
==== Front
Ther Adv Med Oncol
Ther Adv Med Oncol
TAM
sptam
Therapeutic Advances in Medical Oncology
1758-8340
1758-8359
SAGE Publications Sage UK: London, England

10.1177/17588359241275387
10.1177_17588359241275387
Original Research
Antithrombotic utilization, adverse events, and associations with treatment outcomes in multiple myeloma: pooled analysis of three clinical trials
Almansour Sara A. Department of Pharmacy Practice and Pharmacotherapeutics, University of Sharjah, Sharjah, United Arab Emirates
Conceptualization Data curation Formal analysis Investigation Methodology Visualization Writing – original draft Writing – review & editing
Alqudah Mohammad A. Y. Department of Pharmacy Practice and Pharmacotherapeutics, University of Sharjah, Sharjah, United Arab Emirates
Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
Investigation Methodology Writing – original draft Writing – review & editing
Abuhelwa Ziad Department of Hematology and Medical Oncology, University of South Florida/H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
Formal analysis Methodology Writing – original draft Writing – review & editing
Al-Shamsi Humaid O. Department of Oncology, Burjeel Cancer Institute, Burjeel Medical City, Abu Dhabi, United Arab Emirates
College of Medicine, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
Emirates Oncology Society, Dubai, United Arab Emirates
Gulf Medical University, Ajman, United Arab Emirates
Gulf Cancer Society, Alsafa, Kuwait
Methodology Validation Writing – review & editing
Alhuraiji Ahmad Department of Haematology, Kuwait Cancer Control Center, Kuwait
Methodology Validation Writing – review & editing
Semreen Mohammad H. Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
Department of Medicinal Chemistry, University of Sharjah, Sharjah, United Arab Emirates
Formal analysis Methodology Writing – original draft Writing – review & editing
Bustanji Yasser College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
School of Pharmacy, The University of Jordan, Amman, Jordan
Formal analysis Writing – original draft Writing – review & editing
Alzoubi Karem H. Department of Pharmacy Practice and Pharmacotherapeutics, University of Sharjah, Sharjah, United Arab Emirates
Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
Formal analysis Methodology Writing – original draft Writing – review & editing
Modi Natansh D. College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
Formal analysis Methodology Writing – original draft Writing – review & editing
Mckinnon Ross A. College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
Formal analysis Methodology Writing – original draft Writing – review & editing
Sorich Michael J. College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
Formal analysis Methodology Writing – original draft Writing – review & editing
Hopkins Ashley M. College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
Formal analysis Investigation Methodology Supervision Writing – original draft Writing – review & editing
https://orcid.org/0000-0002-4182-065X
Abuhelwa Ahmad Y. Department of Pharmacy Practice and Pharmacotherapeutics, University of Sharjah, Sharjah, United Arab Emirates
Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
Conceptualization Data curation Formal analysis Funding acquisition Investigation Methodology Project administration Resources Software Supervision Validation Visualization Writing – original draft Writing – review & editing
Ahmad.Abuhelwa@sharjah.ac.ae
2 9 2024
2024
16 1758835924127538725 3 2024
30 7 2024
© The Author(s), 2024
2024
SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses
https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
Background:

Patients with multiple myeloma (MM) are at risk of venous thromboembolism (VTE), worsened by immunomodulatory drugs. Although antithrombotics are recommended for prophylaxis, existing guidelines are suboptimal and treatment outcomes remain unclear.

Objectives:

This study aimed to investigate adverse events, antithrombotic utilization, and their associations with survival outcomes in patients with MM initiating multi-drug immunomodulatory combinations.

Design:

A posthoc analysis of individual-participant level data (IPD).

Methods:

IPD from three daratumumab clinical trials (MAIA, POLLUX, and CASTOR) were pooled. Adverse events incidence and antithrombotic utilization were assessed. Logistic and Cox regression were utilized to examine associations between antithrombotics use with adverse events and survival outcomes at the baseline and 6-month landmark.

Results:

Among 1804 patients, VTE occurred in 10%, bleeding in 14%, ischemic heart disease in 4%, and stroke in 2%. Patients with these adverse events demonstrated elevated rates of any grade ⩾3 events. Antiplatelet (primarily aspirin) and anticoagulant (primarily LMWH and direct oral anticoagulants) prescriptions have seen an increase from baseline (25% and 14%, respectively) to 6 months (35% and 31%). The primary indication for their use was prophylaxis. Anticoagulant use within 6 months was associated with reduced VTE (OR (95% CI) = 0.45 (0.26–0.77), p = 0.004), while antiplatelet use showed no associations with any evaluated adverse events. Antithrombotics and survival outcomes had no significant associations.

Conclusion:

This study underscores the complexities of antithrombotic therapy and adverse events in MM and highlights the need for vigilant and proactive management due to increased grade ⩾3 adverse events. While anticoagulant use was associated with reduced VTE risk, further research is needed to optimize thromboprophylaxis guidelines and explore antithrombotic efficacy and safety in patients with MM.

Trial registration:

MAIA (NCT02252172), POLLUX (NCT02076009), CASTOR (NCT02136134).

Plain language summary

Blood clot prevention drugs in multiple myeloma: usage and impact on patient outcomes

Aims and Purpose of the Research

This study aimed to understand how blood-thinning medications are used by patients with multiple myeloma, a type of blood cancer. Specifically, we wanted to find out how often these medications are used, what side effects they might cause, and whether they are linked with how long the patients live.

Background of the Research

This study is important because patients with multiple myeloma often have a higher risk of blood clots, especially when they are taking certain anticancer treatments. Blood-thinning drugs are usually recommended to prevent these clots, but it’s not always clear how well these drugs work or what side effects they might cause.

Methods and Research Design

This study looked at data from three clinical trials involving a multiple myeloma drug called daratumumab. We looked at how often side effects occurred and how often blood-thinning drugs were used. Two groups of blood thinning drugs were investigated: antiplatelets and anticoagulants. We used two types of statistical methods, called logistic and Cox regression, to see if there was a connection between the use of these blood-thinning drugs and the occurrence of side effects or survival rates at the start of the study and after six months.

