Bortezomib, powder for injection, 3.5 mg, 1 mg, Velcade®
Public summary document for Bortezomib, powder for injection, 3.5 mg, 1 mg, Velcade®
Page last updated: 30 October 2009
Public Summary Documents
Product: Bortezomib, powder for injection, 3.5 mg, 1 mg, Velcade®
Sponsor: Janssen-Cilag Pty Ltd
Date of PBAC Consideration: July 2009
1. Purpose of Application
The submission requested listing on the Intravenous Chemotherapy
Supply Program (ICSP) for treatment in combination with a
corticosteroid and melphalan or cyclophosphamide, of previously
untreated symptomatic multiple myeloma or multiple myeloma with
related organ or tissue damage, in a patient with a WHO performance
status of 2 or less, and who is ineligible for high dose
The ICSP is a measure announced in the 2008 Budget to introduce more efficient arrangements for funding certain infusible and injectable chemotherapy medicines.
At its July 2007 meeting, the PBAC recommended the listing of
bortezomib on the PBS for the third line treatment of patients with
refractory multiple myeloma (MM) on the basis of acceptable
cost-effectiveness when compared to a mixture of salvage
3. Registration Status
Bortezomib was TGA registered for the additional indication of previously untreated multiple myeloma in patients not suitable for high dose chemotherapy, on 29 January 2009. The approved indications for bortezomib are:
Treatment of multiple myeloma patients who have received at least one prior therapy, and who have progressive disease.
Treatment, in combination with melphalan and prednisone, of patients with previously untreated multiple myeloma, who are not suitable for high dose chemotherapy.
4. Listing Requested and PBAC’s View
The submission proposed two restriction options for previously
untreated MM patients who are not transplant eligible, that are
based on the format of the existing bortezomib restriction. The
first is sourced from the VISTA trial, where patients were
discontinued when they experienced progressive disease (PD) or a
confirmed best (complete) response (CR); while the second is
derived from the current PBS restriction for bortezomib in
relapsed/refractory MM where only patients achieving at least a
partial response (PR) [i.e. PR or CR] are able to continue PBS
subsidised treatment beyond 4 cycles. A minor change was also
requested to the current bortezomib PBS restriction for
relapsed/refractory multiple myeloma, in anticipation of a
first-line listing for thalidomide, to move bortezomib from third
to second line therapy.
The submission proposed the listing of two vial sizes, the currently available 3.5 mg vial and a new 1 mg vial. Once reconstituted, both vial sizes contain a concentration of 1 mg/mL of bortezomib
For PBAC’s view, see Recommendations and Reasons.
5. Clinical Place for the Proposed Therapy
Multiple myeloma (MM) is a progressive haematological disease,
which is incurable. If recommended, bortezomib would be an
alternative first-line treatment for multiple myeloma.
The submission nominated two comparators for first-line use in
previously untreated and not transplant eligible multiple myeloma
patients: (1) thalidomide, melphalan and prednisone (MPT) and (2)
MP alone if thalidomide was not recommended for first-line multiple
myeloma at the March 2009 PBAC meeting. Thalidomide was recommended
as first-line treatment at the March 2009 PBAC meeting. Therefore,
thalidomide was considered the more appropriate comparator.
7. Clinical Trials
For the comparison between melphalan and prednisone (MP) and
bortezomib, melphalan and prednisone (VcMP), the submission
presented one randomised trial comparing melphalan, prednisone and
bortezomib with melphalan and prednisone (VISTA trial) in patients
with previously untreated multiple myeloma who are ineligible for
transplant. Doses of melphalan and prednisone were equivalent in
each treatment arm and the dose of bortezomib was
1.3mg/m2 as an intravenous bolus injection. For the
first four cycles (24 weeks), bortezomib was given twice weekly for
two consecutive weeks, followed by a ten day rest period. For the
remaining five cycles (30 weeks), a less dose-intense regimen of
bortezomib was used, with four doses per six-week cycle. Nine
cycles is the maximum number recommended in the TGA-Approved
Bortezomib Product Information.
For the comparison between thalidomide, melphalan and prednisone and bortezomib, melphalan and prednisone, the submission presented a meta-analysis of five randomised trials comparing thalidomide, melphalan and prednisone with melphalan and prednisone (Facon 2007, Palumbo 2006/2008, Hulin 2007, Wijermans 2007 and Gulbrandsen 2008/07), and performed an indirect comparison with one randomised trial comparing bortezomib, melphalan and prednisone with melphalan and prednisone (VISTA trial), with melphalan and prednisone as the common reference. Details of these trials are shown below.
