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Bortezomib and Dexamethasone Therapy for Newly Diagnosed Patients With Multiple Myeloma Complicated by Renal Impairment
Brief Communication
Bortezomib and Dexamethasone Therapy for Newly Diagnosed Patients With Multiple Myeloma Complicated by Renal Impairment Jian Li, Dao-Bin Zhou, Li Jiao, Ming Hui Duan, Wei Zhang, Yong Qiang Zhao, Ti Shen Abstract Background: Renal impairment is a common complication of multiple myeloma (MM) and is related to shorter overall survival and increased rates of early death. Bortezomib is a new agent for the treatment of patients with myeloma, with high response rates and controllable side effects. In this study, we will evaluate the efficacy and safety of bortezomib and dexamethasone in patients with newly diagnosed MM complicated by renal impairment. Patients and Methods: This is a prospective study of the general characteristics, reversibility of renal impairment, response of myeloma, and side effects of 18 consecutive newly diagnosed patients with MM and renal impairment who received ≥ 2 cycles of bortezomib and dexamethasone. Results: Of 18 patients newly diagnosed with MM, the median age was 60 years, and the median serum creatinine was 5.3 mg/dL. Patients received a median of 4 cycles of bortezomib and dexamethasone. Reversal of renal impairment was documented in 38.9% of the patients, and the median time to reversal was 16 days. Moreover, 33.3% of the patients achieved renal response (a 50% decrease in serum creatinine). The overall response rate of MM was 83.3%, including a 33.3% complete response (CR) rate, a 16.7% near-CR rate, a 16.7% very good partial response (PR) rate, and a 16.7% PR rate. Grade 3/4 adverse events consisted of infection (n = 3), peripheral neuropathy (n = 3), and ileus (n = 1). After a median follow-up of 15.7 months, the median progression-free survival for all patients was 12.6 months. Conclusion: Bortezomib plus dexamethasone is a safe and effective regimen for newly diagnosed patients with MM complicated by renal impairment. Clinical Lymphoma & Myeloma, Vol. 9, No. 5, 394-398, 2009; DOI: 10.3816/CLM.2009.n.077 Keywords: Combination therapy, Creatinine clearance, Hemodialysis, Proteasome inhibitor
Introduction Renal impairment is one of the common complications of multiple myeloma (MM) and can often cause major management problems. This complication occurs in 20%-40% of newly diagnosed patients with MM, depending on the definition of renal failure. Studies reveal that the presence of renal impairment is associated with shorter overall survival (OS) and increased early death rates compared with those of patients with normal renal function, and the median survival of patients with renal impairment is < 2 years.1 Otherwise, renal impairment is one of the important factors for the staging of myeloma. The patients with renal impairment (serum
Department of Hematology, Peking Union Medical College Hospital, Beijing, China
Submitted: Mar 11, 2009; Revised: May 17, 2009; Accepted: May 27, 2009
Address for correspondence: Dao-Bin Zhou, MD, Department of Hematology, Peking Union Medical College Hospital, Beijing 100730, China Fax: 010-65295024; e-mail: [email protected]
creatinine ≥ 2 mg/dL) are defined as having sub-stage B disease for stages I, II, and III in the Durie-Salmon staging system. However, the investigators developing the International Staging System (ISS) revealed that patients with Durie-Salmon stages IB, IIB, and IIIB had similar OS, irrespective of tumor burden. These patients were categorized collectively as high-risk groups (ie, stage III) in the ISS because 82% of the patients with serum creatinine ≥ 2 mg/dL had a serum β2-microglobulin value > 5.5 mg/L.2 Melphalan as a conventional agent against myeloma has been limited in the treatment of patients with MM and renal impairment by the need for dose adjustment.3 Lenalidomide is an active agent for MM confirmed by some randomized clinical trials. However, it is mainly excreted through the kidney and is not suitable to treat patients with MM complicated by renal impairment.4 Recently, the combination of bortezomib and dexamethasone has achieved high response rates and disease-free survival for patients with both refractory/relapsed MM and newly diagnosed MM.5,6 However, there are few reports regarding the treatment of patients
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
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with newly diagnosed MM complicated by renal impairment with bortezomib-based regimens. In this study, we analyzed the efficiency and safety of bortezomib and dexamethasone in 18 patients with newly diagnosed MM complicated by renal impairment treated at Peking Union Medical College Hospital.
