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.

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.

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.

scholarly journals Short-course lenalidomide plus low-dose dexamethasone in the treatment of newly diagnosed multiple myeloma— a single-centre pragmatic study

2017 ◽  
Vol 24 (5) ◽  
pp. 361 ◽  
Author(s):  
W.M. Jose ◽  
K. Pavithran ◽  
T.S. Ganesan
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Deep Vein Thrombosis ◽  
Low Dose ◽  
Progression Free Survival ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Vein Thrombosis ◽  
Deep Vein

Purpose We assessed response to treatment, toxicity, time to progression, progression-free survival, and overall survival in patients newly diagnosed with multiple myeloma who were ineligible for or unwilling to undergo transplantation and who were treated with a combination of lenalidomide and low-dose dexamethasone for a fixed 6 cycles in a resource-constrained environment.Methods This pragmatic study, conducted in a single tertiary cancer centre in South India, enrolled patients from May 2009 till April 2011. Treatment included lenalidomide 25 mg daily for 21 days, with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle, for 6 cycles. Response was evaluated after the 3rd and 6th cycles of treatment. All patients were followed for 5 years.Results The study enrolled 51 patients. Median age in the group was 61 years (range: 38–76 years). Immunoglobulin G or A myeloma constituted 70.6% of the diagnoses, and light-chain myeloma constituted 29.4%. Stages i, ii, and iii (International Staging System) disease constituted 21.4%, 28.6%, and 50% of the diagnoses respectively. All patients were transplantation-eligible, but 34 (66.7%) refused for economic reasons. After treatment, 19.6% of the patients achieved a stringent complete response; 35.3%, a complete response; 5.9%, a very good partial response; and 29.4%, a partial response, for an overall response rate of 90.2%. Stable disease was seen in 3.9% of patients, and progressive disease, in 5.9%. Grade 3 or greater nonhematologic and hematologic toxicity occurred in 35.2% and 11.7% of patients respectively. Pulmonary embolism occurred in 1 patient. No patient experienced deep-vein thrombosis or peripheral neuropathy. The median follow-up duration was 66 months. All patients experienced disease progression. Median progression-free survival was 16 months. In 10 patients, re-challenge with lenalidomide and dexamethasone achieved a second complete response. At the time of writing, 19 patients had died. The overall survival rate at 5 years was 62.74%. Median overall survival is not yet reached.Conclusions In a resource-constrained setting, lenalidomide with low-dose dexamethasone is an effective treatment with acceptable toxicity in patients newly diagnosed with multiple myeloma and not planned for transplantation. Complete responses were significantly more frequent than reported in the Western literature. Occurrence of clinical deep-vein thrombosis was rare, but hyperglycemia was common. An abbreviated course of treatment is suboptimal in multiple myeloma. Maintenance regimens should be advocated.

Subgroup Analysis of Patients with Cancer in Xalia - a Non-Interventional Study of Rivaroxaban in Routine Treatment of Deep Vein Thrombosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1438-1438 ◽  
Author(s):  
Alexander G G Turpie ◽  
Lorenzo G Mantovani ◽  
Sylvia Haas ◽  
Reinhold Kreutz ◽  
Danja Monje ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Venous Thromboembolism ◽  
Major Bleeding ◽  
Research Funding ◽  
Incidence Rates ◽  
Vein Thrombosis ◽  
All Cause Mortality ◽  
Recurrent Vte ◽  
Deep Vein ◽  
Active Cancer

