 55 25 10 12 0.1868/0.0221 2.64 (0.9–7.75) 0.078 del (IGH) del(16q) 60 21 5 16 0.392/<0.0001 9.14 (2.7–35.1) <0.001 del(17p) loss 1p 87 8 7 0 −0.079/0.7881 – 1.0 del(17p) gain 1q 76 4 18 4 0.1713/0.0208 4.22 (0.7–24.57) 0.064 del(17p) del(16q) 76 5 18 3 0.1053/0.1083 2.53 (0.36–14.31) 0.356 loss 1p gain 1q 78 2 17 5 0.2687/0.0004 11.47 (1.65–125.5) 0.005 loss 1p del(16q) 76 5 19 2 0.0445/0.2942 1.6 (0.14–10.68) 0.631 gain 1q del(16q) 67 13 14 8 0.2045/0.0194 2.95 (0.87–9.40) 0.070 * Absence(−)/Presence(+) of CA#1/CA#2. Disclosures: Nagler: medac, germany: Research Funding.

Interrelation of 5q-Deletions and Mutations of TP53 in Patients with Myelodysplastic Syndromes and Complex Aberrations

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-7
Author(s):  
Christina Ganster ◽  
Lea Naomi Eder ◽  
Katayoon Shirneshan ◽  
Katharina Rittscher ◽  
Paolo Mazzeo ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Nature Medicine ◽  
Strong Association ◽  
Snp Array ◽  
P Value ◽  
Entire Cohort ◽  
Cytogenetic Aberrations ◽  
Two Factors ◽  
Tp53 Locus

Introduction: Cytogenetic changes occur in 50% of patients (pts) with Myelodysplastic Syndromes (MDS). Complex aberrations (cA, = 3 or more) are associated with a very poor outcome. In about 50% of the cases with cA aberrations of the TP53 locus are detectable. Those pts show an even worse outcome with a significantly shortened median overall survival (OS) compared to pts with wildtype TP53 (wtTP53). One of the most common cytogenetic aberrations in MDS is an interstitial deletion of the long arm of chromosome 5 (5q). As an isolated aberration, it is associated with a rather favorable prognosis. As part of a cA, 5q deletions however are assumed to even worsen the prognosis further. We wanted to find out in which prevalence 5q deletions and TP53 changes appear together and how those two factors in combination or not influence the OS of pts with MDS and cA. Methods: 218 pts with MDS or sAML and cA were identified and extensively characterized. 126 of them were diagnosed with MDS, 89 with sAML and 3 with CMML. Cytogenetic analysis by chromosome banding (CBA) and fluorescence in situ hybridization (FISH) of the TP53 locus on 17p as well as sequencing of TP53 either by Sanger or by Next Generation Sequencing was available for all pts. Multicolour FISH (mFISH) was available for 146 pts, SNP array analysis for 42 pts. The median number of cytogenetic aberrations was 8 (range 3-50). At the time of first diagnosis with cA the median age was 72 (range: 29-95). Median OS of the entire cohort was 10.7 months (95% CI: 8.0-16.4). Results: In 146 of 218 pts we found alterations of TP53: a single hit mutation in 32 pts, a single deletion in 22 pts, a combined mutation and deletion in 67 pts and more than 1 mutation in 25 pts. The OS of those 146 pts was 6.6 months compared to 22 months of the pts with wtTP53 (p-value &lt;0.0001). In 161 of 218 pts we found deletions of 5q (del(5q)). The median OS of those pts was significantly shorter than those of pts without del(5q) (8.4 vs. 20 months, p-value 0.001). 130 of 218 pts both had a del(5q) and an alteration of TP53, 31 pts only had a del(5q) and wtTP53 and 16 pts showed different types of TP53 alterations without del(5q). The median OS of pts with TP53 multi hit status as defined by Bernard (Bernard et al., Nature Medicine 2020) was 6.6 months, 5.3 months in pts with single hit TP53 mutations and a del(5q) and 21.6 months in pts, with wtTP53 and del(5q) (p-value = 0.0025, figure 1). Conclusion: Mutations and/or deletions of TP53 show a strong association with del(5q). Both were frequent in our cohort of 218 pts with MDS and cA. There also was a large intersection of 130 pts with both del(5q) and TP53 alteration. The combination of both changes seems to further worsen the already poor prognosis of pts with MDS and cA. Our observation that those two factors appear together frequently supports the hypothesis that the presence of del(5q) may promote the acquisition of cA. This is in accordance with Hsu´s hypothesis that in small clones with a mono-allelic TP53 mutation a del(5q) may favor the loss of heterozygosity of TP53 which could in a next step lead to a higher complexity of cytogenetic aberrations (Hsu et al, 2019). It is remarkable that the presence of del(5q) in combination with a single hit status of TP53 confers the same bad prognosis compared to multi hit TP53 status (figure 1).We will continue analyzing pts with MDS and cA to examine the influence of different TP53 and 5q alterations on the prognosis, the disease progression and median OS of those pts with cA. Figure 1 Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

scholarly journals Initial experience with novel CGRP-receptor inhibitor therapy in Migraine in the United Arab Emirates: a retrospective observational study