Patients and Methods From August 2006 to October 2008, 18 consecutive patients with newly diagnosed MM complicated by renal impairment were treated with ≥ 2 cycles of bortezomib plus dexamethasone at Peking Union Medical College Hospital. Review boards at the local institution approved the study, and all patients provided written informed consent. Renal impairment was defined as a serum creatinine level ≥ 2 mg/dL. All 18 patients received bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 plus dexamethasone 40 mg on days 1-4 every 21 days. Two patients also received epirubicin 40 mg/m2 on day 1. Four cycles of bortezomib and dexamethasone were planned. Thalidomide 100-200 mg/day was used as maintenance therapy after maximal efficacy of the treatment was reached. In addition to chemotherapy, all patients received intensive supportive care, including intravenous hydration, alkalization of urine, and correction of hypercalcemia and hyperuricemia. Standard European Group for Blood and Marrow Transplantation criteria were used for the evaluation of response.7 Two additional categories were also included: near-complete remission (nCR; CR) was defined as no detectable paraprotein by electrophoresis with positive immunofixation, and very good partial remission (VGPR; PR) was defined as > 90% reduction in paraprotein. Assessment for MM was performed after each cycle of chemotherapy, and time to initial response was calculated for patients with ≥ PR. Reversal of renal impairment was defined as a decrease in serum creatinine to a stable level < 1.5 mg/dL after treatment. Renal response was defined as a 50% decrease in serum creatinine level in patients who were not undergoing dialysis or were independent of dialysis after treatment. Improvement of renal function included both reversal of renal impairment and renal response. Serum creatinine level was tested weekly during chemotherapy, and creatinine clearance rate was calculated by the Cockroft-Gault formula. Time to reversal or improvement of renal function was also documented. Adverse events were documented and classified by Common Terminology Criteria for Adverse Events during chemotherapy.
Results Among the 18 patients with newly diagnosed MM (Tables 1A and 1B), 10 were men, and 8 were women. The median age was 60 years (range, 46-76 years). The median pretreatment serum creatinine level was 5.3 mg/dL (range, 2.1-10.5 mg/dL), and the median creatinine clearance rate calculated by the Cockroft-Gault formula was 11.9 mL/min (range, 4.7-28.4 mL/min). Twelve patients had a serum creatinine level > 4 mg/dL, of whom 5 were undergoing hemodialysis. The distribution of MM type was as follows: 5 with immunoglobulin (Ig)G, 4 with IgA, 2 with IgD, 2 with κ light chain only, and 5 with λ light chain only. All patients had stage III disease according to the ISS. In addition, there were 4 patients with hypercalcemia, 5 with hyperuricemia, and 12 with anemia.
After treatment, reversal of renal impairment was achieved in 7 (38.9%) of 18 patients. All 6 patients with serum creatinine level < 4 mg/dL achieved reversal of renal impairment. Only 1 of the other 12 patients with serum creatinine ≥ 4 mg/dL experienced reversal of renal impairment. Six of these 12 patients had a > 50% decrease in serum creatinine level. Therefore, 13 patients demonstrated improved renal function, including both reversal of renal impairment and renal response. The median times to reversal and to renal response were 16 days and 38 days, respectively. It was noted that only 1 of the 5 patients undergoing hemodialysis had reversed renal function (reversal of renal impairment) and became independent of hemodialysis after treatment; the other 4 patients continued to be hemodialysis dependent. Patients received a median of 4 cycles of bortezomib and dexamethasone chemotherapy (range, 2-5 cycles), of whom 1 patient received 2 cycles, 3 received 3 cycles, 11 received 4 cycles, and 3 received 5 cycles. Fifteen patients received thalidomide 100-200 mg/day as maintenance therapy. The overall response rate (ORR) was 83.3%, including 6 CRs, 3 nCRs, 3 VGPRs, and 3 PRs. Of the 3 nonresponding patients, 2 had stable disease (SD), and 1 had progressive disease (PD). The response rate including CR, nCR, and VGPR was 66.7%. The median time to response was 42 days (2 cycles). Among 15 patients who had ≥ PR, 7 had a reversal of renal impairment, and 6 had a renal response. Renal impairment persisted in the other 2 patients. The renal function improvement rate in this subgroup was 86.7% (13 of 15 patients). Renal function was not improved in patients with SD or PD. In addition, 3 of 5 patients undergoing dialysis reached CR, and the other 2 patients had SD. No treatment-related mortalities were reported during chemotherapy. One patient discontinued treatment because of recurrent ileus, and 3 patients discontinued treatment because of grade 3 peripheral neuropathy. Hematologic adverse events were all grade 1/2, including thrombocytopenia (22.2%) and leukopenia (27.7%); grade 1/2 nonhematologic adverse events included peripheral neuropathy (33.3%), diarrhea (27.7%), fatigue (38.8%), nausea (22.2%), and constipation (22.2%). All grade 3/4 adverse events were nonhematologic, including infection (1 case of bacterial pneumonia and 2 cases of herpes zoster virus infection), peripheral neuropathy (3 cases), and recurrent ileus (1 case). All adverse events were well controlled after symptomatic treatment. Among the initial 4 patients who did not receive acyclovir prophylaxis, 2 developed herpes zoster virus infection during chemotherapy. The subsequent 14 patients received acyclovir prophylaxis (acyclovir doses at 0.2 g once every other day for 3 months after bortezomib chemotherapy), and none developed herpes zoster infection. After a median follow-up of 15.7 months, the median progression-free survival (PFS) for responding patients was 18.1 months, and the median PFS for all patients was 12.6 months.
