High‐dose glucocorticoids improve renal failure reversibility in patients with newly diagnosed multiple myeloma
Authors: Ulas Darda Bayraktar, Sean Warsch,, Denise Pereira
Journal: American Journal of Hematology (2010)

One-fifth of the newly diagnosed multiple myeloma (MM) patients present with renal failure (RF) [1-3]. Glucocorticoids (GCs) may improve RF in MM by (1) rapid reduction of paraprotein production, (2) lessening inflammation and fibrosis in renal parenchyma, and (3) decreasing serum calcium level. We hypothesized that lower dose GCs may be less effective in restoring renal function and retrospectively compared the RF reversibility between the newly diagnosed MM patients who were treated with GCs equivalent to ≥160 mg DX over 4 days (high-dose GC group, n = 16) versus those who were treated with <160 mg (low-dose/no GC group, n = 8). There was no difference in age, baseline calcium, and creatinine levels between the two groups. Renal function was restored in seven patients in the high-dose GC group (44%) and in none of the patients in the low-dose/no GC group (P = 0.026). The only other factor found to impact the RF reversibility was the delay of GC initiation. Four and 1 patients developed a severe infection in the high- and low-dose/no GC groups, respectively. The use of higher dose GCs in the newly diagnosed MM patients who present with RF increases the likelihood of renal function restoration. Major causes of acute RF in MM are the precipitation of light chains in the renal tubules, hypercalcemia, dehydration, hyperuricemia, and administration of nephrotoxic agents. RF is associated with poor prognosis in patients with MM and poses a major management problem [4-6]. In 26–73% of patients, renal function may be restored, [1, 2, 7] simplifying management and improving survival [8]. RF in MM patients is associated with a high-tumor burden, and abnormal protein production should be promptly decreased in those patients [9]. Optimal management of acute RF in MM still remains controversial. GCs are thought to exert their effect on myeloma cells through inhibition of NF-κB and IL-6 [10-12]. GCs are highly efficacious in myeloma treatment, as dexamethasone (DX) was accounted for most of the responses to once-standard VAD chemotherapy [13]. VAD regimen consisted of DX 40 mg administered orally for 4 days in addition to vincristine and doxorubicin [14]. The same DX regimen was later used in different studies, either alone or in combination with other chemotherapeutics [15, 16]. GCs may improve RF in MM patients through reduction of paraprotein production and serum calcium levels. Furthermore, GCs may also hinder inflammation and fibrosis in renal parenchyma that is exacerbated by the proinflammatory cytokines secreted by renal tubular cells upon endocytosis of light chains [17, 18]. The cytokine production in renal tubular cells is mediated through NF-κB that may be inhibited by both GCs [10] and proteasome inhibitors [19]. Kastritis et al. [7] reported reversal of RF in 69% of newly diagnosed MM patients treated with high-dose DX alone or with VAD/VAD-like chemotherapy/melphalan. Whether GC dose impacts the reversibility of RF in newly diagnosed MM patients remains unknown. We hypothesized that lower dose GCs may be less effective in restoring renal function and retrospectively compared to the RF reversibility between the newly diagnosed MM patients who were treated with GCs equivalent to ≥160 mg DX over 4 days versus those who were treated with <160 mg. Of 144 patients diagnosed with MM at Jackson Memorial Hospital (JMH) between 2000 and 2008, 27 (19%) presented with RF. Two and 1 patients were excluded from the study due to pre-existing RF and a follow-up period of less than 1 month. Sixteen patients received ≥160 mg DX or equivalent GCs over 4 days (high-dose GC group). Of the remaining eight patients (low-dose/no GC group), three did not receive any GC while in the hospital. The basis for lower dose or no GC administration was to avoid interference with wound healing after plasmacytoma resection in one patient, synchronous diagnosis of lung cancer in one patient, and history of HIV/AIDS in one patient. Additionally, the consulting hematologist elected to use lower dose GCs in three patients without any identifiable rationale, and two patients were not evaluated by a hematologist while in the hospital. The demographic and clinical characteristics of patients are summarized in Table