Results and Importance

The study found that the use of blood-thinning drugs increased over time and that using anticoagulants within the first six months was linked to a lower risk of blood clots. However, blood-thinning drugs were not linked with how long the patients lived. These results are important because they can help doctors better manage the use of blood-thinning drugs in patients with multiple myeloma. The key message is that more research is needed to improve guidelines for preventing blood clots and to better understand the safety and effectiveness of blood-thinning drugs in these patients.

antithrombotics
immunomodulatory drugs (IMiDs)
multiple myeloma
survival outcomes
venous thromboembolism
National Health and Medical Research Council, Australia APP2005294 National Health and Medical Research Council, Australia APP2008119 University of Sharjah Seed Grant 2301110380 cover-dateJanuary-December 2024
typesetterts1
==== Body
pmcIntroduction

In the last decade, significant advancements have transformed the therapeutic landscape for patients with multiple myeloma (MM) with the introduction of immunomodulatory drugs (IMiDs), proteasome inhibitors, and monoclonal antibodies. Despite these strides, the administration of these agents has presented distinct challenges, particularly in managing adverse events such as venous thromboembolism (VTE), cardiac events, or stroke.1–5 Notably, patients with MM face a VTE risk that is 7–9 folds higher than non-MM patients do. 4 Additionally, treatment with IMiDs in conjunction with dexamethasone (DEX) further increases the risk of VTE in MM patients initiating these regimens, resulting in a mean VTE incidence of 21.5% in studies devoid of thromboprophylaxis. 5 VTE and pulmonary embolism in MM are correlated with increased mortality, 4 with death rates being three folds higher compared to patients with MM but without these complications. 6 To address this concern, several scientific panels proposed a VTE risk assessment guide to stratify patients with MM based on patients’ disease, or therapy-related risk factors, and recommend prophylactic use of antithrombotic drugs such as aspirin, warfarin, or low-molecular-weight heparin (LMWH) for patients with ⩾1 risk factors.1,7–9

Despite the availability of clinical guidelines, determining optimal thromboprophylaxis and treatment choice for VTE events in patients with MM remains a clinical challenge.1,8–10 An analysis published in 2020 on patients with MM initiating IMiDs reported a VTE rate of 13.2% despite 80.5% of patients being on thromboprophylaxis. 11 While numerous studies have reviewed the efficacy and safety of antithrombotic drugs including aspirin, warfarin, LMWH, and direct oral anticoagulants (DOAC) in patients with MM, the data is limited. Comparative effects of various antithrombotic drugs concerning VTE, or bleeding events, remain inconclusive and cannot confirm or exclude beneficial or detrimental effects.1,11,12 Hence, existing scientific literature on thromboprophylaxis in MM falls short in providing evidence-based recommendations. 7

The association of antithrombotic drugs with survival outcomes in patients with MM remains uncertain. 13 Several studies on solid tumors, such as head and neck cancers, report significant associations between the use of different anticoagulants and increased overall or cancer-specific survival.14–16 Moreover, literature suggests that widely used anticoagulants, such as LMWH and warfarin, or antiplatelets such as aspirin, may exhibit anticancer effects, hinting at their potential use to improve survival and prevent cancer progression or metastasis.14,17,18 Conversely, other studies report worse survival outcomes or inconclusive results with concomitant anticoagulant use.19–22

The aims of this study were to (1) investigate the incidence of adverse events, including VTE, ischemic heart diseases, stroke, and bleeding, associated with antithrombotic treatment, and assess whether there is a significant difference in the pattern of these adverse events between MM treatment types, (2) assess the incidence of documented use and indications for antithrombotics in patients with MM initiating daratumumab, lenalidomide, or bortezomib combination treatments, and (3) investigate the association of antithrombotic therapy with adverse events and survival outcomes.

Ultimately, this study aims to elucidate the complex interplay between antithrombotics, adverse events, and survival outcomes and provide insights into optimizing treatment strategies and improving outcomes in patients with MM.

Methods

Patient population

Individual patient data were pooled from three randomized, open-label trials: MAIA (NCT02252172, data cut-off: February 19, 2021), 23 POLLUX (NCT02076009, data cut-off: March 7, 2016), 24 and CASTOR (NCT02136134, data cut-off: January 11, 2016). 25

All these studies enrolled patients who were 18 years or older. The efficacy of daratumumab on patients with relapsed or refractory MM who had undergone at least one prior line of therapy was evaluated in the POLLUX and CASTOR trials. The MAIA trial enrolled newly diagnosed MM patients who were not candidates for high-dose chemotherapy or autologous stem cell transplantation due to their age (65 years or older) or the presence of coexisting conditions that could lead to unacceptable side effects.

In the MAIA and POLLUX trials, patients were treated with a combination of daratumumab (administered as 16 mg/kg IV infusion), lenalidomide (25 mg capsule taken orally), and dexamethasone (40 mg taken orally or intravenously; DRd). This was compared to a regimen of lenalidomide plus dexamethasone (Rd). In the CASTOR trial, daratumumab (16 mg/kg IV infusion) was combined with bortezomib (1.3 mg/m2 administered subcutaneously) and dexamethasone (20 mg taken orally; DVd) and compared to a regimen of bortezomib plus dexamethasone alone (Vd).

All trials adhered to the International Conference on Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki.26,27 Participants provided written informed consent. The secondary analysis of de-identified data reported in this study was considered negligible risk research and has been approved by the University of Sharjah Ethics Committee (Approval reference number: REC-23-11-07-01-F). Data were accessed according to the Johnson & Johnson policy and made available through Vivli, Inc. (www.vivli.org). The reporting of this study adhered to The Strengthening the Reporting of Observational Studies in Epidemiology Statement Guidelines (Supplemental Table 2). 28

Outcomes

The primary objectives were as follows: (a) the incidence of adverse events that encompassed VTE, ischemic heart disease, bleeding, and stroke occurring throughout treatment duration and (b) the incidence of documented use and indications for antithrombotics (anticoagulants and antiplatelets) at baseline (i.e., prior to treatment initiation) and within a landmark of 6 months from treatment initiation. Adverse events were reported in MAIA, POLLUX, and CASTOR trails using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTAE) version 4.0. 29

The secondary objective was to investigate the association of antithrombotic use with overall survival (OS), progression-free survival (PFS), and adverse events at baseline and 6-month landmark. OS was defined as the time from the date of randomization to the date of the participant’s death, and PFS was defined as the time from patient randomization to either disease progression according to the International Myeloma Working Group (IMWG) response criteria or death, whichever occurred first.

