scholarly journals Differences in the Original Diagnostic Markers Including the "CRAB" Criteria in Multiple Myeloma Patients from Different Ethnicities: A Single Center Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5673-5673
Author(s):  
Ahmad Hatem Mattour ◽  
Joshua Vollstaedt ◽  
Philip Kuriakose
Keyword(s):  
Multiple Myeloma ◽  
Conflicts Of Interest ◽  
Final Analysis ◽  
Epidemiological Studies ◽  
Study Data ◽  
Diagnostic Markers ◽  
Newly Diagnosed ◽  
Chi Square ◽  
Single Center Experience ◽  
Significant Difference

Abstract LEARNING OBJECTIVES: Determine if there are any differences in the original diagnostic markers, including the “CRAB” criteria, in Multiple Myeloma patients from different ethnicities. BACKGROUND: About 24,050 new cases of Multiple Myeloma are expected to be diagnosed in 2014. In a metropolitan institution, such as Henry Ford Hospital, newly diagnosed patients are drawn from multiple ethnic backgrounds. While several epidemiological studies have demonstrated a positive correlation between race and values of several diagnostic markers (such as hemoglobin, creatinine and albumin), most of the research focused on molecular and genetic, as opposed to clinical, differences in patients from multiple ethnicities. Our study, therefore attempted to offer a more customized diagnostic approach to patients with newly diagnosed Multiple myeloma, based on their ethnicity, and to determine if there was a correlation between the patients' races and common diagnostic elements, including the CRAB criteria, at time of diagnosis. METHODS: We conducted a retrospective study. Data from 300 patients over 5 years (2007-2012) with newly diagnosed with Multiple myeloma was collected. Only 197 patients fulfilled the diagnostic criteria and were included in the final analysis. The following data was extracted: Age at diagnosis, gender, diagnostic elements according to the CRAB criteria (serum Calcium, serum Creatinine, Anemia, Bone lytic lesions) at date of diagnosis, serum beta-2-microglobulin level, M-protein serum concentration, and whether Urine monoclonal protein excretion was present. The patients were divided into two groups by race: African American and Caucasian. An overall score was created by summing the incidence of each diagnostic marker. RESULTS: Categorical data was compared between the two groups using chi-square tests, and CRAB score was compared using a Wilcoxon rank-sum test due to its ordinal nature. Our study demonstrated that there were no statistically significant differences between the two groups in any of the components collected, or in the final total score CONCLUSIONS: Our study demonstrated that there was no statistically significant difference in the original diagnostic markers, including the CRAB criteria, in Multiple Myeloma Patients from Different Ethnicities presenting to our Institution.The effect of baseline cytogenetic characteristics on the diagnostic markers between multiple myeloma patients from different ethnicities is still not fully understood, and might be a factor that needs to be studied further. Disclosures No relevant conflicts of interest to declare.

TIMP-1 and TIMP-2 Levels Are Directly Correlated with Neoangiogenesis and Are Prognostic Factors in Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4866-4866
Author(s):  
Luciana Correa Oliveira de Oliveira ◽  
Juliana Alves Uzuelli ◽  
Ana Paula Alencar de Lima Lange ◽  
Barbara Amelia Aparecida Santana-Lemos ◽  
Marcia Sueli Baggio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Bone Disease ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4866 Background Multiple myeloma (MM) is an incurable malignant disease, characterized by increased angiogenesis in the bone marrow (BM) microenvironment and aberrant BM metabolism. Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases implicated in tumour progression, invasion, metastasis and angiogenesis, via proteolytic degradation of extracellular matrix. MMPs are inhibited by tissue inhibitors of metalloproteinase (TIMP). Although recent studies have implicated MMP 9 in MM bone disease, little is known about the role of the TIMPs. Objectives a) to compare levels of sRANKL, OPG, MMP-2, MMP-9, TIMP-1, TIMP-2, VEGF, bFGF, microvessel density (MVD) between newly diagnosed MM patients and healthy controls; b) to determine the association of these molecules with disease progression, bone disease and neoangiogenesis and c) to evaluate the impact of these variables on survival. Patients and Methods As of July 2009 38 newly diagnosed and untreated multiple myeloma patients were enrolled in the study. The median age was 61years-old (range 39-91) with 24 (63%) males. Patients were diagnosed and categorized according The International Myeloma Working Group criteria and ISS, respectively. Bone involvement was graded according to standard X-ray: patients with no lesions, or with one/ two bones involved or diffuse osteoporosis were classified as low score, whereas patients with lesions in more than two bones or presence of bone fracture were classified as high score. MMP-2 and MMP-9 were determined by PAGE gelatin zymography from plasma as previously described. MMP-9, TIMP-1 and TIMP-2, OPG and sRANKL concentrations were measured by ELISA. The levels of VEGF, bFGF were obtained using cytometric bead array. Ten healthy volunteers were used as controls. Bone marrow MVD measured in hotspots was evaluated in 26 out of 38 patients at diagnosis and 15 patients with Hodgkin Lymphoma stage IA and IIA (used as controls) by staining immunohistochemically for CD34. Comparisons among groups were analyzed by ANOVA and the correlation by the Spearman's correlation coefficient. Cox regression were performed for overall survival (OS) analysis. Results Patients with MM had elevated TIMP-1, TIMP-2 and OPG values compared with controls. No significant difference was found between plasma sRANKL, pro-MMP2, pro-MMP9 and MMP-9 levels. We found that plasma TIMP-1 levels correlated positively with bFGF, VEGF, MVD, beta-2 microglobulin (B2M) and OPG (r: 0.514, p=0,001, r: 0.350, p=0,031; r: 0.610, p<0.0001; r: 0.760, p<0.0001 and r: 0.701, p<0.0001, respectively) and TIMP-2 levels with bFGF, DMV, B2M and OPG (r: 0.512, p=0.002; r: 0.595, p<0.0001; r: 0.587, p<0.0001 and r: 0.552, p<0.0001, respectively). TIMP-1 and TIMP-2 levels correlated with the ISS stage (p<0.0001, p=0.006, respectively). The only variables that correlated with clinical bone disease staging were hemoglobin, B2M and albumin levels, whereas TIMP-1, TIMP-2, bFGF, VEGF and OPG correlated with DMV. On the univariate analyses, age, gender, proMMP2, TIMP-1, TIMP-2, creatinine, B2M and MVD were significantly associated with overall survival. In Cox regression model, TIMP-1, TIMP-2 and B2M levels remained to be significantly associated with OS. In conclusion, our results suggest that TIMP-1 and TIMP-2 levels are strongly associated with neoangiogenesis and are independent prognostic factors in MM. Disclosures No relevant conflicts of interest to declare.

