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Associated Trial(s):- NCT02951819 - Daratumumab Plus Cyclophosphamide, Bortezomib and Dexamethasone (Dara-CyBorD) in Previously Untreated and Relapsed Subjects With Multiple Myeloma
- NCT02195479 - A Phase 3, Randomized, Controlled, Open-label Study of VELCADE (Bortezomib) Melphalan-Prednisone (VMP) Compared to Daratumumab in Combination With VMP (D-VMP), in Subjects With Previously Untreated Multiple Myeloma Who Are Ineligible for High-dose Therapy
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Data Request Status
Status: OngoingResearch Proposal
Project Title: Thrombotic risk in patients with newly diagnosed multiple myeloma treated with a non-immunomodulatory drug containing quadruplet
Scientific Abstract: Background: Venous thromboembolism (VTE) continues to be a significant issue for all patients with multiple myeloma (MM) and VTE prophylaxis guidelines are outdated and not routinely utilized. Objective: The overall objective of the project is to determine the incidence of VTE and investigate the impact of various VTE prophylactic strategies on the rate of VTE in patients with newly diagnosed MM. Study design: The present study will retrospectively investigate the incidence of VTE and investigate the impact of various VTE prophylactic strategies on the rate of VTE based on SAVED risk stratification. Participants: All patients treated on the LYRA and ALCYONE studies. Primary outcome: Rates of VTE for patients treated with non-immunomodulatory drug regimens. Secondary outcomes: Rates of VTE within SAVED and IMPEDE risk stratification models for patients treated on the LYRA and ALCYONE trials. Additional secondary outcomes to be measured include time from treatment initiation to VTE onset, CTCAE grade of VTE events, type and duration of thromboprophylaxis, and rate and grade of bleeding events. Statistical analysis: Incident VTE rates will be estimated overall, and separately within IMPEDE and SAVED risk strata, along with exact 95% confidence intervals. Comparisons of VTE rates across IMPEDE and SAVED risk strata will be conducted in the context of logistic regression models, in univariate analyses as well as multivariable analyses adjusted for patient characteristics.
Brief Project Background and Statement of Project Significance:
Patients with multiple myeloma (MM) have a nine-fold increased risk of developing venous thromboembolism (VTE) compared to the general population and have increased risk of mortality associated with these events. The incidence of VTE in MM is historically thought to be highest during the first 6 months after diagnosis. Given significant advances in the treatment of newly diagnosed patients, the incidence as well as the prevalence, of venous thromboembolism complications in MM with these newer approaches are currently undefined.
Routine administration of VTE prophylaxis with anticoagulation is an effective way to decrease the burden of VTE in cancer patients and multiple trials have shown that low molecular weight heparin (LMWH) and various direct oral anticoagulants (DOAC) reduce VTE risk without increased risk of major bleeding. Despite the significant amount of data available for cancer patients, the applicability of these findings for patients with MM is limited because very few MM patients were included in these trials (some 80, and Asian race.
Numerous significant questions exist in respect to VTE prophylaxis in patients with MM including the effect of modern multi-drug induction regimens on the incidence of VTE and optimal choice of VTE thromboprophylaxis regimen based on SAVED and other risk stratification models. In the past 5 years, a number of landmark trials investigating novel multi-drug combinations for the treatment of patients with MM have been published, including ENDURANCE, GRIFFIN, CASSIOPEIA, MAIA, SWOG S0777, POLLUX, and CASTOR amongst other. In each of these trials, thromboprophylaxis per IMWG guidelines was recommended but the rates of VTE and bleeding based on type of anticoagulation has not been reported. Understanding modern practice patterns in patients with MM via retrospective analysis of these trials will determine the impact of various thromboprophylactic strategies on incidence of VTE, and ultimately, guide the design of prospective clinical trials aimed at minimizing VTE and optimizing patient safety.
Specific Aims of the Project:
Aim 1: Calculate the baseline SAVED risk scoring and stratification of newly diagnosed multiple myeloma (NDMM) patients enrolled on the LYRA and ALCYONE trials.
Aim 2: Calculate the baseline IMPEDE risk scoring and stratification of newly diagnosed multiple myeloma (NDMM) patients enrolled on the LYRA and ALCYONE trials.
Aim 3: Determine the incidence of venous and arterial thromboembolism and investigate the impact of various thromboembolism prophylaxis strategies [low vs high dose aspirin, prophylactic vs therapeutic dose anticoagulants [e.g. low molecular weight heparin, direct oral anticoagulants (DOACs), warfarin etc.] on the rate of thromboembolism based on SAVED risk stratification (low, intermediate or high risk) and IMPEDE if adequate data is available.