Discussion Renal insufficiency is a common complication of MM that occurs in 20%-40% of newly diagnosed patients.1 Renal impairment in patients with MM results mainly from “myeloma nephropathy.” Other contributing factors include hypercalcemia, hyperuricemia, dehydration, and use of nephrotoxic drugs (contrast and nonsteroidal anti-inflammatory drugs).8 Thus, rapid suppression of myeloma
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Bortezomib and Dexamethasone in Patients With MM With Renal Impairment Table 1A General Clinical Characteristics of the 18 Patients Patient Number Sex
Age, Years
Multiple Myeloma Type
ISS
24-Hour Urine Bence-Jones Protein, g
Creatinine Before Treatment, mg/dL
1
M
61
IgDL
III
10.8
8.7
2
F
56
K
III
3.2
8.0
3
F
75
IgAK
III
5.3
10.5
4
M
54
IgGL
III
1.9
3.2
5
F
76
L
III
6.8
4.2
6
M
65
L
III
4.2
9.9
7
F
54
L
III
8.3
2.1
8
M
54
IgGL
III
0.9
4.3
9
M
68
L
III
3.5
6.2
10
M
64
IgAL
III
4.4
2.2
11
F
70
IgGK
III
2.1
4.0
12
F
53
IgAL
III
5.3
3.1
13
M
57
IgAL
III
2.4
7.5
14
M
46
L
III
2.3
3.6
15
F
61
K
III
7.3
5.4
16
M
60
IgGL
III
13.4
9.0
17
F
59
IgGK
III
12.7
5.2
18
M
59
IgDK
III
2.6
6.6
Abbreviations: F = female; Ig = immunoglobulin; ISS = International Staging System; M = male
is key to the reversal of renal dysfunction. As a novel antimyeloma agent, bortezomib is a proteasome inhibitor metabolized mainly in the liver and is independent of renal clearance. Therefore, dosage adjustment is not required in patients with renal impairment.9 Several studies have demonstrated that bortezomib is active against both newly diagnosed and refractory/relapsed MM, with relatively high remission rates and rapid responses.6,10,11 Also, a recent study revealed that bortezomib had an influence on apoptosis and antiapoptotic gene expression through the nuclear factor-κB pathway in proximal tubular cells, which suggests that bortezomib might protect renal function through mechanisms independent of its antimyeloma activity.12 Several small retrospective studies have shown that bortezomib is not only effective and safe in the treatment of patients with refractory/relapsed and newly diagnosed MM with renal impairment, but it can also reverse renal function (reverse renal impairment) in these patients. In a retrospective analysis of 20 patients with MM (4 newly diagnosed and 16 refractory/relapsed) receiving bortezomib, reversal of renal function (serum creatinine < 1.5 mg/dL) was observed in 8 patients (40%), with a median time to reversal of 17 days; reversal of renal function was observed in only 3 of 8 patients with serum creatinine > 4 mg/dL. The ORR for MM itself was 65%, with 1 CR, 11 PRs, and 1 minor response (MR).13 In another study of 7 patients with newly diagnosed MM and 1 patient with refractory/relapsed MM receiving bortezomib plus dexamethasone, reversal of renal function was observed in 2 patients, and improvement of renal function was observed in 3 patients. In terms of MM, all 5 of these patients showed response to the treatment, including 3 CRs or nCRs, 1 VGPR, and 1 PR.14 In patients with more severe
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renal impairment, a multicenter, retrospective study of 24 patients with MM who were undergoing hemodialysis received bortezomibbased treatment; 30% achieved a CR or nCR, with PRs observed in 40% of the patients, and 4 patients became independent of dialysis following treatment.15 In a subgroup analysis of 2 phase II clinical trials, SUMMIT (Study of Uncontrolled Multiple Myeloma Managed With Proteasome Inhibition Therapy) and CREST (Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma; the renal eligibility criterion of each trial was measured or calculated creatinine clearance ≥ 10 mL/min), bortezomib was found to yield an ORR of 30% (2 PRs, 1 MR) in 10 patients with refractory/relapsed MM with creatinine clearance ≤ 30 mL/min, whereas the toxicity was comparable with that seen in patients with creatinine clearance > 30 mL/min.16 In a subgroup analysis of the APEX trial (Assessment of Proteasome Inhibition for Extending Remissions; the renal eligibility criterion was creatinine clearance ≥ 20 mL/min), bortezomib combined with dexamethasone was found to be superior, with an ORR of 40% in patients with refractory/relapsed MM with creatinine clearance ≤ 30 mL/min. Time to response and time to progression were 1.4 months and 4.9 months, respectively, and OS was 22.8 months, which was comparable with that of patients with normal renal function and significantly better than that of the subgroup of patients with renal impairment receiving single-agent dexamethasone.17 Our study is the first prospective study of a bortezomib-based regimen in patients with newly diagnosed myeloma with renal insufficiency. A total of 18 newly diagnosed patients with varying degrees of renal impairment received a median of 4 cycles of