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bui Bao Khanh Dinh ◽  
Waseem Hamed Aziz ◽  
Alessandro Terruzzi ◽  
Derk Wolfgang Krieger
Keyword(s):  
Observational Study ◽  
Odds Ratio ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Real Life ◽  
Retrospective Observational Study ◽  
Lower Probability ◽  
P Value ◽  
Cgrp Receptor ◽  
Number Of Patients

Abstract Background Erenumab is a calcitonin gene-related peptide (CGRP)-receptor antibody inhibiting CGRP function. CGRP is prominently involved in the pathophysiology of migraine through nociceptive modulation in the trigeminovascular system. This study aims to explore the treatment effect of erenumab in a real-life setting. Methods In this retrospective observational study, we analyzed the data of 91 patients with migraine receiving at least three consecutive monthly injections of erenumab and followed up for 3–12 months. The primary objective was to describe the reduction in monthly migraine days throughout the follow-up period. To identify patients who responded to treatment, we analyzed the association between different patient characteristics and their treatment outcomes. Results Seventy-three patients (80.2%) responded to erenumab treatment, defined as ≥50% reduction of migraine days per month, across all migraine types. It was noted that ethnicity (p-value = 0.015) and older age (p-value = 0.035) were associated with clinically relevant improvement of symptoms. Middle Eastern ethnicity was related to less improvement of symptoms while Europeans were more likely to benefit from erenumab therapy (odds ratio: 12.788, p = 0.037). Patients aged from 31 to 40 and 41–65 years benefited most from erenumab treatment with a response rate of 77.8 and 89.9%, respectively, also confirmed by logistic regression (p = 0.047). Neither gender nor dose increase of erenumab showed association with the reported clinically relevant improvement of the symptoms. An association between clinically relevant improvement of headaches and the type of migraine was also noted. Around 87.9% of patients with episodic migraine responded to treatment, followed by 84.1% of chronic migraine patients and 50% of medication overuse headache patients. Medication overuse headache showed a lower probability of therapy success with erenumab (odds ratio: 0.126, p = 0.039). An improvement of headaches was eminent in patients who received 140 mg erenumab monthly (2 × 70 mg injections) and patients who had one injection every two weeks. Conclusions Erenumab is a novel preventive treatment for all migraine types. Clinically relevant improvement of headaches and reduction of monthly migraine days were demonstrated in patients that continued the treatment course. In real-life, a substantial number of patients suspended therapy early, reasons for which need further investigation.

scholarly journals Original Versus Generic Lenalidomide in Patients with Relapsed Multipl Myeloma: Comprasion of Effectivity and Adverse Events

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5594-5594
Author(s):  
Zahit Bolaman ◽  
Sehmus Ertop ◽  
Atakan Turgutkaya ◽  
Selim Cem ◽  
Ayse Hilal Eroglu Kucukerdiler ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Adverse Events ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Muscle Cramp ◽  
P Value ◽  
Medicine Department ◽  
School Of Medicine ◽  
Number Of Patients

