Changing Incidence of Major Cardiovascular Events in Multiple Myeloma Patients over Time
Authors: Rosenberg Aaron Seth , Li Qian , Brunson Ann M , Tuscano Joseph , Wun Ted , Keegan Theresa H.M. 
Published: October 2019

Abstract
Background: While multiple myeloma (MM) comprises only 2% of all cancer diagnoses, the prevalence of the disease in the US has markedly increased from 46,865 patients in 2000 to 124,733 in 2015. New therapeutic classes have led to longer survival, and allowed older patients to undergo life-prolonging therapy. Survivorship issues are now becoming relevant for this population, as ongoing therapy may have as yet unappreciated long term sequelae. MM is a disease of older patients, with a median diagnosis age of 69, and the incidence is greatest among African Americans (AA), populations at higher risk of cardiovascular disease (CVD). We therefore designed a retrospective study to quantify the incidence of new CVD in this population, as well as changes in incidence over time, hypothesizing that CVD incidence would increase due to both longer survival times, and increased utilization of potentially cardiotoxic drugs.
Methods: Using the California Cancer Registry linked to the California Patient Discharge Database, we identified 15,404 patients diagnosed with MM between 1991-2012 with follow-up through 2014. CVD was defined as a hospital admission for coronary artery disease (CAD), congestive heart failure (CHF), or stroke (CVA) using ICD9 codes or if the cause of death due to CVD was the first report of CVD. Patients with prior CVD or in whom CVD was diagnosed within 60 days of MM diagnosis were excluded. All patients had a minimum of 60 days of follow up. Changes in CVD rates were assessed by era: 1991-97 (era 1), 1998-2002 (era 2), 2003-07 (era 3) and 2008-12 (era 4). The cumulative incidence of CVD was estimated from date of MM diagnosis to first CVD event, accounting for the competing risk of death. Adjusted hazard ratios (aHR) for developing CVD were estimated accounting for the competing risk of death per the methods by Fine and Grey.
Results: Of the 15,404 patients, 8,056 (52%) were male, 9154 (59%) were non-Hispanic white (NHW), 1890 (12%) were African American, 2839 (18%) were Hispanic, and 1360 (9%) were Asian. Median age at diagnosis was 65, with 12% of patients <50 and11%>80. Stem cell transplant was utilized by 2989 (19%) patients. The most common insurers were private/military (42%), followed by Medicare (31%), Medicaid/other public (7%), and unknown (19%) insurance. The median age of patients who developed CVD was 68 vs 63 who were never admitted for CVD (p<0.001). The 2 and 5 year cumulative incidence of developing CVD was 15.8% (95% confidence interval (CI): 15.2% - 16.3%) and 26.3% (CI: 25.6% - 27.0%). This was significantly less in era 4 (2008-12): 12.6% (11.6% - 13.7%) and 22.3% (20.9% - 23.8%) (p<0.001) (Figure). When examining types of CVD, CVA was less common in era 1 (1991-97) compared to eras 2-4 (5 year cumulative incidence rates in eras 1-4 respectively: 3.9% [3.4% - 4.5%], 4.6% [4.0% - 5.4%], 5.0% [4.3% - 5.7%], 4.6% [3.9% - 5.4%]) (p=0.002). CAD was less common in era 4 (5 year cumulative incidence rates in ears 1-4 respectively: 10.3% [9.4% - 11.2%], 11.5% [10.5% - 12.7%], 10.8% [9.9% - 11.9%], 9.4% [8.5% - 10.5%]) (p = 0.003). CHF was less common in era 4 (5 year cumulative incidence rates in eras 1-4 respectively: 17.9% [16.7% - 19.1%], 18.6% [17.3% - 20.0%], 17.7% [16.5% - 19.0%], 13.8% [12.6% - 15.0%].
In multivariable analysis, increased age, male sex, AA race/ethnicity, increased Elixhauser comorbidity score were associated with increased risk of CVD. Surprisingly, after accounting for age Medicare insurance was associated with increased risk of CVD, while socioeconomic status was not. Use of stem cell transplant was associated with decreased risk, likely due to pre-transplant screening for CVD. Diagnosis during era 4 (2008 - 12) was associated with decreased risk of new CVD (adjusted hazard ratio 0.70 [CI: 0.63, 0.77]).
Conclusion: CVD is a common complication in MM patients: within 5 years of a MM diagnosis, over 25% develop CVD requiring hospitalization. Contrary to our hypothesis, we did not find increased CVD admissions in the most recent era. Decreased admissions due to CHF and CAD in the most recent era of diagnosis may indicate a greater awareness of this issue, routine thromboprophylaxis with anti-platelet agents in patients being treated with immunomodulatory agents, or changes in secular trends in the diagnosis and treatment of CVD. CVD is an ongoing source of morbidity for MM patients requiring further study and the vigilance of clinicians.
Figure. Figure.

Disclosures
Rosenberg: Amgen: Research Funding, Speakers Bureau.