Risk Factors of Thromboembolic Events in Multiple Myeloma Treated with IMiDs-Based Therapy While on LMWH Prophylaxis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3340-3340
Author(s):  
Xavier Leleu ◽  
Simona Iacobelli ◽  
Alain Barrois ◽  
Benjamin Pelle ◽  
Liz Clark ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Research Funding ◽  
Autologous Transplantation ◽  
Working Party ◽  
Routine Practice ◽  
Thromboembolic Events ◽  
Minor Response ◽  
Oral Agents ◽  
Increased Risk

Abstract Abstract 3340 Background. Immunomodulator drugs (IMiDs) are promising oral agents in Multiple Myeloma (MM); and MM that cannot benefit from novel agents, including IMiDs, only have 9 months survival. On the other hand IMiDs are associated with an increased risk of thromboembolic events (TE) in MM, and must be stopped when TE occurs with a potential shortened life expectancy. Although DVT (Deep Venous Thrombosis), including PE (Pulmonary Embolism), was primarily observed, arterial events were also described. Guidelines have proposed LWMH for VTE prophylaxis for patients that displayed greater than 2 risk factors of VTE. Studies have showed a decrease incidence of TE since a prophylaxis was mandatory; however TE remained despite use of LMWH. We sought to characterize and study the incidence of TE in MM treated with an IMiDs-based regimen and having LMWH as TE prophylaxis, and to determine risk factors for patients to develop TE. Method. MMVAR/IFM 2005–04 is a large multicenter, prospective, randomized, open-label, phase 3, EBMT and IFM combined study that compared VTD to TD for MM patients in first progression after autologous transplantation. Treatment comprised 8 cycles of bortezomib 1.3 mg/m2 IV bolus on days 1, 4, 8 and 11 of a 21-days cycle and then on days 1, 8, 15 and 22 of a 42-days cycle for 4 more cycles. In both arms, oral thalidomide was administered at 200 mg/day for 1 year with dexamethasone at 40 mg/day for 4 days every 3 weeks for 1 year. A TE prophylaxis was mandatory in both arms using enoxaparin 40 mg/day during one year. TTP was the primary end point. Response was assessed by EBMT criteria. Adverse events were graded by the NCI-CTCAE, Version 3.0. Results. The MMVAR trial was stopped because of superiority of VTD over TD at first interim analysis, as 157 relapsed were recorded out of 267 patients randomized in arm VTD (n=135) and arm TD (n=132), respectively. With a median follow-up of 27 months, the probability of achieving CR and CR+PR during the first year, the median TTP and PFS were greater in the VTD arm, although it did not translate into a better OS, yet. In the VTD and TD arms, the mean number of treatment cycles for the 12 cycles was 7.56 vs 9.93, respectively. Treatment was discontinued due to toxicity in 48 patients, including 8 (17%) related to occurrence of TE, and 33 patients died during the treatment period. There were 24 (8.9%) TE recorded, 12 in either arm; we have then decided to pool the 2 groups for the subsequent analysis. The characteristics of the MM with TE were not different from the overall population, 14 male/10 female, median age (range) was 63 (42–76) with 25% patients older than 65. The median (min-max) time from start of MMVAR to occurrence of TE was 3.4 months (0.3–11.9), not different in either arm. TE occurred in 16 (66%) vs. 8 (33%) patients in the first 4 months and after 4 months, respectively. 15 (62.5%) pts had at least some tumor burden reduction (minor response and better) at time of occurrence of TE, while 12.5% had progression of MM, 12.5% stable disease, and 12.5% were non evaluable. All TE occurred while pts were on LMWH prophylaxis since the initiation of the study treatment but one. The occurrence of TE impacted the treatment of MM as 16 (67%) pts did stop their IMiDs-based treatment, either transiently for 8 (33%) pts or definitely for 8 (33%) pts. The doses of the IMiDs were reduced for 5 pts when IMiDs were reintroduced. Overall only 5 pts had no change applied to their MM treatment while TE occurred. The occurrence of TE might have impacted response rate, CR rate, and the survival end points, TTP, PFS and OS. An update of this sub analysis will be presented at ASH with multivariate analysis to determine risk factors for occurrence of TE while on LMWH prophylaxis. Conclusion. Although LMWH is recommended to patients with high risk of TE, the optimal dose and duration of LMWH remains to be determined. More studies are needed to determine risk factors of TE in MM patients treated with IMiDs-based regimen, and to guide physician in their routine practice with the optimal TE prophylaxis. On behalf of the Myeloma Subcommittee of the Chronic Leukemia Working Party of the EBMT (European Group for Blood and Marrow Transplantation) and the IFM (Intergroupe Francophone du Myélome). Disclosures: Leleu: Amgen: Honoraria; Roche: Research Funding; Janssen Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; LeoPharma: Honoraria, Research Funding; Novartis: Research Funding. Masszi:Centocor Ortho Biotech Research & Development: Research Funding. Hajek:Merck:; Janssen: Honoraria; Celgene: Honoraria.

