Thalidomide Plus Dexamethasone for Untreated Newly Diagnosed Multiple Myeloma Patients and Deep Vein Thrombosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5093-5093 ◽  
Author(s):  
Victor H. Jiménez ◽  
Virginia J. Domínguez ◽  
Eduardo E. Reynoso
Keyword(s):  
Multiple Myeloma ◽  
Deep Vein Thrombosis ◽  
Oral Dose ◽  
Newly Diagnosed ◽  
First Line ◽  
Factor V Leiden Mutation ◽  
Vein Thrombosis ◽  
First Line Therapy ◽  
Line Therapy ◽  
Deep Vein

Abstract Background The combination of thalidomide/dexamethasone (TD) induces remission in approximately 70% of previously untreated patients with low or intermediate tumor mass. TD appeared superior to previous programs because of the high response rate and reasonable survival and its low frequency of serious complications. The aim of our study was to assess the efficacy of thalidomide plus dexamethasone as first line therapy and the incidence of deep vein thrombosis. Material and methods Patients with newly diagnosed and symptomatic MM (untreated patients) were evaluated. We enrolled all patients who fulfilled entire criteria for multiple myeloma between January 1998 and December 2005. Patients were divided into 2 groups: thalidomide plus dexamethasone (TD) and VAD group. The present study is a prospective, descriptive, longitudinal and observational one. Thalidomide was prescribed in an oral dose of 100 mg qhs and increased by 50 mg every 7 days to a maximum dose of 300 mg, depending on side effects. Dexamethasone was given in an oral dose of 20 mg/m2 each morning after breakfast on days 1–4, 9–12 and 17–20, followed by 10 days without therapy prior to the next cycle. Treatment with the combination was continued for at least 6 months or until the earliest occurance of maximum plateau of myeloma protein reduction, autologous transplant-supported intensification or other treatments. VAD was given as an Out-patient regimen including: vincristine (0.4mg/day, continuous IV), doxorubicin (9mg/m2/day, continuous IV) and dexamethasone (40 mg/day PO) with a median of 6 courses. Citrate plasma was used to investigate coagulation and anticoagulation parameters. Results Sixty newly diagnosed multiple myeloma patients were included in the study, 35 (58%) male and 25 (42%) female, aged 45–85 (mean 63). Underlying diagnosis was IgG MM in 44 (73.3%), IgA in 12 (20%) and light chain disease in 4 (6.7%). Clinical characteristics were similar for both groups. According to Durie Salmon criteria patients were grouped into: IA (n6, 10%), IB (n3, 5%), IIA (n12, 20%), IIB (n6, 10%), IIIA (n19, 31.6%) and IIIB (n14, 23.4%). The frequency of response (CR, NCR/VGPR and PR) in the group of thalidomide and dexamethasone was 73% being higher than VAD (53%)p0.005. CR was observed in 5 patients treated with thalidomide/dexamethasone (16%). Thrombosis complications DVT was observed in 7 patients. DVT occurred in 4 patients treated with TD and 3 with VAD. From the last 40 patients, 5 presented APC-R and 3 of them developed DVT. A significant shorter time to DVT was observed in patients exposed to VAD chemotherapy (first 2 cycles p 0.007). Patients developing APC-R were tested for Factor V Leiden mutation resulting negative. After patients developed any response criteria were retested for acquired activated protein C resistance, all of them went back to normal. Finally we conclude TD is an effective, less toxic therapy in comparison with VAD as first line therapy and in order to reduce incidence of DVT effective prophylactic anticoagulation should be implemented in all controlled trials, at least during the first few cycles of treatment.

Rapid Control of Previously Untreated Multiple Myeloma with Bortezomib-Lenalidomide-Dexamethasone (BLD).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3611-3611 ◽  
Author(s):  
Michael Wang ◽  
Kay Delasalle ◽  
Sergio Giralt ◽  
Raymond Alexanian
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Deep Vein Thrombosis ◽  
Intensive Therapy ◽  
Primary Treatment ◽  
Short Exposure ◽  
Newly Diagnosed ◽  
Vein Thrombosis ◽  
Grade 3 ◽  
Deep Vein