Study Design: Individual trial analysis
What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment safety Confirm or validate previously conducted research on treatment safety Research on clinical prediction or risk prediction
Software Used: R
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: All patients enrolled on the phase 2 LYRA and randomized phase 3 ALCYONE trials will be included in this analysis.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
Primary: Rate of VTE for patients treated with non-immunomodulatory triplet and quadruplet regimens include in the LYRA and ALCYONE trials including; 1) daratumumab, cyclophosphamide, bortezomib, and dexamethasone, 2) bortezomib, mephalan, and dexamethasone, and 3) daratumumab, bortezomib, melphalan, and dexamethasone. Rates of VTE will be defined as any grade 1 - 5 arterial or venous thromboembolic event as defined by CTCAE v4 grading criteria.
Secondary: Rates of VTE within SAVED and IMPEDE risk stratification models for patients treated with the above listed 3 regimens. Addition secondary outcomes include time from treatment initiation to VTE onset, CTCAE grade of VTE events, type of thromboprophylaxis treatment, duration of thromboprophylaxis treatment, rate and grade of bleeding events per CTCAE v4, overall drug exposure as defined as time of treatment initiation to end of study drug including dose holds and dose modifications, and rates of grade 3 or higher thrombocytopenia
Main Predictor/Independent Variable and how it will be categorized/defined for your study: NA
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:
Others variables of interest will include the following:
1) Demographics including age, race, myeloma subtype, R-ISS/ISS risk at diagnosis, tumor burden as measured by serum/urine biomarkers, bone marrow aspirate/biopsy, and diagnostic imaging
2) IMPEDE risk score calculation includes Patient BMI at screening, presence of absence of fracture (pelvis, hip, or femur), use of erythropoietin stimulating agents (ESA), race (Asian/Pacific Islander vs other), history of prior VTE, presence of absence of central venous catheter, pretreatment use of prophylactic or therapeutic anticoagulation
3) SAVED risk score calculation includes Surgery within 90 days, Asian race, VTE history, age > 80, treatment with dexamethasone (low (120-160 mg) vs high (> 160 mg) dose)
Statistical Analysis Plan:
A descriptive analysis describing disease clinical and biologic features, treatments, and outcomes is planned. Continuous variables will be summarized as means or medians including standard deviations and range, respectively. Differences between continuous variables will be examined using the t-test, and the Mann-Whitney test will be used to examine non-normally distributed measurements. Categorical variables will be summarized as frequencies and associations between these variables will be tested via the chi-squared test. Incident VTE rates will be estimated overall, and separately within IMPEDE and SAVED risk strata, along with exact 95% confidence intervals. Comparisons of VTE rates across IMPEDE and SAVED risk strata will be conducted in the context of logistic regression models, in univariate analyses as well as multivariable analyses adjusted for patient characteristics. VTE rates will be estimated and compared across VTE prophylactic strategies, again based on logistic regression models, in univariate analyses separately within IMPEDE and SAVED risk strata as well as multivariable analyses adjusted for potential confounders. Patient characteristics will also be considered as moderators of VTE prophylactic strategy comparisons, to assess evidence that particular VTE prophylactic strategies need to be tailored to particular types of patients.
In secondary analyses, VTE prophylactic strategies will be compared via matching weighted logistic regressions. Multinomial propensity models will be constructed based on potential confounders via random forest. Balancing of potential confounders across strategy comparison groups will be assessed in terms of standardized mean differences. Effect moderation and patient tailoring will be assessed in subgroup analyses, accompanied by tests of moderator by treatment interaction.
Narrative Summary: Thromboembolic complications continue to be frequently seen in patients with multiple myeloma (MM) and are an important source of morbidity and mortality. An analysis of the GRIFFIN study showed a 10-15.7% incidence of venous thromboembolism (VTE) in NDMM patients treated with contemporary regimens and our recent analysis showed a 15% risk of thrombotic events in NDMM patients treated on MAIA independent of daratumumab exposure; approximately 65% of these patients were on prophylactic anticoagulation. However, the rate of VTE in NDMM patients not treated with an immunomodulatory drug containing regimen is yet unknown and this study aims to characterize VTE in this population.
Project Timeline: The proposed timeline for completion of this project including data retrieval, review, and analysis is 6 months.
Dissemination Plan: The proposed plan for data dissemination is for submission to the 2025 American Society of Hematology Annual Meeting. In conjunction with presentation of this data at ASH, our group plans to submit for publication in Blood Advances in December, 2025.
Bibliography:
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9. Dima D, Li A, Granat LM, Dhillon P, Chamseddine F, Yalamanchali A et al. External validation of the SAVED score for venous thromboembolism risk stratification in patients with multiple myeloma receiving immunomodulatory drugs. British journal of haematology 2023; 201(2): 280-284. e-pub ahead of print 20230105; doi: 10.1111/bjh.18630