A Better Mobilization Regimen for Newly Diagnosed Multiple Myeloma Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4051-4051
Author(s):  
Ahmed Y Abuabdou ◽  
Eric R Rosenbaum ◽  
Saad Usmani ◽  
Bart Barlogie ◽  
Michele Cottler-Fox
Keyword(s):  
Multiple Myeloma ◽  
Conflicts Of Interest ◽  
Optimal Number ◽  
P Value ◽  
Newly Diagnosed ◽  
The Poor ◽  
Cd34 Cells ◽  
Significant Difference ◽  
Minimum Number ◽  
Poor Mobilizer

Abstract Abstract 4051 Introduction: What constitutes an acceptable mobilization regimen for collecting CD34+ cells depends on whether the goal of collection is to obtain a minimum number versus optimal number of cells. When treating patients with high-risk myeloma it may be important to obtain an optimal number. Here we compare retrospectively our earlier mobilization regimen, VTD-PACE, with MVTD-PACE in newly diagnosed, previously untreated multiple myeloma patients. Materials and Methods : We reviewed data for all patients who collected hematopoietic progenitor cells on Total Therapy protocols TT3a/TT3b with VTD-PACE (n=394) from February 2004 to September 2008 (138 females and 256 males, median age 59y; range 31–75), and on TT4/TT5 with MVTD-PACE (n=188) from August 2008 to May 2011 (78 females and 110 males, median age 61y, range 30–76). Based on their predicted first day collection with a large volume leukapheresis (30L processed), using our center's predictive formula (Blood 2010; 116(21):1182a), patients were stratified into 4 mobilizer types: poor (<2×106 CD34+ cells/kg), intermediate (≥2 to 10×106), good (>10 to 20×106) and excellent (>20×106). Variables examined included number of CD34+ cells/μl blood on day 1 and day 2 of collection (we have a minimum 2 day collection requirement), number of collection days to reach our minimum goal of 20×106 CD34+ cells/kg, and total CD34+ cells/kg collected for both chemotherapy groups. Variables for both groups stratified by mobilizer type were compared using two-tailed student's t-tests, except for the poor mobilizer group, where population size was too small for formal statistical analyses (VTD-PACE n=7, MVTD-PACE n=4), although averages were calculated. Results : There was no significant difference between VTD-PACE and MVTD-PACE for CD34+ cells/μl blood on day 1 of collection among the excellent [mean 368.9 (n=184) vs. 434.6 x106 (n=92); p-value 0.07], good [mean 138.6 (n=102) vs. 128.6 x106 (n=40); p-value 0.19], and intermediate [mean 60.1 (n=100) vs. 55.9 x106 (n=52); p-value 0.39] groups. A statistically significant difference between VTD-PACE and MVTD-PACE was found for CD34+ cells/μl blood on day 2 of collection for excellent mobilizers [mean 333.8 (n=184) vs. 460 ×106 (n=92); p-value <0.001], but not for the good [mean 165.7 (n=102) vs. 189.5×106 (n=40); p-value 0.21] and intermediate [mean 80.1 (n=101) vs. 102.3 ×106 (n=52); p-value 0.07] groups. When CD34+ cell/kg collection totals with VTD-PACE and MVTD-PACE were compared, a significant difference was seen for the intermediate mobilizer group only [mean 23.6 (n=101) vs. 26.3 ×106 (n=52); p-value 0.03]. For the poor mobilizer group, VTD-PACE had an average CD34+ cells/μl blood of 13.5×106 for day 1 of collection and 17.0 ×106 for day 2, with a total of 14.5×106 CD34+cells/kg collected; while MVTD-PACE had an average of 13.2×106 CD34+ cells/μl blood for day 1 of collection, 24.9×106 for day 2, with a total of 24.2×106CD34+ cells/kg collected. The number of collection days was similar between VTD-PACE and MVTD-PACE in the excellent mobilization group (2 days), but was slightly more for VTD-PACE compared to MVTD-PACE for the good (2.1 vs. 2 days), intermediate (3.2 vs. 2.9 days), and poor (6.1 vs. 5.8 days) groups. Conclusion : Both regimens allow more than minimum collections, but MVTD-PACE provides a higher peak number of CD34+ cells/μl blood, resulting in a slightly lower mean number of days of collection than VTD-PACE to reach an optimal collection. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinical Impact of Enrollment of Clinical Trial in Multiple Myeloma; Single Center Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5525-5525
Author(s):  
Seo-Yeon Ahn ◽  
Sung-Hoon Jung ◽  
Ga-Young Song ◽  
Deok-Hwan Yang ◽  
Jae-Sook Ahn ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Conflicts Of Interest ◽  
Entire Treatment Period ◽  
Entire Cohort ◽  
Single Center Experience ◽  
Significant Difference ◽  
National University ◽  
Entire Treatment