Missing data were imputed via the Transcan function in the Hmisc (version 5.1-0) R package. 30 Transcan is a nonlinear additive transformation and imputation function.

Statistical analysis

Data were assessed for statistical significance and tabulated with descriptive statistics. Statistical comparisons between categorical variables were performed using the Chi-square test, while the Kruskal–Wallis test was employed to evaluate the statistical significance of continuous variables.

Logistic regression was employed to examine the association between anticoagulant or antiplatelet use and the occurrence of adverse events. Results were reported as odds ratios (ORs) with their corresponding 95% confidence intervals (95%CI). For the assessment of associations between anticoagulant and antiplatelet use with OS and PFS, a Cox proportional hazards regression was employed. Results were reported as hazard ratios (HR) with 95% CI. Analyses were done at baseline and at the 6-month landmark. For the landmark analyses, patients experiencing an event or censored before the 6-month cutoff time was excluded. 31 Statistical significance was set at p-value <.05. All analyses were adjusted for age, gender, weight, MM international staging system (ISS) stage, Eastern Cooperative Oncology Group performance status (ECOG-PS) score, and comorbidity count and stratified by clinical trial and treatment arms. 32 All analyses were performed using R version 4.2.

Results

Overall incidence of adverse events across the study population

Data from a total of 1804 patients was pooled from the three clinical trials. A summary of patients’ baseline characteristics and adverse events incidence by study cohort is provided in Table 1. The duration of anticancer treatment was (median (IQR)) 32.7 (41.1) months for MAIA, 12.6 (5.5) months for the POLLUX, and 5.3 (2.4) months for CASTOR. The median follow-up time was 56.2, 7.43, and 13.5 months for MAIA, CASTOR, and POLLUX, respectively.

Table 1. A summary of patients’ baseline characteristics by study cohort.

Variable	Total No. 1804	CASTOR No. 498	MAIA No. 737	POLLUX No. 569	p-Value	
Arm of the clinical study					<0.001	
 Bortezomib and dexamethasone	247 (14%)	247 (50%)	0 (0%)	0 (0%)		
 Daratumumab plus bortezomib and dexamethasone	251 (14%)	251 (50%)	0 (0%)	0 (0%)		
 Daratumumab plus lenalidomide and dexamethasone	654 (36%)	0 (0%)	368 (50%)	286 (50%)		
 Lenalidomide and dexamethasone	652 (36%)	0 (0%)	369 (50%)	283 (50%)		
Age (years)	66 (58–72)	58 (48–68)	72 (64–72)	65 (59–71)	<0.001	
Gender					0.029	
 Men	1005 (56%)	284 (57%)	384 (52%)	337 (59%)		
 Women	799 (44%)	214 (43%)	353 (48%)	232 (41%)		
 Weight (kg)	73 (63–85)	76 (67–88)	72 (63–84)	72 (61–85)	<0.001	
ISS disease stage at study entry					<0.001	
 I	672 (37%)	194 (39%)	201 (27%)	277 (49%)		
 II	692 (38%)	194 (39%)	319 (43%)	179 (31%)		
 III	440 (24%)	110 (22%)	217 (29%)	113 (20%)		
ECOGPS					<0.001	
 ⩾2	180 (10%)	32 (6%)	122 (17%)	26 (5%)		
 0	762 (42%)	223 (45%)	250 (34%)	289 (51%)		
 1	862 (48%)	243 (49%)	365 (50%)	254 (45%)		
RACE					<0.001	
 Asian	130 (7%)	24 (5%)	5 (1%)	101 (18%)		
 Black or African American	81 (4%)	23 (5%)	31 (4%)	27 (5%)		
 Other	77 (4%)	15 (3%)	22 (3%)	40 (7%)		
 White	1516 (84%)	436 (88%)	679 (92%)	401 (70%)		
Comorbidity count	5.0 (3.0–7.0)	4.0 (2.0–6.0)	6.0 (4.0–8.0)	4.0 (3.0–6.0)	<0.001	
Anticoagulants (Y/N)	248 (14%)	39 (8%)	160 (22%)	49 (9%)	<0.001	
Anti-platelet (Y/N)	457 (25%)	88 (18%)	254 (34%)	115 (20%)	<0.001	
Thromboembolism	178 (10%)	15 (3%)	125 (17%)	38 (7%)	<0.001	
Bleeding	250 (14%)	41 (8%)	156 (21%)	53 (9%)	<0.001	
Ischemic heart disease	65 (4%)	8 (2%)	43 (6%)	14 (2%)	<0.001	
Stroke	31 (2%)	5 (1%)	23 (3%)	3 (1%)	<0.001	
Grade ⩾ 3 AE	1469 (81%)	347 (70%)	681 (92%)	441 (78%)	<0.001	
Data are median (IQR) or number of patients (%). p Values per Chi-Square test for categorical data and Kruskal–Wallis test for continuous data.

ECOGPS, Eastern Cooperative Oncology Group performance status; ISS Stage, international staging system (ISS) stage.

Of the 1804 patients, antiplatelets were the most frequently utilized antithrombotic class (457/1804 patients, 25%) followed by anticoagulants (248/1804 patients, 14%) across all trials. The utilization of antithrombotics (i.e., antiplatelet and anticoagulants) was significantly prevalent in the MAIA and POLLUX trials compared to CASTOR. Antiplatelets were prescribed for (254/737 patients, 34%) in MAIA, (115/569 patients, 20%) in POLLUX, and (88/498, 8%) in CASTOR. whereas anticoagulants were prescribed for (160/737 patients, 22%), (49/569 patients, 9%), and (39/498, 8%), in MAIA, POLLUX, and CASTOR trials, respectively.

VTE occurred in 178 (10%) patients, with higher rates in MAIA (125/737 patients, 17%) and POLLUX (38/569 patients, 7%), compared to CASTOR (15/498 patients, 3%). As for bleeding, a total of 250 (14%) events occurred, with significantly higher rates in MAIA (156/737 patients, 21%), followed by POLLUX (53/569 patients, 9%), and CASTOR (41/498 patients, 8%).

Ischemic heart disease and stroke were observed in (65/1804 patients, 4%) and (31/1804 patients, 2%), respectively. A significantly higher incidence of these events occurred in MAIA compared to the POLLUX and CASTOR trials. Notably, the MAIA trial had significantly higher age, ISS stage, ECOG score, and comorbidity count.