Abstract Introduction: Both bortezomib (B) and lenalidomide (L) are effective against relapsed/refractory and newly-diagnosed multiple myeloma (MM). The 3-drug combination of bortezomib-thalidomide-dexamethasone had induced remission in 87% of patients with untreated myeloma, significantly higher than the frequency of 66% observed with thalidomide dexamethasone. Patients and Method: We conducted a retrospective review of a pilot study in 17 previously-untreated patients with MM who were treated with bortezomib-lenalidomide dexamethasone between 4/06–4/07. Median age was 60 (35–71), median B2M was 3.7 mg/L (1.8–11.7) and median Hgb was 11 g/dl (6–14.7). Serum creatinine was greater than 2 mg/dl in one patient (6%). Bortezomib was given at 1.3 mg/m2 intravenously on days 1,4, 8 and 11; lenalidomide was at 25 mg orally daily for 21 days; and dexamethasone was at 20 mg/m2 daily orally for 4 days beginning on days 1, 9 and 17. Each cycle was 28 days. After the first cycle, a second cycle was given to 10 patients so that the median cycles of therapy was 2. As prophylaxis for deep vein thrombosis, all patients received warfarin with a targeted INR range between 2–3. All patients received daily orally vancyclovir to prevent herpes zoster. Results: Applying the Blade criteria of response (PR: greater than 50% reduction of serum myeloma protein and/or greater than 90% reduction of Bence Jones protein), remission of disease was observed in 14/17 patients (82%), including 2 patients (12%) with CR based on negative immunofixations and 12 patients (70%) with PR. All but one patient achieved remission after 1 cycle of treatment. Three patients were resistant to bortezomib-lenalidomide-dexamethasone after 2 cycles. One patient had deep vein thrombosis with pulmonary emboli. One patient had short-term grade 3 neuropathy. One patient had grade 3 thrombocytopenia and one patient had nonneutropenic pneumonia. Median nadir neutrophil count was 3000/ul (range 1400–5400/ul), and median nadir platelet count was 174 k/ul (range 38–270 k/ul). After a median 3.6 months (range 3.3–5.5), intensive therapy supported by autologous blood stem cells was given to 11 patients. Three of the 11 patients in PR after induction with bortezomib-lenalidomide-dexamethasone were converted to CR with intensification. Consequently, the CR rate after intensification 29%. Intensification is planned for the 3 patients with primary resistant MM. Discussion: Overall response and CR rates were similar to those observed previously among similar patients treated with bortezomib-thalidomide-dexamethasone. All reported primary treatment programs based on bortezomib-dexamethasone have induced high response rates of 82–92%, regardless of whether melphalan, lenalidomide, or thalidomide were included. Conclusions: One or two cycles of bortezomib-lenalidomide-dexamethasone were associated with rapid onset of response in patients with newly-diagnosed multiple myeloma. Toxicity was infrequent due to short exposure to bortezomib-lenalidomide-dexamethasone. There was early access to intensive therapy supported by autologous stem cells. Reduced exposure to drugs given as primary treatment should help preserve disease sensitivity to later treatment upon relapse.

Elevated Levels of Circulating Nucleosomes Are Not Associated with Venous Thrombosis or Neutrophil Activation in Patients with Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 274-274
Author(s):  
Mandy N. Lauw ◽  
Frank W.G. Leebeek ◽  
Moniek P.M. de Maat ◽  
Gerard J. van Mierlo ◽  
Saskia Middeldorp ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Deep Vein Thrombosis ◽  
Human Neutrophil ◽  
Research Funding ◽  
Neutrophil Activation ◽  
Extracellular Dna ◽  
Human Neutrophil Elastase ◽  
Newly Diagnosed ◽  
Vein Thrombosis ◽  
Deep Vein

