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Letter to the Editor
Corticosteroid therapy has been a long-standing component in the treatment of multiple myeloma, in which it is believed to reduce monoclonal protein levels and increase chemotherapeutic response. Earlier, high doses of dexamethasone were empirically chosen given the paucity of specific trial data to guide optimal dosing. However, with the advent of agents with increasing activity in multiple myeloma, such as lenalidomide and bortezomib, the necessity for high dose dexamethasone has been questioned. It is noted that in the Eastern Cooperative Oncology Group trial E4A03, in which participants were randomized to receive either low- or high-dose dexamethasone in combination with lenalidomide (1), it was the low dose dexamethasone regimen that was associated with significantly better 1- and 2-year overall survival rates (especially among patients under 65 years of age), as well as significantly lower toxicity (major grade 3 or higher toxicities, including deep vein thrombosis, pulmonary embolism and infections) despite the high dose regimen producing higher response rates. However, it was not clear from this trial whether the dexamethasone doses had a differential impact on adrenal suppression and whether this played any role in the observed outcomes.
High dose dexamethasone-based regimens for the treatment of myeloma have most frequently involved administration of oral dexamethasone 40 mg on days 1–4, 9–12, and 17–20 of each 28 day cycle; low dose regimens (as in Eastern Cooperative Oncology Group E4A03) have utilized oral dexamethasone 40 mg on days 1, 8, 15, and 22 of each 28 day cycle. With physiologic corticosteroid replacement estimated to be approximately 0.5-0.75 mg/day of dexamethasone, the high dose regimen translates into more than 30-fold, and low dose more than 10-fold, of the normal physiologic levels. Some authors suggest that any patient who has received the equivalent of 20 to 30 mg/day of prednisolone (approximately equivalent to 0.5-0.75 mg/day of dexamethasone) for more than five days may be at risk of adrenal suppression (2), whereas others contend that several weeks of exogenous glucocorticoid administration at replacement dosing are required for the development of adrenal insufficiency (3). Further, there is significant individual variability in susceptibility to suppression of the hypothalamic-pituitary-adrenal axis by exogenous glucocorticoids, making it difficult to reliably predict the occurrence of adrenal suppression from the dose and duration of glucocorticoid used alone (4). Thus it is of interest to determine whether the difference in clinically favorable outcomes found with low-dose compared to high-dose dexamethasone regimens was associated with differences in adrenal suppression.
From our myeloma database, we were able to identify 11 patients who have received high-dose dexamethasone, and 34 patients who have received low-dose dexamethasone, and who had also had early morning 8 AM serum cortisol levels determined both at baseline and again at 3 months after initiation of their dexamethasone-based chemotherapeutic treatment regimens. The 3 month 8 AM serum cortisol levels were routinely obtained at the end of a weekly treatment cycle (i.e. 4-7 days after the last dose of dexamethasone). Median ages were 56 years (range 44-70) in the high-dose and 67 years (range 50-89) in the low-dose dexamethasone groups, respectively. Chi-square and Fisher's exact tests were used to compare differences among the patient groups for nominal variables and the Wilcoxon rank-sum test was used for continuous variables (Table 1). At baseline, the high- and low-dose dexamethasone groups demonstrated no significant differences in their 8AM serum cortisol levels. At 3 months however, 72.7% of subjects in the high-dose dexamethasone group had a decline (from baseline) in 8AM cortisol levels, compared with 32.4% of subjects in the low dose dexamethasone group (P = 0.03). The proportion of patients with a 3-month 8AM serum cortisol level below 3 mcg/dL (a level considered to be presumptive evidence of adrenal suppression) (5, 6) was significantly higher in patients receiving high-dose dexamethasone compared to subjects receiving low-dose dexamethasone (45.5% vs. 8.8%, P = 0.01). Similarly, the proportion of patients with a 3-month 8AM serum cortisol level below 10 mcg/dL (a level considered to be “suggestive” of adrenal suppression) (7) was higher in the high dose group (63.6 % vs. 32.4%, P=0.09), although this did not reach statistical significance. Overall, patients in the high dose group experienced a mean decline of 6.4 mcg/dL in their 8AM serum cortisol levels after 3 months (95% CI; -10.7, -2.1), whereas those in the low dose group showed no significant change (95% CI; -0.2, 4.3).
These data suggest that high dose dexamethasone regimens may induce substantial adrenal suppression in a significant proportion of patients. Further, approximately one-third of patients receiving low-dose dexamethasone, the current dexamethasone regimen of choice, had 8AM cortisol levels below 10 mcg/dL, including approximately 9% with cortisol levels < 3 mcg/dL, after 3 months of treatment, suggesting that a proportion of patients receiving even low-dose dexamethasone is at risk of developing adrenal insufficiency.
We acknowledge that there are several limitations to our study. First, this is retrospective study carried out on stored serum and hence endogenous cortisol secretion was assessed by determination of 8AM serum cortisol levels rather than by a provocative stimulation test, which may have provided more objective results. Second, while the 3-month samples were routinely obtained at the end of a weekly treatment cycle in which dexamethasone is ingested on the first day each week, it is possible that for some subjects this may not have been the case, which might lead to erroneous assessments of adrenal suppression. Despite these limitations, we hope the data presented here will alert clinicians to consider evaluating adrenal function in patients with multiple myeloma who receive dexamethasone-based chemotherapeutic regimens. Finally, additional prospective studies are needed to determine the impact of corticosteroid-induced adrenal insufficiency on important treatment outcomes, such as symptom relief and disease prognosis.
This work was supported by a Mayo Hematologic Malignancies Program Grant and a Mayo Career Development Award