Abstract Background: XALIA is a prospective, non-interventional study of rivaroxaban in the treatment of acute deep vein thrombosis. The overall XALIA results showed that rivaroxaban was associated with similarly low rates of major bleeding and symptomatic recurrent venous thromboembolism (VTE) as standard anticoagulation. A subset of patients in XALIA had active cancer at the time of enrolment into the study. Purpose: To describe the demographics, clinical characteristics, treatment strategies and outcomes of patients in XALIA with cancer and VTE. The primary outcomes were major bleeding, recurrent VTE and all-cause mortality. Methods: Patients with deep vein thrombosis with or without concomitant pulmonary embolism aged ≥18 years who had active cancer and were scheduled to receive ≥3 months of anticoagulation with rivaroxaban or standard therapy were eligible. Therapy type, dose and duration were at the physician's discretion. For the purpose of this substudy, we defined the following treatment cohorts: rivaroxaban cohort (patients treated with rivaroxaban alone or who received heparin/fondaparinux for ≤48 hours before switching to rivaroxaban); early switchers cohort (patients treated with rivaroxaban who received heparin/fondaparinux for >48 hours-14 days and/or a vitamin K antagonist [VKA] for 1-14 days before changing to rivaroxaban); standard anticoagulation cohort (patients treated with heparin/fondaparinux and a VKA or a VKA only); and heparin/fondaparinux cohort (patients treated with heparin/fondaparinux alone). Results: Of 5136 patients in XALIA who received study medication, 587 (11.4%) had active cancer at baseline. Of these, 146 (24.9%) received rivaroxaban, 30 (5.1%) were early switchers, 167 (28.4%) received standard anticoagulation (of which 26 [4.4%] received a VKA only) and 244 (41.6%) received heparin/fondaparinux only, of whom 223 (38.0%) received low molecular weight heparin and the remainder other heparins or fondaparinux. Demographics are shown in Table 1. The most common type of active cancer at baseline in all cohorts was genitourinary, with the exception of the heparin/fondaparinux cohort where gastrointestinal cancer was the most common type (Table 2). The incidence rates for the primary outcomes for each cohort are shown in Figure 1. The rates of major bleeding were highest in the standard anticoagulation cohort (n=8 [4.8%]) and lowest in the early switchers (no major bleeding events occurred). The rates of recurrent VTE were similar in the in the rivaroxaban, early switcher and standard anticoagulation cohorts (n=5 [3.4%], n=1 [3.3%] and n=6 [3.6%], respectively) and were highest in the heparin/fondaparinux cohort (n=12 [4.9%]). All-cause mortality was highest in the heparin/fondaparinux cohort (n=61 [25.0%]) and lowest in the early switchers (no deaths occurred). Conclusions: In the real-world XALIA study, 38.0% of patients with cancer received treatment with low molecular weight heparin, which was in line with guidelines. The remaining patients received rivaroxaban, standard anticoagulation or were early switchers. For the three primary outcomes, the lowest incidence rates were observed in the early switcher cohort. The highest rates were in the standard anticoagulation cohort for major bleeding and the heparin/fondaparinux cohort for recurrent VTE and all-cause mortality; rates for all three primary outcomes were low in the rivaroxaban cohort, suggesting that rivaroxaban may be a safe and effective treatment option for patients with VTE and active cancer. Figure 1 Primary outcomes in patients with active cancer at baseline by treatment group. VTE, venous thromboembolism. Figure 1. Primary outcomes in patients with active cancer at baseline by treatment group. / VTE, venous thromboembolism. Disclosures Turpie: Janssen Research & Development, LLC: Consultancy, Honoraria; Bayer Pharma AG: Consultancy, Honoraria. Mantovani:Janssen-Cilag Ltd: Research Funding; Boehringer Ingelheim: Research Funding; Daiichi Sankyo: Consultancy; Bayer Pharma AG: Consultancy; Pfizer Inc: Research Funding. Haas:Sanofi SA: Consultancy; Pfizer Inc: Consultancy; Daiichi Sankyo: Consultancy; Bristol-Myers Squibb: Consultancy; Bayer Pharma AG: Consultancy; Aspen Pharmacare: Consultancy. Kreutz:Bayer Pharma AG: Honoraria; Servier Laboratories Ltd: Consultancy; Lundbeck Ltd: Consultancy; Daiichi Sankyo: Consultancy; Berlin-Chemie Menarini: Consultancy; Bayer Pharma AG: Consultancy; Bristol-Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria. Monje:Bayer Pharma AG: Employment. Schneider:Bayer Pharma AG: Employment. van Eickels:Bayer Pharma AG: Employment. Gebel:Bayer Pharma AG: Employment. Ageno:Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Bayer Pharmaceuticals: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Bayer Pharma AG: Consultancy, Honoraria.

