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| | | Year : 2010 | Volume : 21 | Issue : 1 | Page : 63-68 | | | Rapid improvement in renal function in patients with multiple myeloma and renal failure treated with bortezomib | | | Abdul Qayum, Aamer Aleem, Abdel Rehman Al Diab, Faraz Niaz, Abdel Karim Al Momen
Department of Medicine, Division of Hematology, Oncology, and Division of Nephrology, King Khalid University Hospital, King Saud University College of Medicine, Riyadh, Saudi Arabia
Click here for correspondence address and email | Date of Web Publication | 8-Jan-2010 | | |      | |  Abstract | | | Multiple Myeloma (MM) frequently presents with renal dysfunction apart from other manifestations. Development of renal failure in patients with MM carries a poor prognosis. Bortezomib is a new addition to drugs used in MM and has shown good efficacy and safety profiles. Previous trials have shown its efficacy in relapsed and refractory MM as well. Studies have also shown that bortezomib is also effective in patients with MM who present with renal failure. We report here six cases of renal failure secondary to MM treated with bortezomib. All patients had poor performance status of 3-4 on ECOG scale. Five out of six patients showed satisfactory anti-myeloma response to bortezomib. Reversal of renal failure was observed in all six patients. Adverse effects to bortezomib were mild and manageable. Reversal of renal failure persisted despite incomplete response to MM in two cases, and progression of disease in one patient. It appears that bortezomib may have an effect on the kidneys in reversal of renal failure, other than its anti-myeloma effect. In conclusion, bortezomib appears to be an effective treatment for patients with advanced MM and renal failure irrespective of performance status and age. How to cite this article:
Qayum A, Aleem A, Al Diab AR, Niaz F, Al Momen A. Rapid improvement in renal function in patients with multiple myeloma and renal failure treated with bortezomib. Saudi J Kidney Dis Transpl 2010;21:63-8 |
How to cite this URL:
Qayum A, Aleem A, Al Diab AR, Niaz F, Al Momen A. Rapid improvement in renal function in patients with multiple myeloma and renal failure treated with bortezomib. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2014 Mar 4];21:63-8. Available from: http://www.sjkdt.org/text.asp?2010/21/1/63/58712 |
| Introduction | |  |
Multiple Myeloma (MM) is a disease of elderly and middle-aged population with a median age of 71 years at diagnosis. [1] Treatment of MM in this age-group poses specific problems due to high incidence of co-morbid conditions and presence of certain complications like renal impairment. Various prognostic factors which have shown to influence the outcome of treatment in MM include performance status, serum beta 2 microglobulin, high plasma cell labeling index, hypoalbuminemia, low platelet count and renal impairment. [2] Renal impairment assigns the patients to a particular high-risk for increased morbidity and mortality. The incidence of patients with MM presenting with advanced renal failure has been described to be approximately 20-30%. [3] Renal failure in MM can be reversible with treatment, with recovery of renal function seen in approximately 25% of patients after chemotherapy. [4]
Treatment of MM is not curative, but the development and use of novel agents has improved the outlook for these patients. Bortezomib is a synthetic boronic acid dipeptide which acts as a reversible proteosome inhibitor, which has shown multiple effects on MM cell lines [5] and primary MM. [6] Bortezomib has shown good activity in MM and carries a favorable safety profile. Previous trials have shown its efficacy in relapsed and refractory MM as well as newly diagnosed cases, and it was approved for the treatment of MM by the US Food and Drug Administration (FDA). [7] It has been shown in small studies that bortezomib is also effective in patients with MM who present with renal failure.