Purpose : Many clinical trials have been conducted to prove the efficiacy of the new agrent or treatment regimen in patients with multiple myeloma (MM), but there was no analysis of the effect of enrollment in clinical trials on survival in patients with MM. Therefore, we evaluate the survival outcome in patients with multiple myeloma who participated in clinical trial. Method: Retrospective data of 446 patients with newly diagnosed MM between January 2003 and December 2016 in Chonnam National University Hwasun Hospital were analyzed. Patients diagnosed with monoclonal gammopathy of undetermined significance, asymptomatic MM, and plasma cell leukemia were excluded. In addition, non-interventional study was not included as a clinical trial in this study. Results: The median overall survival (OS) for the entire cohort was 62.5 months (95%CI 52.4-72), and median OS has gradually improved (46.5 months in 2003-2008 vs. 64.9 months in 2009-2014 vs. not reached in 2015-2016, P = 0.007). A total of 197 patients (44.2%) participated in the clinical trial and 7.4% participated in more than two clinical trials during the entire treatment period. Participation rates in clinical trials were significantly higher in transplant-eligible patients than transplant-ineligible patients (55.7% vs. 34.8%, P <0.001). There was no significant difference in OS according to the enrollment of clinical trial in entire patients (62.9 months vs. 64.9 months, P = 0.265). In transplant-eligible patients, patients who participated clinical trial showed improved OS than patients who did not participate clinical trial (77.0 months vs. 52.1 months, P = 0.058). However, in transplant-ineligible patients, no survival benefits were showed from participation in clinical trial (50.3 months vs. 66.0 months, P = 0.811) Conclusion: This study showed survival benefit of enrollment of clinical trial in transplant-eligible patients. Further analysis is needed to analysis the effects of clinical trial in elderly patients. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals Bortezomib: Once-Weekly 1.6mg/m2 Maybe a Better Choice Compared with Twice-Weekly 1.3mg/m2 in Newly Dignosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5558-5558
Author(s):  
Yubin Li ◽  
Fangfang Li ◽  
Wangshan Song ◽  
Zhumei Zhan ◽  
Xiangxin Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Statistical Difference ◽  
Clinical Observation ◽  
Conflicts Of Interest ◽  
Combined Chemotherapy ◽  
Newly Diagnosed ◽  
Nccn Guidelines ◽  
Significant Difference ◽  
Induction Regimen

