A Study of Lenalidomide Based Chemotherapy in Multiple Myeloma in Indian Population: Special Appraisal of Thromboembolic Risk.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4206-4206
Author(s):  
Velu Nair ◽  
Satyaranjan Das ◽  
Sanjeevan Sharma ◽  
V. K. Jha ◽  
S. Bhattacharya ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Conflicts Of Interest ◽  
Treatment Regime ◽  
Lower Limbs ◽  
Newly Diagnosed ◽  
Experienced Radiologist ◽  
Highly Effective ◽  
Dexamethasone Therapy ◽  
D Dimer

Abstract Abstract 4206 Introduction Multiple myeloma is a plasma cell tumor which accounts for about 10% of hematological malignancies. In recent years some advances in the management of this malignancy have been achieved, especially the newer drugs like thalidomide, lenalidomide and bortezomib. Lenalidomde, a second generation immunomodulatory drug has been shown in various series to be a highly effective agent in management of newly diagnosed as well as relapsed cases of myeloma. The incidence of venous thromboembolism in patients of myeloma taking Lenalidomide – Dexamethasone therapy has been reported as high as 17 %. The risk of thromboembolism is to some extent determined by genetic predisposition of a population. There are no published reports from the Indian subcontinent addressing the incidence of venous thromboembolism in patients with newly diagnosed or relapsed multiple myeloma treated with Lenalidomide – Dexamethasone. Patients and Methods Forty one consecutive patients diagnosed at our centre with multiple myeloma either afresh (n=30) or relapsed on a previously different treatment regime (n=11), were studied between Oct2007 to Jul 2009. Diagnosis was based on serum electrophoresis and immunofixation, bone marrow plasmacytosis, and relevant tissue involvement. Patients were staged as per Durie Salmon system, and all our cases were found to be in stage 3 (3A = 34 cases, 3B = 7 cases). Detailed baseline clinical, haematological, and biochemical parameters were recorded. Colour Doppler flow imaging (CDFI) using a Philips 5000 imager of the lower limbs by an experienced radiologist was performed in all patients for DVT. D dimer using immunoturbidometric semi quantitative slide agglutination assay which measures fibrinogen equivalent units which is usually twice the actual D dimer value (<1.0 mcg/ml as normal cut off, 1.0 – 2.5 mcg/ml as indeterminate) was measured in all cases at diagnosis. All patients were started on therapy with Lenalidomide 25 mg a day for 21 consecutive days every month, with dose modification for renal insufficiency as per GFR. Dexamethasone 40 mg a day for first four days was given to all cases. Low dose aspirin 75 mg / d was used as thromboprophylaxis. Patients were followed up monthly with clinical, haematological and biochemical monitoring, specifically looking for any progression of myeloma parameters. Screening for occurrence of DVT was done using CDFI, D dimer, and thorough clinical examination at baseline and at one, three and six months interval from initiation of therapy. Results We report an overall response of 95% (nCR + CR : 30%) in newly diagnosed cases of multiple myeloma and 81.8% (nCR + CR : 36%) in patients with thalidomide failure / intolerant group. The primary toxic effect of lenalidomide was haematological and was manageable with dose adjustment of lenalidomide and supportive care. D dimer levels were found to be in the range of 0.5 to 2.4 mcg/ml (mean = 1.46 mcg/ml). On detailed follow up for upto six months there was no episode of venous thromboembolism recorded in any of the patients. All patients were asymptomatic for DVT and CDFI of lower limbs was normal at all points of examination in all patients of myeloma, newly diagnosed or relapsed. Conclusion Lenalidomide – Dexamethasone therapy is a highly effective regime for treatment of newly diagnosed and relapsed myeloma patients. In our cohort of both relapsed and fresh cases (n=41), on thromboprophylaxis with 75 mg asprin, not a single case of DVT was documented, proving its safety profile for venous thromboembolism. Larger trials would however be required to ascertain the exact risk of thromboembolism in patients of myeloma taking this treatment regime. Disclosures: No relevant conflicts of interest to declare.