Abstract Background: Patients with multiple myeloma (MM) are at a 9-fold increased risk of venous thromboembolism (VTE). Mechanisms underlying the increased VTE risk in MM have not yet been clarified. Recently, extracellular DNA, e.g. nucleosomes, has been shown to play a central role in coagulation activation and propagation in vivo and in animal models. Increased nucleosome levels were demonstrated in patients with VTE, supporting their role in VTE development. The prothrombotic activity of nucleosomes may be of importance in systemic inflammatory states, in which activated immune cells can release nucleosomes, such as neutrophils by forming neutrophil extracellular traps (NETs). However, during inflammation and upon chemotherapy, parenchymal cells and tumor cells, respectively, can also release extracellular DNA in the form of nucleosomes, which could promote coagulation. As MM is regarded as a systemic inflammatory disease, we hypothesized to find elevated levels of nucleosomes in MM patients, with an association between the highest levels of nucleosomes and development of VTE. Therefore, we assessed levels of nucleosomes and neutrophil activation, and their association with VTE, in a cohort of patients with newly diagnosed MM. Methods: We assessed levels of circulating nucleosomes and systemic neutrophil activation, by presence of elastase-α1-antitrypsin (EA) complexes, in 131 patients with newly diagnosed MM using plasma samples. Interleukin (IL)-6 and IL-8 levels were also assessed to estimate the inflammatory state. We used a case-cohort design to investigate the association between nucleosomes, neutrophil activation and VTE, by calculating odds ratios (ORs) with corresponding 95% confidence intervals (CIs) using nucleosomes and EA complexes as categorical variables, based on the 80th percentile for MM patients without VTE, with ≤80th percentile being the reference category. To compare levels of nucleosomes and neutrophil activation complexes in MM patients with patients with other malignancies, a comparison was made with a cohort of cases with objectified deep-vein thrombosis (DVT) of the leg and screened controls without DVT, stratified by malignancy status. Results: 19 of 131 MM patients (14.5%) developed VTE during MM treatment. Levels of nucleosomes (median 39.5 U/mL; interquartile range [IQR] 7.9-156.8, vs. median 25.6 U/mL; IQR 10.9-76.4; p=0.61) and neutrophil activation, as evidenced by presence of EA complexes (median 30.1 U/mL; IQR 22.6-39.3, vs. median 31.6 U/mL; IQR 24.3-46.0; p=0.45), did not differ between MM patients with and without VTE. No association was found between high levels (>80th percentile of non-VTE MM patients) of nucleosomes or neutrophil activation, and VTE (OR 0.5; 95% CI 0.2-1.6, and OR 2.1; 95% CI 0.5-9.7, respectively) in MM patients. IL-6 and IL-8 levels were low in all MM patients, irrespective of VTE. Nucleosome levels were similarly high in MM patients compared with DVT patients with other malignancies, and significantly higher compared with DVT patient without malignancies, and with DVT controls, irrespective of malignancy status (Fig. 1A). In contrast, levels of neutrophil activation were significantly lower in MM patients in all comparisons (Fig. 1B). Conclusions: Elevated levels of nucleosomes were found in MM patients, but without correlating high levels of neutrophil activation. Nucleosome levels in MM patients with and without VTE were similar, and there was no association between high levels of circulating nucleosomes or neutrophil activation, and VTE in MM patients. Our results suggest that elevated levels of nucleosomes in MM patients are independent of neutrophil activation or inflammatory status, but rather a marker of plasma cell injury or death. This could also explain absence of a clear association with VTE. Future studies are necessary to confirm the source and the clinical relevance of high levels of nucleosomes in MM patients. Figure 1 Levels of nucleosomes and neutrophil activation (by presence of human neutrophil elastase-α1-antitrypsin (EA) complexes) in patients with multiple myeloma (MM), compared with cases with deep vein thrombosis (DVT) of the leg with other malignancies or without malignancies, and DVT controls with other malignancies or without malignancies Median levels of circulating nucleosomes (1A), and median levels of EA complexes (1B). Bars represent median with interquartile ranges (IQR). Figure 1. Levels of nucleosomes and neutrophil activation (by presence of human neutrophil elastase-α1-antitrypsin (EA) complexes) in patients with multiple myeloma (MM), compared with cases with deep vein thrombosis (DVT) of the leg with other malignancies or without malignancies, and DVT controls with other malignancies or without malignancies. / Median levels of circulating nucleosomes (1A), and median levels of EA complexes (1B). Bars represent median with interquartile ranges (IQR). Disclosures Leebeek: Baxter: Research Funding; UniQure: Consultancy; Netherlands Hemophilia Foundation: Research Funding; CSL Behring: Research Funding.

Deep-vein thrombosis in patients with multiple myeloma receiving first-line thalidomide-dexamethasone therapy

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2272-2272 ◽  
Author(s):  
Michele Cavo ◽  
Elena Zamagni ◽  
Claudia Cellini ◽  
Patrizia Tosi ◽  
Delia Cangini ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Deep Vein Thrombosis ◽  
First Line ◽  
Vein Thrombosis ◽  
Dexamethasone Therapy ◽  
Deep Vein

The Efficacy and Safety of RAD (Lenalidomide, Adriamycin and Dexamethasone) In Newly Diagnosed Multiple Myeloma – First Results of a Phase II Trial by the German DSMM Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1945-1945
Author(s):  
Stefan Knop ◽  
Christian Langer ◽  
Monika Engelhardt ◽  
Lars O Muegge ◽  
Albrecht Reichle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Current Phase ◽  
Newly Diagnosed ◽  
First Line ◽  
Peripheral Blood Stem Cells ◽  
First Line Therapy ◽  
Line Therapy

Abstract Abstract 1945 Background Prognosis of patients with multiple myeloma (MM) has significantly improved by the introduction of autologous (auto) stem cell transplantation (SCT). The “novel drugs” which have shown activity in relapsed MM are increasingly used in first-line therapy aiming at maximized response prior to SCT. Whether allogeneic (allo) SCT adds to further disease control remains a matter of debate. Our group has shown the RAD regimen (lenalidomide, adriamycin and dexamethasone) to be highly effective and relatively well tolerated in relapsed and refractory MM. Therefore, we decided to explore RAD in the up-front management. Patients and Methods The current phase-II trial (DSMM XII) was designed to include patients (pts) up to the age of 65 years with newly diagnosed MM requiring treatment. We chose four cycles of RAD (lenalidomide 25 mg d-21; infusional adriamycin 9 mg/m2 per day d1-4; dexamethasone 40 mg d1-4 and 17–20; pegfilgrastim 6 mg d 6) every 4 weeks for induction followed by chemomobilization of peripheral blood stem cells. Low molecular weight heparin is mandatory during RAD treatment for thromboprophylaxis. All pts are to undergo one cycle of melphalan 200 mg/m2 followed by auto SCT. A subsequent allo SCT after reduced intensity conditioning (treosulfan/fludarabin) is scheduled for pts featuring at least one previously identified (cytogenetic or serologic) risk factor. Those with very favourable risk are to proceed to a second auto SCT. All patients will receive 12 months of lenalidomide maintenance (10 mg per day) on a continuous basis. Here, we present results of a planned safety analysis. Results 75 pts with a median age of 57 (range, 35–66) years have been enrolled by 11 German centers between 9/2009 and 7/2010. Currently, 51 pts are evaluable for toxicity during RAD induction: In all, 25 severe adverse events (SAEs) were reported for 16 subjects (31%). 68% of SAEs were assessed to be drug-related. Most frequent events were venous thrombosis (VTE; n=4), pyrexia (n=3) and syncope (n=2). Neutropenia, extravasation, pleural effusion, and allergic dermatitis accounted for one SAE each. 17 patients, 10 of whom (59%) had ISS stage II/III disease, are evaluable for post-induction response. Ten subjects (59%) achieved VGPR or better: 6 pts had VGPR and 2 patients each CR and stringent CR as assessed by the investigator. Conclusions Our preliminary results suggest RAD to be a well tolerated and effective novel induction protocol in up-front treatment of MM. Notably, incidence of severe hematotoxicity observed so far is significantly lower than was in our previous study in relapsed/refractory pts. Incidence of VTE was acceptable while no neurotoxicity occurred. Updated results will be presented. Disclosures: Knop: Celgene Germany: Consultancy, Honoraria. Off Label Use: Lenalidomide in combination with doxorubicin in myeloma first-line therapy. Reichle:Celgene Germany: Research Funding. Einsele:Celgene Germany: Consultancy, Honoraria. Bargou:Celgene Germany: Consultancy, Research Funding.

Deletion 17p in Unselected Newly Diagnosed Symptomatic Patients with Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5081-5081
Author(s):  
Efstathios Kastritis ◽  
Evangelos Terpos ◽  
Maria Gkotzamanidou ◽  
Maria Roussou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Elevated Serum ◽  
Initial Therapy ◽  
Novel Agents ◽  
Newly Diagnosed ◽  
First Line ◽  
Poor Outcome ◽  
First Line Therapy ◽  
Line Therapy

Abstract Abstract 5081 Multiple myeloma is characterized by significant genetic heterogeneity. Cytogenetic abnormalities are almost always present and specific cytogenetic features may be associated with poor outcome. Deletion of the short arm of the chromosome 17, involving the p53 locus, has been associated with poor outcome of the disease and the frequency of this abnormality increases in more advanced phases of the disease. Novel drugs may overcome, to a certain degree, the poor prognosis that is associated with certain cytogenetic abnormalities, but recent data indicate that neither bortezomib nor thalidomide or lenalidomide may overcome the deleterious effect of del17p either in newly diagnosed or in patients with relapsed disease. These data come from selected patients who have been treated within the context of clinical trials, most of which included intensified treatment such as single or double transplants. In order to assess the prognostic importance of del 17p in unselected patients with multiple myeloma, most of which received upfront novel agents, we analyzed 168 consecutive previously untreated patients, who were treated in a single center (Department of Clinical Therapeutics, University of Athens, Greece) who had available data on del17p, assessed by standard FISH methodology. Some of these patients were included in clinical trials, however, several patients who were ineligible because of poor performance status, significant renal impairment or comorbidities were also included in the analysis, thus, being more representative of the general myeloma population. IMWG criteria were used for the assessment of response, progression-free (PFS) and overall survival (OS). Twenty-five (15%) of patients had del17p detected at initial diagnosis. The baseline clinical characteristics and conventional prognostic factors of patients with and without del17p were not significantly different. First line therapy was based on novel agents (thalidomide, bortezomib or lenalidomide) in 91% of patients and was similar for patients with or without del17p (p=0.887). Response to first line therapy was also similar (83% for those with del 17p versus 78% for those without, p=0.529). The quality of responses (CR, VGPR & PR) was also similar. Sixty percent of patients with a del17p and 39% of those without del17p have relapsed or progressed after initial therapy. The median progression free survival for patients with and without del17p was 18.5 versus 22.5 months respectively (p=0.065). In multivariate analysis, del17p was associated independently with shorter PFS (HR: 1.77, 95% CI: 1.021–3.07, p=0.042). Other factor that were independently associated with shorter PFS included age>65 years (p<0.001), ISS stage (p=0.028), low platelet counts (<130×109/L; p=0.032) and elevated serum LDH ≥300 IU/L (p<0.001). The median survival was significantly shorter for patients with del17p (29.5 versus 51 months, p=0.007). When we adjusted for other prognostic factors, including treatment with novel versus conventional agents, then the presence of del17 was independently associated with shorter survival (HR: 2.29, 95% CI: 1.15–4.6, p=0.019). Other factors associated with shorter survival included age >65 years (p=0.005), ISS-3 disease (p=0.038), low platelet counts (<130×109/L; p=0.005) and elevated serum LDH ≥300 IU/L (p=0.001). Importantly, median survival after first disease relapse for patients with del17p was 14 months while for patients without del17p was 42 months (p=0.01), despite the fact that in almost all patients novel agents were used as salvage treatment. In conclusion del17p remains an independent prognostic factor associated with poor survival in unselected patients with newly diagnosed MM, even when novel agents are used as initial therapy. Patients with del17p have very poor outcome after relapse, even with the use of novel agents as salvage therapy. Our data indicate that novel treatment and innovative strategies should be considered for these patients and that patients with del17p should be considered for participation in clinical trials of novel agents as soon as they relapse, since currently available treatment options offer limited benefit in these high risk patients. Disclosures: No relevant conflicts of interest to declare.

The Incidence of Deep Vein Thrombosis Is Lower in Japanese Patients with Multiple Myeloma Treated with Thalidomide and Corticosteroids or Chemotherapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5215-5215
Author(s):  
Naoko Takei ◽  
Masahiro Kami ◽  
Masaharu Tsubokura ◽  
Yuji Miura ◽  
Takehiro Issiki ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Deep Vein Thrombosis ◽  
Combination Treatment ◽  
Medical Center ◽  
Japanese Patients ◽  
Chemotherapeutic Agents ◽  
Ultra Sound ◽  
Newly Diagnosed ◽  
Vein Thrombosis ◽  
Deep Vein

Abstract Background: Deep vein thrombosis (DVT) is an important complication of thalidomide therapy especially when it is combined with corticosteroids or chemotherapy. Japanese patients with multiple myeloma (MM) are currently prescribed thromboprophylaxis after ASCO guideline, although there are limited data for asian population. We examined the incidence of DVT in Japanese patients with MM. Methods: We reviewed the records of 145 patients receiving thalidomide for newly diagnosed or relapsed/refractory MM at Kameda Medical Center and Tsukuba Memorial Hospital during the 10-year period 1998–2008. Patients were considered to have developed DVT if they presented with suggestive symptoms of leg swelling and had a Doppler ultra-sound study confirming acute thrombosis. Results: 95 of the 145 patients received thalidomide in combination with a corticosteroid or other chemotherapeutic agents. 70 of 95 patients were prescribed thromboprophylaxis; of these, 53 patients received warfarin, 17 patients received aspirin during combination treatment. 38 of 70 patients were newly diagnosed. Only 1 of 70 patients (1.4%) developed DVT. None of the patients who were not received any prophylaxis developed DVT during combination treatment. Conclusion: The incidence of deep vein thrombosis is lower in Japanese patients with MM treated with thalidomide and corticosteroids or chemotherapy than previous report from western countries.

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