During the course of treatment, a large proportion of patients (1469/1804, 81%) experienced any grade ⩾3 adverse event, with a notable prevalence in the MAIA and POLLUX cohorts.

In the pooled cohort, 905 (50%) patients received a daratumumab-containing regimen. Daratumumab arms had significantly higher incidences of grade ⩾3 adverse events (780 patients, 53%). However, there were no significant differences in the incidence of VTE, bleeding, ischemic heart disease, and stroke between the two treatment types (Supplemental Table 1).

Anticoagulants’ use and indications

Table 2 provides an overview of the documented use and indications of anticoagulants and antiplatelets at baseline and within 6 months of treatment initiation.

Table 2. Documented use and indications of anticoagulants and antiplatelets at baseline and within 6 months of treatment initiation.

Indications	Anticoagulants	Antiplatelets	
	Baseline	Within 6 months	Baseline	Within 6 months	
Prophylaxis	143 (58%)	367 (66%)	315 (69%)	574 (92%)	
Medical history	102 (41%)	36 (6%)	139 (30%)	13 (2%)	
Adverse events treatment	3 (1%)	146 (26%)	1 (<1%)	34 (5%)	
Other	0	9 (2%)	2 (<1%)	2 (<1%)	
Total (n)	248	558	457	623	

Within the pooled cohort, a total of 248 (14%) patients were on anticoagulants at baseline, with the most common indications being prophylaxis (143 patients, 58%) and comorbidity management (102 patients, 41%). Heparin (135 patients, 54%) and warfarin (61 patients, 26%) were the most frequently prescribed anticoagulant classes. Other anticoagulant classes used included direct factor XA inhibitors (43 patients, 17%), indirect factor XA inhibitors (5 patients, 2%), and direct thrombin inhibitors (4 patients, 2%).

Table 3 summarizes the incidence of AE by anticoagulant use at baseline. Among the 248 patients receiving anticoagulant therapy at baseline, the vast majority (225 patients, 91%) experienced grade ⩾ 3 AE. The incidence of VTE did not show a significant difference when compared with patients on anticoagulants (34 patients, 14%) and those without (144 patients, 9%). Furthermore, there was no remarkable difference in bleeding rates between patients using anticoagulants (39 patients, 16%) versus nonusers (211 patients, 14%).

Table 3. Incidence of adverse events based on the anticoagulant use at baseline.

Variable	Total
No. 1804	No
No. 1556	Yes
No. 248	p Value	
Study	<0.001	
 CASTOR	498 (28%)	459 (29%)	39 (16%)		
 MAIA	737 (41%)	577 (37%)	160 (65%)		
 POLLUX	569 (32%)	520 (33%)	49 (20%)		
Arm of the clinical study	<0.001	
 Bortezomib and dexamethasone	247 (14%)	225 (14%)	22 (9%)		
 Daratumumab plus bortezomib and dexamethasone	251 (14%)	234 (15%)	17 (7%)		
 Daratumumab plus lenalidomide and dexamethasone	654 (36%)	555 (36%)	99 (40%)		
 Lenalidomide and dexamethasone	652 (36%)	542 (35%)	110 (44%)		
Any AE Grade ⩾ 3	1469 (81%)	1244 (80%)	225 (91%)	<0.001	
Venous thromboembolism	178 (10%)	144 (9%)	34 (14%)	0.038	
Bleeding	250 (14%)	211 (14%)	39 (16%)	0.41	
Ischemic heart disease	65 (4%)	51 (3%)	14 (6%)	0.094	
Stroke	31 (2%)	27 (2%)	4 (2%)	1.00	
Data are median (IQR) or number of patients (%). p-Values per Chi-Square test for categorical data and Kruskal–Wallis test for continuous data.

Transitioning to the first 6 months of the study period, 558 (31%) patients were initiated on anticoagulants. Prophylaxis (367 patients, 66%) and treating active adverse events (146 patients, 26%) were the predominant indications. The anticoagulant classes initiated included heparin (480 patients, 86%), direct factor XA inhibitors (38 patients, 7%), warfarin (18 patients, 3%), indirect factor XA inhibitors (18 patients, 3%), and direct thrombin inhibitors (4 patients, <1%).

Antiplatelets use and indications

A total of 457 (25%) patients received antiplatelets at baseline, primarily for prophylaxis (315 patients, 69%) and comorbidity management detailed in medical history (139 patients, 30%; Table 2). The antiplatelets prescribed fell into two classes: salicylic acid derivatives, primarily aspirin (428 patients, 94%), and platelet aggregation inhibitors (29 patients, 6%), which comprised clopidogrel and ticagrelor.

Table 4 summarizes the incidence of AE by antiplatelet use at baseline. Bleeding events (88 patients, 19%), VTE (58 patients, 13%), ischemic heart disease (30 patients, 7%), stroke (15 patients, 3%), and grade ⩾3 adverse events occurred at significantly higher rates in patients with antiplatelets.

Table 4. Incidence of adverse events based on antiplatelet use at baseline.

Variable	Total
No. 1804	No
No. 1347	Yes
No. 457	p Value	
Study	<0.001	
 CASTOR	498 (28%)	410 (30%)	88 (19%)		
 MAIA	737 (41%)	483 (36%)	254 (56%)		
 POLLUX	569 (32%)	454 (34%)	115 (25%)		
Arm of the clinical study	<0.001	
 Bortezomib and dexamethasone	247 (14%)	205 (15%)	42 (9%)		
 Daratumumab plus bortezomib and dexamethasone	251 (14%)	205 (15%)	46 (10%)		
 Daratumumab plus lenalidomide and dexamethasone	654 (36%)	474 (35%)	180 (39%)		
 Lenalidomide and dexamethasone	652 (36%)	463 (34%)	189 (41%)		
Any AE Grade ⩾ 3	1469 (81%)	1076 (80%)	393 (86%)	0.005	
Venous thromboembolism	178 (10%)	120 (9%)	58 (13%)	0.024	
Bleeding	250 (14%)	162 (12%)	88 (19%)	<0.001	
Ischemic heart disease	65 (4%)	35 (3%)	30 (7%)	<0.001	
Stroke	31 (2%)	16 (1%)	15 (3%)	0.006	
Data are median (IQR) or number of patients (%). p Values per Chi-Square test for categorical data and Kruskal–Wallis test for continuous data.

A total of 623 patients initiated antiplatelet use within 6 months of the study period. The predominant indication for antiplatelet use was prophylaxis 574 (92%), followed by addressing adverse events 34 (5%; Table 2). The antiplatelets prescribed consisted of salicylic acid derivatives (604 patients, 97%) and platelet aggregation inhibitors (19 patients, 3%).

Association of antithrombotic drugs use with adverse events

Table 5 summarizes the associations between anticoagulant and antiplatelet use at baseline and the 6-month landmark.

Table 5. Association of anticoagulants or antiplatelet use with adverse events at baseline and the 6-month landmark.

Pooled	Anticoagulants	Antiplatelets	
Adjusteda,b analysis for antithrombotic drug use and adverse events at baseline	
	OR (95% CI)	p-Value	OR (95% CI)	p-Value	
Any Adverse events (grade ⩾ 3)	1.41 (0.88–2.26)	0.154	0.74 (0.42–1.32)	0.307	
Venous thromboembolism	1.13 (0.74–1.72)	0.580	1.05 (0.74–1.51)	0.770	
Ischemic heart disease	1.17 (0.62–2.20)	0.632	1.86 (1.09–3.14)	0.022	
Bleeding	0.88 (0.59–1.29)	0.502	1.30 (0.96–1.76)	0.092	
Stroke	0.58 (0.20–1.71)	0.327	1.83 (0.86–3.88)	0.117	
Adjusteda,b analysis for antithrombotic use and adverse events at the 6-month landmark	
Any adverse events (grade ⩾ 3)	1.24 (0.97–1.58)	0.083	1.04 (0.81 –1.32)	0.780	
Venous thromboembolism	0.39 (0.22–0.69)	0.001	1.12 (0.68–1.84)	0.656	
Ischemic heart disease	1.46 (0.71–3.00)	0.308	1.03 (0.48–2.20)	0.946	
Bleeding	0.89 (0.60–1.31)	0.54	1.10 (0.74–1.63)	0.649	
Stroke	0.70 (0.23–2.12)	0.532	0.52 (0.14–1.92)	0.325	
a Analyses stratified by study and arms.

b Analysis adjusted for age, gender, ISS disease stage, weight, ECOG score, and comorbidity count.

At baseline, the use of anticoagulants did not show any significant associations with any of the adverse events evaluated. Antiplatelet use at baseline was significantly associated with higher odds of ischemic heart disease (OR (95% CI) = 1.86 (1.09–3.14), p = 0.022) but did not show significant associations with other adverse events.

At the 6-month landmark, the use of anticoagulants within 6 months was significantly associated with decreased odds of VTE events (OR (95% CI) = 0.45 (0.26–0.77), p = 0.004). There were no significant associations between the use of anticoagulants and the other adverse events. For antiplatelets, no significant associations were observed (Table 5).

Association of antithrombotic use with survival outcomes

Table 6 presents the prognostic associations between anticoagulant and antiplatelet use with OS and PFS. Anticoagulant and antiplatelet use was not significantly associated with OS or PFS at both baseline and the 6-month landmark. At the 6-month landmark, there were 1568 and 1348 of 1804 patients included in the analysis for OS and PFS, respectively.

Table 6. Association of anticoagulant and antiplatelet use with survival outcomes.

Outcome	Anticoagulantsa,b	Antiplateletsa,b	
	HR (95% CI)	p Value	HR (95% CI)	p Value	
OS at baseline	1.27 (1.00–1.61)	0.051	1.12 (0.91–1.39)	0.288	
PFS at baseline	1.09 (0.89–1.33)	0.426	1.01 (0.85–1.19)	0.939	
OS – 6-month landmark	1.18 (0.93–1.48)	0.170	0.85 (0.66–1.10)	0.218	
PFS – 6-month landmark	1.09 (0.90–1.33)	0.379	0.94 (0.77–1.16)	0.572	
a Analyses stratified by study and arms.

b Analysis adjusted for age, gender, ISS disease stage, weight, ECOG score, and comorbidity count.

ECOGPS, Eastern Cooperative Oncology Group performance status; ISS Stage, international staging system.

Discussion

This study aimed to provide comprehensive insights into the utilization of antithrombotic drugs and their potential associations with adverse events and survival outcomes in patients with MM initiating contemporary immunomodulatory regimens. The analysis revealed a notable incidence of VTE, ischemic heart disease, bleeding, and stroke among the studied population cohort. Patients experiencing any of the evaluated adverse events demonstrated elevated rates of any grade ⩾3 adverse events. The study also highlighted a substantial increase in the prescription of both antiplatelets (mainly aspirin) and anticoagulants (primarily LMWH and direct oral anticoagulants) from baseline to the 6-month landmark, with prophylaxis being the primary indication. Notably, while anticoagulant use was associated with reduced odds of VTE, antiplatelet therapy did not show a similar association with adverse events. Furthermore, there were no significant associations between antithrombotic use and OS or PFS. To our knowledge, this is the first study to comprehensively examine the interplay between antithrombotics, adverse events, and survival outcomes in patients with MM initiating multi-drug immunomodulatory combinations.

In the pooled cohort, a total of 705 (39%) patients were on anticoagulants or antiplatelets at baseline, while 1181 (65%) patients initiated these medications within the first 6 months of the study period. The primary indication for starting antithrombotics at both time points was prophylaxis, with 25% of patients receiving antithrombotics at baseline and 52% within the initial 6 months. Interestingly, the rate of VTE incidence was 10% despite preventative measures. This finding aligns with updated studies involving patients with MM who receive ImiDs and thromboprophylaxis per existing guidelines.5,33,34 For instance, in the recent GRIFFIN clinical trial on patients with MM initiating daratumumab + lenalidomide/bortezomib/dexamethasone, the efficacy endpoint was not met due to high venous VTE rates reaching 12.9%.5,35 These findings underscore that VTE continues to pose critical complications and reaffirm that thromboprophylaxis guidelines may be suboptimal in these patient populations.