scholarly journals D-Dimer Improves Risk Prediction of Venous Thromboembolism in Patients with Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-27
Author(s):  
Kristen M. Sanfilippo ◽  
Mark A Fiala ◽  
Harsha Tathireddy ◽  
Dan Feinberg ◽  
Ravi Vij ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
High Risk ◽  
Board Of Directors ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Unit Increase ◽  
Soluble P ◽  
D Dimer ◽  
Increase In Risk

Introduction: Venous thromboembolism (VTE) is a common cause of morbidity and mortality among patients with multiple myeloma (MM). Thromboprophylaxis is a safe and effective way to decrease VTE in other high-risk populations. Recently, a clinical prediction model was developed to identify patients with newly diagnosed MM starting chemotherapy at highest risk of VTE. The model, IMPEDE VTE, found the following clinical risk factors for VTE: immunomodulatory drugs, body mass index, recent pathologic fracture of the femur or hip, erythropoietin stimulating drugs, dexamethasone, doxorubicin, Asian ethnicity/race, history of VTE, tunneled line or central venous catheter, and existing use of aspirin or anticoagulation. External validation of the model has yielded a c-statistic for VTE risk prediction of 0.64 to 0.65. Laboratory parameters can predict VTE in some patients with cancer. Accordingly so, the addition of laboratory parameters to IMPEDE VTE has the ability to improve model performance. Thus, we sought to determine the association between soluble P-selectin and D-dimer with the development of VTE in patients with newly diagnosed MM starting chemotherapy. Methods: We identified 545 patients from the Washington University in St. Louis MM banking protocol, with available plasma from time of diagnosis (2007-2019). Thirty-eight cases of VTE were identified within 6 months following treatment initiation. An additional 137 patients were randomly selected as controls. D-dimer and soluble P-selectin ELISA assays were performed on the banked plasma by Eve Technologies, who was blinded to case vs. control status. Both assays were performed in duplicate and results averaged. All additional variables were collected through manual chart abstraction. IMPEDE VTE scores were calculated as we previously described (Sanfilippo et al.). The association of D-dimer and soluble P-selectin with VTE risk was assessed using Cox regression, adjusting for IMPEDE VTE score. Results: The median age of all 545 patients was 65 (range 32-79), 54% were male, and 85% were white. All patients received novel chemotherapy agents for first-line MM therapy and 66% underwent autologous stem cell transplant. Of the 38 cases with VTE, 20 patients had deep vein thrombosis, 17 had pulmonary emboli, and 1 patient had concurrent events. The median time from chemotherapy initiation to VTE was 51 days (range 4-193). The median IMPEDE VTE score was 5 (range -1 to 12). Each unit increase in IMPEDE VTE score was associated with a 21% increase in risk for VTE (HR 1.21; 95% CI 1.04-1.40; p = 0.01). Median D-dimer was 11,795 ng/mL (range 280-144,832). Each 1000 ng/mL unit increase in D-dimer was associated with a 2% increase risk for VTE after controlling for IMPEDE VTE score (aHR 1.02; 95% CI 1.01-1.04; p &lt; 0.001). Patients in the highest quartile of D-dimer levels, above the 75th percentile, had a 2-fold increase in risk of VTE after adjusting for IMPEDE VTE score (aHR 2.04; 95% CI 1.03-4.02; p = 0.04). Median soluble P-selectin was 189 ng/ml (range 23-638). There was no association between soluble P-selectin level and VTE risk in patients with MM. Conclusions and Relevance: D-dimer is predictive of VTE in patients with MM starting chemotherapy. The combination of D-dimer and the IMPEDE VTE score can improve identification of patients at high risk of VTE and therefore allow for selection of primary thromboprophylaxis among patients with MM. Disclosures Sanfilippo: Bayer HealthCare Pharamceuticals: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Other: Travel Support for Investigator Meeting; Pfizer: Membership on an entity's Board of Directors or advisory committees; Covington & Burling LLP: Consultancy; Luther & Associates: Consultancy; Health Services Advisory Group: Consultancy; Amgen: Other: Trasfer of Value (food) during discussion of research.

