Introduction
Multiple myeloma (MM) is a clonal plasma cell proliferative disorder characterized by elevated serum monoclonal immunoglobulins. It is primarily diagnosed in older adults, with a median age of approximately 70 years [ 1 , 2 ] . MM accounts for around 2% of all cancer diagnoses and about 10% of hematologic malignancies in the United States. Its incidence has increased by nearly 40%, highlighting a growing healthcare burden [ 3 , 4 ] . Diagnosis requires ≥10% clonal plasma cells in the bone marrow, along with at least one defining feature: hypercalcemia, renal impairment, anemia, or bone lesions (CRAB criteria) [ 5 ] . Conversely, cardiovascular disease (CVD) remains the leading cause of death in the U.S. [ 4 ] . In 2022, there were 702,880 heart disease deaths (rate: 210.9 per 100,000), with the majority occurring in adults aged ≥65 years [ 4 ] . The coexistence of MM and CVD is common in older patients, due to overlapping risk factors and treatment-related toxicity, contributing to high cardiovascular comorbidity in this population. HIGHLIGHTS Patients with coexistent MM and CVDs have an increased risk of mortality. Trends in MM and CVD-related AAMRs were analyzed in the U.S. Males reported twice AAMR compared with females by the end of the study. NH African Americans had triple the AAMRs of other racial/ethnic groups. Metropolitan areas consistently had higher AAMRs than non-metropolitan areas.
Many individuals with newly diagnosed multiple myeloma also have current or past cardiovascular disease, largely due to shared risk factors and age. Myeloma itself, along with its treatments such as chemotherapy, corticosteroids, and immunomodulators, can directly or indirectly contribute to cardiovascular complications like arrhythmias, hypertension, and heart failure. Given these overlapping disease burdens, understanding trends in mortality where both MM and CVD are contributing causes of death is essential for informing survivorship care and public health policy [ 6 – 8 ] . This study aims to analyze national mortality trends in older adults who have both MM and CVD as causes of death from 1999 to 2023. Utilizing the CDC database, we explore demographic and geographic variations to better understand the overlapping burden of cancer and cardiovascular conditions in the aging population.
Methods
Data source
This study analyzed mortality data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database to evaluate trends in MM and CVD–related mortality among adults aged 65 years and older in the United States from 1999 through 2023 [ 9 ] . The analysis was based on the public-use Multiple Cause of Death (MCD) files, which are available from U.S. death certificates. MM was identified using ICD-10 code C90.0 (malignant neoplasm of plasma cells), and CVDs were classified under ICD-10 codes I00–I99 (diseases of the circulatory system). Both were required to be listed as causes of death, regardless of whether they were identified as the underlying or contributing causes. This study was exempt from institutional review board (IRB) review due to the use of publicly available and de-identified data.
Data extraction
Data were extracted through the CDC WONDER interface for all 50 states and the District of Columbia. The study population included individuals aged 65 years and older. Demographic variables included sex, race, and ethnicity. Racial/ethnic groups included non-Hispanic (NH): Whites, African Americans, Asians/Pacific Islanders, and Hispanics or Latinos following CDC Wonder classification. Geographic variables included U.S. Census Bureau regions (Northeast, Midwest, South, West) and the National Center for Health Statistics (NCHS) urban–rural classification scheme [ 10 ] .
Statistical analysis
Age-adjusted mortality rates (AAMRs) per 100,000 population were calculated using the direct method and the 2000 U.S. Standard Population as the reference [ 11 ] . Temporal trends were evaluated using Joinpoint Regression Software (version 5.0; National Cancer Institute), which identifies statistically significant changes in mortality trends over time. Annual percentage changes (APCs) and corresponding 95% confidence intervals (CIs) were computed [ 12 ] . Subgroup analyses were performed by sex, race/ethnicity, and regions to examine demographic and geographic disparities. A two-sided P-value <0.05 was considered statistically significant. All results were interpreted in accordance with CDC data use guidelines.
Results
Proportional mortality rate across different variables from 1999 to 2023
Both MM and CVD were listed on a total of 99,637 death certificates, from which males (55.61%) experienced higher mortalities than females (44.39%). NH Whites (79.82%) contributed to the majority of deaths, followed by NH African Americans (17.47%), Hispanics or Latinos (6.26%), and NH Asians or Pacific Islanders (2.22%). Mortalities reported the highest Inpatient settings (38.85%) with lesser frequencies in the decedent’s home (29.89%), nursing home/long-term care (17.07%), hospice facilities (5.45%), outpatient care (4.5%), and other places (3.69%), respectively. Deaths were more prevalent in metropolitan areas (82.22%) than in non-metropolitan areas (17.78%), while the region of the South (34.89%) had the highest deaths compared to the West (22.7%), Northeast (21.28%) and Midwest (21.13%) regions (Supplemental Digital Content Figure 1, Available at, http://links.lww.com/MS9/A925 ) (Supplemental Digital Content Table 1, Available at, http://links.lww.com/MS9/A925 ).
Overall and sex stratified age-adjusted trends for multiple myeloma and cardiovascular disease-related mortality among older adults in the United States, 1999 to 2023
The overall AAMR experienced a slight incline from 9.6 in 1999 to 9.9 in 2023. However, a marked increase in overall AAMR was observed from 2018 to 2021 (APC: 6.82; 95% CI: 4.07 to 8.46), followed by a steep decline till 2023 (APC: − 4.44; 95% CI: − 8.48 to −0.25). Total AAMR in males (12.5) reported by 2023 was doubled compared to females (7.0). Female mortality rates after following a sharp decline until 2015 (APC: − 1.74; 95% CI: − 2.83 to −1.13) increased significantly up to 2023 (APC: 2.68; 95% CI: 0.91 to 5.8). Males AAMR rose sharply from 1999 to 2002 (APC: 2.04; 95% CI: 0.3 to 5.15) followed by a steep decline till 2009 (APC: − 1.67; 95% CI: − 3.78 to −1.05) and after maintaining stability up to 2018 the AAMR surged rapidly till 2021 (APC: 7.49; 95% CI: 5.85 to 8.59) before declining again by 2023 (APC: − 5.84; 95% CI: − 7.7 to −3.84) (Figure 1 , 2 ) (Supplemental Digital Content Tables 2, 3, Available at, http://links.lww.com/MS9/A925 ). Figure 1. Overall, trends in Multiple Myeloma and Cardiovascular Diseases-related age-adjusted mortality rates per 100,000 among older adults in the United States, 1999 to 2023. APC = Annual Percentage Change, CI = Confidence Interval. *Indicates that the Annual Percentage Change (APC) is significantly different from zero at α = 0.05. Figure 2. Trends in Multiple Myeloma and Cardiovascular Diseases-related age-adjusted mortality rates per 100,000, stratified by sex among older adults in the United States, 1999 to 2023. APC = Annual Percentage Change, CI = Confidence Interval. *Indicates that the Annual Percentage Change (APC) is significantly different from zero at α = 0.05.
Race/ ethnicity stratified
NH African Americans exhibited AAMR (18.6) almost 3 times that of noted in NH Whites (8.5), Hispanics or Latinos (8.3), and NH Asians or Pacific Islanders (5.5), respectively. From 1999, AAMR declined greatly till 2009 in Hispanic or Latino and up to 2015 in NH African American by annual rates of 2.48% and 0.97 respectively, and after which it increased significantly up to 2023 among both these races/ethnicities by annual rates of 1.15% and 1.96%, respectively. No significant variances were observed in mortality trends of NH Asian or Pacific Islanders throughout the study. However, a massive increase in mortality rates was observed from 2018 to 2021 in NH Whites (APC: 6.81; 95% CI: 4.32 to 8.49) (Fig. 3 ) (Supplemental Digital Content Tables 3, 4, Available at, http://links.lww.com/MS9/A925 ). Figure 3. Trends in Multiple Myeloma and Cardiovascular Diseases-related age-adjusted mortality rates per 100,000, stratified by race and ethnicity among older adults in the United States, 1999 to 2023. APC = Annual Percentage Change, CI = Confidence Interval. *Indicates that the Annual Percentage Change (APC) is significantly different from zero at α = 0.05.