Recognizing the potential risks associated with VTE, the International Myeloma Working Group (IMWG), European Myeloma Network, and National Comprehensive Cancer Network (NCCN) proposed a risk stratification algorithm based on expert opinion and available data from clinical trials.9,10,36–40 These consensus-based guidelines recommended aspirin for low-risk patients and low-molecular-weight heparin (LMWH) or a therapeutic dose of warfarin for high-risk patients. In our study, a higher proportion of patients were on antiplatelets at baseline (25%) and within 6 months (35%), compared to anticoagulants (14% at baseline and 31% within 6 months). Notably, the association analysis revealed a significant reduction in the odds of VTE at the 6-month landmark compared to baseline for patients using anticoagulants. However, antiplatelet use was not associated with reduced risk of any of the evaluated adverse events. Several studies have reported on the superiority of anticoagulants such as LMWH or DOAC over aspirin in preventing VTE.38,39,41,42 For instance, the MELISSE observational study on patients with MM initiating thalidomide or lenalidomide found a VTE incidence of 7% with aspirin and only 3% with LMWH prophylaxis. 43 Furthermore, in a study comparing DOAC rivaroxaban to aspirin, the VTE rate surpassed 16% for patients initiating aspirin and was 4.8% in the DOAC group. 44 Recently, the American Society of Clinical Oncology (ASCO) recommended the use of DOACs for VTE treatment for cancer patients. 45 However, DOAC use was not updated in MM guidelines for the prevention or treatment of VTE and remains uncertain and requires further clinical evidence. 1 Our findings, alongside existing literature, underscore the pressing need for additional studies and updated guidelines offering more effective thromboprophylaxis alternatives to aspirin. 46

Our findings demonstrate a significantly higher prevalence of all reported adverse events and antithrombotic utilization in the MAIA trial, reflecting the distinct characteristics inherent in the patient population who were ineligible for autologous stem cell transplantation or high-dose chemotherapy and were significantly older than the patient population in CASTOR and POLLUX (p < 0.001). The “transplant-ineligible” patients enrolled in the MAIA trial were characterized by a significantly higher comorbidity burden and poor performance status (p < 0.001), which are frequently associated with older age, thereby placing them at an elevated risk of treatment-related adverse events. 47

Patients with MM initiating regimens from MAIA and POLLUX exhibited a higher incidence of VTEs, ischemic heart disease, bleeding, and stroke. The heightened risk of VTE associated with IMiDs plus dexamethasone, reflected in the study cohort, has been well established in the literature. 48 Notably, patients in MAIA and POLLUX trials exhibited a higher incidence of VTE despite initiating antithrombotic drugs more frequently than those in the CASTOR trial. Interestingly, the lower rates in CASTOR might suggest a potential protective role of bortezomib against VTE, as demonstrated in a previous study. 38 Further, an investigation into thalidomide-based regimens and antithrombotic drugs revealed a 1.38 times higher risk of VTE among patients receiving thalidomide without bortezomib. 49 This points toward potential treatment regimens with anticoagulants. As for daratumumab arms in the pooled cohort, there was no significant difference between the incidence of VTE between daratumumab versus non-daratumumab containing regimens, aligning with findings reported in prior studies.7,35

While antithrombotic drugs are primarily prescribed for thromboprophylaxis, they also play a role in managing comorbidities and treatment-related adverse events in patients with MM, including CVD and stroke. 50 Therefore, investigating their impact on survival and other adverse events, such as bleeding, which may lead to a worse prognosis, is important, as these associations are poorly explored. In a recent systematic review, the efficacy and safety of aspirin, DOAC, LMWH, and warfarin were evaluated for preventing VTE in 1042 patients with MM. Notably, no significant associations between all-cause mortality and bleeding risks were reported for the prophylactic use of these drugs. 13 Similarly, in our findings, there were no significant associations between antithrombotics and OS or PFS. As for bleeding, patients on antiplatelets exhibited a higher frequency of bleeding events, although antiplatelet use was not statistically associated with increased odds. A recent publication evaluated bleeding rates in a real-world computed analysis of around 1300 MM patients and reported that antiplatelets are associated with bleeding risk (HR, 2.4; 95% CI, 1.03–5.68). 51

In our study population, patients who had a VTE event were predominantly of white race (89%). However, it’s worth noting that the majority of the study population included in the analysis was white (84%) with a limited representation of Blacks, Hispanics, and other ethnicities. This is in keeping with published data about Blacks and Hispanic patients being underrepresented in global MM clinical trials. 52

The limitations of this study include the lack of detailed information on the specific types, durations, and dosages of the antithrombotic drugs administered, which impedes our capacity to directly investigate the association of distinct antithrombotic types, their varying doses and regimens, with the treatment outcomes. Moreover, the strict eligibility criteria applied in clinical trials can limit generalizability. For instance, the examination of specific subsets like refractory or relapsed MM in POLLUX and CASTOR, and newly diagnosed MM in MAIA. Another limitation is the completeness of the data. Despite having low missing data percentages and the use of imputation methods for minimizing uncertainty, some potential bias possibility remains. Finally, we acknowledge that the identified associations observed in our study do not establish causality. The statistical relationships identified between antithrombotic use and adverse events should be interpreted as correlations, not causal links. Future studies are warranted to further investigate these associations.

Conclusion

In conclusion, this study comprehensively examined the intricate association between antithrombotic therapy and adverse events in patients with MM initiating contemporary immunomodulatory regimens. The higher occurrence of grade ⩾3 adverse events in patients facing these complications emphasizes the necessity for monitoring and proactive management approaches in clinical practice. While anticoagulant use was associated with a reduction in VTE risk, antiplatelet therapy did not exhibit a similar association. These findings emphasize the need for continued research to optimize thromboprophylaxis guidelines and improve patient care.

Supplemental Material

sj-docx-1-tam-10.1177_17588359241275387 – Supplemental material for Antithrombotic utilization, adverse events, and associations with treatment outcomes in multiple myeloma: pooled analysis of three clinical trials

Supplemental material, sj-docx-1-tam-10.1177_17588359241275387 for Antithrombotic utilization, adverse events, and associations with treatment outcomes in multiple myeloma: pooled analysis of three clinical trials by Sara A. Almansour, Mohammad A. Y. Alqudah, Ziad Abuhelwa, Humaid O. Al-Shamsi, Ahmad Alhuraiji, Mohammad H. Semreen, Yasser Bustanji, Karem H. Alzoubi, Natansh D. Modi, Ross A. Mckinnon, Michael J. Sorich, Ashley M. Hopkins and Ahmad Y. Abuhelwa in Therapeutic Advances in Medical Oncology

This study, carried out under YODA Project # 2022-5048, used data obtained from the Yale University Open Data Access Project, which has an agreement with JANSSEN RESEARCH & DEVELOPMENT, L.L.C. The interpretation and reporting of research using these data are solely the responsibility of the authors and do not necessarily represent the official views of the Yale University Open Data Access Project or JANSSEN RESEARCH & DEVELOPMENT, L.L.C.

Declarations

ORCID iD: Ahmad Y. Abuhelwa https://orcid.org/0000-0002-4182-065X

Supplemental material: Supplemental material for this article is available online.

Ethics approval and consent to participate: Secondary analysis of anonymized clinical-trial data was confirmed as negligible-risk research and has been approved by the University of Sharjah Research and Ethics Committee (Approval reference number: REC-23-11-07-01-F).

Consent for publication: All authors have approved the final version of this article and given their consent for its publication.

Author contributions: Sara A. Almansour: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Visualization; Writing – original draft; Writing – review & editing.

Mohammad A. Y. Alqudah: Investigation; Methodology; Writing – original draft; Writing – review & editing.

Ziad Abuhelwa: Formal analysis; Methodology; Writing – original draft; Writing – review & editing.

Humaid O. Al-Shamsi: Methodology; Validation; Writing – review & editing.

Ahmad Alhuraiji: Methodology; Validation; Writing – review & editing.

Mohammad H. Semreen: Formal analysis; Methodology; Writing – original draft; Writing – review & editing.

Yasser Bustanji: Formal analysis; Writing – original draft; Writing – review & editing.

Karem H. Alzoubi: Formal analysis; Methodology; Writing – original draft; Writing – review & editing.

Natansh D. Modi: Formal analysis; Methodology; Writing – original draft; Writing – review & editing.

Ross A. Mckinnon: Formal analysis; Methodology; Writing – original draft; Writing – review & editing.

Michael J. Sorich: Formal analysis; Methodology; Writing – original draft; Writing – review & editing.

Ashley M. Hopkins: Formal analysis; Investigation; Methodology; Supervision; Writing – original draft; Writing – review & editing.

Ahmad Y. Abuhelwa: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Supervision; Validation; Visualization; Writing – original draft; Writing – review & editing.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the University of Sharjah Targetted Research Grant No. 2301110392. A.M.H is a National Health and Medical Research Council (NHMRC) Fellow (APP2008119) who is supported by research funding from Tour De Cure (RSP-117-FY2023). N.D.M is supported by funding from The Hospital Research Foundation (2023-S-DTFA-005) and Tour De Cure (RSP-117-FY2023).

HOA is on the advisory board of ROCHE, MSD, BMS, ASTRAZENECA, and Novartis. All other authors have no competing interests to disclose.

Availability of data and materials: Data were accessed according to YODA policy and process for clinical study data sharing and is available for request at https://yoda.yale.edu/
==== Refs
References