Final Analysis of MELISSE, a Large Multicentric Observational Study to Determine Risk Factors of Venous Thromboembolism in Patients with Multiple Myeloma Treated with Immunomodulator Drugs

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1235-1235 ◽  
Author(s):  
Xavier Leleu ◽  
Laurent Daley ◽  
Philippe Rodon ◽  
Cyrille Hulin ◽  
Charles Dauriac ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
High Risk ◽  
Incidence Rate ◽  
Research Funding ◽  
Final Analysis ◽  
Vte Prophylaxis ◽  
High Risk Patients ◽  
Increased Risk ◽  
Risk Patients

Abstract Abstract 1235 Background. Immunomodulator drugs (IMiDs) are associated with an increased risk of thromboembolic events (TE). Multiple Myeloma patients (MM) that can not benefit from novel agents, including IMiDs, only have 9 months survival. IMiDs must be stopped when TE occurs with the consequence of potential shortened life expectancy. MELISSE was designed to prospectively evaluate the incidence and risk factors of venous TE (VTE) associated with IMiDs in MM. We have presented the interim analysis of MELISSE at ASH 2010. A reduced incidence rate of early VTE was observed when a prophylaxis for VTE was started as compared to patients that had no prophylaxis. Interestingly, we also reported that most of the patients had received aspirin, while aspirin is not considered to exert any venous prophylactic effect. LMWH was primarily proposed to patients with high risk of TE according to physician's evaluation. We present the final analysis of MELISSE with updated results at 1 year. Method. A total of 524 MM treated with IMiDs-based therapy were included in 52 IFM centers. VTE prophylaxis was recommended prior to start IMiDs, the choice of which was left at the discretion of the investigator. Patients gave written informed consent according to the declaration of Helsinki. The physicians were to record the risk of VTE occurrence, categorized as low, moderate and high, based on guidelines and their own appreciation of the risk. Occurrence of any VTE was to be recorded along with the management of the event and the patient's outcome. The data were collected at entry in the study, and then after 4 and 12 months. Results. The median age was 70 years old, with 64.67% of patients >65 years old. Overall 36.0% had thalidomide-based and 64.0% had lenalidomide-based therapy, with 180 patients in first line and the remaining patients in 2nd and 3rd lines of therapy. The observed repartition of TE risk factors was as expected in a European population with myeloma. The risk of VTE was assessed as high in 14.2% patient and small or intermediate otherwise. Interestingly, approximately 70% of patients rated as low and intermediate risk received aspirin as a routine prophylaxis for VTE as compared to 20% in high risk patients. LMWH was primarily given to high risk patients, 45.8%. Surprisingly, 16.0% of patients had no VTE prophylaxis. Investigators recorded 29 (5.5% annual incidence rate) TE at 12 months, including 12 associated with PE. The incidence rate of TE was similar within the first 4 months (early occurrence, 3.5%) versus after 4 months (late, 2.5%). We have not identified any risk factor that would explain early versus late occurrence of VTE. Interestingly, the incidence of VTE was higher in patients that had no prophylaxis treatment, 8.5%, as compared to 4.4% and 5.9% in the LMWH and aspirin groups, respectively. There was no PE recorded in patients that were on LMWH prophylaxis. The VTE was equally breakdown across the 3 groups of risk factors. The bleeding adverse events were reported for 27 patients, mainly patients with aspirin. We isolated a model with 3 variables that independently predicted a higher risk to develop VTE in the multivariate model, and that comprised the male gender [OR 4.31 (95% CI 1.60 – 13.90)], the smoking habit [6.76 (1.73–22.42)] and the association to EPO [2.66 (1.04–6.58)]. Aspirin showed no significance, but with a p value at 0.55. The multivariate analysis is limited as certain subgroups with high risk factors might have received the optimal VTE prophylaxis, such as patients with bed rest and patients with prior history of VTE. These 2 groups rarely had aspirin. Survival data will be updated and presented at ASH 2011. Conclusion. This study further demonstrates that TE prophylaxis is required for MM treated with IMiDs-based therapy. There is a slight increase risk of VTE/PE with the use of aspirin as compared to LMWH, but a significant increase in bleeding events. Although we have identified risk factors of VTE in MM treated with IMiDs, for the first time, we could not identified VTE risk factors to guide investigators between LMWH and aspirin-based prophylaxis. The optimal dose and duration of LMWH remains to be determined. Disclosures: Leleu: LeoPharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Research Funding; Amgen: Honoraria; Novartis: Research Funding. Daley:LeoPharma: Employment. Hulin:Janssen: Honoraria; Celgene: Honoraria. Lamblin:LeoPharma: Employment. Natta:LeoPharma: Employment.

scholarly journals Incidence of Second Primary Malignancies and Association with Treatment in US Veterans with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1806-1806
Author(s):  
Nathanael Fillmore ◽  
Sarvari Venkata Yellapragada ◽  
Cenk Yildirim ◽  
Aimaz Afrough ◽  
Adanma Anji Ayanambakkam Attanathi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Research Funding ◽  
Treatment Initiation ◽  
Smoking Status ◽  
Agent Orange ◽  
Second Primary ◽  
Increased Risk ◽  
Second Primary Malignancies ◽  
Central Cancer Registry

Background: In the recent decade, there have been dramatic improvements in multiple myeloma (MM) survival, owing principally to developments in therapeutic options. However, these developments have also raised concerns as to increase in second primary malignancies (SPMs) attributable to these therapies. For example, a Swedish study showed an increased risk of developing acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) in MM patients (11.51 fold), along with 1.19-fold increased risk of non-hematologic malignancies. However, it is presently unclear whether this increase is related to therapy or other factors such as host, environment or behavioral patterns. Here, we study incidence of SPM and association with demographics, exposure, and therapy in a large population in the US Veterans Affairs (VA) healthcare system. Methods: We used the VA's nationwide Corporate Data Warehouse to identify patients diagnosed with MM from 1999 to 2017, as well as their age, race, therapy at induction, stem-cell transplant status, and exposure status. For each patient, we identified the first SPM after MM treatment initiation using the VA Central Cancer Registry. We excluded patients who had records of malignancies prior to MM treatment initiation. Results: We identified 14,261 patients meeting the inclusion criteria, of whom 552 (3.9%) had SPMs, consistent with prior literature. Median age at MM diagnosis was 69.22 years overall (95% CI 51.98-84.76), 66.7 years (52.03-83.86) for those with SPM, and 69.32 years (51.99-) for those without SPM. Median age at diagnosis of SPM was 70.2 years (55.43-86.75). Median time from MM treatment initiation to SPM was 2.38 years (0.09-9.37). Of the 552 observed SPMs, 69 (12.4%) were hematologic (25 MDS, 19 lymphoma, 15 acute leukemia, 6 chronic leukemia, 4 MPN) while 84.5% (466) were oncologic. Prostate cancer was the most common SPM (n=125, 22.6%). We did not observe statistically significant differences in incidence of SPM by smoking status (4.1% among current/former smokers vs 3.7% among never smokers; P=0.347), or Agent Orange exposure (4.2% among those exposed vs 3.8% among those not exposed; P=0.476). We also examined the relationship of common treatments to SPM. SPM is more common among those exposed to lenalidomide (4.3% vs 3.4%, p=0.003), bortezomib (4.8 vs 3.3%, p<0.001), and transplant (7.5% vs 3.5%, p<0.001). Considering only therapy at induction, SPMs occur among 3.3% of those receiving lenalidomide/dexamethasone (Rd), 4.0% of those receiving bortezomib/dexamethasone (Vd), and 4.5% of those receiving RVd (p=0.11). Among those who also received transplant, SPM occurs in 6.0%, 6.6%, and 8.7% of those receiving Rd, Vd, and RVd, respectively (p=0.49). And, among those who did not receive transplant, SPM occurs in 3.1%, 3.5%, and 3.7% of cases, respectively (p=0.52). Conclusion: In comparison to data from the VA Central Cancer Registry on cancer incidence at the VA in general, the incidence of SPM (3.9%) that we report among MM patients is substantially higher than the overall incidence of malignancy in the VA (0.78%). Moreover, we find that common risk factors for developing malignancy, including smoking status and exposure to Agent Orange, are not significantly associated with developing SPM after MM diagnosis. In contrast, we find that therapy utilization, particularly transplant, is associated with significant increases in susceptibility to SPM. Better understanding of these risk factors is needed to appropriately assess the tradeoff of decreased myeloma-related mortality, but potentially increased risk of secondary malignancies with common myeloma therapy options. Disclosures Yellapragada: Novartis: Employment, Other: Spouse Employment ; Celgene: Research Funding; BMS: Research Funding; Takeda: Research Funding. Munshi:Abbvie: Consultancy; Adaptive: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Oncopep: Consultancy; Abbvie: Consultancy.

Risk of Venous Thromboembolism in Multiple Myeloma: Identification of Risk Factor

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4726-4726 ◽  
Author(s):  
Kristen M. Sanfilippo ◽  
Natasha Catherine Edwin ◽  
Brian F. Gage ◽  
Suhong Luo ◽  
David Calverley ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Multivariate Analysis ◽  
Venous Thromboembolism ◽  
Research Funding ◽  
Laboratory Data ◽  
Cell Transplant ◽  
Filter Placement ◽  
Blood Institute ◽  
Increased Risk

Abstract Background Compared to the general population, patients with multiple myeloma (MM) have a 9-fold increased risk of developing venous thromboembolism (VTE). VTE is a preventable disease that causes death and morbidity. Thromboprophylaxis is a safe and effective way to decrease VTE in other high-risk populations (i.e. atrial fibrillation). Current guidelines recommend pharmacologic thromboprophylaxis in patients with MM receiving an immunomodulatory agent in the presence of additional VTE risk factors. However, putative risk factors vary across guidelines and lack validation. Recently, an attempt to validate the International Myeloma Working Group 2014 guidelines for thromboprophylaxis found current risk factors to be inadequate. Identification of risk factors for VTE in MM can allow for effective risk-stratification to clarify thromboprophylaxis in the MM population. We sought to identify risk factors for VTE in patients with MM. Methods We identified patients diagnosed with MM within the Veterans Administration Central Cancer Registry from September 1, 1999 and December 31, 2013 and followed them through October 2014. We excluded patients who did not receive MM-directed therapy within 6 months of diagnosis. Using a previously validated algorithm, (Thromb Res, 2015), we identified patients diagnosed with VTE after MM diagnosis by a combination of ICD-9 code for VTE plus pharmacologic treatment for VTE or IVC filter placement. We obtained information on baseline patient demographics, medical comorbidities, laboratory data, MM-directed therapy, and use of aspirin and/or warfarin. Univariate analyses identified the association between individual variables and VTE in the cohort. Clinically meaningful and significant associations were included in the multivariate model. Multivariate analysis was done using competing risks regression modeling. The study was approved by the Saint Louis VHA Medical Center and Washington University institutional review boards. Results A total of 3,384 patients comprised the final cohort of whom 414 developed a VTE. Patients who developed VTE were more likely to be younger (66.2 vs 68.5, p < .001), have a body mass index (BMI) ≥ 25 (p < .001), be diagnosed with MM prior to 2007 (p < .001), have a VTE before MM diagnosis (p < .001), have a lower comorbidities (p < .001), have received autologous stem cell transplant (ASCT) (p < .001), have received lenalidomide, thalidomide, or bortezomib (p < .001), and less likely to have received warfarin (p < .001). Among predefined risk factors, age (Hazard Ratio (HR) 0.99, 95% Confidence Interval (CI) 0.98-1.00, p = 0.02), VTE before MM diagnosis (HR 4.13, 95% CI 2.81-6.05, p < .001), heart failure (HR 0.70, 95% CI 0.51-0.96, p = 0.03), treatment with thalidomide (HR 2.02, 95% CI 1.63-2.50, p < 0.001), BMI ≥ 30 (HR 1.34, 95% CI 1.03-1.74, p = 0.03), and diabetes mellitus (HR 0.79, 95% CI 0.63-0.99, p = 0.04) were associated with VTE. After inclusion into multivariate analysis and adjusting for warfarin/aspirin use; age, BMI, year of MM diagnosis, VTE before MM, thalidomide, warfarin, and aspirin were all associated with VTE in MM (Table 1). Conclusion We identified several risk factors associated with VTE in MM. Incorporation of these risk factors into a MM-specific risk model has the potential to reduce risk of VTE in MM. Disclosures Sanfilippo: National Heart, Lung, and Blood Institute: Research Funding. Gage:National Heart, Lung, and Blood Institute: Research Funding. Carson:American Cancer Society: Research Funding.

scholarly journals Younger Age at Diagnosis Is Associated with an Increased Risk of Venous Thromboembolism in Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1223-1223 ◽  
Author(s):  
Aisling Barrett ◽  
John Quinn ◽  
Siobhan Glavey ◽  
Jeremy Sargent ◽  
Michelle Lavin ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Logistic Regression ◽  
Venous Thromboembolism ◽  
Research Funding ◽  
P Value ◽  
Younger Age ◽  
Increased Risk ◽  
The Mean