Original versus generic lenalidomide in patients with relapsed multipl myeloma: Comprasion of effectivity and adverse events Ali Zahit Bolaman1, Sehmus Ertop2 Atakan Turgutkaya1, Cem Selim, 1 Ayse Hilal Eroglu Kucukerdiler1, Birsen Sahip2, Irfan Yavasoglu1. 1 Adnan Menderes University, School of Medicine, Department of Hematology AYDIN/TURKEY 2 Bulent Ecevit University School of Medicine, Department of Hematology ZONGULDAK/TURKEY Backround: Lenalidomide is an effective IMID derivative drug in the treatment of patients with multiple myeloma. Lenalidomide is available as original and generic forms in our country. So far, there is no any clinical study comparing generic and original lenalidomine for effectivity and adverse events. We compared generic and original lenalidomide effects and adverse events (AEs) in patients with relapsed multiple myeloma (RMM). Methods: The patients with RMM using original or generic lenalidomide were evaluated as retrospectively. Overall response (OR), complete response (CR), very good partial response (VGPR), partial response (PR), stable disease and progressive disease rates and also for adverse events, development rates of neutropenia, anemia, thrombocytopenia, febrile neutropenia, anorexia, constipation diarrhea, nausea, vomiting, creatinine increase, transaminase increase, asthenia, fatigue, pyrexia, peripheral edema, upper respiratory system infection, pneumonia, another infection, muscle cramp, back pain, bone pain, muscle weakness, arthralgia, headache, tremor, paresthesia, deep vein thrombosis, pulmonary embolism, hyperglycemia, hypokalemia, hypocalcemia, hypomagnesaemia, skin dry and skin erythema were investigated in myeloma patients. All data were analyzed using the PASW for Windows version 19.0 (SPSS Inc., Chicago, IL, USA). The results were described as a number, frequency, and percentage. The chi-squared test and Fisher's exact test were used for the analysis of categorical data and independence between variables. The results were assessed at 95% confidence interval and p-value of less than 0.05 was accepted as significant. Results: The number of patients using original lenalidomide was 55 and the number of patients using generic lenalidomide was 43. OR rate was 60 % versus 39.5% in patients using original and generic lenalidomide, respectively. CR rate was 14.5%, VGPR was rate 45.4% in original group while CR rate was 20.9 and VGPR 18.6 in patients using generic lenalidomide. AEs were low in original lenalidomide group than generic group. AEs were usually grade 1 or 2. Response and AEs rates are shown in Table 1. Conclusion: Our study showed original and generic forms of lenalidomide are effective for the treatment of RMM. OR rate was higher in original lenalidomide than generic lenalidomide. The AEs of original lenalidomide were lower than generic lenalidomide without statistically significance. Further studies involving a larger number of patients with RMM would be useful for comparing the efficacy and AEs of original or generic lenalidomide. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bortezomib administration is a risk factor associated with the development of tumor lysis syndrome in male patients with multiple myeloma: A retrospective study

2020 ◽  
Author(s):  
Masahiro Kondo ◽  
Yuji Hotta ◽  
Karen Yamauchi ◽  
Akimasa Sanagawa ◽  
Hirokazu Komatsu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Odds Ratio ◽  
Tumor Lysis Syndrome ◽  
Low Risk ◽  
Primary Therapy ◽  
Novel Therapies ◽  
Tumor Lysis ◽  
Number Of Patients ◽  
Increased Risk

Abstract Background Many novel medicines such as proteasome inhibitors have been developed during the last decade to treat multiple myeloma. Although multiple myeloma is defined as a low-risk disease for developing tumor lysis syndrome (TLS), treatment with these novel therapies might increase TLS risk. In fact, there have been some prior reports of bortezomib-induced TLS in patients with multiple myeloma. However, almost all of them have been case reports or case series. Thus, we investigated the risk factors for TLS in multiple myeloma patients. Methods We retrospectively investigated incidences of laboratory and clinical TLS (LTLS and CTLS, respectively) in patients who received primary therapy for treatment-naive, symptomatic multiple myeloma between May 2007 and January 2018. We used multivariate logistic regression analyses to evaluate the associations between LTLS and several parameters previously reported to be associated with increased risk. Results This study included 210 patients, seventeen (8.1%) and seven (3.3%) patients with LTLS and CTLS, respectively. The characteristics of the administered anticancer or prophylactic antihyperuricemic agents were similar between the patients with and without LTLS. Multivariate analyses revealed that LTLS was most strongly associated with bortezomib-containing therapy (odds ratio = 3.40, P = 0.069), followed by male sex (odds ratio = 2.29, P = 0.153). In a subgroup analysis focused on men, treatment with bortezomib-containing therapy was significantly associated with increased risk of LTLS (odds ratio = 8.51, P = 0.046). Conclusion In the present study, we investigated the risk factors for developing TLS in 210 multiple myeloma patients, which, to the best of our knowledge, is the largest number of patients reported to date. Furthermore, this study is the first to evaluate TLS risk factors in MM by adjusting for the effects of potential confounding factors in patients’ backgrounds. Consequently, we found that bortezomib-containing therapy increases the risk of TLS in male multiple myeloma patients. TLS risk should be evaluated further in low-risk diseases such as multiple myeloma, as an increasing number of novel therapies can achieve high antitumor responses.

Doxil, Vincritine, Reduced Frequency Dexamethasone in Combination with Thalidomide (DVd-T) Is Associated with Higher Overall and Progression Free Survival as Compared to DVd in Patients with Multiple Myeloma (MM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2557-2557 ◽  
Author(s):  
Khaldoun Almhanna ◽  
Revathi Suppiah ◽  
Rachid Baz ◽  
Mary Ann Karam ◽  
Beth Faiman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow Involvement ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Disease Stage ◽  
P Value ◽  
Free Survival ◽  
Number Of Patients

Abstract Background: Although initially responsive to chemotherapy, multiple myeloma ultimately relapses. Replacing Adriamycin with pegylated liposomal doxorubicin in the VAD regimen results in a regimen with better safety profile (less neutropenia, alopecia, fewer hospital and clinic visit). DVd resulted in normalizing the angiogenic process however this did not improve PFS or OS. Thalidomide because of its antiangiogenic, immunomodulatory effects and chemo-sensitizing activity through modulating integrins was added to the DVd regimen. Adding the thalidomide to the DVd regimen resulted in an overall response rate of 89% with a CR/NCR rate of 49 % as compared to 60% and 18 % respectively for the DVd. At this stage it is not clear if the quality of response affects outcome in multiple myeloma patients receiving conventional dose therapy. To better assess the prognostic implication of improved quality responses and to define the role of up front Thalidomide, we compared the DVd to the DVd-T regimen by retrospectively reviewing the two trial data, the follow up for both trials is mature. It is still not clear whether thalidomide is more appropriately used up front or in the management of relapse. Methods: we recruited a total of 68 patients in our DVd trial versus 105 patient in the DVd-T trial. A total of 155 patients in both groups were evaluable for follow-up and response (58 received DVd and 97 received DVd-T). Patients were matched for age, disease prognosticators, disease stage, and bone marrow involvement. The newly diagnosed patients were comparable in both groups except for the b 2 microglobulin which was higher in the DVd-T group as compared to the DVd (3.2 vs. 5.0; respectively. p0.05). In the relapsed/refractory group of patients, all variables were comparable. Results: The median follow up was 5 years for the DVd group and 2 years for the DVd-T group. Median age for the DVd was 62 years, which was similar to the DVd-T. For the DVd vs. the DVd-T group of patients achieving complete and near complete remission was 17% vs. 49.5% respectively with a p value of 0.001. Progression free survival was significantly longer for the DVd-T regimens vs. the DVd (28 vs. 13 months p= 0.0002) Figure 1., and for over all survival the median is not reached for the DVd-T vs. 28 months for he DVd (p=0.006). Conclusion: we conclude that the addition of thalidomide significantly improved the quality of response and this appears to translate in to a PFS and OS benefit. While, recently published SWOG data suggests that the overall survival is determined by the duration of the PFS and not the quality of the response, this discrepancy could be related to the small number of patients in our study or the lack of use of biologic immune modulators among SWOG patients. Figure Figure

Spectrum of Cerebrovascular Disease in Multiple Myeloma Patients Undergoing Chemotherapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5498-5498
Author(s):  
Archana Hinduja ◽  
Kaustubh Limaye ◽  
Rahul Ravilla ◽  
Appalanaidu Sasapu ◽  
Xenofon Papanikolaou ◽  
...  
Keyword(s):  
Risk Factors ◽  
Atrial Fibrillation ◽  
Multiple Myeloma ◽  
Odds Ratio ◽  
Small Vessel Disease ◽  
Stage I ◽  
P Value ◽  
Medical Sciences ◽  
Vessel Disease ◽  
Ischemic Attack

Abstract Introduction: The objective of study was to determine the risk factors, stroke mechanisms and outcome following a stroke in Multiple myeloma (MM) patients. Materials and Methods: We conducted a matched cohort study from a prospective database of MM patients enrolled in TT2, TT3A, TT3B protocols who developed a vascular event (transient ischemic attack, ischemic stroke and intracerebral hemorrhage) from 1998 to 2014 with age, sex and treatment matched controls. Comparison of baseline demographics, risk factors, myeloma characteristics, laboratory values and mortality between both groups was performed using Pearson's Chi-square test for categorical variables and student T test for continuous variables. Multivariate logistic regression analysis was performed to identify risk factors associated with stroke. For statistical analysis SAS 9.4 software was used and p value of ≤ 0.05 was considered significant. Strokes were classified using the modified Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Results: Of 1148 patients, 46 developed a vascular event (Ischemic stroke (TIA)-33, Transient ischemic attack-11, Hypertensive intracerebral hemorrhage-2). On univariate analysis, predictors of stroke were a positive smoking history (26.1% vs 13% p=0.0381), renal insufficiency (23.9% vs 8.0% p=0.0039), hemodialysis (10.9 vs 0.7% p=0.004) and MM Stage I and II as opposed to Stage III (Stage I - 23.9% vs 9.4%, Stage II - 17.4% vs 12.3, Stage III - 58.7% vs 78.3% p=0.025). Despite the lack of significant difference in the baseline laboratory values between both groups, among the cases, there was a significant decrease in the platelet count (112.6 vs 255.2, p<0.0001) and elevation in INR (1.25 vs 1.08, p=0.0096) during the vascular insult when compared to their baseline values. On multivariate analysis, independent predictors of stroke were renal insufficiency (Odds Ratio, 3.528, 95% CI, 1.36-9.14; p=0.0094) and MM Stage I and II (Odds Ratio, 2.770, 95% CI, 1.31-5.81; p=0.0073). The ischemic strokes subtypes were: Large vessel disease 6%, cardioembolic 18%, small vessel disease 21%, other known etiologies 49% (hypercoaguable state; watershed; others) and cryptogenic in 6%. Following ischemic event, antiplatelet agents were used in 16 patients, anticoagulation in 7 patients but 23 patients were ineligible for both due to thrombocytopenia. In our cohort, 78% were discharged home or rehabilitation facility, 4% were transferred to long-term nursing facility and in hospital mortality was 15%. Conclusion: In MMpatient'srenal insufficiency andMM Stage I and II were associated with increased stroke risk. Besides hypercoagulability other mechanisms like atrial fibrillation, watershed strokes and small vessel disease played major role. Table 1.Demographic and disease characteristics of multiple myeloma patients experiencing a stroke compared to controlsVariableStroke (N=46)No Stroke (N=138)p-valueAge [mean (sd)]60.6 (7.7)60.7 (7.8)0.8960Female50.0 (23)41.6 (57)0.3023Race Caucasian95.7 (44)90.6 (125)0.3635#Hypertension54.4 (25)43.5 (60)0.2003HPL33.3 (15/45)26.1 (36)0.3464Diabetes17.4 (8)9.4 (13)0.1409CAD10.9 (5)10.9 (15)>0.99CHF4.4 (2)8.7 (12)0.5237AFIB17.4 (8)9.4 (13)0.1409Smoking26.1 (12)13.0 (18)0.0381ETOH2.2 (1)1.5 (2)>0.99Malignancy8.7 (4)16.1 (22/137)0.2159Nephropathy23.9 (11)8.0 (11)0.0039Hemodialysis10.9 (5)0.7 (1)0.0040Protocol TT2 TT3A TT3B54.4 (25) 32.6 (15) 13.0 (6)57.2 (79) 21.0 (29) 21.7 (30)0.3036MM Stage I II III23.9 (11) 17.4 (8) 58.7 (27)9.4 (13) 12.3 (17) 78.3 (108)0.0182MM Isotype IgG IgA FLC-κ FLC-λ Other58.7 (27) 21.7 (10) 8.7 (4) 10.9 (5) 049.3 (68) 24.6 (34) 10.1 (14) 10.9 (15) 5.1 (7)0.6128MM Risk [mean (sd)] Death-0.13 (0.61; N=37) 65.2(30)0.09 (0.67; N=88) 51.5(71)0.0941 0.19OSA: Obstructive sleep apnea, CAD: coronary artery disease, CHF: Congestive heart failure, AFIB: Atrial fibrillation, HPL hyperlipidemia. Table 1. Results on multivariable logistic model Variable Odds Ratio 95% CI p-value Nephropathy 3.528 1.36 to 9.14 0.0094 MM Stage I or II 2.770 1.31 to 5.81 0.0073 Disclosures Hinduja: University of Arkansas for Medical Sciences: Employment. Limaye:University of Arkansas for Medical Sciences: Employment. Ravilla:University of Arkansas for Medical Sciences: Employment. Sasapu:University of Arkansas for Medical Sciences: Employment. Waheed:University of Arkansas for Medical Sciences: Employment.

The Chronic Kidney Disease-Epidemiology Collaboration-Cystatin C (CKD-EPI-CysC) Equation Has an Independent Prognostic Value for Overall Survival in Newly-Diagnosed Patients with Symptomatic Multiple Myeloma: Comparison with 3 Other Equations for GFR Estimation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1849-1849
Author(s):  
Meletios A Dimopoulos ◽  
Efstathios Kastritis ◽  
Eirini Katodritou ◽  
Anastasia Pouli ◽  
Eurydiki Michalis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Cystatin C ◽  
Prognostic Value ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
P Value ◽  
Newly Diagnosed ◽  
Number Of Patients ◽  
Ckd Stage

Abstract Abstract 1849 Renal impairment (RI) is a frequent complication in multiple myeloma (MM). The estimation of glomerular filtration rate (GFR) is based on equations that use serum creatinine (sCr) as a marker of RI (i.e. MDRD or CKD-EPI). The IMWG has recommended the use of the MDRD formula for the estimation of GFR in MM patients with stabilized sCr, while the classification of RI is based on the 5 stages of the KDIGO classification (Dimopoulos et al, JCO 2010;28:4976–84). However, the equations based on sCr are imprecise and thus novel markers of renal injury have been used in patients with renal damage, including cystatin-C (CysC). CysC is considered as a more sensitive marker of GFR than sCr. Recently, the CKD-EPI investigators have reported that a combined sCr-CysC (CKD-EPI-sCr-CysC) equation correlated better with GFR than equations based on either of these markers alone (CKD-EPI or CKD-EPI-CysC; Inker et al, NEJM 2012;367:20–9). Although cysC has been reported by our group to be elevated in MM patients, the CKD-EPI equations and their value on MM patients' survival have never been evaluated. Therefore, we studied 220 newly-diagnosed, previously untreated, symptomatic MM patients. The median age was 69 years (range: 36–94 years) and 16% had sCr ≥2 mg/dl. Serum CysC was measured on the BN ProSpec analyser using a latex particle-enhanced nephelometric immunoassay (Dade Behring-Siemens Healthcare Diagnostics, Liederbach, Germany). Serum CysC was increased in MM patients compared to 52 age- and gender-matched controls [median: 1.07 mg/l vs. 0.72 mg/l, p<0.0001]. The median values for eGFR calculated by the MDRD, CKD-EPI, CKD-EPI-CysC and CKD-EPI-sCr-CysC equations were 63.45 ml/min/1.73m2, 68.13 ml/min/1.73m2, 68.11 ml/min/1.73 m2, and 64.87 ml/min/1.73 m2, respectively (p<0.01). Patients were divided in the 5 CKD stages of KDIGO classification, according to eGFR (stage 1: eGFR >90 ml/min/1.73 m2; stage 2: 60–89 ml/min/1.73m2; stage 3: 30–59 ml/min/1.73 m2; stage 4: 15–29 ml/min/1.73 m2; stage 5: <15 ml/min/1.73 m2 or on dialysis). For each studied equation, the number of patients with RI stage 3–5 (i.e. eGFR <60 ml/min/1.732) was 39.5% for MDRD vs. 42.2% for CKD-EPI vs. 43.1% for CKD-EPI-CysC vs. 45% for CKD-EPI-sCr-CysC (p<0.01; see also the table). Concordance for CKD stage allocation for the 4 equations of estimating eGFR was 97% for MDRD vs. CKD-EPI, 60% for MDRD vs. CKD-EPI-CysC and 84% for MDRD vs. CKD-EPI-sCr-CysC. A significant correlation was found between ISS stage and all studied equations (p<0.01 for all). The median overall survival (OS) for all patients was 52 months. In the univariate analysis per CKD stage, the 4 equations could predict for OS (the higher CKD stage had poorer survival) with the following significance: MDRD (p=0.057), CKD-EPI (p=0.01), CKD-EPI-CysC (p<0.0001), and CKD-EPI-sCr-CysC (p=0.006). When we tested the 4 equations as continuous variables, all had prognostic value for OS but the CKD-EPI-CysC had the strongest prognostic value (p<0.0001 and Wald=24.0 vs. p<0.0001 and Wald=19.7 for CKD-EPI-sCr-CysC, p=0.003 and Wald=8.9 for CKD-EPI and p=0.005 and Wald=7.7 for MDRD). In the multivariate analysis, that included ISS stage, LDH ≥300 U/l and eGFR for each different equation (as a continuous variable) only eGFR that included CysC but not sCr (CKD-EPI-CysC and not CKD-EPI-sCr-CysC) had independent significance (p=0.013) along with high LDH (p=0.029). Our data suggest that the CKD-EPI-sCr-CysC equation for the estimation of GFR detects more MM patients with stage 3–5 RI than the MDRD, CKD-EPI or CKD-EPI-CysC equations. However, CKD-EPI-CysC was the only equation that could predict for OS, possibly due to the very strong correlation of CysC with ISS (as myeloma cells produce CysC also). The confirmation of these data will lead to the broader use of equations based on CysC (CKD-EPI-CysC with or without sCr) for the evaluation of RI in patients with MM, as it has been suggested for patients with several other renal disorders. Table. Evaluation of Renal Function Stage by Different Equations CKD stage MDRD equation CKD-EPI equation CKD-EPI-CysC equation CKD-EPI-sCr-CysC equation p-value 1 60 (27%) 57 (26%) 67 (30%) 44 (20%) 2 73 (33%) 70 (32%) 58 (26%) 77 (35% Friedman-test 3 53 (24%) 55 (25%) 57 (26%) 62 (28%) p<0.01 4 21 (9.5%) 25 (11%) 27 (12%) 24 (11%) 5 13 (6%) 13 (6%) 11 (5%) 13 (6%) Disclosures: No relevant conflicts of interest to declare.