Jian Li et al Table 1B General Clinical Characteristics of the 18 Patients (Continued) Number Creatinine After Patient Number Creatinine Clearance, Dialysis Hypercalcemia Hyperuricemia Anemia Efficacy of Cycles Treatment, mg/dL mL/min 1
7.5
Yes
Yes
Yes
No
2
1.4
CR
2
6.2
No
No
Yes
Yes
4
3.5
CR
3
4.7
Yes
No
No
Yes
3
2.6/Dialysis
CR
4
20.2
No
No
No
Yes
5
0.9
CR
5
15.1
No
No
Yes
Yes
5
1.9
CR
6
6.8
Yes
Yes
No
No
4
2.9/Dialysis
CR
7
27.2
No
No
No
No
4
1.1
nCR
8
15.1
No
Yes
No
Yes
4
0.7
nCR
9
12.1
No
No
No
Yes
4
2.6
nCR
10
28.4
No
Yes
No
No
4
1.4
VGPR
11
11.6
No
No
No
Yes
4
1.3
VGPR
12
19.4
No
No
Yes
Yes
4
0.9
VGPR
13
9.9
No
No
No
Yes
3
2.3
PR
14
16.6
No
No
No
No
4
1.3
PR
15
11.8
No
No
No
No
3
2.4
PR
16
5.5
Yes
No
No
Yes
4
5.5/Dialysis
SD
17
12.0
Yes
No
Yes
Yes
4
3.8/Dialysis
SD
18
11.6
No
No
No
Yes
5
4.0
PD
Abbreviations: CR = complete remission; nCR = near-complete remission; PD = progressive disease; PR = partial response; SD = stable disease; VGPR = very good partial response
bortezomib plus dexamethasone in this study, and improvement of renal function was observed in 72.2% of the patients, including a 38.9% rate of reversal of renal impairment and a 33.3% renal response rate. The median time to renal function reversal and time to renal response were 16 days and 38 days, respectively. However, we observed that all 6 patients with serum creatinine ≤ 4 mg/dL achieved reversal of renal function, whereas only 1 out of 12 patients with serum creatinine ≥ 4 mg/dL showed such a response. This correlates with previous studies in which serum creatinine level was considered as an independent prognostic factor associated with renal function recovery.18 In addition, 1 out of 5 patients undergoing dialysis achieved independence from dialysis and recovered renal function after treatment. It was also observed that the combination of bortezomib and dexamethasone leads to a good response of the MM itself in such patients. The ORR was 83.3%, including a 50% CR rate or nCR rate (including 3 patients undergoing dialysis), a 16.7% VGPR rate, and a 16.7% PR rate, with a median time to response of 2 cycles. Simultaneously, improvement of renal function was observed in 13 of 15 patients with an MM response, whereas renal impairment persisted in 2 patients who had SD and 1 patient who had PD. It suggested that myeloma response is associated with renal function improvement. Considering that the median time to renal response was 38 days and the median time to myeloma response was 2 cycles, it was suggested that if patients cannot achieve PR and renal response after 2 cycles of bortezomib and dexamethasone, other agents that can be used in renal insufficiency, eg, doxorubicin, cyclophosphamide, or thalidomide, may be added to improve renal function.
No treatment-related deaths were observed in this study. Grade 1/2 hematologic toxicities were thrombocytopenia and leukopenia. Grade 1/2 nonhematologic toxicities included peripheral neuropathy and gastrointestinal reactions. The 7 grade 3/4 adverse events reported in this study, including 3 cases of infection (bacterial pneumonia and herpes zoster virus infection), 3 cases of peripheral neuropathy, and 1 case of ileus, were comparable with those in patients with normal renal function.6,10,11 In this study, 2 of 4 patients without prophylaxis had herpes zoster virus infection, whereas the other 14 patients receiving acyclovir 0.2 g prophylaxis once every other day were not infected. Recent studies suggest a high prevalence of herpes zoster virus infection in patients receiving bortezomib and, thus, the importance of acyclovir prophylaxis in such patients.19
Conclusion Our data indicate that combination bortezomib and dexamethasone can improve renal function and disease control in patients with MM with renal impairment. It is one of the safe and effective regimens that can be reserved as a treatment option for such patients. A large, multicenter, controlled study is needed to confirm this conclusion.
Disclosures The authors have no relevant relationships to disclose.