Risk of Venous Thromboembolism Recurrence: High Negative Predictive Value of D-dimer Performed after Oral Anticoagulation Is Stopped

2002 ◽  
Vol 87 (01) ◽  
pp. 7-12 ◽  
Author(s):  
Cristina Legnani ◽  
Benilde Cosmi ◽  
Giuliana Guazzaloca ◽  
Claudia Pancani ◽  
Sergio Coccheri ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Negative Predictive Value ◽  
Predictive Value ◽  
Recurrent Events ◽  
Oral Anticoagulant Therapy ◽  
Lower Limbs ◽  
First Episode ◽  
Vein Thrombosis ◽  
D Dimer

SummaryIn some patients with previous venous thromboembolism (VTE) D-dimer levels (D-Dimer) tend to increase after oral anticoagulant therapy (OAT) is stopped. The aim of our study was to evaluate the predictive value of D-Dimer for the risk of VTE recurrence after OAT withdrawal. After a first episode of deep vein thrombosis (DVT) of the lower limbs and/or pulmonary embolism (PE), 396 patients (median age 67 years, 198 males) were followed from the day of OAT discontinuation for 21 months. D-dimer was measured on the day of OAT withdrawal (T1), 3-4 weeks (T2) and 3 months (+/− 10 days, T3) thereafter. The main outcome events of the study were: objectively documented recurrent DVT and/or PE. D-dimer was found to be increased in 15.5%, 40.3% and 46.2% of the patients at T1, T2 and T3, respectively. In 199 (50.2%) patients, D-dimer levels were elevated in at least one measurement. During a follow-up of 628.4 years, 40 recurrences were recorded (10.1% of patients; 6.4% patient-years of follow-up). D-dimer was increased in at least one measurement in 28 of these cases, but remained normal in 11 subjects (three of whom had recurrent events triggered by circumstantial factors, three with malignancyassociated factors) (in one subject D-dimer was not measured). The negative predictive value (NPV) of D-dimer was 95.6% (95% CI 91.6-98.1) at T3 and was even higher (96.7%; 95% CI 92.9-98.8) after exclusion of the six recurrences due to circumstantial factors. Only five idiopathic recurrences occurred in the 186 patients with consistently normal D-dimer. In conclusion, D-dimer has a high NPV for VTE recurrence when performed after OAT discontinuation.

scholarly journals Prevalence and characteristics of venous thromboembolism in severe exacerbation of chronic obstructive pulmonary disease in a tertiary care hospital in India

2021 ◽  
Author(s):  
Soibam Pahel Meitei ◽  
Sudheer Tale ◽  
Arjun Kumar Negi ◽  
Ruchi Dua ◽  
Rohit Walia ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Venous Thromboembolism ◽  
Tertiary Care Hospital ◽  
Tertiary Care ◽  
Lower Limbs ◽  
Chronic Obstructive ◽  
Care Hospital ◽  
Obstructive Pulmonary Disease ◽  
Test Probability ◽  
D Dimer

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) carries a high risk of venous thromboembolism (VTE). Pulmonary embolism (PE) and AECOPD increase the mortality and morbidity risk associated with each other. Racial and ethnic differences in VTE risk have been documented in multiple studies. However, there is a dearth of reliable Indian data on the same. This study was planned to find the prevalence of VTE in the setting of severe AECOPD in a tertiary care hospital in India and to identify the clinical, laboratory and radiological characteristics of VTE in severe AECOPD. A total of 156 consecutive patients admitted with severe AECOPD and meeting the specified inclusion and exclusion criteria were recruited. Thorough workup of all patients was done including ABG, serum D dimer, ECG, compression ultrasound of lower limbs and 2-D echocardiography. Patients with high pre-test probability score, or intermediate pre-test probability score at presentation with serum D dimer above the age adjusted cut-off underwent computerised tomography pulmonary angiography (CTPA).  Results were analysed using SPSS version 23.  Sixteen (10.3%) patients had VTE, 15 (93.75%) of them being cases of isolated PE. Female gender, higher cumulative past exposure to corticosteroid, higher alveolar-arterial gradient, right ventricular dysfunction, and higher mean pulmonary artery pressure were associated with increased risk for VTE. The prevalence of VTE in AECOPD in this study among an Indian population is higher than among other Asians, but lower than among the Blacks, the Caucasians and the Middle-East ethnicities. Since a vast majority of VTE presents as PE without DVT in the setting of AECOPD, the absence of deep vein thrombosis of lower limbs does not rule PE in the setting.

scholarly journals VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1835-1835 ◽  
Author(s):  
Katrina M Piedra ◽  
Hani Hassoun ◽  
Larry W. Buie ◽  
Sean M. Devlin ◽  
Jessica Flynn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cancer Trial ◽  
Oncology Research ◽  
Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

scholarly journals Efficacy of Bortezomib plus dexamethasone as a first line treatment in newly diagnosed cases of Multiple Myeloma: A Single Centre Study in a Tertiary Care Hospital

2020 ◽  
Vol 28 (1) ◽  
pp. 34-41
Author(s):  
Mahbuba Sharmin ◽  
Mohammad Manirul Islam ◽  
Abdul Aziz ◽  
Salauddin Shah ◽  
Md Jalilur Rahman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Intracranial Haemorrhage ◽  
Response Rate ◽  
Malignant Tumors ◽  
Tertiary Care ◽  
Care Hospital ◽  
Newly Diagnosed ◽  
Overall Response ◽  
Highly Effective

Background: Multiple Myeloma (MM) accounts for 1% of malignant tumors and 10%–15% of hematopoietic neoplasms. Bortezomib, a first in class proteasome inhibitor, induces apoptosis and growth arrest and reverse chemoresistence in Myeloma cell and has demonstrated no irreversible adverse effect on haemopoietic stem cell. Dexamethasone increases the response rate. Thus, Bortezomib plus dexamethasone represent highly effective regimen for previously untreated Multiple Myeloma cases and significantly higher response rates approximately 70%– 90% have been observed.This combination thus may serve the basis of future strands of care in Multiple Myeloma patients. Objective: The aim of the study was to assess the efficacy , safety and tolerability of Bortezomib in newly diagnosed cases of Multiple Myeloma patients in Bangladesh. Materials & Methods: This prospective observational study was carried out in the Haematology department of BSMMU from June 2017 to December 2018. Patients received inj. Bortezomib (1.3mg/m2 ) 4 cycles as an intravenous bolus on days 1,4,8,11 in a three week cycle (twice weekly administration) in indoor and same patients as day care basis in outpatients department. Dexamethasone at 40 mg was given intravenously or orally on the day of and day after inj Bortezomib.A self administered questionnaire containing different set of questions regarding Multiple Myeloma were used for data collection. Results: Among the study population, 93% of patients had anaemia followed by bone pain (86%) and renal impairment (39%). Out of 25 patients,complete response achieved in 13 patients (52%), where 4 patients(16%) showed partial response,6 (24%) showed very good partial response and 2 (8%) patients showed no response. The overall response rate was 92% belonged to partial,very goofd partial and no respone respectively. Death occurred in 3 cases (12%). 5 patients (20%) developed Bortezomib induced peripheral neuropathy.Life threatening intracranial haemorrhage occurred in two patients (8%). Death occurred in 3 cases (12%),2 patients due to intracranial haemorrhage and another from cardiac arrest. In this study,S. creatinine, â2 microglobulin and bony lesion variables showed significant association with treatment response. Conclusion: Bortezomib plus dexamethasone is a highly effective and safe regimen for previously untreated multiple myeloma patients. This novel therapy in myeloma represent a new trearment paradigm targeting both tumor and microenvironment which has markedly improve overall response(OR), long progression free survival (PFS) and overall survival (OS)across in all risk groups. Moreover,it can be administered safely in the outpatient setting provided by clinicians. J Dhaka Medical College, Vol. 28, No.1, April, 2019, Page 34-41

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.

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.

Once Weekly Bortezomib Plus Dexamethasone in Newly Diagnosed Multiple Myeloma: A Preliminary Study in Chinese Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5128-5128
Author(s):  
Yadan Wang ◽  
Yu Hu ◽  
Lisha Ai ◽  
Bhuveshwarnath Gowrea ◽  
Guohui Cui ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Treatment Group ◽  
Conflicts Of Interest ◽  
Rest Period ◽  
Chinese Patients ◽  
Weekly Schedule ◽  
Newly Diagnosed ◽  
Weekly Treatment ◽  
Grade 3