I. There was no difference in age, comorbidities, body surface area (BSA), and laboratory findings at the time of admission between the two groups. There were more black patients in the low-dose/no GC group. Corrected serum calcium level was >11 mg/dL in 9 (38%) patients. All 22 patients, for whom a urine immunofixation was performed, had monoclonal protein identified in the urine. Creatinine clearance (CrCl) increased by a median of 36.8 mL/min/1.73 m2 (range, 0.0–96.3) and 9.5 mL/min/1.73 m2 (range, 0.0–24.7) in the high-dose and low-dose/no GC groups, respectively (P = 0.029). CrCl has risen above 60 mL/min/1.73 m2 within 6 months of admission in seven patients in the high-dose GC group (44%) and in none of the patients in the low-dose/no GC group (P = 0.026). The delay of GC initiation from admission and the cumulative dose of GCs administered within 4 days of initiation were the only factors found to affect the RF reversal rate on univariate analyses (Table II). Age, calcium, and LDH levels on admission, the use of hemodialysis (HD)/plasma exchange (PE), and the use of other myeloma agents did not have an impact on RF reversibility. Of seven patients whose RF reversed, only two received novel antimyeloma agents (Fig. 1A). A: Scatter plot demonstrating the glucocorticoid (GC) dose administered within 4 days of GC initiation and the magnitude of change in creatinine clearance within 6 months of hospital admission individually with separate markers for patients who received GCs alone (•) or with novel anti-myeloma agents (bortezomib, thalidomide, and lenalidomide: ⋄) or with antimyeloma agents (▵). B: Kaplan–Meier curves depicting overall survival in the high-dose and low-dose/no GC groups Three patients in the high-dose GC group received HD, of whom two also received PE. In all three patients, HD/PE was started either before or on the day of GC initiation. In two of these three patients, renal function was restored after GC initiation. At the time of last follow-up, one patient (6%) in high-dose and two patients (25%) in low-dose/no GC groups were still dialysis dependent. Four patients (25%) in the high-dose GC group developed severe infections within 1 month of GC initiation and three of them died due to these infections. In contrast, only one patient (13%) in the low-dose/no GC group developed a severe infection. Of those who died due to infections in the high-dose GC group, one patient received methylprednisolone 1 g IV for 3 days followed by oral DX, one patient received DX 100 mg IV on day 1 followed by 8 mg IV every 6 h for 4 days, and one patient received DX 40 mg orally for 5 days followed by tapering oral prednisone. One diabetic patient in low-dose/no GC group developed hyperosmolar coma after being discharged on tapering GCs. Median overall survival (OS) among all 24 patients who presented with RF was 9.0 months (95% CI: 0.9–23.5). OS was similar in both the groups (Fig. 1B). In this retrospective study of 24 patients with newly diagnosed MM, we found that treatment with higher dose GCs was associated with a higher RF reversibility rate. To our knowledge, this is the first study assessing the impact of GC dose on RF reversibility in newly diagnosed MM patients. The prevalence of RF at the time of MM diagnosis in our study was similar to those reported previously illustrating the still high occurrence of RF among newly diagnosed MM patients [1-3]. One-third of the patients in our study received either low-dose GCs or none at all. A medical rationale for using lower dose or no GCs could not be found in five of the eight patients, possibly indicating an area of improvement in MM management. We found that GC dose and the delay of GC initiation were the only factors affecting the RF reversibility. The impact of GCs can be explained by (1) their rapid apoptotic effect on myeloma cells decreasing paraprotein production and, consequently, protein precipitation in renal tubules and (2) their anti-inflammatory properties hindering the infiltration of the inflammatory cells and the fibrosis in renal parenchyma that ensues after light chain endocytosis by renal tubular cells [17, 18]. GCs would also have helped to decrease serum calcium levels that were elevated in 38% of our patients. However, considering that all 22 tested patients had monoclonal paraprotein in urine, and there was not an association between serum calcium level and RF reversibility, we cannot attribute GCs' impact primarily