Abstract Introduction Multiple Myeloma (MM) patients are at an approximately 9-fold increased risk of developing venous thromboembolism (VTE), with risk being highest in the first year following diagnosis1. VTE is associated with significant morbidity and negatively influences survival in MM2. Although the Khorana score has been shown to predict rate of thrombosis in solid tumors, the validity of this score in haematological malignancies has yet to be assessed. Given the elevated rates of VTE in these conditions, in particular MM, clinically relevant risk prediction scores are essential. Additionally, data from the MRC-XI trial indicates that standard thromboprophylaxis may not prevent VTEs in MM3. Therefore identification of risk factors for MM-VTE are required to improve our understanding of the pathophysiology of thrombosis and to develop risk-adapted clinical practice guidelines. Through interrogation of an extensive clinical database we sought to identify factors predictive for VTE in our MM population. Methods We performed a retrospective cohort study of all newly diagnosed MM patients at our centre from 2001-2017. Patient medical records were reviewed for clinical and laboratory data including FBC parameters, beta-2-microglobulin, paraprotein and serum free light chain on the day of diagnosis, to minimize steroid effect. All VTE events were recorded, along with MM treatment regimen and thromboprophylaxis at time of event. History of thrombosis was defined as occurring within 6 month prior to, or following a diagnosis of MM. Patients with MGUS or smoldering MM were excluded. Statistical analysis including logistic regression and cox proportional hazard modelling was performed using SPSS (IBM Analytics, USA). A comparison of mortality was also performed between age matched cases with VTE and controls without VTE. Results Over a period of 17 years, 266 patients were diagnosed with myeloma, of which 34 (12.7%) developed VTE following MM diagnosis or within the preceding six months. The mean age of the VTE cohort at MM diagnosis was younger than the mean age of the non-VTE cohort (62.5 years vs. 68.6 years). Pulmonary embolisms and deep vein thromboses were equally represented (44% and 56% respectively) and additional risk factors for thrombosis were present in 46% of patients, not related to MM therapy. Of the patients on immunomodulatory drugs or corticosteroids at time of VTE, all were receiving thromboprophylaxis with either low molecular weight heparin (LMWH) or aspirin at time of VTE. The mortality odds ratio was 3.3 (95% CI 2.4-4.5) in patients who developed VTE in comparison to age matched controls with MM. Younger age at MM diagnosis (<64 years) predicted for VTE occurrence in logistic regression univariate (p-value=0.002) and multivariate analysis (p=0.004). Higher white cell count (WCC) at MM diagnosis showed a trend toward significance in univariate analysis (p-value=0.06) and, in combination with age, demonstrated an area under the curve of 0.72 on ROC analysis for prediction of VTE. Interestingly, the increased risk of VTE in younger patients was not related to longer duration of MM exposure or longer follow up as there was no statistically significant difference in time to VTE between all age groups (median 9 months). Other parameters incorporated in the Khorana score, such as haemoglobin and platelet count did not increase the risk of VTE (p-value=0.57, and 0.25 respectively). Conclusions Our data confirms that VTE is associated with an increased mortality in MM patients and estimates the risk of death to be 3.3 fold higher in these patients. As recently reported in a large cohort of MM patients, younger age is associated with an increased risk of VTE development4, our data support this finding and excludes longer duration of MM, and follow-up time, as confounding variables. Importantly, our data confirms, in unselected "real world" patients the signal that is now apparent from analysis of VTE in the MRC-XI trial3, that thromboprophylaxis with LMWH or aspirin is suboptimal for VTE prevention. This may point to alternative thrombotic mechanisms in MM-VTE and further data in larger MM cohorts is needed to develop risk adapted strategies for prevention strategies for these patients. References Kristinsson SY et el, Blood. 2008 Nov 1;112(9):3582-6. Schoen MW et al. J Clin Oncol 36, 2018 (suppl; abstr 8051). Bradbury CA et al, Blood 2017 130:553. Sanfilippo KM et al. Blood 2016;128:4726. Disclosures Quinn: Janssen: Honoraria. Lavin:Shire: Honoraria, Research Funding, Speakers Bureau. O'Donnell:Baxter: Research Funding, Speakers Bureau; Octapharma: Speakers Bureau; CSL Behring: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau; Leo Pharma: Speakers Bureau.

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

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

Abstract Background: Novel agents such as proteasome inhibitors have been developed for several years to treat multiple myeloma. Although multiple myeloma is a low-risk disease for developing tumor lysis syndrome (TLS), treatment with these novel therapies might increase TLS risk. Previous studies, mostly case reports or case series, have reported bortezomib-induced TLS in patients with multiple myeloma. This study aimed to investigate risk factors associated with TLS development in multiple myeloma patients.Methods: We retrospectively investigated incidences of laboratory and clinical TLS (LTLS and CTLS, respectively) in patients who received primary therapy for treatment-naive, symptomatic multiple myeloma between May 2007 and January 2018. We used multivariate logistic regression analyses to evaluate the associations between TLS and several parameters previously reported to be associated with increased risk.Results: This study included 210 patients with multiple myeloma, of which ten (4.8%) had LTLS and seven (3.3%) had CTLS. The characteristics of the administered anticancer or prophylactic antihyperuricemic agents were similar between patients with and without TLS. Multivariate analyses revealed that TLS was most strongly associated with bortezomib-containing therapy (odds ratio = 3.40, P = 0.069), followed by male sex (odds ratio = 2.29, P = 0.153). In a subgroup analysis focused on men, treatment with bortezomib-containing therapy was significantly associated with increased risk of TLS (odds ratio = 8.51, P = 0.046).Conclusion: In the present study, we investigated the risk factors associated with TLS development in 210 multiple myeloma patients, which, to the best of our knowledge, is the largest number of patients reported to date. Furthermore, this study is the first to evaluate TLS risk factors in MM by adjusting for the effects of potential confounding factors in patients’ backgrounds. Consequently, we found that bortezomib-containing therapy increases the risk of TLS in male patients with multiple myeloma. TLS risk should be evaluated further in low-risk diseases such as multiple myeloma, since a significant number of novel therapies can achieve high antitumor responses.

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 Incidence, Management and Outcomes of Arterial and Venous Thromboembolism after Chimeric Antigen Receptor Modified T Cells for B-Cell Lymphoma and Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-7
Author(s):  
Anna L. Parks ◽  
Swetha Kambhampati ◽  
Bita Fakhri ◽  
Charalambos Andreadis ◽  
Lissa Gray ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
T Cells ◽  
Venous Thromboembolism ◽  
B Cell ◽  
Research Funding ◽  
Vte Prophylaxis ◽  
Therapeutic Anticoagulation ◽  
Car T ◽  
History Of

Introduction: Chimeric antigen receptor modified T Cell (CAR-T) therapy is a rapidly developing treatment for patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). Although this population is at high risk for thrombosis, there are few data about rates of venous thromboembolism (VTE) and arterial thromboembolism (ATE) with CAR-T. Additionally, treatment with anticoagulation is complicated because of the prevalence of thrombocytopenia following CAR-T. Our goal was to determine the incidence, associated risk factors, management and outcomes of VTE and ATE in the 60 days following CAR-T therapy. Methods: We performed a single-center, retrospective cohort study of all patients who received inpatient CAR-T cells at UCSF Medical Center between January 2018 and May 2020 for R/R NHL or MM as standard-of-care or on a clinical trial. The outcomes of incident VTE and ATE were identified by ICD-10 codes and medical record review. Patient characteristics, pre-existing thrombosis risk factors, laboratory results, medications, and major or clinically relevant non-major bleeding or recurrent thrombotic complications were obtained through chart review. We used descriptive statistics to delineate risk factors, incidence, management and outcomes of thrombotic events. Results: Ninety-one patients who underwent CAR-T therapy were included in the analysis, 37 with NHL and 54 with MM. For NHL, mean age was 63 (range 38-82), and 41% were women. For MM, mean age was 62 (range 33-77), and 50% were women. Patients with NHL were treated with either investigational or Federal Drug Administration-approved CD19-directed therapies, and patients with MM were treated with a variety of investigational B-cell maturation antigen-directed (BCMA) therapies. For thrombotic risk factors, 13% of patients with NHL had a history of VTE, 3% had a history of ATE, 27% had a BMI ≥30, 59% had a recent procedure including central venous catheter (CVC) placement, 14% had an intensive care unit (ICU) stay, and 22% had an infectious complication in the 30 days pre- or post-CAR-T. Forty-one percent of patients with NHL had neurotoxicity of any grade, and 59% had CRS of any grade. At 30 days, 57% had a complete response, 41% had a partial response, 3% had stable disease. For MM, 6% of patients had a pre-existing history of VTE, 2% had a history of ATE, 19% had a BMI ≥30, 96% had a recent procedure, 11% had an ICU stay and 19% had an infection. Seventeen percent had neurotoxicity, and 85% had CRS. Thirty-two percent of patients with NHL and 48% with MM received pharmacologic VTE prophylaxis while undergoing CAR-T. For those who did not receive VTE prophylaxis, thrombocytopenia was the reason for holding prophylaxis, which occurred in 51% and 50% of NHL and MM patients, respectively. In the 60 days post-CAR-T, 4 (11%) patients with NHL were diagnosed with VTE-3 pulmonary embolism (PE) and 1 lower extremity deep vein thrombosis (DVT) associated with a previously placed inferior vena cava filter. Four (7%) patients with MM were diagnosed with VTE-1 PE and 3 upper extremity DVTs associated with CVCs. Five out of these 8 (63%) patients had symptomatic VTE, while the remainder were incidental on PETCT. Mean time from CAR-T infusion to VTE diagnosis was 20 days (range 6-39 days). There were no documented ATEs. Six out of 8 (75%) were treated with therapeutic anticoagulation. Of those who were anticoagulated, 4 patients received direct oral anticoagulants and 2 received low-molecular-weight-heparin. Duration was 3 months in 3 patients, 11 days in 1, 150 days in 1, and indefinitely in 1 with atrial fibrillation. Among all 8 patients with VTE, there were no bleeding events or recurrent thromboses regardless of whether or not they received anticoagulation. Discussion: In this cohort of patients with R/R NHL or MM who received either CD19- or BCMA-directed therapies, almost 1 in 10 developed VTE in the 60 days post-CAR-T. This occurred in the context of a high prevalence of risk factors for thrombosis and low rates of pharmacologic prophylaxis. Among those who developed VTE, the majority were treated with therapeutic anticoagulation for at least 3 months, without documented bleeding or recurrent VTE. Our findings provide crucial information on a common complication that can inform patients, clinicians and researchers and should be expanded upon in larger, prospective studies to identify optimal preventive and therapeutic strategies. Disclosures Fakhri: University of California San Francisco: Current Employment. Andreadis:Jazz Pharmaceuticals: Honoraria; Karyopharm: Honoraria; Incyte: Consultancy; Merck: Research Funding; Gilead/Kite: Consultancy; Novartis: Research Funding; BMS/Celgene/Juno: Honoraria, Research Funding; Genentech: Consultancy, Current equity holder in publicly-traded company. Wong:Janssen: Research Funding; Amgen: Consultancy; Roche: Research Funding; Fortis: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; GSK: Research Funding. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy.

Is prolonged immobilization a risk factor for symptomatic venous thromboembolism in elderly bedridden patients?

2004 ◽  
Vol 91 (03) ◽  
pp. 538-543 ◽  
Author(s):  
Ora Paltiel ◽  
Michael Bursztyn ◽  
Moshe Gatt
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Early Period ◽  
Thromboembolic Events ◽  
Historical Cohort ◽  
Increased Risk ◽  
Venous Thromboembolic Events ◽  
Venous Thromboembolic ◽  
Prolonged Immobilization ◽  
The Impact

SummaryProlonged immobilization and advanced age are considered to be important risk factors for venous thromboembolism (VTE). Nevertheless, the need for VTE prophylaxis in long-term bedridden patients is not known. To assess whether very prolonged immobilization (i.e. over three months) carries an increased risk for clinically apparent VTE, we performed a historical-cohort study of nursing home residents during a ten-year period. Data concerning patient’s mobility and incidence of overt deep vein thrombosis or pulmonary embolism were registered. The mean resident age was 85 ± 8.4 years. Eighteen mobile and eight immobile patients were diagnosed with clinically significant thromboembolic events, during 1137 and 573 patient-years of follow up, respectively. The incidence of venous thromboembolic events was similar in both chronically immobilized and mobile patient groups, 13.9 and 15.8 per thousand patient years, respectively (p = 0.77). The rate ratio for having a VTE event in the immobilized patient group as compared with the mobile group was 0.88 (95% Confidence Interval (CI) 0.33 to 2.13). When taking into account baseline characteristics, risk factors and death rates by various causes, no differences were found between the two groups. In conclusion, chronically immobile bedridden patients are no more prone to clinically overt venous thromboembolic events than institutionalized mobile patients. Until further studies are performed concerning the impact of very prolonged immobilization on the risk of VTE, there is no evidence to support primary prevention after the first three months of immobilization. Evidence for efficacy or cost effectiveness beyond this early period is not available.

Influence of Cytogenetics in Patients with Relapsed and Refractory Multiple Myeloma (MM) Treated with Carfilzomib (CFZ).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1827-1827 ◽  
Author(s):  
Andrzej Jakubowiak ◽  
Luhua Wang ◽  
Robert Z Orlowski ◽  
Sundar Jagannath ◽  
David Siegel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Single Agent ◽  
Entire Group ◽  
Fish Analysis ◽  
Advisory Committees ◽  
Minor Response