Two phase-2 trials, SUMMIT and CREST studies, achieved an overall response rate of 35% and 33% respectively, in refractory or relapsed cases of MM to bortezomib as first-line chemotherapy. In the SUMMIT trial, [8] bortezomib was used alone whereas in the CREST trial, bortezomib was combined with high-dose dexamethasone. [9] Superiority over high-dose dexamethasone in re-lapsed MM was shown in a phase-3 trial. [10] Bortezomib has shown acceptable toxicity profile, with nausea, vomiting, diarrhea and mild peripheral neuropathy as the most common adverse effects observed. [8],[11] Jaganath et al reported that bortezomib could be safely administered to patients with MM and renal failure. [12] Recently, Chanan-Khan et al have reported that bortezomib therapy is a well-tolerated and effective option in the sub-group of MM patients with severe renal dysfunction. [13] Our study assessed the therapeutic effects of bortezomib in MM patients with renal failure and poor performance status.
| Materials and Methods | | |
We reviewed the records of six patients with MM and renal impairment, who were treated with bortezomib at our centre. These patients had either newly diagnosed MM or relapsed/refractory disease. Patients had detailed hematological and biochemical evaluation at initial diagnosis and at each subsequent visit. The creatinine clearance was calculated using the CockroftGault formula. Patients gave informed consent after explanation about the treatment and side effects. Bortezomib was administered intravenously (i.v.) at a dose of 1.0 mg/m 2 in three patients and 1.3 mg/m 2 in three other patients, on days 1, 4, 8, and 11. The whole cycle was repeated every 21 days. Two patients received steroids as well. Patients also received zoledronic acid, 4 mg i.v. every four weeks. Complete blood counts, serum urea, creatinine, calcium, albumin, LDH and liver enzymes were estimated before each dose of bortezomib. Enquiries about possible adverse effects were made on every visit. The dose of bortezomib was increased to the standard 1.3 mg/m 2 as soon as the serum creatinine reached near the normal range, in patients who initially received 1.0 mg/m 2 .
Data about response, renal function and side effects were collected from patients' notes and computer records and analyzed statistically.
| Results | | |
The patients' baseline characteristics are shown in [Table 1]. Mean age of the patients at the start of bortezomib treatment was 71.8 ± 7.2 years (range 57-79 yrs); all except one patient belonged to the elderly group. ECOG performance status was three or four in all cases. Three patients had relapsed or refractory disease while three other patients had newly diagnosed MM. The three patients with relapsed or refractory disease had received melphalan and prednisone as first-line therapy. The patients had varying degrees of renal failure with a mean serum creatinine of 328 ± 124 ΅mol/L (range 193-551 ΅mol/L). All patients had creatinine clearance of less than 30 mL/min (mean 15.6 ± 4.3 mL/ min) at the initiation of bortezomib therapy and three patients required 1-2 sessions of hemodialysis before the first cycle of bortezomib.
Five patients received at least six cycles of bortezomib. One patient showed progressive disease after the fourth cycle of bortezomib, as evidenced by increasing serum monoclonal protein level; [14] hence, bortezomib treatment was stopped.
ECOG performance status improved in all patients by at least one grade, by the end of second cycle of treatment. The changes in hematological parameters are depicted in [Table 2]. Mild anemia, not requiring transfusions, persisted throughout the treatment period in spite of erythropoietin treatment which was regularly administered along with zoledronic acid. Mean hemoglobin level after fourth cycle of bortezomib was 11.3 mg/dL. Platelet count was monitored before each dose of bortezomib and the mean pre-treatment platelet count was 94.5 ± 46 Χ 10 9 /L. Mild thrombocytopenia persisted throughout the treatment in three patients, but did not result in clinical bleeding. Platelet transfusions were not required at any time in any of these patients. There was no significant effect of bortezomib on white blood cell (WBC) count.
There was progressive improvement in renal function as shown in [Figure 1]. The mean serum creatinine at the time of commencement of the fifth cycle of bortezomib was 116 ± 26.6 ΅mol/ L, as opposed to pre-treatment mean of 328.6 ± 124 ΅mol/L. Renal function remained stable in all six patients as indicated by stable lower creatinine levels even after completion of treatment.
Two patients had complete response to MM [Table 2] and three patients showed partial response while one patient experienced progressive disease with no response to bortezomib. The serum creatinine and creatinine clearance of the non-responding patient also remained low. Discontinuation of bortezomib in responders, partialresponders and non-responder was not associated with any deterioration in renal function.
The treatment with bortezomib was tolerated well by all patients. Grade-4 toxicity was not observed. One patient developed Grade-3 neuropathy but responded to reduction in dose of bortezomib from 1.3 to 1 mg/m 2 . Another patient developed maculopapular skin rash during first cycle of chemotherapy, which settled after local treatment. Further treatment in this patient was continued without interruption. One responding patient had an episode of pulmonary edema six hours after bortezomib administration. He responded to appropriate treatment without any further episodes. Common adverse effects observed in our patients are shown in [Figure 2].
| Discussion | | |
The etiology of renal failure in MM is multifactorial. [15],[16] Important contributing factors to renal failure include light chain nephropathy, hypercalcemia, and dehydration. Presence of renal failure in MM patients usually indicates high tumor burden. [17] Some improvement in renal function can be achieved by correcting hypercalcemia and dehydration. Without addressing the issue of main pathogenic mechanism(s) of myeloma kidney, any correction of renal function does not carry long-lasting benefits. Traditional chemotherapy regimens, consisting mainly of melphalan and/or high dose dexamethasone improve the renal function in approximately one-fourth of the cases of MM. [18] Most patients eventually present with relapsed disease, which may prove to be refractory to further treatment with these agents. Bortezomib has proven to be effective in this subset of patients.
Our study has shown the effectiveness of bortezomib in reversing renal failure in MM patients presenting with renal dysfunction. Bortezomib used in combination with high-dose dexamethasone has been reported to result in higher response rates in patients with MM and renal failure. [18] Milani et al reported rapid reversal of renal failure in four patients with MM and renal dysfunction. [19] Ludwig et al treated eight cases of MM and renal failure with bortezomib. [20] Seven of these patients were newly diagnosed and had not received any chemotherapy before. Five patients showed reversal of renal failure. The treatment regimen included dexamethasone in three cases, and doxorubicin in three other patients. Jaganath et al described their experience with 10 patients of MM with impaired renal function and observed that serum creatinine levels improved after treatment with bortezomib and high-dose dexamethasone. [12] Our observations are consistent with these previous reports of effectiveness of bortezomib in reversing renal function in MM patients. Additionally, our results show that bortezomib is effective as a single agent in reversing renal failure in MM patients.
Most of our patients presented with poor performance status and advanced age. Mean ECOG performance score was 3.3, and five out of six patients were 70 years of age or older. These patients tolerated the treatment well. Although it was initially recommended to reduce the dose of bortezomib in patients with renal failure, more recently, the standard dose (1.3 mg/m 2 ) has been used in this group of patients. We used full dose in three patients without encountering any severe adverse effects. Side-effects observed in our patients were thrombocytopenia, nausea and mild peripheral neuropathy. Only one patient developed Grade-3 neuropathy, and one other patient had an episode of pulmonary edema. None of these adverse effects necessitated discontinuation of the treatment. Mild thrombocytopenia was observed in three patients, which persisted throughout treatment with bortezomib but did not result in clinical bleeding. These observations suggest that bortezomib can be safely used in elderly MM patients who present with renal failure and poor performance status. The researchers in the SUMMIT study observed that old age (> 65 yrs) is associated with poorer response to bortezomib. Our study included predominantly elderly population and the response to bortezomib was uniformly observed except in one case. Other co-morbidities, not mentioned in the SUMMIT study, may have accounted for lower response rate observed in the elderly patients. It is not possible, however, to draw any conclusions from our study because of very small numbers.
Continued improvement of renal function in patients who showed progressive disease is an interesting observation, indicating a possible separate renal effect of bortezomib. It has previously been described that bortezomib inhibits NF K -B, a transcription factor which shows strong activation in renal tubular cells in patients with protienuria. [21] Activation of this factor leads to enhanced inflammatory effect, and inhibition of NF K -B results in significant reduction of inflammation in experimental models of glomerulo nephritis. [22] It is possible that part of the efficacy of bortezomib in MM is mediated by reduction of inflammation in myeloma kidneys via inhibition of NF K -B.
In conclusion, we observed beneficial effect of bortezomib in reversing renal failure in elderly MM patients with renal dysfunction and poor performance status. This effect of bortezomib does not appear to be totally dependent on achieving MM remission, and direct effect on renal tubular cells may be a possible mechanism. Treatment was well tolerated in this group of poor risk patients with acceptable adverse effects.
| References | | |
| 1. | Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer Statistics 2001. CA Cancer J Clin 2001;51:15-36.  | | 2. | Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78:21-33. | | 3. | Blade΄ J, Fernandez-Llama P, Bosch F, et al. Renal failure in multiple myeloma: Presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med 1998;158:1889-93. | | 4. | Pineda-Roman M, Tricot G. High dose therapy in patients with plasma cell dyscrasias and renal dysfunction. Contrib Nephrol 2007;153:182-94. | | 5. | Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteosome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003;101:2377-80. | | 6. | Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteosome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 2002;20:4420-7. | | 7. | Kane RC, Farrell AT, Sridhara R, Pazdur R. United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. Clin Cancer Res 2006;12:2955-60. | | 8. | Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003;348:2609-17. | | 9. | Jaganath S, Richardson PG, Barlogie B, et al. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/ or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica 2006;91:929-34. | | 10. | Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487-98. | | 11. | San Miguel J, Blade J, Boccadoro M, Cavenagh J, Glasmacher A, Jagannath S, et al. A practical update on the use of bortezomib in the management of multiple myeloma. Oncologist 2006;11: 51-61. | | 12. | Jagannath S, Barlogie B, Berenson JR, et al. Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impaired renal function. Cancer 2005;103:1195-200. | | 13. | Asher A, Chanan-Khan AA, Kaufman JL, Mehta J. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 2007; 109:2604-6. | | 14. | Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high dose therapy and haemopoietic stem cell transplantation. Br J Haematol 1998;102:1115-23. | | 15. | Sanders PW. Pathogenesis and treatment of myeloma kidney. J Lab Clin Med 1994;124:484-8. | | 16. | Alexanian R, Barlogie B, Dixon D. Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 1990; 150:1693-5. | | 17. | Knudsen LM, Hjorth M, Hippe E. Renal failure in multiple myeloma: reversibility and impact on the prognosis. Eur J Haematol 2000;65:175-81. | | 18. | Kastritis E, Anagnostopoulos A, Roussou M, et al. Reversibility of renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone-containing regimens and the impact of novel agents. Haematologica 2007; 92:546-9. | | 19. | Malani AL, Gupta V, Rangineni R. Bortezomib and dexamethasone in previously untreated multiple myeloma associated with renal failure and reversal of renal failure. Acta Haematol 2006;116:255-8. | | 20. | Ludwig H, Drach J, Graf H, Lang A, Meran JG. Reversal of acute renal failure by bortezomibbased chemotherapy in patients with multiple myeloma. Haematologica 2007;92:1411-4. | | 21. | Mezzano SA, Barria M, Droguett MA, et al. Tubular NF-kappa B and AP-1 activation in human proteinuric renal disease. Kidney Int 2001;60:1366-77. | | 22. | Wardle EN. Antagonism of nuclear factor kappa B. Nephron 2002;90:239. |
Correspondence Address:
Abdul Qayum
Division of Oncology and Hematology, Department of Medicine, King Khalid University Hospital, P.O. Box 7805, Riyadh 11472
Saudi Arabia
PMID: 20061695
[Figure 1], [Figure 2]
[Table 1], [Table 2] | |
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