Immunoglobulin Expression Is a Major Determinant Of Patient Sensitivity To Proteasome Inhibitors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1903-1903
Author(s):  
Brian B Tuch ◽  
Andrea Loehr ◽  
Jeremiah D Degenhardt ◽  
Kevin A Kwei ◽  
Jonathan J Keats ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Strong Association ◽  
Single Agent ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Training Data ◽  
P Value ◽  
Tumor Cell Death ◽  
Employment Equity ◽  
Equity Ownership

Abstract Several therapies for multiple myeloma are now approved and many more are in development, promising improved outcomes for patients with this incurable cancer. With expanding treatment options, however, comes a pressing need to pair each patient with the most efficacious and safe treatment. Proteasome inhibitors, such as carfilzomib and bortezomib, have become a standard therapy across all lines of multiple myeloma treatment. Despite extensive study, the mechanism of selective tumor cell death following proteasome inhibition is poorly understood. However, the uniquely high sensitivity of myeloma cells to proteasome inhibition, the uniquely high burden of protein (immunoglobulin) secretion these cells experience, and the key role of the proteasome in maintaining protein homeostasis, together point toward a unifying model in which protein load drives proteasome inhibitor sensitivity. This simple model is supported by published studies of murine and human myeloma cell lines (e.g., Meister et al. & Bianchi et al.). As part of company-sponsored Phase II & III clinical trials of proteasome inhibitors, CD138+ tumor cells collected during patient screening were banked for comprehensive genomic analyses. Patient samples banked on bortezomib trials were utilized in now-published microarray-based RNA studies, while samples from carfilzomib trials are currently being used for NGS-based DNA and RNA studies. Here, examining our early carfilzomib data along with publically-available bortezomib data, we find a strong association between higher immunoglobulin expression and sensitivity to each compound (Wilcoxon P-value = 3x10-3 and P-value = 2x10-4, respectively). In fact, using IGH expression alone, we are able to classify response with 55% sensitivity and 91% specificity in our carfilzomib training data. As expected for a bona fide predictive biomarker of proteasome inhibition, an association between IG expression and response was not found in patients treated with single agent dexamethasone (Wilcoxon P-value = 0.82). Median time to progression for IGH-high carfilzomib patients was 6-fold longer than for IGH-low carfilzomib patients (7.6 months vs. 1.4 months; log-rank P-value = 0.003). This is the first report that high levels of IG expression correlate with response to proteasome inhibitors and therefore IG expression represents, to our knowledge, the first validated biomarker for this important class of anti-tumor agents. Disclosures: Tuch: Onyx Pharmaceuticals: Employment, Equity Ownership. Loehr:Onyx Pharmaceuticals: Employment, Equity Ownership. Degenhardt:Onyx Pharmaceuticals: Employment, Equity Ownership. Kwei:Onyx Pharmaceuticals: Employment, Equity Ownership. Kirk:Onyx Pharmaceuticals: Employment, Equity Ownership.

scholarly journals Perioperative Outcomes of Major Noncardiac Surgery in Adults with Congenital Heart Disease

2013 ◽  
Vol 119 (4) ◽  
pp. 762-769 ◽  
Author(s):  
Bryan G. Maxwell ◽  
Jim K. Wong ◽  
Cindy Kin ◽  
Robert L. Lobato
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Odds Ratio ◽  
Congenital Heart ◽  
Noncardiac Surgery ◽  
Perioperative Outcomes ◽  
P Value ◽  
Perioperative Morbidity ◽  
Number Of Patients ◽  
Comparison Cohort

