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BRIEF COMMUNICATION
Year : 2020  |  Volume : 9  |  Issue : 1  |  Page : 56-59

Reduced weekly subcutaneous doses of bortezomib in combination with cyclophosphamide and dexamethasone for newly diagnosed multiple myeloma


1 Department of Internal Medicine, Hematology and Oncology Section, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Clinical Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran

Date of Submission15-Oct-2018
Date of Acceptance17-Jun-2019
Date of Web Publication28-Mar-2020

Correspondence Address:
Dr. Ali Darakhshandeh
Department of Internal Medicine, Hematology and Oncology Section, Isfahan University of Medical Sciences, Isfahan
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrpp.JRPP_18_82

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  Abstract 


Objective: A combination of bortezomib, cyclophosphamide, and dexamethasone is highly effective in the treatment of newly diagnosed multiple myeloma. Neuropathy is a dose-limiting adverse effect of this regimen. Subcutaneous and weekly injection instead of biweekly intravenous administration are used to reduce neuropathy. In this study, patients treated with subcutaneous weekly reduced the dose of bortezomib to reduce neuropathy and cost of treatment. Methods: This is an interventional study, including 16 patients. Enrolled patients received bortezomib 1 mg/m2 subcutaneously, cyclophosphamide 300 mg/m2 intravenously, and dexamethasone 40 mg intravenously days 1, 8, 15, and 22 of a 28 cycle. Findings: The overall response rate (≥partial response [PR]) was 93.8%. Thirteen of 16 patients (81.3%) were in an acceptable PR and complete response. Two patients (12.5%) achieving a PR. Meantime to achievement, the best response was 71 (55–87) days. Median progression-free survival was 33 (2–56) months, and autologous stem cell transplantation was performed for 68.8% of patients. Five patients (31.25%) experienced Grade I and one patient (6.25%) Grade III (no Grade 2 or 4) of peripheral neuropathy. Dose reduction and drug discontinuation was required in one patient (6.25%). Conclusion: A reduced subcutaneous, weekly dose of bortezomib in combination with cyclophosphamide and dexamethasone is effective with manageable profile toxicity and acceptable cost.

Keywords: Bortezomib, multiple myeloma, neuropathy


How to cite this article:
Ashrafi F, Moghaddas A, Darakhshandeh A. Reduced weekly subcutaneous doses of bortezomib in combination with cyclophosphamide and dexamethasone for newly diagnosed multiple myeloma. J Res Pharm Pract 2020;9:56-9

How to cite this URL:
Ashrafi F, Moghaddas A, Darakhshandeh A. Reduced weekly subcutaneous doses of bortezomib in combination with cyclophosphamide and dexamethasone for newly diagnosed multiple myeloma. J Res Pharm Pract [serial online] 2020 [cited 2020 May 25];9:56-9. Available from: http://www.jrpp.net/text.asp?2020/9/1/56/281543




  Introduction Top


Multiple myeloma is a plasma cell neoplasia characterized by hypercalcemia, anemia, renal failure, and bony lytic lesions. Over the past two decades, the diagnosis and treatment of disease have improved, and the myeloma has changed from a fatal disease to a treatable but incurable disease. The incidence of disease increased by 126% from 1990 to 2016.[1] Multiple myeloma accounts for 17% of hematologic malignancy in the United States.[2] Newly diagnosed patients should be assessed for autologous bone marrow transplantation. Patients eligible for hematopoietic cell transplantation (HCT) receive induction chemotherapy, followed by high-dose chemotherapy and HCT. Patients ineligible for HCT generally receive induction chemotherapy followed by maintenance therapy until the progression. Various combinations of regimens for induction therapy are used. Corticosteroid, immunomodulatory agents, proteasome inhibitors, and alkylating agents are most common drugs that generally used in a combination regimen.

Bortezomib is a 1st-generation proteasome inhibitor that used for de novo and relapsed myeloma.[3],[4] The use of bortezomib seems to be a significant evolution in the treatment of the disease. The response rate with bortezomib varies by a combination regimen that used. Peripheral neuropathy is a significant side effect of bortezomib, albeit it seemed reversible in a majority of patients, but dose reduction and drug discontinuation are necessary for palliation.[5] Subcutaneous injection and weekly injections can be used to reduce bortezomib induce neuropathy. Subcutaneous infusion of bortezomib compared to intravenous administration had an improved safety profile with noninferior efficacy.[6] Weekly injection compared to twice-weekly dose in relapsed/refractory myeloma had comparable outcomes with lower rate neuropathy.[7]

Irrespective of these side effects, bortezomib is an expensive drug but is likely to be cost effective compared with other combinations such as melphalan, prednisolone, thalidomide, or lenalidomide.[8] Jagannath et al. reported that in relapsed or refractory multiple myeloma reduced doses of bortezomib, 1 mg/m2, compared to standard treatments, had comparable overall response rate and lower toxicity, such as neuropathy.[9]

Bortezomib had used in a various combination regimen. Three drug combinations of bortezomib, cyclophosphamide, and dexamethasone (CyBorD) are the first-line regimen for the initial treatment in newly diagnosed patients with high response rate.[10]

This study designed to evaluate the efficacy of reduced doses of bortezomib in the treatment of newly diagnosed multiple myeloma patients. In this study, we assess the effectiveness and adverse effects of once weekly subcutaneous reduced doses of bortezomib 1 mg/m2 in the CyBorD regimen.