1 De Stefano V Larocca A Carpenedo M , et al . Thrombosis in multiple myeloma: risk stratification, antithrombotic prophylaxis, and management of acute events. A consensus-based position paper from an ad hoc expert panel. Haematologica 2022; 107 (11 ): 2536.35861017
2 Reneau J Asante D Van Houten H , et al . Cardiotoxicity risk with bortezomib versus lenalidomide for treatment of multiple myeloma: a propensity-matched study of 1,128 patients. Blood 2015; 126 (23 ): 3046.
3 El-Cheikh J Moukalled N Malard F , et al . Cardiac toxicities in multiple myeloma: an updated and a deeper look into the effect of different medications and novel therapies. Blood Cancer J 2023; 13 (1 ): 83.37208317
4 Schoen MW Carson KR Luo S , et al . Venous thromboembolism in multiple myeloma is associated with increased mortality. Res Pract Thromb Haem 2020; 4 (7 ): e12411.
5 Mai EK. Vascular thrombotic events in the era of modern myeloma therapy. Brit J Haematol 2022; 199 (5 ): 642–644.36120817
6 Kristinsson SY Pfeiffer RM Björkholm M , et al . Thrombosis is associated with inferior survival in multiple myeloma. Haematologica. 2012; 97 (10 ): 1603.22511493
7 Wang J Park C Arroyo-Suarez R. Venous thromboembolism in patients with multiple myeloma receiving daratumumab-based regimens: a post hoc analysis of phase 3 clinical trials. Leukemia & Lymphoma 2021; 62 (9 ): 2219–2226.33836624
8 Kristinsson SY Landgren O. Thromboprophylaxis in multiple myeloma: is the evidence there? Expert Rev Anticancer Ther 2012; 12 (3 ): 291–294.22369320
9 Fotiou D Gavriatopoulou M Terpos E. Multiple myeloma and thrombosis: prophylaxis and risk prediction tools. Cancers 2020; 12 (1 ): 191.31940972
10 Palumbo A Rajkumar S Dimopoulos M , et al . Prevention of thalidomide-and lenalidomide-associated thrombosis in myeloma. Leukemia 2008; 22 (2 ): 414–423.18094721
11 Bradbury CA Craig Z Cook G , et al . Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials. Blood 2020; 136 (9 ): 1091–104.
12 Crowther Z Doyle J Taylor S , et al . Clinical outcomes of multiple myeloma patients treated with direct oral anticoagulants for immunomodulatory drug associated venous thromboembolism. Blood 2019; 134 : 4964.
13 Kahale LA Matar CF Tsolakian I , et al . Antithrombotic therapy for ambulatory patients with multiple myeloma receiving immunomodulatory agents. Cochrane Database Syst Rev 2021; 9 (9 ): CD014739.
14 Lee C-L Chen W-S Wee Y , et al . Direct oral anticoagulants are associated with superior survival outcomes than warfarin in patients with head and neck cancers. Cancers 2022; 14 (3 ): 703.35158969
15 Khan AM Chiasakul T Redd R , et al . Survival outcomes with warfarin compared with direct oral anticoagulants in cancer-associated venous thromboembolism in the United States: a population-based cohort study. PLoS Med 2022; 19 (5 ): e1004012.
16 Chiasakul T Redd R Patell R , et al . Overall survival with warfarin vs. low-molecular-weight heparin in cancer-associated thrombosis. J Thromb Haemost 2021; 19 (11 ): 2825–2834.34490999
17 Tagalakis V Blostein M Robinson-Cohen C , et al . The effect of anticoagulants on cancer risk and survival: systematic review. Cancer Treat Rev. 2007; 33 (4 ): 358–368.17408861
18 Marinac CR Colditz GA Rebbeck T , et al . Regular aspirin use and mortality in multiple myeloma patients. SSRN 3890705.
19 Kinnunen PT Murtola TJ Talala K , et al . Prostate cancer-specific survival among warfarin users in the Finnish Randomized Study of Screening for Prostate Cancer. BMC Cancer 2017; 17 : 1–9.28049525
20 Kilpeläinen TP Tammela TL Malila N , et al . Prostate cancer mortality in the Finnish randomized screening trial. J Natl Cancer Inst 2013; 105 (10 ): 719–725.23479454
21 O’Rorke M Murray L Hughes C , et al . The effect of warfarin therapy on breast, colorectal, lung, and prostate cancer survival: a population-based cohort study using the Clinical Practice Research Datalink. Cancer Causes Control 2015; 26 : 355–366.25534917
22 Kinnunen P Murtola T Talala K , et al . Anticoagulants and cancer mortality in the Finnish randomized study of screening for prostate cancer. Cancer Causes Control 2019; 30 : 877–888.31209595
23 Facon T Kumar SK Plesner T , et al . Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 2021; 22 (11 ): 1582–1596.34655533
24 Dimopoulos MA Oriol A Nahi H , et al . Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2016; 375 (14 ): 1319–1331.27705267
25 Palumbo A Chanan-Khan A Weisel K , et al . Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 2016; 375 (8 ): 754–766.27557302
26 Goodyear MD Krleza-Jeric K Lemmens T . The declaration of Helsinki. BMJ 335 (7621 ): 624–625.
27 Dixon JR . The international conference on harmonization good clinical practice guideline. QualAssur 1999; 6 (2 ): 65–74.
28 Von Elm E . STROBE initiative. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med 2007; 147 : 573–577.17938396
29 Department of Health and Human Services NIoH, National Cancer Institute. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, May 28, 2009.
30 Harrell FE Jr . Hmisc: Harrell Miscellaneous Version 5.1-3) [R package]. 2022, https://CRAN.R-project.org/package=Hmisc
31 Morgan CJ. Landmark analysis: a primer. J Nucl Cardiol 2019; 26 (2 ): 391–393.30719655
32 Almansour SA Alqudah MA Abuhelwa Z , et al . Association of proton pump inhibitor use with survival and adverse effects outcomes in patients with multiple myeloma: pooled analysis of three clinical trials. Sci Rep 2024; 14 (1 ): 591.38182614
33 Voorhees PM Kaufman JL Laubach J , et al . Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood 2020; 136 (8 ): 936–945.32325490
34 Charalampous C Goel U Kapoor P , et al . Thrombosis in multiple myeloma: risk estimation by induction regimen and association with overall survival. Am J Hematol 2023; 98 (3 ): 413–420.36588396
35 Sborov DW Baljevic M Reeves B , et al . Daratumumab plus lenalidomide, bortezomib and dexamethasone in newly diagnosed multiple myeloma: analysis of vascular thrombotic events in the GRIFFIN study. Br J Haematol 2022; 199 (3 ): 355–365.36111391
36 Dimopoulos M Leleu X Palumbo A , et al . Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. Leukemia 2014; 28 (8 ): 1573–1585.24496300
37 Dimopoulos M Palumbo A Attal M , et al . Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement. Leukemia 2011; 25 (5 ): 749–760.21293488
38 Palumbo A Cavo M Bringhen S , et al . Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol 2011; 29 : 986–993.21282540
39 Larocca A Cavallo F Bringhen S , et al . Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 2012; 119 (4 ): 933–99.
40 Fotiou D Gerotziafas G Kastritis E , et al . A review of the venous thrombotic issues associated with multiple myeloma. Exp Rev Hematol 2016; 9 (7 ): 695–706.
41 Swan D Rocci A Bradbury C , et al . Venous thromboembolism in multiple myeloma–choice of prophylaxis, role of direct oral anticoagulants and special considerations. Br J Haematol 2018; 183 (4 ): 538–556.30450656
42 Khorana AA Soff GA Kakkar AK , et al . Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med 2019; 380 (8 ): 720–728.30786186
43 Leleu X Rodon P Hulin C , et al . MELISSE, a large multicentric observational study to determine risk factors of venous thromboembolism in patients with multiple myeloma treated with immunomodulatory drugs. Thromb Haemost 2013; 110 (10 ): 844–51.
44 Piedra K Peterson T Tan C , et al . Comparison of venous thromboembolism incidence in newly diagnosed multiple myeloma patients receiving bortezomib, lenalidomide, dexamethasone (RVD) or carfilzomib, lenalidomide, dexamethasone (KRD) with aspirin or rivaroxaban thromboprophylaxis. Br J Haematol 2022; 196 (1 ): 105–109.34396516
45 Key NS Khorana AA Kuderer NM , et al . Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO guideline update. J Clin Oncol 2023; 41 (16 ): 3063–3071.37075273
46 Frenzel L Decaux O Macro M , et al . Venous thromboembolism prophylaxis and multiple myeloma patients in real-life: results of a large survey and clinical guidance recommendations from the IFM group. Thromb Res 2024; 233 : 153–164.38064842
47 Grant SJ Mian HS Giri S , et al . Transplant-ineligible newly diagnosed multiple myeloma: Current and future approaches to clinical care: a Young International Society of Geriatric Oncology Review Paper. J Geriatr Oncol 2021; 12 (4 ): 499–507.33342724
48 Covut F Sanfilippo KM. Mitigating the risk of venous thromboembolism in patients with multiple myeloma receiving immunomodulatory-based therapy. Hematology 2022; 2022 (1 ): 363–367.36485142
49 Richardson PG Weller E Lonial S , et al . Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010; 116 (5 ): 679–686.20385792
50 Plummer C Driessen C Szabo Z , et al . Management of cardiovascular risk in patients with multiple myeloma. Blood Cancer J 2019; 9 (3 ): 26.30808934
51 Adrianzen-Herrera D Lutsey PL Giorgio K , et al . Bleeding risk in patients with multiple myeloma treated for venous thromboembolism: a MarketScan analysis. Res Pract Thromb Haemost 2023; 7 (1 ): 100024.36873562
52 Kanapuru B Fernandes LL Fashoyin-Aje LA , et al . Analysis of racial and ethnic disparities in multiple myeloma US FDA drug approval trials. Blood Adv 2022; 6 (6 ): 1684–1691.35114691