References 1. Eleutherakis-Papaiakovou V, Bamias A, Gika D, et al. Renal impairment in multiple myeloma: incidence, correlations, and prognostic significance. Leuk
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Bortezomib and Dexamethasone in Patients With MM With Renal Impairment Lymphoma 2007; 48:337-41. 2. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23:3412-20. 3. Boccadoro M, Pileri A. Standard chemotherapy for myelomatosis: an area of great controversy. Hematol Oncol Clin North Am 1992; 6:371-82. 4. Kastritis E, Dimopoulos MA. The evolving role of lenalidomide in the treatment of hematologic malignancies. Expert Opin Pharmacother 2007; 8:497-509. 5. Harousseau JL, Attal M, Leleu X, et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica 2006; 91:1498-505. 6. 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. 7. 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. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998; 102:1115-23. 8. Dimopoulos MA, Kastirtis E, Rosinol L, et al. Pathogenesis and treatment of renal impairment in multiple myeloma. Leukemia 2008; 22:1485-93. 9. Mulkerin D, Remick S, Ramanathan R, et al. A dose-escalating and pharmacologic study of bortezomib in adult cancer patients with impaired renal function. J Clin Oncol 2006; 24(18 suppl):87s (Abstract 2032). 10. 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. 11. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and
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prednisone for initial treatment of multiple myeloma. N Engl J Med 2008; 359:906-17. 12. Sarkozi R, Perco P, Hochegger K, et al. Bortezomib-induced survival signals and genes in human proximal tubular cells. J Pharmacol Exp Ther 2008; 327:645-56. 13. Roussou M, Kastritis E, Migkou M, et al. Treatment of patients with multiple myeloma complicated by renal impairment with bortezomib-based regimens. Leuk Lymphoma 2008; 49:890-5. 14. Ludwig H, Drach J, Graf H, et al. Reversal of acute renal impairment by bortezomib-based chemotherapy in patients with multiple myeloma. Haematologica 2007; 92:1411-4. 15. Chanan-Khan AA, Kaufman JL, Mehta J, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal impairment: a multicenter retrospective study. Blood 2007; 109:2604-6. 16. Jagannath S, Barlogie B, Berenson JR, et al. Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impared renal function. Cancer 2005; 103:1195-200. 17. San-Miguel JF, Richardson PG, Sonneveld P, et al. Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. Leukemia 2008; 22:842-9. 18. Blade J, Fernandez-Llama P, Bosch F, et al. Renal impairment in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med 1998; 158:1889-93. 19. Chanan-Khan A, Sonneveld P, Schuster MW, et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol 2008; 26:4784-90.
Bortezomib and Dexamethasone Therapy for Newly Diagnosed Patients With Multiple Myeloma Complicated by Renal Impairment Jian Li, Dao-Bin Zhou, Li Jiao, Ming Hui Duan, Wei Zhang, Yong Qiang Zhao, Ti Shen Abstract Background: Renal impairment is a common complication of multiple myeloma (MM) and is related to shorter overall survival and increased rates of early death. Bortezomib is a new agent for the treatment of patients with myeloma, with high response rates and controllable side effects. In this study, we will evaluate the efficacy and safety of bortezomib and dexamethasone in patients with newly diagnosed MM complicated by renal impairment. Patients and Methods: This is a prospective study of the general characteristics, reversibility of renal impairment, response of myeloma, and side effects of 18 consecutive newly diagnosed patients with MM and renal impairment who received ≥ 2 cycles of bortezomib and dexamethasone. Results: Of 18 patients newly diagnosed with MM, the median age was 60 years, and the median serum creatinine was 5.3 mg/dL. Patients received a median of 4 cycles of bortezomib and dexamethasone. Reversal of renal impairment was documented in 38.9% of the patients, and the median time to reversal was 16 days. Moreover, 33.3% of the patients achieved renal response (a 50% decrease in serum creatinine). The overall response rate of MM was 83.3%, including a 33.3% complete response (CR) rate, a 16.7% near-CR rate, a 16.7% very good partial response (PR) rate, and a 16.7% PR rate. Grade 3/4 adverse events consisted of infection (n = 3), peripheral neuropathy (n = 3), and ileus (n = 1). After a median follow-up of 15.7 months, the median progression-free survival for all patients was 12.6 months. Conclusion: Bortezomib plus dexamethasone is a safe and effective regimen for newly diagnosed patients with MM complicated by renal impairment. Clinical Lymphoma & Myeloma, Vol. 9, No. 5, 394-398, 2009; DOI: 10.3816/CLM.2009.n.077 Keywords: Combination therapy, Creatinine clearance, Hemodialysis, Proteasome inhibitor
Introduction Renal impairment is one of the common complications of multiple myeloma (MM) and can often cause major management problems. This complication occurs in 20%-40% of newly diagnosed patients with MM, depending on the definition of renal failure. Studies reveal that the presence of renal impairment is associated with shorter overall survival (OS) and increased early death rates compared with those of patients with normal renal function, and the median survival of patients with renal impairment is < 2 years.1 Otherwise, renal impairment is one of the important factors for the staging of myeloma. The patients with renal impairment (serum
Department of Hematology, Peking Union Medical College Hospital, Beijing, China
Submitted: Mar 11, 2009; Revised: May 17, 2009; Accepted: May 27, 2009
Address for correspondence: Dao-Bin Zhou, MD, Department of Hematology, Peking Union Medical College Hospital, Beijing 100730, China Fax: 010-65295024; e-mail: [email protected]
creatinine ≥ 2 mg/dL) are defined as having sub-stage B disease for stages I, II, and III in the Durie-Salmon staging system. However, the investigators developing the International Staging System (ISS) revealed that patients with Durie-Salmon stages IB, IIB, and IIIB had similar OS, irrespective of tumor burden. These patients were categorized collectively as high-risk groups (ie, stage III) in the ISS because 82% of the patients with serum creatinine ≥ 2 mg/dL had a serum β2-microglobulin value > 5.5 mg/L.2 Melphalan as a conventional agent against myeloma has been limited in the treatment of patients with MM and renal impairment by the need for dose adjustment.3 Lenalidomide is an active agent for MM confirmed by some randomized clinical trials. However, it is mainly excreted through the kidney and is not suitable to treat patients with MM complicated by renal impairment.4 Recently, the combination of bortezomib and dexamethasone has achieved high response rates and disease-free survival for patients with both refractory/relapsed MM and newly diagnosed MM.5,6 However, there are few reports regarding the treatment of patients
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
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| Clinical Lymphoma & Myeloma
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with newly diagnosed MM complicated by renal impairment with bortezomib-based regimens. In this study, we analyzed the efficiency and safety of bortezomib and dexamethasone in 18 patients with newly diagnosed MM complicated by renal impairment treated at Peking Union Medical College Hospital.