  Methods Top


This was an interventional study conducted on patients with multiple myeloma from 2014 to 2017. Sixteen newly diagnosed patients (age range: 44–64-year-old) based on the International Myeloma Working Group updated the criteria included in the study,[11] who referred to Omid Hospital, Isfahan, Iran. Before starting treatment benefits and side effects of treatment clearly explained to the patients, and then, all of them read and signed the consent form. Patients with concurrent disease that induced neuropathy, severe heart and pulmonary disease, signs of amyloid light-chain amyloidosis, and recurrent or refractory myeloma excluded from the study. Patients treated with bortezomib 1 mg/m2 subcutaneously, cyclophosphamide 300 mg/m2 intravenously, and dexamethasone 40 mg intravenously days 1, 8, 15, and 22 of a 28 days cycle. All medications were administered weekly for 4 consecutive weeks. At the end of each cycle, laboratory findings were evaluated, and patients categorized as complete, acceptable partial, and partial response (PR) based on the International Myeloma Working Group consensus criteria.[12] Patients with at least PRs, who were eligible for HCT, referred for transplantation, and for patients with stable disease after two cycles and patients with progressive disease alternative treatment were used. Neurologic examination was performed for all patients at baseline and beginning of each period. Bortezomib induces peripheral neuropathy graded per National Cancer Institute common toxicity criteria for adverse events.[13]


  Results Top


Sixteen patients with newly diagnosed multiple myeloma were evaluated. The mean age was 54 (44–64) years. Sixty-two percent were men, and 38% were women. 37.5%, 50%, and 12.5% of patients were in International Staging System, Stage I, II, and III, respectively. Fifteen patients had symptomatic disease (Durie–Salmon Stage II or III). Other baseline disease characteristics are summarized in [Table 1].
Table 1: Baseline patient demographics and disease characteristics (mean, n=16)

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The overall response rate (≥PR) was 93.8% (15/16). Thirteen of 16 patients (81.3%) were in very good PR and complete response. Two patients (12.5%) achieving a PR. One patient (6.2%) had progressive disease after two cycle chemotherapy. Meantime to achievement, the best response was 71 (55–87) days. After a median follow-up of 36 (20–57) months from the time of diagnosis, four of 16 patients died. Median progression-free survival was 33 (2–56) months, and HCT was performed for 68.8% (11 patients) of patients. Ten of 11 patients referred for HCT were able to mobilize peripheral blood stem cells with granulocyte colony-stimulating factor (G-CSF) alone and the other with G-CSF and plerixafor [Table 2].
Table 2: Case-by-case description of the toxicity and efficacy of the regimen

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All patients were assessed for peripheral neuropathy. Fourteen patients completed all four cycle chemotherapy. Of the two patients who did not complete treatment, one patient had progressive disease, and another had Grade III peripheral neuropathy that had not resolved by drug discontinuation. Five patients experienced Grade I peripheral neuropathy and one patient Grade III (no Grade 2 or 4). Only one patient (6.25%) required doses reduction and drug discontinuation.


  Discussion Top


The availability of new drugs with different mechanisms has revolutionized the treatment of multiple myeloma. One of the regimens used is CyBorD, which has been associated with a high response rate in various studies. Data from three phase II studies in newly diagnosed multiple myeloma have shown high response rates with CyBorD.[14],[15],[16] Reeder et al. reported an overall response rate of 89%, with 62% of them had good PR.[14] Analysis of Deutsche Studiengruppe Multiples Myelom (DSMM) Xia trial indicated overall response rate and complete response rate of 84% and 10%, respectively.[15] In EVOLUTION trial, CyBorD in newly diagnosed myeloma patients led to overall response rate of 75%.[16] In all three studies, bortezomib was administrated at the doses of 1.3 mg/m2 intravenously 1, 4, 8, and 11 of 21 days cycle.[14],[15],[16]

The overall response rate in our study was 93.5% that was comparable with three previous studies although no head-to-head comparison was made between this study and prior studies. One of the most critical complications of this combination is neuropathy, with an estimated up to 39%.[15] In this study, to reduce this complication, bortezomib was administered subcutaneously at weekly doses of 1 mg/m2 in combination with cyclophosphamide and dexamethasone.