on their hypocalcemic effect. Bortezomib induces rapid myeloma response [20] and inhibits NF-κB activity, as GCs do. Moreover, its clearance is independent of renal function, [21] positioning itself as an advantageous drug in MM patients presenting with RF. Recently, Ludwig et al. [22] reported 63% RF reversal rate in a phase II trial of bortezomib–doxorubicin-DX—incorporating DX 40 mg on days 1, 4, 8, and 11—in 68 patients with de novo and previously treated MM presenting with RF. Based on the association we found between the RF reversibility and GC dose intensity, we can conjecture that an up-front dose-intense DX schedule of 40 mg on days 1–4 could have led to a better RF reversibility. Although the likelihood for renal function restoration was improved with high-dose GCs, the risk of severe infection was also numerically higher in those patients. Yet, all three patients who died of infections within 1 month of GC initiation received considerably higher doses of GCs than the much utilized regimen of 40 mg DX daily for 4 days. As RF itself also increases the risk of infection, hematologists may prefer to use prophylactic antibiotics in this setting. Our study is limited by its retrospective nature. Because of the small sample size, we could not control our findings in a multivariate analysis for confounding factors, most importantly, for the more common use of novel antimyeloma agents in the high-dose GC group. Second, we were not able to assess the possible association between the myeloma response and RF reversibility due to the lack of or incomplete staging evaluations in 11 patients. In conclusion, our results suggest that the use of high-dose GCs in the newly diagnosed MM patients who present with RF increases the likelihood of renal function restoration. Keeping the limitations of our study in mind, we believe that such patients should be started on GCs as soon as the diagnosis of MM is made and would benefit from a regimen of DX 40 mg daily for 4 days in combination with novel antimyeloma agents. Future studies assessing the efficacy of novel antimyeloma agents in patients with MM presenting with acute RF should incorporate a DX schedule of 40 mg on days 1–4 instead of twice weekly dosing. After approval by our institutional review board, we identified patients who were diagnosed with MM at JMH between 2000 and 2008 through our institutional tumor registry. Patients with serum creatinine >2.0 g/dL at the time of MM diagnosis were included in the study. Patients with previous history of RF and those with less than 1 month of follow-up were excluded. All patients were admitted to the hospital for the management of RF. Using a standardized data collection form, the following data were gathered from the patient medical records: demographics, comorbid diseases, date of admission, laboratory findings, and height and weight on admission; data on GCs administered during the admission including date, dose, and duration; other therapies prescribed for MM and RF, and the minimum creatinine level within 6 months of admission. Survival data were obtained from medical records and social security death index searches. CrCl was calculated according to Cockcroft–Gault formula [23] and normalized to a BSA of 1.73 m2. BSA was calculated using Mosteller method [24]. Methylprednisolone and prednisone doses were converted into equivalent doses of DX with ratios of 4:0.75 and 5:0.75, respectively [25]. RF reversal was defined as an increase of CrCl above 60 mL/min/1.73 m2 within 6 months of admission without renal replacement therapy. The cumulative dose of GCs administered within 4 days of GC initiation was calculated for each patient. Those who received ≥160 mg of DX equivalent in 4 days were included in the high-dose GC group and the rest in the low-dose/no GC group. Demographics, clinical characteristics, and RF reversal rate were compared to the two-sided Student's t-test and chi-square test. Multivariate logistic regression analysis was not performed due to small sample size. OS was calculated from the admission date until the date of death or last follow-up and compared between the two groups using log-rank test. A P value less than 0.05 was considered statistically significant. PASW Statistics 17.0 (SPSS, Chicago, IL) was used for all statistical analyses. Ulas Darda Bayraktar*, Sean Warsch*, Denise Pereira*, * Division of Hematology/Oncology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida.