The combination of cyclophosphamide, bortezomib and dexamethasone for the treatment of multiple myeloma was initially shown to be effective using regimens administering the bortezomib on a twice-weekly schedule (days 1, 4, 8 and 11 of a 21-day cycle). Refer to protocol Multiple Myeloma CyBorD (twice weekly). There are no randomised studies directly comparing twice-weekly vs weekly bortezomib administration in any of the combination regimens. The strongest evidence for the efficacy of weekly bortezomib administration is found in an analysis of its use in combination with melphalan and prednisone (VMP).r
Mateos et al., performed a detailed analysis of 3 large randomised controlled trials (RCTs) (VISTA, GIMEMA MM-03-05, GEM2005MAS65) studying a total of 705 transplant-ineligible patients receiving bortezomib, melphalan and prednisone. They looked specifically at different dosing schedules for bortezomib and found that the patients who received weekly dosing of bortezomib had similar, high response rates (74-87% across the studies), similar cumulative bortezomib dose and reduced toxicity (grade 3 to 4 peripheral neuropathy (PN) reduced from 13-14% with twice weekly dosing to 2-7% with weekly). Bortezomib was given intravenously (IV) in all three studies.r
The evidence for administering bortezomib weekly in combination with cyclophosphamide and dexamethasone includes two small prospective phase 2 studies. Tuchman et al., reported a study of 14 patients which administers subcutaneous (SC) bortezomib at 1.3 mg/m2, cyclophosphamide 300 mg/m2 and dexamethasone 40 mg on days 1, 8 and 15 every 28 days for 8 cycles, followed by indefinite alternative bortezomib and lenalidomide maintenance in very old (43% older than 80 years old) or toxicity-vulnerable patients.r It showed an overall response rate (ORR) of 64%, with a median overall survival (OS) of 29.7 months.
Tanaka et al, published a prospective phase 2 trial of transplant eligible Japanese patients using the eviQ advocated dosing (bortezomib 1.3 mg/m2 subcutaneously (SC), cyclophosphamide 300 mg/m2 (PO), and dexamethasone 40 mg (PO) on days 1, 8, 15, 22 on 28 day cycle x 4 cycles). The trial demonstrated an ORR (pre-autograft) of 73.7% and minimal PN with no patients experiencing grade 3 or higher neuropathy.r
Another phase 2 study compares sequential cohorts given IV bortezomib at 1.3 mg/m2 twice-weekly or 1.5 mg/m2 weekly with cyclophosphamide weekly and high dose dexamethasone.r In the two cohorts of newly diagnosed patients with multiple myeloma, response rates were equivalent whilst the rate of PN was markedly reduced in the weekly dosing group. There are also two retrospective studies of weekly bortezomib combined with cyclophosphamide 500 mg weekly and low dose dexamethasone 40 mg weekly, both of which reported excellent response rates in newly diagnosed myeloma.rr Again, rates of severe PN were very low. There is one very small prospectiver and one retrospectiver study of weekly bortezomib plus cyclophosphamide and steroid in relapsed/refractory multiple myeloma. These patients also responded well with minimal toxicity.
More recently, the majority of retrospective studies evaluating bortezomib, cyclophosphamide and dexamethasone in real world datasets have utilised once-weekly dosing regimens.
Retrospective review of 1156 transplant-ineligible patients from the Canadian Myeloma Research Group databaser compared outcomes from CyBorD, VMP and VD/P (bortezomib, dexamethasone/prednisone) and Rd (lenalidomide, dexamethasone). 562 patients received CyBorD, of which 97% received SC or IV bortezomib 1.5 mg/m2 weekly, cyclophosphamide 300 mg/m2 per week and dexamethasone 20-40 mg weekly. ORR for CyBorD was 84.7% (at least very good partial response (VGPR) in 54.6%) with a median overall survival of 52 months. This study was limited by lack of toxicity data.
Another Swedish retrospective studyr compared VRd (bortezomib, lenalidomide and dexamethasone) and CyBorD in 681 newly diagnosed patients. 564 CyBorD patients were included, of which 351 transplant-ineligible utilised a once-weekly bortezomib in 5-week cycles. ORR for weekly CyBorD was 79% (at least VGPR in 41%) with PFS 32% and OS 81% at 18 months.
A United Kingdom studyr of 158 transplant-ineligible patients using bortezomib subcutaneously (SC) 1.3 mg/m2, cyclophosphamide 300 mg/m2 (PO) on D 1,8,15 and dexamethasone 20 mg (D 1,2,8,9,15,16) every 21 days for 6-8 cycles demonstrated an ORR 72.1%, median event-free survival (EFS) of 10.5 months and median OS of 46.9 months. Similarly, a New Zealand studyr of 155 transplant-ineligible patients achieved an ORR 79.4% after 3 cycles of weekly bortezomib SC 1.5-1.6 mg/m2, cyclophosphamide 300 mg/m2 and dexamethasone 20-40 mg.
In the transplant setting, an Australian retrospective studyr of 70 patients using the eviQ advocated dosing achieved a pre-allograft ORR 76%. There was limited data on toxicity, but no bortezomib dose reductions were required during induction.
