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Saudi Journal of Kidney Diseases and Transplantation
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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


Department of Medicine, Division of Hematology, Oncology, and Division of Nephrology, King Khalid University Hospital, King Saud University College of Medicine, Riyadh, Saudi Arabia

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Date of Web Publication8-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 2020 Sep 28];21:63-8. Available from: http://www.sjkdt.org/text.asp?2010/21/1/63/58712

   Introduction Top


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 Top


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 Top


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 Top


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 Top

1.Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer Statistics 2001. CA Cancer J Clin 2001;51:15-36.  Back to cited text no. 1      
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.  Back to cited text no. 2      
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.  Back to cited text no. 3      
4.Pineda-Roman M, Tricot G. High dose therapy in patients with plasma cell dyscrasias and renal dysfunction. Contrib Nephrol 2007;153:182-94.  Back to cited text no. 4      
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.  Back to cited text no. 5      
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.  Back to cited text no. 6      
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.  Back to cited text no. 7      
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.  Back to cited text no. 8      
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.  Back to cited text no. 9      
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.  Back to cited text no. 10      
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.  Back to cited text no. 11      
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.  Back to cited text no. 12      
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.  Back to cited text no. 13      
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.  Back to cited text no. 14      
15.Sanders PW. Pathogenesis and treatment of myeloma kidney. J Lab Clin Med 1994;124:484-8.  Back to cited text no. 15      
16.Alexanian R, Barlogie B, Dixon D. Renal fai­lure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 1990; 150:1693-5.  Back to cited text no. 16      
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.  Back to cited text no. 17      
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.  Back to cited text no. 18      
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.  Back to cited text no. 19      
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.  Back to cited text no. 20      
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.  Back to cited text no. 21      
22.Wardle EN. Antagonism of nuclear factor kappa B. Nephron 2002;90:239.  Back to cited text no. 22      

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Correspondence Address:
Abdul Qayum
Division of Oncology and Hematology, Department of Medicine, King Khalid University Hospital, P.O. Box 7805, Riyadh 11472
Saudi Arabia
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