Geographic trends
Mortality rates significantly differed among different geographical subgroups. States of top 90th percentile AAMR: North Dakota (11.4), Nebraska (11.6), California (11.9), New York (12.5) and District of Columbia (13.5) had AAMRs nearly doubled those of states: Nevada (5.6), Arizona (5.8), New Mexico (6.2), Florida (6.6) and Utah (6.6) in bottom 10th percentile. Regionally, the highest AAMR was recorded in the Northeast (10.1), followed by the West (9.8), while the Midwest and South reported equally lower rates of 8.8. Furthermore, metropolitan regions (9.2) represented higher mortality rates than non-metropolitan regions (9). Initially the AAMRs declined significantly in non-metropolitan areas until 2013 (APC: − 1.31; 95% CI: − 2.34 to −0.73) after which they began to rise, while metropolitan regions saw rise commencing in 2018; both increasing trends continued through 2020 with associated APCs of 2.41 and 6.94 respectively (Fig. 4 ) (Supplemental Digital Content Figure 2, Available at, http://links.lww.com/MS9/A925 ) (Supplemental Digital Content Tables 3, 5, 6, 7, Available at, http://links.lww.com/MS9/A925 ). Figure 4. Trends in Multiple Myeloma and Cardiovascular Diseases-related age-adjusted mortality rates per 100,000, stratified by urbanization among older adults in the United States, 1999 to 2020. APC = Annual Percentage Change, CI = Confidence Interval. *Indicates that the Annual Percentage Change (APC) is significantly different from zero at α = 0.05.
Discussion
This study examined mortality rates among older individuals in the United States from 1999 to 2023 related to cardiovascular disease (CVD) and multiple myeloma (MM) across a range of demographic regions and urbanization levels. In contrast to the general population, Multiple Myeloma Patients are faced with a greater risk of Cardiovascular-Related Mortality [ 13 ] .
CVD in individuals with MM can arise from factors such as aging, diabetes, high cholesterol, obesity, or a history of heart conditions, which aren’t directly related to the cancer itself, as well as from MM related causes including increased blood viscosity, high-output heart failure, arteriovenous shunts, anemia, or kidney dysfunction. Research also proves that treatments for MM, such as anthracyclines, corticosteroids, alkylating agents, immunomodulatory drugs and proteosome inhibitors, can also elevate risks for cardiac complications [ 14 ] . A session held in November 2019 on Cardio-Oncology, led by Dr. Breccia and Dr. Jurczak explored the impact of cancer treatments on the heart. While the pre-established concept that anthracyclines continue to present challenges due to their potential to induce left ventricular dysfunction and heart failure was discussed, light was also shone on newer therapeutic agents, which are associated with distinct cardiovascular toxicities [ 15 ] . The risks of myelomaspecific mortality and utilization of newly developed treatments and prescription of antineoplastic drugs in myeloma patients have historically been matched, but recent advancements have improved the situation significantly [ 16 ] . However, the detrimental impact of the disease itself, alongside its treatment, poses presumed greater risks to cardiovascular mortality [ 17 ] . In broader terms, the condition and its management strategies both can worsen the risk of cardiovascular related complications [ 18 ] .
The findings from this CDC indicate an overall increase in AAMRs due to Multiple Myeloma and cardiovascular-related mortality, from 9.6 per 100,000 in 1999 to 9.9 per 100,000 in 2023. A significant 22.73% surge in AAMR was visualized between 2018 and 2020, followed by a notable decline up until 2023. These sequential trends are portrayed in Fig. 1 of the supplementary file, which presents age-adjusted mortality rates for MM and CVD over the study period. These observed patterns warrant further investigation into the underlying factors influencing these trends, with particular attention to diagnostic practices, clinical management and drug therapies, public health strategies, and the role of demographic disparities and geographic variations, as indicated by other research showing significant differences based on geography, sex, race, and other sociodemographic factors [ 19 ] .