Patients and Methods From August 2006 to October 2008, 18 consecutive patients with newly diagnosed MM complicated by renal impairment were treated with ≥ 2 cycles of bortezomib plus dexamethasone at Peking Union Medical College Hospital. Review boards at the local institution approved the study, and all patients provided written informed consent. Renal impairment was defined as a serum creatinine level ≥ 2 mg/dL. All 18 patients received bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 plus dexamethasone 40 mg on days 1-4 every 21 days. Two patients also received epirubicin 40 mg/m2 on day 1. Four cycles of bortezomib and dexamethasone were planned. Thalidomide 100-200 mg/day was used as maintenance therapy after maximal efficacy of the treatment was reached. In addition to chemotherapy, all patients received intensive supportive care, including intravenous hydration, alkalization of urine, and correction of hypercalcemia and hyperuricemia. Standard European Group for Blood and Marrow Transplantation criteria were used for the evaluation of response.7 Two additional categories were also included: near-complete remission (nCR; CR) was defined as no detectable paraprotein by electrophoresis with positive immunofixation, and very good partial remission (VGPR; PR) was defined as > 90% reduction in paraprotein. Assessment for MM was performed after each cycle of chemotherapy, and time to initial response was calculated for patients with ≥ PR. Reversal of renal impairment was defined as a decrease in serum creatinine to a stable level < 1.5 mg/dL after treatment. Renal response was defined as a 50% decrease in serum creatinine level in patients who were not undergoing dialysis or were independent of dialysis after treatment. Improvement of renal function included both reversal of renal impairment and renal response. Serum creatinine level was tested weekly during chemotherapy, and creatinine clearance rate was calculated by the Cockroft-Gault formula. Time to reversal or improvement of renal function was also documented. Adverse events were documented and classified by Common Terminology Criteria for Adverse Events during chemotherapy.
Results Among the 18 patients with newly diagnosed MM (Tables 1A and 1B), 10 were men, and 8 were women. The median age was 60 years (range, 46-76 years). The median pretreatment serum creatinine level was 5.3 mg/dL (range, 2.1-10.5 mg/dL), and the median creatinine clearance rate calculated by the Cockroft-Gault formula was 11.9 mL/min (range, 4.7-28.4 mL/min). Twelve patients had a serum creatinine level > 4 mg/dL, of whom 5 were undergoing hemodialysis. The distribution of MM type was as follows: 5 with immunoglobulin (Ig)G, 4 with IgA, 2 with IgD, 2 with κ light chain only, and 5 with λ light chain only. All patients had stage III disease according to the ISS. In addition, there were 4 patients with hypercalcemia, 5 with hyperuricemia, and 12 with anemia.
After treatment, reversal of renal impairment was achieved in 7 (38.9%) of 18 patients. All 6 patients with serum creatinine level < 4 mg/dL achieved reversal of renal impairment. Only 1 of the other 12 patients with serum creatinine ≥ 4 mg/dL experienced reversal of renal impairment. Six of these 12 patients had a > 50% decrease in serum creatinine level. Therefore, 13 patients demonstrated improved renal function, including both reversal of renal impairment and renal response. The median times to reversal and to renal response were 16 days and 38 days, respectively. It was noted that only 1 of the 5 patients undergoing hemodialysis had reversed renal function (reversal of renal impairment) and became independent of hemodialysis after treatment; the other 4 patients continued to be hemodialysis dependent. Patients received a median of 4 cycles of bortezomib and dexamethasone chemotherapy (range, 2-5 cycles), of whom 1 patient received 2 cycles, 3 received 3 cycles, 11 received 4 cycles, and 3 received 5 cycles. Fifteen patients received thalidomide 100-200 mg/day as maintenance therapy. The overall response rate (ORR) was 83.3%, including 6 CRs, 3 nCRs, 3 VGPRs, and 3 PRs. Of the 3 nonresponding patients, 2 had stable disease (SD), and 1 had progressive disease (PD). The response rate including CR, nCR, and VGPR was 66.7%. The median time to response was 42 days (2 cycles). Among 15 patients who had ≥ PR, 7 had a reversal of renal impairment, and 6 had a renal response. Renal impairment persisted in the other 2 patients. The renal function improvement rate in this subgroup was 86.7% (13 of 15 patients). Renal function was not improved in patients with SD or PD. In addition, 3 of 5 patients undergoing dialysis reached CR, and the other 2 patients had SD. No treatment-related mortalities were reported during chemotherapy. One patient discontinued treatment because of recurrent ileus, and 3 patients discontinued treatment because of grade 3 peripheral neuropathy. Hematologic adverse events were all grade 1/2, including thrombocytopenia (22.2%) and leukopenia (27.7%); grade 1/2 nonhematologic adverse events included peripheral neuropathy (33.3%), diarrhea (27.7%), fatigue (38.8%), nausea (22.2%), and constipation (22.2%). All grade 3/4 adverse events were nonhematologic, including infection (1 case of bacterial pneumonia and 2 cases of herpes zoster virus infection), peripheral neuropathy (3 cases), and recurrent ileus (1 case). All adverse events were well controlled after symptomatic treatment. Among the initial 4 patients who did not receive acyclovir prophylaxis, 2 developed herpes zoster virus infection during chemotherapy. The subsequent 14 patients received acyclovir prophylaxis (acyclovir doses at 0.2 g once every other day for 3 months after bortezomib chemotherapy), and none developed herpes zoster infection. After a median follow-up of 15.7 months, the median progression-free survival (PFS) for responding patients was 18.1 months, and the median PFS for all patients was 12.6 months.
