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Multiple Myeloma |
From the Department of Clinical Therapeutics, Alexandra Hospital, University of Athens, School of Medicine, Athens, Greece.
Correspondence: Meletios Athanasios Dimopoulos, 227 Kifissias Avenue, Kifissia, Athens 14561, Greece. E-mail: mdimop{at}med.uoa.gr
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ABSTRACT |
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Key words: dexamethasone, renal failure, myeloma, thalidomide, bortezomib.
Renal failure is a common feature of multiple myeloma, providing a clue to the diagnosis of the disease and may pose a major management problem. Depending on the definition of renal impairment, this complication occurs in 20% to 40% of newly diagnosed MM patients.1–3 The major causes of renal failure are the precipitation of monoclonal light chains in distal and collecting renal tubules and hypercalcemia. Dehydration, hyperuricemia and administration of analgesics and antibiotics with nephrotoxic potential also contribute to its development.1–3 It has been reported that with supportive measures and antimyeloma treatment renal failure is reversible in 25 to 58% of patients.1,2,4 In these series almost all patients were treated with alkylating agent-based regimens, usually with standard dose steroids.1,2,4 In the late 80s, the introduction of high dose dexamethasone-based regimens in the treatment of MM resulted in both higher and more rapid responses compared to older low-intensity steroid regimens.5–7 The impact of these high-dose dexamethasone-based regimens in the reversibility of RF in newly diagnosed patients has not been adequately reported. Furthermore, new agents such as thalidomide or bortezomib, either as a monotherapy or in combination with dexamethasone, have been very active in newly diagnosed MM patients.8,9 There is some evidence that both thalidomide and bortezomib can be safely used in relapsed patients with renal impairment,10–13 but their role in the management of newly diagnosed patients with myeloma and renal failure, and their impact in the reversibility of this complication, has not been studied.
The purpose of our study was to assess the reversibility rate of renal failure in newly diagnosed patients with myeloma who were treated in a single institution with high dose dexamethasone–based regimens, including patients who received thalidomide and/or brtezomib.
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Design and Methods |
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TOPABSTRACTDesign and MethodsResults and DiscussionReferences |
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2 mg/dL at the time of diagnosis. Besides antimyeloma treatment, all patients received intensive supportive care including intravenous hydration, alkalinization of urine, correction of hypercalcemia and discontinuation of all potential nephrotoxic agents. Renal dialysis was offered to all patients with an appropriate indication. All patients were eligible for assessment of reversibility of renal failure which was defined as a sustained decrease of serum creatinine to <1.5 mg/dL. Standard EBMT criteria14 were used for assessment of response. In order to asses the impact of new agents in the reversibility of RF, patients were separated into two groups. Group A: 26 patients who received VAD, VAD-like regimens, melphalan plus high-dose dexamethasone or high-dose dexamethasone alone, and Group B: 15 patients who received high-dose dexamethasone with thalidomide and/or bortezomib. More specifically, 13 patients received dexamethasone 40 mg daily on days 1–4 and 9–12 with thalidomide 100 mg PO daily every 4 weeks. One patient received the same dose of dexamethasone with bortezomib 1.3 mg/m2 IV on days 1,4,8,11 every 3 weeks and one patient received the latter regimen with added thalidomide 100 mg PO.
All analyses were performed using the SPSS statistical software (SPSS for Windows, version 13.1, SPSS Inc Chicago, IL, USA). Differences between groups were examined with a 
2 test for categorical variables, whereas the t-test was used for continuous variables. Survival curves were produced with the Kaplan-Meier method. Multivariate analysis was performed by logistic regression for reversibility of RF. Throughout the analysis a level of 5% was used to denote statistical significance.
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Results and Discussion |
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TOPABSTRACTDesign and MethodsResults and DiscussionReferences |
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Several variables were evaluated for their potential impact on renal failure reversal (Table 2). Patients who presented with light chain only myeloma or with Bence Jones proteinuria (2 gr/day or creatinine 4 mg/dL) had a lower probability of renal failure reversal. Furthermore, myeloma response to primary treatment was associated with higher probability of renal failure reversal (p=0.046). A multivariate analysis showed that there was a trend only for Bence Jones proteinuria 2 gr/day to be associated with a lower probability of renal failure reversal (p=0.075). There was no statistically significant difference in the rate of renal failure reversal among patients who were treated with or without new agents (Table 2). However, the median time to renal failure reversal was 2 months for patients of Group A and 0.8 months for patients of Group B (p=0.005) (Figure 1). Several other factors were evaluated for their impact on rapidity of renal failure reversal including myeloma type, degree of renal failure, hypercalcemia and amount of Bence Jones proteinuria. None of these factors were predictive.