Most MM patients are elderly, a demographic more susceptible to cardiovascular damage due to reduced physical fitness and complications related to body mass index, which can lead to serious health issues during cancer treatment [ 20 ] . Gender-specific analysis of MM and CVD-related mortality in the United States reveals a consistent trend of higher mortality rates among males. By 2023, the total age-adjusted mortality rate in males (12.5 per 100,000) was notably double that observed in females (7.0 per 100,000). Furthermore, the temporal trends in mortality differed significantly between sexes, as illustrated in Fig. 2 . These findings align with trends observed in prior studies, which consistently show that men are approximately 1.5 times more likely to develop MM [ 21 ] . Further, assessment of underlying biological, behavioral, or health-care-related factors can explain this divergence in mortality between men and women. Existing research exploring hormonal effects, treatment responses, and prevalence of risk factors between men and women can help understand these discrepancies better [ 13 ] . A thorough investigation into MM survival differences between the two genders is crucial, given that men get diagnosed with MM more commonly than women with potentially poorer survival rates and higher adverse outcomes [ 22 ] . According to research, high levels of Treg cells warrant adverse clinical outcomes, such as severe MM progression [ 23 ] , and men are found to have naturally inflated amounts of Treg cells compared to their parallels explaining these variations. However, lifestyle and dietary practices cannot be disregarded either. Research provides insights that women can still have higher CVD mortality risks in contrast to men if they have a history of smoking, which is a modifiable risk factor for not only CVD but also MM and is critically important to be terminated to mitigate its menacing consequences on overall health [ 24 ] . However, women adhering to healthier lifestyle practices, maintaining healthy diets, and staying athletically active present with lower risks of cardiac-related mortality, and this paves the way for gender tailored lifestyle intervention choices [ 25 ] .
CDC data indicates that mortality trends for MM and CVD vary by race and ethnicity [ 26 ] . Currently, Hispanics constitute the largest ethnic group in the United States, making up 15% of the total population. And yet non-Hispanic African Americans are still evidently the highest AAMR displaying group among all others for MM and consequently CVD mortality despite the smaller populations [ 27 – 29 ] . Generally, white individuals are observed to have higher endurance and survival rates compared to non-White populations. A recent study formed an association between the Black race and a higher acute coronary heart disease incidence which, in the broader view, makes this population more susceptible to higher cardiovascular morbidity and mortality incidence too [ 30 ] . Consistently, Non-Hispanic African Americans experienced a higher mortality rate from coronary artery disease compared to other racial and ethnic groups, including non-Hispanic Whites [ 31 ] . Additionally, disparities in MM care for Hispanics and Non-Hispanics in the U.S. persist despite recent advancements in MM therapy [ 32 ] . The most crucial contributor to these discrepancies is the prevalence of widespread overweight and obesity across non-Hispanic African Americans, which predisposes them to chronic conditions with poorer outcomes and hence the alarming number of deaths in this demographic [ 33 ] . However, addressing socio-economic factors is also compulsory to mitigate these inequities. Variations in areas such as diagnosis timing, treatment choices and availability, comorbidity control and assessment, and supportive care also confer disparities among MM survivors from different racial backgrounds [ 34 ] . These differences may stem from lower median incomes and higher unemployment rates among this demographic which confines their healthcare choices to less effective ones [ 35 ] . On a genetic basis of evaluation, Monoclonal Gammopathy of Undetermined Significance (MGUS), a precursor lesion to MM, is a possible contributor to the greater MM mortality seen among non-Hispanic African Americans, with its commonness across this population unparalleled by other racial groups [ 36 – 38 ] . It is required to Further investigate disparities within this community for access to health care facilities, genetic predispositions, and prevalence of risk factors, both genetic and socio-economic, to emphasize the significance of tackling both Multiple Myeloma and Heart disease risk factors and to eradicate outcome discrepancies across racial groups [ 39 ] .
Variations across different geographical levels are significant and have been comprehensively documented across several regions with states like North Dakota, Nebraska, California, and New York exhibiting the highest AAMRs, almost twice as high as those like Nevada, Arizona, Florida, and Utah [ 40 ] . On a region-wise analysis, it was noted that the Northeast exhibited the highest AAMR, followed by the West, Midwest, and South respectively [ 41 ] . Metropolitan areas generally presented with higher mortality rates than non-metropolitan areas, highlighting the need for public health decisions tailored to specific regions and further research into health inequalities in urban-rural settings. This is due to lifestyle factors common in metropolitan areas, such as Obesity which, as mentioned previously also, is a known risk factor for MM and is predominantly widespread across metropolitan areas due to several convenience stores, fast food restaurants, and easily accessible junk. Other factors frequently observed in urban areas like less physical activity and exercise habits, and high stress levels might also influence the risk of MM [ 42 ] . As suggested by existing research, cancer rates differ based on locations indicating a strong connection between disease incidence and environmental influences. Similarly, the geographic clustering of MM across specific areas is also tied to environmental exposures like high levels of benzene in the air, which have been identified as contributing factors to a high incidence rate of MM in Georgia and South Carolina [ 42 ] . Prior studies have also indicated a link between exposure to benzene and a higher occurrence of MM providing further evidence to this theory [ 43 ] .
The significant rise in MM and CVD-related mortality among older adults across specific demographics and geographic areas of United States necessitates targeted public health interventions. Strategies designated to enhance healthcare access across neglected areas and cater to the need to mitigate environmental risks associated with MM and CVD-related mortality to control the situation are needed [ 44 ] . Furthermore, detailed investigations are needed to explicate underlying reasons leading to observed discrepancies to eradicate inequities. Also, since research indicates that the 65-85 age group most commonly shows the highest hospitalization rates, it is important to carry out age-specific interventions [ 45 ] .
Study limitations
Our analysis has several limitations to be considered when interpreting the findings. First, the use of the CDC WONDER database, while comprehensive and extensive, is based on death certificate data, which may have some misclassifications or inaccuracies in cause-of-death reporting. The attribution of mortality to either multiple myeloma or cardiovascular disease may not fully capture cases where both conditions contributed, potentially leading to underestimation or overestimation of cause-specific mortality rates. Second, the analysis is ecological and retrospective in nature, which limits the ability to establish causal relationships or control for confounding variables such as comorbidities, treatment types, or lifestyle factors that may influence mortality. Third, the database doesn’t have granular clinical data, including treatment history, medication use, disease stage, and patient-level cardiovascular risk profiles, which are important for a more nuanced understanding of the MM and CVD relationship. Additionally, demographic subgroup analyses, particularly by race and geographic region, may depend on healthcare access or diagnostic accuracy, which may affect subgroup comparisons. Lastly, although trends were analyzed over a 24-year period, medical innovations like new drugs and therapies of MM treatment and cardiovascular care may not yet be fully reflected in the latest mortality data, especially given potential lag times in public health reporting.
Conclusions
This study sheds light on significant trends in multiple myeloma and cardiovascular disease-related mortality among older adults in the United States from 1999 to 2023, using data from the CDC WONDER database. Our findings highlight the complex interplay between MM and CVD. Although advancements in MM treatment have contributed to a decrease in tumor-specific mortality, cardiovascular mortality remains a major concern, particularly due to treatment-associated toxicity, aging, comorbidities, and sociodemographic disparities. A pronounced spike was observed between 2018 and 2020, likely reflecting pandemic-related disruptions. Notably, disparities based on sex, race, ethnicity, geography, and levels of urbanization emphasize the urgent need to promote equitable healthcare reforms and to develop targeted, population-specific interventions.
Acknowledgements
None.
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s website, www.lww.com/annals-of-medicine-and-surgery .
Ethical approval
Ethical approval was not required as the study utilized publicly available, de-identified data from the CDC WONDER database, which does not contain information identifiable to individual subjects.
Consent for publication
This study utilized publicly available, de-identified data from the CDC WONDER database, which does not contain information identifiable to individual subjects; therefore, consent from the patient was not required.
Sources of funding
There are no sources of funding to declare, and no study sponsors were involved in any aspect of the study.
Author contributions
Author M. S. B. F.: contributed to Conceptualization, Writing - Original Draft, Writing - Review & Editing, Data curation, Visualization, Formal Analysis, and Supervision. Author S. T. H.: contributed to Conceptualization, Investigation, Software, Data Curation, Formal Analysis, Visualization, and Project administration. Author S. U. M.: contributed to Validation, Writing - Original Draft, and Resources. Author N. Z.: contributed towards Methodology, Validation and Resources. Author M. I. K.: contributed to Investigation and Resources.
Conflicts of interest disclosure
The authors report no relationships that could be construed as a conflict of interest.
Guarantor
Muhammad Idrees Khan.
Research Registration Unique Identifying Number (UIN)
This article is a review based on secondary analysis of publicly available, de-identified data from the CDC WONDER database. It is not a systematic review or clinical trial and therefore is not subject to prospective registration requirements.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Data Availability
The datasets generated and/or analyzed during the current study are available in manuscript and supplementary file.
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