Background: The first-in-class proteasome inhibitor, Bortezomib - based chemotherapy significantly improved the symptoms of multiple myeloma and delayed disease progression. Although the NCCN guidelines recommend twice-weekly 1.3mg/m2, the most appropriate dosage and interval still need to be further observed to improve the tolerability and patients outcomes. Methods: Part I Clinical Observation of MM Therapy in real world The effectiveness and toxicity of bortezomib containing regimen on multiple myeloma (MM) were analyzed retrospectively. From August 2006 to July 2012, 113 MM patients(77 newly diagnosed, and 36 relapsed or refractory patients ) had previously received at least 2 courses of different combined chemotherapy regiments, including 2 patients relapsed after ASCT). Classification: The clinical charateristics of all the 113 MM patients were shown inTable 1. They had received minimal 2 cycles of either Classical VDT regimen (bortezomib 1.0-1.3mg/m2, d1, d8, d15, d22; thalidomide 100-200 mg/d, d1-d14; dexamethasone 20 mg d1, d2, d4, d5, d8, d9, d11, d21; 21 days per cycle) or VDT-A regimen (VTD regimens like the previous; Epirubicin 10mg/d, d1-d4; 21 days per cycle) or modified VTD regimen (bortezomib 1.6mg/m2, d1, d8, d15, d22; thalidomide 100-200 mg/d, d1-d21; dexamethasone 20 mg d1, d2, d8, d9, d15, d16, d22, d23; 35 days per cycle). Results: Of all the patients, 76 were treated with classical VDT regimen, 21 patients treated with VDT-A regimen, 16 patients treated with modified VTD regimen. All were assessed every 2 cycles. After the treatment of four cycles,the rates of overall response ( ORR) and the complete rate ( CR) for the above three regimens of bortezomib with thalidomide and dexamethasone were 77.9% and 28% respectively. As shown in Figure 1, there was no statistical difference of ORRs (77.9% vs 78.3% vs 71%) and CRs (28% vs 26.4 vs 30%) among our single-central (Qilu) and other two international clinical trials ( WOBS and VISTA). Part II Clinical observation of once-weekly 1.6mg/m2 and the twice-weekly 1.3mg/m2 bortezomib in BCD regimen. In the subsequent study, the effectiveness and toxicity of once-weekly 1.6mg/m2 and the twice-weekly 1.3mg/m2 bortezomib of BCD regimen on MM were analyzed retrospectively. From January 2016 to December 2018, 34 NDMM patients (the median age of 58 (35-78) years old) received minimal 4 cycles of 1.6mg/m2 bortezomib, d1, d8, d15, d22; cyclophosphamide 300 mg/m2 d1, d8, d15; dexamethasone 20 mg d1, d2, d8, d9, d15, d16, d22, d23; 35 days per cycle. 32 NDMM patients (the median age of 58.5 (27-74) years old) received minimal 4 cycles of 1.3mg/m2 ( bortezomib 1.3mg/m2, d1, d4, d8, d11; cyclophosphamide 300 mg/m2 d1, d15; dexamethasone 20 mg d1, d2, d4, d5, d8, d9, d11, d12; 21 days per cycle). All were assessed every 2 cycles. The clinical charateristics were shown inTable 2. Results: As shown in Table 3 and Figure 2, the analysis showed that there is no significant difference of effectiveness ORR (=1.941,P=0.164) and CR (=0.289,P=0.591) between the 1.6 mg/m2 group and the 1.3 mg/m2 group after 2 cycles of treatments, which 88.24% (30/34) patients achieved ORR and 5.88% (2/34) patients got CR in the 1.6 mg/m2 group and 75.0%(24/32) patients achieved ORR with 3.1% (1/32) patients in CR in the 1.3 mg/m2 group. After 4 cycles of treatment, the 1.6 mg/m2 group showed significantly higher CR as compared to the 1.3 mg/m2 group (44.1% vs 18.75%, =4.890, p=0.027), however with no statistical difference of ORRs between the two groups (82.35% vs 87.59%, =0.340, P=0.560). In the adverse events, there is no significant difference of peripheral neuropathy (PN) between the 1.6 mg/m2 group and the 1.3 mg/m2 group after 2 cycle treatments (=0.068, p=/0.794). However, the incidence of PN in 4 cycle assessment is lower significantly in the 1.6mg/m2 group than in the 1.3mg/m2 group (5.88% vs 31.25%, =7.131, p=0.008). In respect to hematologic, infective, gastrointestinal toxicities, no significant difference was observed between the two groups. Conclusions: In summary, the 1.6 mg/m2 group achieved deeper and quicker response with reduced PN than the 1.3mg/m2 group in after 4-cycle induction regimen, suggesting more effective and safer outcomes with the treatment of the 1.6mg/m2 BCD regiment on MM. Disclosures No relevant conflicts of interest to declare.

scholarly journals Response Kinetics of Daratumumab-Based Regimens in Patients with Newly Diagnosed or Refractory/Relapsed Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3806-3806
Author(s):  
Jiasheng Wang ◽  
Raul Arroyo-Suarez ◽  
William Tse
Keyword(s):  
Multiple Myeloma ◽  
Clinical Outcomes ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Late Response ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Hematopoietic Cell Transplant ◽  
Significant Difference

Abstract Background: It is controversial in multiple myeloma (MM) whether early and late responders to therapies have similar clinical outcomes. Daratumumab (DARA) is a human anti-CD38 antibody that has been increasingly used in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). The association between response kinetics to DARA and clinical outcomes remains unexplored. Methods: Individual-participant data were obtained from phase 3 trials: POLLUX (Dimopoulos, NEJM, 2016), CASTOR (Palumbo, NEJM, 2016), and MAIA (Facon, NEJM, 2019). Patients were divided into early and late response groups based on the median time to the response of interest. Modified PFS (mPFS) and OS (mOS) were calculated from the time of first response of interest. Minimal residual disease (MRD) negativity was defined as less than 10 5 tumor cells by NGS assays. Results: After a median follow up of 16.1 months, 670 patients achieved a response of very good partial response (VGPR) or better, and 213 achieved MRD negativity. The median time to achieving VGPR or better was similar between NDMM and RRMM (86 vs. 84 days, respectively), while the median time to MRD negativity was longer among NDMM than RRMM (407 vs. 197 days, respectively). Among patients achieving VGPR or better, there was no significant difference of mPFS (HR 1.00, 95%CI 0.69 to 1.44) (fig. a), duration of response (DOR) (HR 1.02, 95%CI 0.68 to 1.53) (fig. b), or mOS (HR 0.98, 95%CI 0.54 to 1.75) (fig. c) between early and late responders. In the subgroup analysis, no significant difference of DOR was observed across all prespecified groups, including sex, age, cytogenetic risk groups, lines of previous therapy, types of measurable disease, NDMM vs. RRMM, prior treatment with autologous hematopoietic cell transplant, immunomodulatory drugs, or proteasome inhibitors. Among patients with NDMM achieving MRD negativity, there was no significant difference of mPFS (p=0.66) (fig. d), DOR (p=0.21) (fig. e) or mOS (p=0.87) (fig. f) between early and late responders. However, among patients with RRMM achieving MRD negativity, late responders had significantly longer mPFS (p=0.038) (fig. g) and DOR (p=0.043) (fig. h) than early responders; mOS was not significantly different (fig. i). In the multivariable Cox analysis among patients achieving MRD negativity, only lower baseline LDH level, NDMM, and IgG type MM were independently associated with later response. Conclusions: For patients with NDMM or RRMM achieving VGPR or better, early and late responders had similar survival; for patients with RRMM achieving MRD negativity, late responders had significantly longer mPFS and DOR. Our data support that in patients who failed to achieve an early or deep response to daratumumab based regimens, therapies should be continued with the goal of achieving ongoing and stepwise improvement of response. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals SPATIAL DISTRUBITON OF CHILDREN TREATED BY CANCER IN ZONGULDAK, TURKEY

2016 ◽  
Vol XLI-B8 ◽  
pp. 231-236
Author(s):  
Aysel Topan ◽  
Dilek Bayram ◽  
Mustafa Özendi ◽  
Ali Cam ◽  
Cam Öztürk ◽  
...  
Keyword(s):  
Disease Diagnosis ◽  
Study Data ◽  
Expert Advice ◽  
Chi Square ◽  
Epidemiological Aspect ◽  
Distribution Maps ◽  
Significant Difference ◽  
Chi Square Test ◽  
Collection Form ◽  
Nonhodgkin Lymphoma

This research is focused on the examination of child cancer cases in Zonguldak (Turkey) descriptively in epidemiological aspect thanks to GIS. Universe of the study is composed of 60 children between 0-19 years old, treated in Children Oncology Clinic of Health Application and Research Center in BEU. Whole universe was reached without selecting a sample in the study. Data were collected by using a form prepared by obtaining expert advice and they were applied to children and their parents at study dates. Results were expressed as percentages. Chi-Square test was used in intergroup comparisons, results were assessed within 95% confidence interval and p&lt;0.05 was considered as statistically significant. Variables that were used in the study were assessed, recorded in prepared data collection form and distribution maps were produced. When disease diagnosis of the children participated in the study were evaluated, it was observed that 33.3% (n=20) were being treated for ALL, 13.3% (n=8) for Medullablastoma and 11.7% (n=7) for Hodgkin-nonHodgkin Lymphoma. It was detected that 31.7% (n=19) were in Ereğli, 31.7% (n=19) were in Central district and 18.3% (n=11) were in Çaycuma, when the places where children were living were evaluated. Statistically significant difference was found (p=0.016) comparing disease diagnosis with living place, and overall distribution map of the number of cancer cases was produced in this context. This is the first research subjecting the distribution of cancer cases for Zonguldak province.

A Phase III Study of Enoxaparin vs Aspirin vs Low-Dose Warfarin as Thromboprophylaxis for Newly Diagnosed Myeloma Patients Treated with Thalidomide Based-Regimens.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 492-492 ◽  
Author(s):  
Antonio Palumbo ◽  
Michele Cavo ◽  
Sara Bringhen ◽  
Maide Cavalli ◽  
Francesca Patriarca ◽  
...  
Keyword(s):  
Cardiovascular Events ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Final Analysis ◽  
Phase Iii ◽  
Fixed Dose ◽  
Minor Bleeding ◽  
Newly Diagnosed ◽  
Dose Warfarin ◽  
Anticoagulant Prophylaxis