Abstract Background: An increasing number of patients with congenital heart disease are surviving to adulthood. Consensus guidelines and expert opinion suggest that noncardiac surgery is a high-risk event, but few data describe perioperative outcomes in this population. Methods: By using the Nationwide Inpatient Sample database (years 2002 through 2009), the authors compared patients with adult congenital heart disease (ACHD) who underwent noncardiac surgery with a non-ACHD comparison cohort matched on age, sex, race, year, elective or urgent or emergency procedure, van Walraven comborbidity score, and primary procedure code. Mortality and morbidity were compared between the two cohorts. Results: A study cohort consisting of 10,004 ACHD patients was compared with a matched comparison cohort of 37,581 patients. Inpatient mortality was greater in the ACHD cohort (407 of 10,004 [4.1%] vs. 1,355 of 37,581 [3.6%]; unadjusted odds ratio, 1.13; P = 0.031; adjusted odds ratio, 1.29; P &lt; 0.001). The composite endpoint of perioperative morbidity was also more commonly observed in the ACHD cohort (2,145 of 10.004 [21.4%] vs. 6,003 of 37,581 [16.0%]; odds ratio, 1.44; P &lt; 0.001). ACHD patients comprised an increasing proportion of all noncardiac surgical admissions over the study period (P value for trend is &lt;0.001), and noncardiac surgery represented an increasing proportion of all ACHD admissions (P value for trend is &lt;0.001). Conclusions: Compared with a matched control cohort, ACHD patients undergoing noncardiac surgery experienced increased perioperative morbidity and mortality. Within the limitations of a retrospective analysis of a large administrative dataset, this finding demonstrates that this is a vulnerable population and suggests that better efforts are needed to understand and improve the perioperative care they receive.

Bortezomib Alters Peripheral Blood Lymphocyte Subsets in Patients with Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2387-2387 ◽  
Author(s):  
Geoffrey L. Uy ◽  
Matthew S. Holt ◽  
Nicholas M. Fisher ◽  
Steven M. Devine ◽  
Michael H. Tomasson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Peripheral Blood Lymphocyte ◽  
Peripheral Blood ◽  
Blood Lymphocyte ◽  
Lymphocyte Subsets ◽  
Day Treatment ◽  
P Value ◽  
Number Of Patients ◽  
Long Term Treatment

Abstract Bortezomib (VELCADE®) is a potent inhibitor of the proteasome which exerts its antimyeloma effect in part by blocking the activation of NF-κB. As NF-κB is critical for lymphocyte development and survival, there is great interest in harnessing the potential immunomodulatory effects of bortezomib. In murine hematopoietic transplantation models, bortezomib inhibits in vitro mixed lymphocyte responses and promotes the apoptosis of alloreactive T cells protecting against acute graft-versus-host disease. However, no data exists on the in vivo effects of bortezomib on human T cells. To characterize the effects of bortezomib on immune function, we profiled peripheral blood lymphocytes subsets and T cell associated cytokines in 39 patients with multiple myeloma. Two cycles of bortezomib 1.3 mg/m2 were administered by intravenous infusion on days 1, 4, 8, and 11 of a 21-day treatment cycle. The patients had received prior induction chemotherapy and would proceed to autologous transplant following treatment with bortezomib. Study population consists of 23 male and 16 female patients with the median age of 56 years (range 38–69). Myeloma characteristics at diagnosis were as follows (number of patients): IgG (28), IgA (10), light chain only (1), with stage I (1), II (12), or stage III (26) disease. Peripheral blood was collected at baseline (cycle 1, day 1) and at one week after the last dose of bortezomib (cycle 2, day 18) and analyzed for lymphocyte subsets by standard multicolor flow cytometry. Th1 and Th2 serum cytokines were measured at the same timepoints using a multiplexed cytometric bead array (BD Biosciences). Following treatment with bortezomib, no significant changes were detected in either Th1 or Th2 serum cytokine levels: IL-2 (p=0.116), TNF-alpha (p=0.854), IFN-gamma (p=0.070), IL-4 (p=0.240), IL-6 (0.236), IL-10 (0.151) as analyzed by Wilcoxon signed ranks test. Analysis of lymphocyte subsets using a paired student’s T-test demonstrated a 38% decrease in CD56+ NK cells (p=0.02) and a 26% increase in CD4/CD8 ratio (p=0.0006) which appears to be secondary to a decrease in CD8+ cytotoxic T-cells (p=0.054). (Table 1.) In conclusion, we observe an alteration of lymphocyte subsets following only two cycles of bortezomib. Further analysis of the effects of long term treatment with bortezomib is warranted. These studies may provide insights into the role of bortezomib as an immunomodulatory agent. Peripheral Blood Lymphocyte Subsets Pre-bortezomib (/mm 3 ) Post-bortezomib(/mm 3 ) Difference(/mm 3 ) P-value CD2 1446 1259 −187 0.085 CD3 1273 1160 −113 0.28 CD4 842 802 −40 0.54 CD8 412 337 −75 0.055 CD19 90 94 4 0.86 CD20 87 95 8 0.78 CD56 206 148 −58 0.022 CD4/CD8 ratio 2.53 3.19 0.66 0.0006

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