Abstract Abstract 1827 Poster Board I-853 Background It is now well established that cytogenetic abnormalities can affect the responses to therapies in multiple myeloma (MM) patients. Bortezomib, used alone or in combination with other agents, has been shown to overcome the adverse impact of several common unfavorable cytogenetic features. More recently, responses with lenalidomide and dexamethasone have been reported in patients with some types of unfavorable cytogenetics. Carfilzomib (CFZ) is a novel proteasome inhibitor that has demonstrated single agent activity in relapsed and/or refractory MM patients. The objective of this analysis was to provide the first preliminary information on the influence of cytogenetics in patients (pts) with relapsed and/or refractory MM treated with CFZ. Methods We evaluated 79 pts treated on two single agent CFZ studies (PX-171-003 and PX-171-004) in relapsed and/or refractory myeloma in which metaphase cytogenetics and/or FISH analysis for del 13q, t(4:14), and t(14;16) chromosomal abnormalities were available. Metaphase cytogenetics was conducted for all pts in the analysis; fluorescence in situ hybridization (FISH) results were available for 28 of the 79 pts. Twenty-one pts with relapsed and refratory MM (PX-171-003) and 58 pts with relapsed or refractory MM (PX-171-004) received CFZ at 20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 in a 28-day cycle for up to 12 cycles. For this analysis, responders were defined as pts who achieved at least a Minor Response (MR) [MR + Partial Response (PR) + Very Good Partial Response (VGPR) + Complete Response (CR)] by IMWG and EBMT criteria. Results The median age of analysed pts was 63 yrs and 100% of pts were relapsed, with 70% refractory to their last therapy. Analysis of their histories demonstrated prior thalidomide treatment in 75% of pts, prior lenalidomide treatment in 57%, prior bortezomib treatment in 55%, and prior stem cell transplantation in 84%. The response rate (≥MR) for the entire group of patients was 40.5%. Twenty three of 79 pts had at least one of the abnormalities. The presence of del 13q, t(4;14), or t(14;16) did not significantly change the response rates, with 43.5% of pts with one or more abnormalities responding compared to 39.3% with none. The median time to progression (TTP) for all patients in this analysis was 203 days. The TTP for pts with one or more of the abnormalities was 195 days and was not significantly different from the TTP of 208 days for pts with none of the abnormalities (Figure; P > 0.05). Conclusion In this preliminary analysis, CFZ showed comparable activity in relapsed and relapsed/refractory MM with del 13q and/or t(4:14), and/or t(14;16) versus none of these abnormalities, with ≥MR in 43.5% vs. 39.3% of patients, and a TTP of 195 vs. 208 days, respectively. Updated efficacy data and TTP data will be presented at the meeting. Disclosures Jakubowiak: Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wang:Proteolix, Inc.: Research Funding. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Kukreti:Celgene: Honoraria. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. McDonagh:Proteolix: Research Funding. Vallone:Proteolix, Inc.: Employment. Kauffman:Proteolix, Inc.: Employment. Vij:Proteolix: Research Funding.

Low Frequency of CD161+CD4+ T Cells Correlate with the Occurrence of Infections in Refractory/Relapsed Multiple Myeloma Patients Receiving Lenalidomide Plus Low-Dose Dexamethasone Treatment

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5621-5621
Author(s):  
Sung-Eun Lee ◽  
Ji-Young Lim ◽  
Da-Bin Ryu ◽  
Tae Woo Kim ◽  
Sung Soo Park ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Peripheral Blood ◽  
Low Dose ◽  
Immune Cell ◽  
Cell Populations ◽  
Absolute Count ◽  
Hla Dr ◽  
Increased Risk ◽  
Univariate Analyses

Abstract Background Although the combination of lenalidomide and low-dose dexamethasone (Len-dex) is known to preserve the efficacy with reduced toxicity than lenalidomide plus high-dose dexamethasone (Len-Dex) in patients with refractory/relapsed multiple myeloma (RRMM), infection is still a leading toxicity. Moreover, the patterns and risks for infection in patients with RRMM during Len-dex treatment remain unclear and there is a need to identify contributing factors associated with increased risk for infection. Considering the disease-related and treatment-related immune deficits in patients with RRMM, we explored the predictive implications of the revelation of the immune cell populations prior to Len-dex initiation for the occurrence of infection. In addition, the various clinical and laboratory parameters were analyzed. Methods Clinical and microbiology records of 90 RRMM patients during Len-dex treatment were reviewed and risk factors for infection were analyzed using the logistic regression. In addition, to develop the new immune cell biomarker, we prospectively examined immune cell populations (CD3, CD4CD161, CD8CD161, Lin-HLA-DR-CD11b+CD33+, CD14+HLA-DR-, NK and NKT cells) of the peripheral blood taken on baseline of Len-dex therapy. Results Forty-eight men and 42 women were enrolled in this study. The median age was 61 years (range, 29-84 years). During a median 11 cycles of Len-dex treatment, 52 (57.8%) patients experienced at least 1 infection episode. Of a total of 92 episodes of infection, 58 (63%) episodes were clinically defined, 29 (31.5%) episodes were microbiologically defined, and 5 (5.4%) episodes were fever of unknown focus. Severe episodes were frequently observed during early 3 cycles. In the univariate analyses, lower Hb (<10 g/dL) and serum albumin (<3.5 mg/dL), and higher serum creatinine (≥2 mg/dL) were associated with increased risk of infections (≥grade 3) during early 3 cycles. After adjusting for risk factors for infection on univariate analyses, multivariate analyses showed that lower Hb (<10 g/dL) was an independent factor for the occurrence of infections and lower frequency (P = 0.009) and absolute count (P = 0.072) of CD4+CD161+ cells in peripheral blood prior to Len-dex were associated with the occurrence of infection, especially during early 3 cycles of Len-dex therapy. Conclusions We demonstrated several clinical predictive factors for the occurrence of infection in patients with RRMM receiving Len-dex treatment. And we found that the frequency and absolute count of CD4+CD161+ cells may provide additional information for predicting the occurrence of infection in early period of Len/dex therapy. Disclosures No relevant conflicts of interest to declare.

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