Abstract Abstract 492 Background. The risk of venous thromboembolism (VTE) is high in newly diagnosed myeloma (MM) patients who receive thalidomide-based regimens. Anticoagulant prophylaxis is recommended. Controversies exist on the best thromboprophylactic regimen to adopt. Aims. In this prospective, multicenter phase III trial we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) or low-fixed dose warfarin (WAR) as anticoagulant prophylaxis. End-points were incidence of VTE, acute cardiovascular events, sudden death, major and minor bleeding. Methods. In a GIMEMA study, 991 newly diagnosed MM patients were randomized to VTD (Velcade 1.3 mg/m2 d 1,4,8,11; Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or TD (Thalidomide 200 mg/d; Dexamethasone 320 mg/21 d) or VMPT (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4; Talidomide 50 mg/d) or VMP (Velcade 1.3 mg/m2 d 1,8,15,22; Melphalan 9 mg/m2 d 1-4; Prednisone 60 mg/m2 d 1-4). In a sub-study, patients treated with VTD or TD or VMPT were randomly assigned to receive LMWH (Enoxaparin 40 mg/d, N=223) or ASA (Aspirin 100 mg/d, N=227) or WAR (Warfarin 1.25 mg/d, N=223) for the duration of the induction therapy; 61 patients were excluded from sub-study because of indication for anticoagulant/antiplatelet therapy or high-risk of bleeding. Patients treated with VMP (N=257) did not receive any prophylaxis and were used as controls. Results. Patient characteristics and distribution of major risk factors were similar in all groups. The incidence of VTE was 5% in the LMWH group, 6% in the ASA group and 8% in the WAR group (p not significant). VTEs were 2% in the VMP group. Median time to onset of VTE for patients who received LMWH or ASA or WAR were 4.7, 2.4 and 2.4 months, respectively. Patients who received higher doses of both steroids and thalidomide (VTD and TD) had a higher VTE incidence (7%) in comparison with those who received lower doses (VMPT, 3%, p=0.06). Patients treated with bortezomib (VTD and VMPT) had a lower VTE incidence (5%) in comparison with patients on TD (8%, p=0.08). The rates of cardiovascular events were 2% in the LMWH group, 1% in the ASA group and 0.5% in the WAR group. The incidence of major and minor bleeding was 2% in the LMWH group, 3% in the ASA group and 1% in the WAR group (p not significant). The incidence of combined thrombosis, bleeding and cardiovascular events was 9% in the LMWH group, 10% in the ASA group and 9% in the WAR group (p not significant). Conclusion. The overall incidence of VTE was less than 10% in all groups and was not superior to that expected during the natural course of MM. The LMWH patients had lower risk of VTE, although no statistical difference was observed. LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens. The final analysis on 991 patients will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

Phase 2 Clinical Trial of Oral Lenalidomide, Cyclophosphamide, and Prednisone (RCP) for Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1970-1970
Author(s):  
Attaya Suvannasankha ◽  
Sherif Farag ◽  
Robin Obryant ◽  
Lisa l Wood ◽  
Nicole Porter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Conflicts Of Interest ◽  
Treatment Protocol ◽  
Sensory Neuropathy ◽  
Hematological Toxicity ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Post Transplant

Abstract Abstract 1970 Background: An effective and convenient regimen is appealing for Multiple Myeloma (MM) therapy. Lenalidomide and dexamethasone combination is highly effective in MM. However, at the FDA approved dose, dexamethasone related toxicity remains challenging. We report the efficacy and side effect profile of an all oral, dexamethasone-sparing combination of lenalidomide, cyclophosphamide and prednisone in newly diagnosed MM. Methods: The treatment protocol consisted of lenalidomide (Revlimid®) given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle, cyclophosphamide at a dose of 50 mg b.i.d. days 1–21 of a 28-day cycle, and prednisone 50 mg q.o.d (RCP). Responses were assessed on intent-to-treat basis based on the International Uniform Response Criteria. Treatment was planned for 6 cycles. Responding patients proceeded to observation, or transplantation, based on patient's preferred choices. All patients received, unless contraindicated, aspirin prophylaxis (81 or 325 mg daily) for prevention of deep-vein thrombosis, acyclovir for herpes zoster prevention, and bisphosphonates. Results: Forty six patients were enrolled from October 2007 to August 2010. Median follow up duration was 5.6 months. At this time, 38 of 46 patients are evaluable for confirmed responses (i.e., off-study or completed at least 4 cycles of therapy). The median age was 63 years (range, 41–76). 16 patients had ISS stage II (42%) and 8 (21%) had stage III disease. The median number of cycles was 6 (range: 1 – 6). Among the 38 evaluable patients, the overall response rate was 95%, consisting of CR: 1 (3%), VGPR: 9 (24%) and PR: 26 (68%). One patient had stable disease (1%) after the first cycle and treatment is ongoing. One patient had progression (3%). Thirty twoof 38 patients have discontinued study treatment. Reasons for treatment discontinuation are: completed study per protocol (24), disease progression (3), adverse event (2), non compliance (1), alternate treatment (1) and withdrawal of consent unrelated to toxicity (1). The most common toxicity was sensory neuropathy (24%): 8 (21%) grade I and 1 (3%) grade II. Other common toxicity included constipation (21%), pruritus (21%) and edema of limbs (18%). The most common hematologic toxicity was neutropenia (18%); 4 grade III and 2 grade IV. Infections were seen in 4 patients (2 febrile neutropenia and 2 with normal ANC). Five patients had grade 4 metabolic abnormalities (2 renal failure attributed to dehydration and tumor lysis, 2 hyperglycemia. and 1 hypokalemia). Thirteen patients had dose adjustments or interruption, most commonly due to hematological toxicity attributed to lenalidomide or cyclophosphamide. Twenty-five patients had stem cell collection. In all, sufficient numbers of stem cells (CD34+ cells ≥ 4.0 × 106 cells/kg) were collected for the transplantation use. To date, fifteen have undergone high dose chemotherapy and stem cell transplantation. Of eight patients with PR on RCP, seven achieved VGPR and one achieved CR post transplant. Of four patients with VGPR on RCP, 2 achieved CR and 2 remained in VGPR post transplant. Post-transplant response is not yet evaluable in the 3 remaining patients. Conclusions: The combination of lenalidomide, cyclophosphamide, and prednisone (RCP) has excellent activity in the setting of newly diagnosed myeloma. Overall toxicities were manageable. The study is still ongoing with the total accrual goal of up to 48 patients. The updated data for response and toxicities will be presented at the ASH Annual Meeting. Disclosures: No relevant conflicts of interest to declare.