Source
|
Study & Year Published
|
Supports Use
|
Is the dose and regimen consistent with the protocol?
|
Comments
|
Phase II trials
|
Tanaka et al. 2019 r |
Yes |
Yes |
Bortezomib SC 1.3 mg/m2, cyclophosphamide PO 300 mg/m2 and dexamethasone PO 40 mg on D1,8,15, 22 q28d for 4 cycles |
Tuchman et al. 2017r |
Yes |
No |
Bortezomib SC 1.3 mg/m2, cyclophosphamide PO 300 mg/m2 and dexamethasone PO 40 mg on D1,8,15 q28d for 8 cycles; No bortezomib and dexamethasone dose on D22; protocol followed by alternating bortezomib and lenalidomide maintenance |
Reeder et al. 2010r
|
Yes
|
No
|
Bortezomib IV 1.5 mg/m2 on D1,8,15,22; cyclophosphamide PO 300 mg/m2 on D1,8,15,22; and dexamethasone PO 40 mg on D1 to 4, 9 to 12 and 17 to 20 (C1 to 2) and 40 mg weekly (C3 to 4).
|
Retrospective Cohort trial
|
Ong et al. 2015r
|
Yes
|
No
|
Bortezomib SC 1.3 mg/m2, cyclophosphamide PO 500 mg and dexamethasone PO 40 mg on D1,8,15,22 q28d
|
Retrospective review
|
Simpson et al. 2013r
|
Yes
|
No
|
Bortezomib SC 1.5 or 1.6 mg/m2 on D1,8,15,22; cyclophosphamide PO 300 mg/m2 on D1,8,15,22; dexamethasone PO 40 mg weekly.
|
|
Rampotas et al. 2021r |
Yes |
No |
Bortezomib SC 1.3 mg/m2 on D1, 8, 15; cyclophosphamide PO 500 mg on D 1, 8, 15; dexamethasone PO 20 mg D1, 2, 8, 9, 15, 16 |
|
Jiminez-Zepeda et al. 2021r |
Yes |
No |
Bortezomib SC or IV 1.5 mg/m2, cyclophosphamide 300 mg/m2, dexamethasone 20-40 mg on D1, 8, 15, 22 q28d |
|
Uttervall et al. 2019r |
Yes |
No |
Bortezomib 1.3 mg/m2 on D 1, 8, 14, 21; cyclophosphamide 1000 mg/m2 IV on D1; dexamethasone PO 20 mg q35d |
|
Chan et al. 2019r |
Yes |
No |
Bortezomib SC 1.5-1.6 mg/m2, cyclophosphamide PO 300 mg/m2, dexamethasone 20-40 mg weekly on D1, 8, 15, 22 q28d |
|
McCaughan et al. 2021r |
Yes |
Yes |
Bortezomib SC 1.3 mg/m2, cyclophosphamide PO 300 mg/m2, dexamethasone 40 mg weekly on D1, 8, 15, 22 q28d |
Guidelines
|
Date published/revised
|
Supports Use
|
Is the dose and regimen consistent with the protocol?
|
Comments
|
NCCN
|
V.1. 2023/24
|
Yes
|
N/A
|
Bortezomib, cyclophosphamide, dexamethasone preferred primarily as initial treatment in patients with acute renal insufficiency or those who have no access to proteasome inhibitor/lenalidomide/dexamethasone.
|
BCCA
|
June 2022
|
Yes
|
No
|
Bortezomib SC/IV 1.5 mg/m2 (may start with 1.3 mg/m2) on D1,8,15,22; cyclophosphamide PO 300 mg/m2 on D1,8,15,22; and dexamethasone PO 40 mg on D1 to 4, 9 to 12 and 17 to 20 (C1 to 2) and 40 mg weekly (C3 to 4).
|
MSAG
|
2022
|
Yes
|
No
|
Bortezomib IV (or SC) 1.5 mg/m2 on D1,8,15,22; cyclophosphamide PO 300 mg/m2 on D 1,8,15,22; dexamethasone PO 20 mg the day of and after bortezomib q28d for 3-4 cycles prior to autologous stem cell transplant.
|
Efficacy
A summary of the evidence supporting the effect of this protocol is below:
Paper |
Study Phase |
Patient population |
Patient Number |
OS |
PFS |
CR |
Tanaka et al. 2019r |
Phase II |
Newly diagnosed Multiple myeloma (NDMM) |
38 |
1 yr: 97.3%
2 yrs: 82.7%
|
1 yr: 78%
2 yrs: 55.3%
3 yrs: 48.4%
|
10.5% |
Tuchman et al. 2017r |
NDMM |
14 |
29.7 months |
Median PFS: 24.2 months |
|
Reeder et al. 2010r |
NDMM |
63 (30 patients in the once-weekly arm) |
|
|
43% |
Toxicity
As noted above, administering bortezomib weekly compared with twice-weekly appears to reduce the rates of significant peripheral neuropathy. Haematological toxicity was also reduced in the weekly group, as noted in the study of Reeder et al where Cohort 1 received twice weekly bortezomib and Cohort 2, weekly.r
Table 1 - Overall response
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