Discussion Renal insufficiency is a common complication of MM that occurs in 20%-40% of newly diagnosed patients.1 Renal impairment in patients with MM results mainly from “myeloma nephropathy.” Other contributing factors include hypercalcemia, hyperuricemia, dehydration, and use of nephrotoxic drugs (contrast and nonsteroidal anti-inflammatory drugs).8 Thus, rapid suppression of myeloma
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Bortezomib and Dexamethasone in Patients With MM With Renal Impairment Table 1A General Clinical Characteristics of the 18 Patients Patient Number Sex
Age, Years
Multiple Myeloma Type
ISS
24-Hour Urine Bence-Jones Protein, g
Creatinine Before Treatment, mg/dL
1
M
61
IgDL
III
10.8
8.7
2
F
56
K
III
3.2
8.0
3
F
75
IgAK
III
5.3
10.5
4
M
54
IgGL
III
1.9
3.2
5
F
76
L
III
6.8
4.2
6
M
65
L
III
4.2
9.9
7
F
54
L
III
8.3
2.1
8
M
54
IgGL
III
0.9
4.3
9
M
68
L
III
3.5
6.2
10
M
64
IgAL
III
4.4
2.2
11
F
70
IgGK
III
2.1
4.0
12
F
53
IgAL
III
5.3
3.1
13
M
57
IgAL
III
2.4
7.5
14
M
46
L
III
2.3
3.6
15
F
61
K
III
7.3
5.4
16
M
60
IgGL
III
13.4
9.0
17
F
59
IgGK
III
12.7
5.2
18
M
59
IgDK
III
2.6
6.6
Abbreviations: F = female; Ig = immunoglobulin; ISS = International Staging System; M = male
is key to the reversal of renal dysfunction. As a novel antimyeloma agent, bortezomib is a proteasome inhibitor metabolized mainly in the liver and is independent of renal clearance. Therefore, dosage adjustment is not required in patients with renal impairment.9 Several studies have demonstrated that bortezomib is active against both newly diagnosed and refractory/relapsed MM, with relatively high remission rates and rapid responses.6,10,11 Also, a recent study revealed that bortezomib had an influence on apoptosis and antiapoptotic gene expression through the nuclear factor-κB pathway in proximal tubular cells, which suggests that bortezomib might protect renal function through mechanisms independent of its antimyeloma activity.12 Several small retrospective studies have shown that bortezomib is not only effective and safe in the treatment of patients with refractory/relapsed and newly diagnosed MM with renal impairment, but it can also reverse renal function (reverse renal impairment) in these patients. In a retrospective analysis of 20 patients with MM (4 newly diagnosed and 16 refractory/relapsed) receiving bortezomib, reversal of renal function (serum creatinine < 1.5 mg/dL) was observed in 8 patients (40%), with a median time to reversal of 17 days; reversal of renal function was observed in only 3 of 8 patients with serum creatinine > 4 mg/dL. The ORR for MM itself was 65%, with 1 CR, 11 PRs, and 1 minor response (MR).13 In another study of 7 patients with newly diagnosed MM and 1 patient with refractory/relapsed MM receiving bortezomib plus dexamethasone, reversal of renal function was observed in 2 patients, and improvement of renal function was observed in 3 patients. In terms of MM, all 5 of these patients showed response to the treatment, including 3 CRs or nCRs, 1 VGPR, and 1 PR.14 In patients with more severe
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renal impairment, a multicenter, retrospective study of 24 patients with MM who were undergoing hemodialysis received bortezomibbased treatment; 30% achieved a CR or nCR, with PRs observed in 40% of the patients, and 4 patients became independent of dialysis following treatment.15 In a subgroup analysis of 2 phase II clinical trials, SUMMIT (Study of Uncontrolled Multiple Myeloma Managed With Proteasome Inhibition Therapy) and CREST (Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma; the renal eligibility criterion of each trial was measured or calculated creatinine clearance ≥ 10 mL/min), bortezomib was found to yield an ORR of 30% (2 PRs, 1 MR) in 10 patients with refractory/relapsed MM with creatinine clearance ≤ 30 mL/min, whereas the toxicity was comparable with that seen in patients with creatinine clearance > 30 mL/min.16 In a subgroup analysis of the APEX trial (Assessment of Proteasome Inhibition for Extending Remissions; the renal eligibility criterion was creatinine clearance ≥ 20 mL/min), bortezomib combined with dexamethasone was found to be superior, with an ORR of 40% in patients with refractory/relapsed MM with creatinine clearance ≤ 30 mL/min. Time to response and time to progression were 1.4 months and 4.9 months, respectively, and OS was 22.8 months, which was comparable with that of patients with normal renal function and significantly better than that of the subgroup of patients with renal impairment receiving single-agent dexamethasone.17 Our study is the first prospective study of a bortezomib-based regimen in patients with newly diagnosed myeloma with renal insufficiency. A total of 18 newly diagnosed patients with varying degrees of renal impairment received a median of 4 cycles of
Jian Li et al Table 1B General Clinical Characteristics of the 18 Patients (Continued) Number Creatinine After Patient Number Creatinine Clearance, Dialysis Hypercalcemia Hyperuricemia Anemia Efficacy of Cycles Treatment, mg/dL mL/min 1
7.5
Yes
Yes
Yes
No
2
1.4
CR
2
6.2
No
No
Yes
Yes
4
3.5
CR
3
4.7
Yes
No
No
Yes
3
2.6/Dialysis
CR
4
20.2
No
No
No
Yes
5
0.9
CR
5
15.1
No
No
Yes
Yes
5
1.9
CR
6
6.8
Yes
Yes
No
No
4
2.9/Dialysis
CR
7
27.2
No
No
No
No
4
1.1
nCR
8
15.1
No
Yes
No
Yes
4
0.7
nCR
9
12.1
No
No
No
Yes
4
2.6
nCR
10
28.4
No
Yes
No
No
4
1.4
VGPR
11
11.6
No
No
No
Yes
4
1.3
VGPR
12
19.4
No
No
Yes
Yes
4
0.9
VGPR
13
9.9
No
No
No
Yes
3
2.3
PR
14
16.6
No
No
No
No
4
1.3
PR
15
11.8
No
No
No
No
3
2.4
PR
16
5.5
Yes
No
No
Yes
4
5.5/Dialysis
SD
17
12.0
Yes
No
Yes
Yes
4
3.8/Dialysis
SD
18
11.6
No
No
No
Yes
5
4.0
PD
Abbreviations: CR = complete remission; nCR = near-complete remission; PD = progressive disease; PR = partial response; SD = stable disease; VGPR = very good partial response
bortezomib plus dexamethasone in this study, and improvement of renal function was observed in 72.2% of the patients, including a 38.9% rate of reversal of renal impairment and a 33.3% renal response rate. The median time to renal function reversal and time to renal response were 16 days and 38 days, respectively. However, we observed that all 6 patients with serum creatinine ≤ 4 mg/dL achieved reversal of renal function, whereas only 1 out of 12 patients with serum creatinine ≥ 4 mg/dL showed such a response. This correlates with previous studies in which serum creatinine level was considered as an independent prognostic factor associated with renal function recovery.18 In addition, 1 out of 5 patients undergoing dialysis achieved independence from dialysis and recovered renal function after treatment. It was also observed that the combination of bortezomib and dexamethasone leads to a good response of the MM itself in such patients. The ORR was 83.3%, including a 50% CR rate or nCR rate (including 3 patients undergoing dialysis), a 16.7% VGPR rate, and a 16.7% PR rate, with a median time to response of 2 cycles. Simultaneously, improvement of renal function was observed in 13 of 15 patients with an MM response, whereas renal impairment persisted in 2 patients who had SD and 1 patient who had PD. It suggested that myeloma response is associated with renal function improvement. Considering that the median time to renal response was 38 days and the median time to myeloma response was 2 cycles, it was suggested that if patients cannot achieve PR and renal response after 2 cycles of bortezomib and dexamethasone, other agents that can be used in renal insufficiency, eg, doxorubicin, cyclophosphamide, or thalidomide, may be added to improve renal function.
No treatment-related deaths were observed in this study. Grade 1/2 hematologic toxicities were thrombocytopenia and leukopenia. Grade 1/2 nonhematologic toxicities included peripheral neuropathy and gastrointestinal reactions. The 7 grade 3/4 adverse events reported in this study, including 3 cases of infection (bacterial pneumonia and herpes zoster virus infection), 3 cases of peripheral neuropathy, and 1 case of ileus, were comparable with those in patients with normal renal function.6,10,11 In this study, 2 of 4 patients without prophylaxis had herpes zoster virus infection, whereas the other 14 patients receiving acyclovir 0.2 g prophylaxis once every other day were not infected. Recent studies suggest a high prevalence of herpes zoster virus infection in patients receiving bortezomib and, thus, the importance of acyclovir prophylaxis in such patients.19
Conclusion Our data indicate that combination bortezomib and dexamethasone can improve renal function and disease control in patients with MM with renal impairment. It is one of the safe and effective regimens that can be reserved as a treatment option for such patients. A large, multicenter, controlled study is needed to confirm this conclusion.
Disclosures The authors have no relevant relationships to disclose.
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