Association of PML Expression with Chemotherapy-Resistance In Multiple Myeloma Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2959-2959
Author(s):  
Daisuke Ohgiya ◽  
Makoto Onizuka ◽  
Hiromichi Matsushita ◽  
Naoya Nakamura ◽  
Hiroshi Kawada ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cellular Proliferation ◽  
Conflicts Of Interest ◽  
Alkylating Agents ◽  
Chemotherapy Resistance ◽  
Nuclear Body ◽  
Rank Test ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 2959 Background: Although several novel agents have improved the prognosis of patients with multiple myeloma (MM), it still remains an incurable disease because of the difficulty to eradicate MM cells by current therapeutic approaches. Recent studies have revealed that a subset of malignant cells, cancer stem cells, contribute to chemotherapy-resistance in cancer treatment. Promyelocytic leukemia gene product (PML), known as a tumor suppressor through a variety of cellular functions in a nuclear macromolecular structure called the PML nuclear body, has been reported to be responsible for the chemotherapy-resistance by regulating cell cycle in chronic myeloid leukemia. We therefore investigated the impact of PML expression on the cellular proliferation status of MM cells and patients' prognoses. Materials/Methods: Bone marrow clot sections from 48 patients with newly diagnosed MM from Jan 1998 to Dec 2009 before any therapy at diagnosis were obtained, and analyzed, according to appropriate procedure approved by IRB at the Tokai University School of Medicine (Kanagawa, Japan) with written informed consent. They were doubly-stained with a combination of anti-PML/anti-CD138 and anti-Ki67/anti-CD138. For evaluation of the relation between PML status and cellular proliferation, the positive rates of PML and Ki67 in CD138 positive cells were compared. For investigation of the impact of PML expression on the prognosis of MM, the patients were divided into 3 groups, according to the PML positive rates in the CD138 positive cells: negative/low (less than 25 percentile: 12 cases), intermediate (from 25 to 75 percentile: 24 cases) and high (more than 75 percentile: 12 cases). Their overall survivals were compared using log-rank test. Furthermore, the PML positive rates between before and after treatments were compared using paired t-test. Results: The median observation period of 48 cases was 915 days. The median age of the patients was 62.5 (38-76) at diagnosis. All the patients were underwent combination chemotherapies containing alkylating agents as initial therapies. Two and nine patients were underwent allogeneic and autologous stem cell transplantation during the clinical courses, respectively. The numbers of patients of international staging system (ISS) stage I, II and III were 17, 14 and 17 cases. The PML positive rates in each case ranged from 0% to 83.8%. They were not correlated with ISS stages (Spearman r = 0.083) and the Ki67 positive rates (Spearman r = -0.13). The PML positive rates in the negative/low, intermediate and the high groups were less than 22.1%, from 22.1 to 56.6% and more than 56.6%, respectively. No significant difference in overall survival was observed among the 3 groups (p>0.05). However, there were significant differences in two year survival rate when the 3 groups were compared (100%, 85.2% and 54.7%; p=0.015) (Fig. 1). In 13 patients whose bone marrow clot sections were sequentially collected, the PML positive rates after treatments were significantly higher than those at diagnosis (p=0.0042) (Fig. 2). Especially, PML positive rates in all the 3 patients from the negative/low group were progressively increased (0.3 to 82.6%, 14.1 to 100%, 19.0 to 37.5%), and 2 of them died due to disease progression. On the other hand, 2 patients whose PML positive rates decreased after treatment were alive more than 5 years without therapies. Conclusion: Our data indicated that the level of the PML expression at diagnosis was a possible prognostic factor for early course of the disease (2 years after diagnosis). Chemotherapies might induce PML expression in MM cells or select PML positive MM cells. These findings suggest that PML expression presumably reflect chemotherapy-resistance in MM cells. The molecular mechanism of the association is now under investigation. Disclosures: No relevant conflicts of interest to declare.

Bortezomib-Thalidomide-Dexamethasone Compared with Thalidomide-Dexamethasone as Induction and Consolidation Therapy Before and After Double Autologous Transplantation In Newly Diagnosed Multiple Myeloma: Results From a Randomized Phase 3 Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 42-42 ◽  
Author(s):  
Michele Cavo ◽  
Giulia Perrone ◽  
Silvia Buttignol ◽  
Elisabetta Calabrese ◽  
Monica Galli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Multivariate Analysis ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Autologous Transplantation ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Significant Difference

Abstract Abstract 42 We prospectively compared thalidomide-dexamethasone (TD) with bortezomib-thalidomide-dexamethasone (VTD) as induction therapy before, and consolidation after, double autologous stem-cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (MM). Three 21-d cycles of either VTD (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or TD were given as induction therapy. Consolidation therapy comprised two 35-d cycles of VTD (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle) or TD. 474 patients randomized to the VTD (n=236) or TD (n=238) arm were analyzed on an intention-to-treat basis for response rate, PFS and OS. Centrally reassessed CR/nCR rate was significantly higher in the VTD compared with the TD arm after all treatment phases, including induction therapy (30% vs 10%, p<0.0001), double autotransplantation (54% vs 42%, p=0.008) and consolidation therapy (60% vs 44%, p=0.001). Best confirmed overall CR/nCR rate was 71% in the VTD arm compared with 52% in the TD arm (p<0.0001); the corresponding values for VGPR or better were 89% vs 72%, respectively (p<0.0001). To evaluate the role of consolidation therapy we performed a per-protocol analysis of 323 patients, 161 treated with VTD and 162 with TD. Overall, upgraded responses with VTD and TD as consolidation therapy were observed in 55% vs 37% of patients, respectively (p=0.01; OR:1.15-3.77). Furthermore, the probability to improve responses from less than CR before consolidation to CR after consolidation was 28% with VTD vs 15% with TD (p=0.02; OR:1.07-4.57) (p=0.003 using the Mc Nemar's test). Post-consolidation molecular detection of minimal residual disease was the objective of a substudy; detailed results are reported in a separate abstract. Briefly, both qualitative and quantitative analyses confirmed the statistically significant superiority of VTD over TD in effecting higher rates of molecular remissions and reducing the burden of residual myeloma cells after ASCT. Any grade 3–4 non-hematologic adverse events were 10% with VTD (peripheral neuropathy: 1.3%, skin rash: 0.6%) vs 12% with TD. With a median follow-up of 31 months, median PFS was 42 months in the TD arm and was not yet reached in the VTD arm (44-month projected rate: 61%) (HR: 0.62 [CI: 0.45–0.87], p=0.006). Superior PFS in the VTD vs TD arm was retained across patient subgroups with poor prognosis, including those with t(4;14) and/or del(17p). Randomization to VTD overcome the adverse influence of t(4;14) on PFS (40-month projected rates: 69% vs 67% according to the presence or absence of this abnormality, respectively; p=0.6). By the opposite, in the TD arm corresponding median PFS values were 24.5 vs 41.5 months, respectively (p=0.01). The small numbers of patients with del(17p) in both arms of the study precluded a statistical comparison with del(17p)-negative group. In a multivariate analysis, variables favorably influencing PFS were beta2-m lower than 3.5 mg/L (HR:0.47; p=0.000), absence of t(4;14) and/or del(17p) (HR:0.52; p=0.000), randomization to VTD arm (HR:0.57; p=0.002), attainment of at least VGPR (HR:0.50; p=0.009) and CR (HR:0.8; p=0.01). No statistically significant difference between the overall treatment protocols was seen in terms of OS, although curves seemed to initially diverge after 40 months (44-month projected rates: 84% vs 74% for VTD and TD arms, respectively). A multivariate analysis showed the independent role of absence of t(4;14) and/or del(17p) (HR:0.42; p=0.003), ISS stage1-2 (HR:0.49; p=0.02) and randomization to VTD (HR:0.53; p=0.04) in prolonging OS. When time-dependent CR entered the model, absence of t(4;14) and/or del(17p) and less advanced ISS stage retained their positive prognostic value; attainment of CR (strictly related to VTD randomization) was an additional favorable variable. In conclusion, in comparison with the TD arm of the study, 1) VTD induction emerges as a new standard of care for maximizing the degree and speedy of tumor reduction in preparation for ASCT; 2) VTD consolidation effected significantly higher rates of upgraded responses, including CR, and of molecular remissions; 3) double ASCT incorporating VTD as induction and consolidation therapy resulted in significantly longer PFS, a benefit confirmed in a multivariate regression analysis and maintained in the subgroup of patients with adverse cytogenetic abnormalities. Disclosures: Cavo: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use of bortezomib and thalidomide as induction therapy before, and consolidation after, autologous transplantation in newly diagnosed multiple myeloma. Baccarani:NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria.

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