In the DSMM Xia trial, 39% of patients had polyneuropathy, but only 3% had Grade 3 polyneuropathy.[15] Reeder et al. reported 46%, 13%, and 7% Grade I, II, and III neuropathy, respectively, in which study 27% of patients required drug discontinuation.[14] Due to high rate adverse events such as neuropathy in twice weekly bortezomib, Reeder et al. modified their regimen to a once-weekly protocol. In their study, overall response rate was similar to the biweekly schedule, but Grade 3/4 adverse effects such as neuropathy were less, besides fewer doses reduction required.[17] In our study, five patients (30.6%) experienced Grade I peripheral neuropathy and one patient (6.25%) Class III (no Grade 2 or 4). Only one patient (6.25%) required doses reduction and drug discontinuation. Compared with the previous studies, incidence of neuropathy, especially Grade 3/4 are less, and fewer patients require doses reduction and drug discontinuation. However, because of the small number of samples in our study, the conclusions should be cautious.

Bortezomib is an expensive drug. Hill et al. reported that target prices for bortezomib in 2016 were £411 per cycle in the United Kingdom.[18] If the cost of the drug is reduced, but its effectiveness has not changed, not only more patients can use this drug but also patients experience fewer adverse effects. In our study, the reduced doses of bortezomib do not appear to affect its efficacy, and the cost of drug has also decreased significantly. The most important limitations of this study are its small sample size.

The most important limitations of this study are its small sample size. Due to the small sample size, we cannot generalize the results of this study to all patients. On the one hand, the small sample size makes it impossible to head compare the results of this study with other studies. Of course, this study can be used as a pilot study to design a study with appropriate sample size.

Reduced subcutaneous, weekly doses of bortezomib in combination with cyclophosphamide and dexamethasone seems to be effective with manageable profile toxicity and acceptable cost.


  Authors' Contribution Top


Farzaneh Ashraf and Azadeh Moghadass performed literature search, prepared, edited, discussed and contributed to the final manuscript. Ali Darakhshandeh devise the project, designed and contributed to the final manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Cowan AJ, Allen C, Barac A, Basaleem H, Bensenor I, Curado MP, et al. Global burden of multiple myeloma: A systematic analysis for the global burden of disease study 2016. JAMA Oncol 2018;4:1221-7.  Back to cited text no. 1
    
2.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7-30.  Back to cited text no. 2
    
3.
Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: Results of the IFM 2005-01 phase III trial. J Clin Oncol 2010;28:4621-9.  Back to cited text no. 3
    
4.
Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: Final time-to-event results of the APEX trial. Blood 2007;110:3557-60.  Back to cited text no. 4
    
5.
Richardson PG, Briemberg H, Jagannath S, Wen PY, Barlogie B, Berenson J, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 2006;24:3113-20.  Back to cited text no. 5
    
6.
Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: A randomised, phase 3, non-inferiority study. Lancet Oncol 2011;12:431-40.  Back to cited text no. 6
    
7.
Moore S, Atwal S, Sachchithanantham S, Streetly M, Khan I, Percy L, et al. Weekly intravenous bortezomib is effective and well tolerated in relapsed/refractory myeloma. Eur J Haematol 2013;90:420-5.  Back to cited text no. 7
    
8.
Garrison LP Jr, Wang ST, Huang H, Ba-Mancini A, Shi H, Chen K, et al. The cost-effectiveness of initial treatment of multiple myeloma in the U.S. with bortezomib plus melphalan and prednisone versus thalidomide plus melphalan and prednisone or lenalidomide plus melphalan and prednisone with continuous lenalidomide maintenance treatment. Oncologist 2013;18:27-36.  Back to cited text no. 8
    
9.
Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 2004;127:165-72.  Back to cited text no. 9
    
10.
Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: High response rates in a phase II clinical trial. Leukemia 2009;23:1337-41.  Back to cited text no. 10
    
11.
Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538-48.  Back to cited text no. 11
    
12.
Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016;17:e328-46.  Back to cited text no. 12
    
13.
Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176-81.  Back to cited text no. 13
    
14.
Reeder CB, Reece DE, Kukreti V, Mikhael JR, Chen C, Trudel S, et al. Long-term survival with cyclophosphamide, bortezomib and dexamethasone induction therapy in patients with newly diagnosed multiple myeloma. Br J Haematol 2014;167:563-5.  Back to cited text no. 14
    
15.
Einsele H, Engelhardt M, Tapprich C, Müller J, Liebisch P, Langer C, et al. Phase II study of bortezomib, cyclophosphamide and dexamethasone as induction therapy in multiple myeloma: DSMM XI trial. Br J Haematol 2017;179:586-97.  Back to cited text no. 15
    
16.
Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012;119:4375-82.  Back to cited text no. 16
    
17.
Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Laumann K, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood 2010;115:3416-7.  Back to cited text no. 17
    
18.
Hill A, Redd C, Gotham D, Erbacher I, Meldrum J, Harada R. Estimated generic prices of cancer medicines deemed cost-ineffective in England: A cost estimation analysis. BMJ Open 2017;7:e011965.  Back to cited text no. 18
    



 
 
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