Abstract Abstract 5128 Introduction: Bortezomib has become a cornerstone in the management of multiple myeloma (MM) and the currently accepted practice is a twice weekly administration at 1.3mg/m2. Recently, several studies have demonstrated a successful treatment with the modified Bortezomib schedule in refractory or elderly newly diagnosed MM. These previous studies suggest that, given at weekly intervals, Bortezomib remains equally efficacious and may even improve tolerability. We here present our institution's experience where we retrospectively compare the efficacy and toxicity parameters between once weekly (1.6mg/m2) and twice weekly (1.3mg/m2) schedule of Bortezomib plus Dexamethasone in newly diagnosed, untreated MM patients. Methods: The once weekly schedule consisted of 5-week cycle of which Bortezomib plus Dexamethsone was administered during the first 4 weeks as follows: Bortezomib 1.6mg/m2 intravenously on days 1, 8, 15, 22 and Dexamethsone 20mg intravenously on days 1–2, 8–9, 15–16 and 22–23 followed by a 12-day rest period. The twice weekly schedule consisted of 3-week cycle as follows: Bortezomib 1.3mg/m2 intravenously on days 1, 4, 8, 11 and Dexamethsone 20mg intravenously on days 1–2, 4–5, 8–9 and 11–12 followed by a 9-day rest period. We retrospectively collected data from Jan 2009 to Dec 2010 of 37 patients with newly diagnosed MM who were either treated with once weekly schedule (n =13) or twice weekly schedule (n = 24). Allocation of patients to their respective treatment group was not randomized but rather on the basis of their means, after they were made fully aware that the once weekly schedule was still under evaluation. Results: The median age was similar between two schedules (53 years vs. 54.5 years, P=0.674). Both treatment groups received a median number of two cycles of chemotherapy. The median follow-up was also similar, being 12 months (range, 4–19) in the once weekly treatment group and 10.5 months (range, 2–19)in the twice weekly treatment group. In the standard twice weekly schedule, the overall response rate of 74.9% including 2(8.3%) CR, 8(33.3%) VGPR and 8(33.3%) PR, while 2(8.3%) patients had stable disease (SD) and 3(12.5%) had progressive disease (PD). Among the patients in the weekly schedule, 10 of 13 patients (77.0%) achieved at least PR with 30.8% at least VGPR. In addition, SD was observed in 1 patient (7.7%) and PD in another 1 patient (7.7%). The responses to treatment were not found to be statistically significant different in our study when comparing the once weekly schedule to the twice weekly schedule. The median time to the best response was 2 cycles (range,2–4) in the once weekly schedule as compared with 2.5 cycles (range,2–4) in the twice weekly schedule (P=0.564). The median survival was not reached in either schedule since the follow-up was not long enough. The median progression free survival (PFS) and duration of response (DOR) of the weekly schedule did not differ significantly from that of the twice weekly schedule (8 months vs. 10 months, P=0.545 and 6 months vs. 7 months, P=0.467; respectively). After a median follow-up of 12 months (range, 2–19), 2 patients (15.4%) in the weekly schedule and 4 patients (16.6%) in the twice weekly schedule had died (P=0.723) thus mortality in the two groups did not differ significantly. Over grade 3 of gastrointestinal symptoms were similar in the once weekly (16%) and twice weekly (20.5%) schedules. Peripheral sensory neuropathy was reported more frequently in the twice weekly schedule, including grade 1 in 4 patients (17%), grade 2 in 4 patients (17%), grade 3 in 3 patients (12.5%), and grade 4 in 1 patient (4%). While grade 1 neuropathy in 2 patients (15%), grade 2 in 1 patient (8%), grade 3 in 1 patient (8%) were reported in the weekly schedule and all had resolved within two months. All grade 3 and 4 hematologic toxic effects were more frequent in the twice- weekly schedule than in the weekly schedule (75% vs. 54%), as was over grade 2 of herpes zoster (16.5% vs. 8%). Incidence of over grade 2 rash remained low and was similar in the two schedules (both 8%). However the difference between the two schedules was not statistical significantly. Conclusions: Our study provides additional evidence that the once weekly Bortezomib (1.6mg/m2) plus Dexamethasone schedule is active and well tolerated in the treatment of patients with newly-diagnosed multiple myeloma, with the similar efficacy and lesser toxicity compared with the twice weekly schedule. 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.

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