Hypertension is commonly reported in patients with MM in clinical trials and may be associated with older age, disease-related complications or consequence of MM treatments [5–7]. However, little is known about the incidence of hypertension or malignant hypertension in the broader population of patients outside of clinical trials. To our knowledge, this is the first study to estimate the incident rates of hypertension and malignant hypertension in a population of newly-diagnosed, MM-treated patients in the US not participating in clinical trials compared with age- and gender-matched non-MM patients. There is a recent study by Kistler and colleagues that reported incidence rates of hypertension in combination with arterial events as part of their evaluation of cardiac events in MM and non-MM patients based on MarketScan data [8]. They found no significant difference in risk of hypertension/arterial events between MM and non-MM patients. This differs from the results of this current study which found a 30% higher risk of hypertension in MM patients versus non-MM patients. There were a couple of significant differences in study design between the two studies. Kistler et al. did not specifically study hypertension events alone; they evaluated the incidence of hypertensive and arterial events combined. In addition, the MM patients in the Kistler study had a longer duration of MM disease, as the inclusion criteria for the MM cohort required patients to have had at least three anti-myeloma treatments (thereby introducing confounding medical issues such as autonomic or adrenal insufficiency, weight loss, etc.), whereas the current study included newly-diagnosed MM patients with at least one anti-myeloma treatment.
In this study, the prevalence rate of hypertension in non-MM patients (33% of patients) is comparable with published data for the US adult population (1 out of 3 adults) [9, 10]. That said, the incidence of hypertension and malignant hypertension is significantly higher in newly-treated MM patients compared with non-MM patients. Multi-variate analyses showed that patients with MM had a statistically significant increased risk of hypertension compared with non-MM patients and also a significantly increased risk of malignant hypertension in both MM patients with or without a history of hypertension compared with non-MM patients. Whether the increased risks of hypertension and malignant hypertension found for MM patients were due to disease-unrelated factors, disease-related comorbidities or a combination of these factors is difficult to determine. Older age and male gender pre-disposes MM patients to an increased risk of hypertension; however, this study controlled for both these factors by using age- and sex-matched non-MM patients.
Results of multi-variable modeling found that the presence of several CV comorbidities increased the risk of hypertension and malignant hypertension in MM patients. In patients without a prior history of hypertension, co-existing ischemic heart disease, renal failure, diabetes and hyperlipidemia increased the risk of hypertension. In patients with a prior history of hypertension, co-existing cardiomyopathy, renal failure or diabetes greatly increased the risk of malignant hypertension. The presence of all of these co-morbidities was significantly higher in the MM population than in the non-MM population at baseline. High levels of CV comorbidities in MM patients have been noted in another non-clinical study of newly-diagnosed MM patients. Chen et al. reported that close to half (47.9%) of all newly-diagnosed MM patients (N = 8239) identified from commercial medical and Medicare claims databases had more than one type of comorbidity at baseline (6 months prior to MM diagnosis), with 43.9% of patients having metabolic comorbidities, 21.4% with CV diseases and 11.5% with renal conditions [11].
Renal dysfunction is very common in MM patients and renal failure is a negative prognostic factor for patient survival [5]. In this study, renal failure at the start of treatment in patients without a history of baseline hypertension did appear to be a risk factor for hypertension during treatment; however, patients were only at risk for malignant hypertension if renal failure was also associated with baseline hypertension.
Hypertension has been reported to be twice as frequent in patients with diabetes than in those without diabetes [12]. The findings from this study also show close to double the rate of hypertension in non-MM patients with diabetes (54%) versus those without diabetes (30%) (data not shown). For MM patients, the rate of hypertension was 54% in those with co-existing diabetes and 36% in patients without diabetes (data not shown). This is of particular concern given that the routine use of corticosteroids in myeloma therapy can lead to new diagnoses of diabetes or worsen glycemic control of those with known diabetes. Taken together, these results show that control and prevention of hypertensive events in MM patients must include management of CV comorbidities.
Per the 8th Joint National Committee of 2014 evidence-based guidelines for management of high blood pressure in adults, “hypertension is one of the most important preventable contributors to disease and death” [13]. The guidelines recommend initiating drug treatment in non-black hypertensive patients with an ACE-I, ARB, calcium channel blocker or thiazide-type diuretic; in black hypertensive patients, initial therapy should include a calcium channel blocker or thiazide-type diuretic. The most common anti-hypertensive medications at baseline for this study were diuretics, ACE-I, calcium channel blockers and ARBs. For patients with a history of hypertension, the same percentage of patients (71%) in the MM and non-MM groups were receiving anti-hypertensive medications, as well as similar numbers of anti-hypertensive medications at baseline. During the follow-up period, similar percentages were seen between the MM patients and non-MM patients with incident hypertension.
The choice of anti-hypertensive therapy in a myeloma patient, however, must take into account myeloma-associated renal failure (hence caution with diuretics and ACE-I/ARB), hypercalcemia or hyperuricemia (which can be exacerbated by thiazides), and steroid-related edema (which can be exacerbated by calcium channel blockers). It should also be noted that grade 3 hypertension in clinical trials does not necessarily equate to markedly elevated blood pressures or malignant hypertension, as the addition of blood pressure medications is considered a grade 3 hypertension adverse event per National Cancer Institute Common Toxicity Criteria definition. Addition of anti-hypertensive medications was not included as a hypertensive event in this study; however, evaluation of anti-hypertensive medications in the follow-up period found approximately 6% more MM patients than non-MM patients had one class of anti-hypertensive medication added.
The results of this study emphasize that CV and hypertensive adverse effects cannot be evaluated in clinical trials without a comparator arm, given the high incidence rates of these complications in MM patients. MM patients entering the trials are already at a high risk for hypertensive events, and existing hypertension is a major risk factor for development of malignant hypertension. Hypertension has been reported as an adverse event in studies of patients undergoing MM treatment [5–7, 14–18].
Although this study evaluated hypertension and malignant hypertension in MM patients undergoing treatment for MM, it did not evaluate results for specific anti-myeloma treatments. There are some other limitations of this study. MarketScan claims database better represents the demographic distribution of employed populations while under-representing the elderly, unemployed and disabled. This may be a reason why the median age of MM diagnosis in this study, 65 years, was close to, but a little younger than that published in the literature for median age of MM incidence (69 years SEER cancer statistics) [2]. The MarketScan database does not include information about race, precluding examining the effect of race on these findings (for example, hypertension rates in black vs. white patients, since MM is two-fold more common than in white patients) [2]. In addition, survival data and hypertension and other CV co-morbidity risk factors such as obesity, diet, physical activity and smoking status are not included in the database. There exists the possibility that malignant hypertension may be underestimated in MM patients for whom hospital admissions were not explicitly coded as such, due to the presence of other acute medical issues such as disease progression. Finally, this study could not control for ascertainment bias; MM patients under treatment would be evaluated more frequently by physicians than non-MM patients and thus have a higher probability of hypertensive events reported.