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2 mg/dL to define renal failure because this value may exclude patients with mild renal impairment that can only be easily corrected with hydration. Our study shows that, in patients treated with high dose dexamethasone-based regimens, renal failure is highly reversible, with 73% of patients restoring renal function within a median of 1.9 months from the initiation of treatment. This rate of reversal appears to be higher than those reported previously in series where patients were primarily treated with alkylating agent-based regimens.1,2,4 High-dose dexamethasone-containing regimens induce a rapid reduction of light chain production5–7 which is the main parameter related to the frequency and severity of renal failure in myeloma.1–3 We also observed that the combination of high dose dexamethasone with thalidomide and/or bortezomib in patients with renal failure did not increase the frequency or severity of side effects and was associated with a more rapid rate of renal failure reversal. If these findings are confirmed by others, they may provide a sound basis to recommend these primary treatments to all patients with myeloma and renal failure regardless of their age and of their eligibility for high-dose therapy.
Previous analyses1,2,4 had shown that large amounts of Bence Jones proteinuria, severe renal impairment and light chain only myeloma were associated with lower rates of renal failure reversal. In our study, creatinine >4 mg/dL, Bence Jones protein excretion of >2 gr/day and light chain only myeloma were associated with a significantly lower probability of renal failure reversal, although 50% of patients with creatinine 4 mg/dL, 50% of patients with high Bence Jones protein, and 53% of patients with light chain only myeloma, achieved creatinine <1.5 mg/dL. In contrast, only 8% of patients with severe renal failure treated with alkylating agents and standard steroid regimens reversed renal failure in an older study.2 In another study, only 24% of patients with light chain only myeloma restored renal function.1 In addition, 80% of our patients who initially required dialysis, became dialysis-independent compared with 0% to 60% of patients in other studies.2,4,18,20 The rate of renal failure reversal among those who responded to chemotherapy was higher (85% vs 55%), although in other analyses objective response was not associated with an increased probability of renal function improvemens.1,4 However, about one half of our patients who do not meet EBMT response criteria recovered their renal function. We did not see a survival advantage in those patients who achieved renal failure reversal compared with those patients who did not. However, the number of our patients was relatively small. This observation is in accordance with some studies.1 However, other studies indicate that restoration of renal function is associated with improved survival.2,4 The fact that the median survival of our patients with non-reversible renal failure was similar to that of patients with reversible renal failure might be due to the severity of persisting renal failure, which was less severe than in the older series.2 In fact, in the present series, 8 of the 10 patients requiring dialysis were dialysis-independent after treatment as opposed to the low rate of dialysis discontinuation in older series treated with alkylating agent-based regimens.2
To summarize, high-dose dexamethasone-based regimens result in high rates of renal function restoration in patients with newly diagnosed myeloma renal failure complications. These regimens were effective even in one-half of patients with poor-risk features for reversal such as extensive proteinuria, light chain only myeloma and significant renal impairment. Even patients presenting with acute severe renal insufficiency may experience an improvement in renal function and become dialysis-independent. Incorporating new biologic agents, such as thalidomide and/or bortezomib in the treatment regimens of these patients is safe, and results in a more rapid improvement of renal function.
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Footnotes |
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EK wrote the manuscript,was involved in the treatment of patients and collected data, AA was involved in the treatment of patients and revised the manuscript, DG analyzed the data, MR, CM, DP, IG, EP were involved in the treatment of the patients, AB analyzed the data and revised the manuscript, MAD treated the patients, designed the study and wrote the manuscript.
The authors reported no potential conflicts of interest.
Received for publication September 12, 2006. Accepted for publication February 15, 2007.
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References |
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TOPABSTRACTDesign and MethodsResults and DiscussionReferences |
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This article has been cited by other articles:
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  R. Sitia, G. Palladini, and G. Merlini Bortezomib in the treatment of AL amyloidosis: targeted therapy? Haematologica, October 1, 2007; 92(10): 1302 - 1307. [Full Text] [PDF]
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