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

Rapid Control of Previously Untreated Multiple Myeloma with Bortezomib-Thalidomide-Dexamethasone Followed by Early Intensive Therapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 784-784 ◽  
Author(s):  
Michael Wang ◽  
Kay Delasalle ◽  
Sergio Giralt ◽  
Raymond Alexanian
Keyword(s):  
Multiple Myeloma ◽  
Side Effects ◽  
Complete Remission ◽  
Intensive Therapy ◽  
Newly Diagnosed ◽  
Bence Jones Protein ◽  
Myeloma Protein ◽  
Disease Remission ◽  
Vein Thrombosis ◽  
Deep Vein

Abstract With the combination of thalidomide - dexamethasone (TD), we had induced disease remission in 62% of 132 newly diagnosed patients with multiple myeloma (MM) usually with preventable or manageable side effects (constipation, insomnia, edema). With added bortezomib, the 3-drug combination (VTD) had induced remission in 55% of patients with myeloma resistant to standard therapies, twice the frequency of 28% observed with bortezomib alone (Zangari et al, 2003). Between 7/03 - 5/05, we prescribed VTD for 36 consecutive, previously untreated patients. Median age was 60 (33–80), median B2M 4.2 mg/L (1.4–19), median Hgb 10.2 g/dl (6.8–15.5), creatinine > 2.0 mg/dl in 19%. Initial dose of thalidomide was 100 mg each evening, increased every 7 days to maximum of 200 mg in accordance with tolerance; dexamethasone was given in a dose of 20 mg/m2 for 4 days beginning on days 1, 9 and 17. Bortezomib was given IV twice weekly for 4 infusions in 3 different doses after one patient inadvertently received 1.9 mg/m2 without side effects and rapid onset of complete remission; 15 patients received 1.3 mg/m2, 11 patients were given 1.5 mg/m2 and 10 patients received > 1.6 mg/m2. As prophylaxis of deep vein thrombosis, all received therapeutic doses of low-molecular weight heparin or coumadin to maintain INR between 2.0–3.0. Applying strict criteria of response (>75% reduction serum myeloma protein and/or 99% reduction Bence Jones protein), disease remission was observed in 28 patients (78%) including 7 patients with complete remission (19%); with prior standard criteria (>50% reduction serum myeloma protein and/or >90% reduction Bence Jones protein excretion), the response rate was 92%. Response rates by either criteria were 30% higher than those observed previously among similar patients treated with TD (p < .01). Response rates with bortezomib doses > 1.5 mg/m2 were similar to those with 1.3 mg/m2, suggesting no added value with a dose higher than 1.3 mg/m2. Remissions were confirmed within 1.5 months in all responding patients so that no more than 2 cycles of therapy were necessary before intensification or maintenance, thus avoiding potential side effects and cost of more therapy. Side effects were often preventable, but otherwise were mild and reversible; deep vein thrombosis occurred in 2 patients, short-term neuropathy of grade 3 degree in 3 patients, serious non-neutropenic infections in 3 patients and orthostatic hypotension in 1 patient. Median nadir of neutrophil count was 2930/μl (range 500 – 8200); median nadir of platelet count was 130,000/μl (range 28,000–268,000). After median 4 months, intensive therapy supported by autologous blood stem cells was given to 22 patients without serious complications; primary resistant disease became responsive in 4 of 6 patients, partial remission was converted to complete in 3 of 13 patients, and 3 patients were intensified in CR. Consequently, the myeloma was in remission in 89% of all patients by strict criteria including 31% with complete remission. This experience supported a limited program of bortezomib-thalidomide-dexamethasone, followed by early intensive therapy, as an effective and safe primary treatment for newly diagnosed patients with multiple myeloma.

Thalidomide and Deep Vein Thrombosis in Multiple Myeloma: Risk Factors and Effect on Survival

2003 ◽  
Vol 4 (1) ◽  
pp. 32-35 ◽  
Author(s):  
Maurizio Zangari ◽  
Bart Barlogie ◽  
Raymond Thertulien ◽  
Joth Jacobson ◽  
Paul Eddleman ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Deep Vein Thrombosis ◽  
Vein Thrombosis ◽  
Deep Vein
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