The studies published at the time of submission are as follows:
|Trial ID/First Author||Protocol title/ Publication title||Publication citation|
|Direct randomised trials|
|VISTA trial/ (San Miguel et al, 2008)||Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.||The New England Journal of Medicine 2008; 359: 906-917|
|Trial GISMM2001-A (Palumbo A, 2008/2006)||Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomised controlled trial. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: Randomised controlled trial.||Blood 2008; 112: 3107-3113. Lancet 2006; 367: 825-831|
|IFM 99-06 (Facon T, 2007)||Melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial.||Lancet 2007; 370: 1209-1218|
|IFM 01/01 (Hulin C, 2007)||Comparison of melphalan-prednisone- thalidomide (MP-T) to melphalan-prednisone (MP) in patients 75 years of age or older with untreated multiple myeloma (MM). Preliminary results of the randomized, double-blind, placebo controlled IFM 01-01 trial. ASCO Annual Meeting Proceedings||Journal of Clinical Oncology. (Abstract) 2007 Part 1. Vol 25, No.18S (June 20 Supplement) 2007:8001.|
|Gulbrandsen 2008 Waage 2007||A randomised placebo controlled study with melphalan prednisone versus melphalan prednisone thalidomide: quality of life and toxicity. Melphalan-prednisone-thalidomide to newly diagnosed patients with multiple myeloma: a placebo controlled randomised phase 3 trial.||European Hematology Association (EHA), 13 th Congress, Copenhagen, Denmark, 2008 Blood: Abstract 78, 2007|
|Wijermans 2008||Melphalan prednisone versus melphalan prednisone thalidomide in induction therapy for multiple myeloma in elderly patients: first interim analysis of the Dutch Cooperative Group HOVON.||European Hematology Association (EHA), 13 th Congress, Copenhagen, Denmark, 2008|
For completeness, an indirect comparison between the VISTA trial and the Facon (2007) trial (the only thalidomide trial presented in the TGA approved product information) was conducted independently during the course of the evaluation.
8. Results of Trials
The results of the VISTA trial comparing melphalan and prednisone directly against
bortezomib, melphalan and prednisone are shown below. The primary outcome of this
trial was time to progression, although the trial was also powered for overall survival.
Results of the primary outcome, Time to Progression (TTP), in the randomised VISTA trial
|Outcome||VcMP n=344||MP n=338|
|15 June 2007 Clinical Cut-Off (third interim analysis)|
|EBMT Assessed TTP|
|Number of events, n (%)||101 (29.4)||152 (45)|
|Number censored, n (%)||243 (70.6)||186 (55)|
|Median, days (95%CI)||631 (535, 751)||456 (428, 545)|
|Median, months b (95%CI)||20.7 (17.6, 24.7)||15.2 (14.3, 18.0)|
|Hazard ratio (95% CI) c [p-value d ]||0.54 (0.417, 0.699) (0.000002)|
|Investigator Assessed TTP|
|Number of events, n (%)||83 (24.1)||146 (43.2)|
|Number censored, n (%)||261 (75.9)||192 (56.8)|
|Median, days (95%CI)||732 (603, NE)||256 (190, 312)|
|Median, months b (95%CI)||24.4 (14, NE)||16.8 (14.8, 19.2)|
|Hazard ratio (95% CI) c [p-value d ]||0.483 (0.367, 0.636) (<0.000001)|
|1 January 2008 Clinical Cut-Off (updated analysis)|
|EBMT Assessed TTP|
|Number of events, n (%)||138 (40.1)||185 (54.7)|
|Number censored, n (%)||206 (59.9)||153 (45.3)|
|Median, days (95%CI)||630 (576, 703)||456 (429, 500)|
|Mean (over trial period), months (95%CI) b,e||21.1 (19.8, 22.4)||15.9 (14.7, 17.2)|
|Median, months b (95%CI)||21.1 (19.2, 8.3)||15.2 (14.3, 16.7)|
|Hazard ratio (95% CI) c [p-value d ]||0.53 (0.422, 0.665) (<0.000001 f )|
|Investigator Assessed TTP|
|Number of events, n (%)||136 (39.5)||207 (61.2)|
|Number censored, n (%)||208 (60.5)||131 (38.8)|
|Median, days (95%CI)||672 (605, 776)||491 (441, 529)|
|Median, months b (95%CI)||22.1 (20.2, 25.9)||16.1 (14.7, 17.6)|
|Hazard ratio (95% CI) c [p-value d ]||0.488 (0.391, 0.609) (< 0.000001)|
Bolded typography indicates statistically significant differences
NE: not estimable
EBMT: European Group for Blood and Bone Marrow Transplant
b Months = days/30
c Hazard ratio estimates is based on a Cox regression model adjusted for stratification factors: B2-microglobulin, albumin and region
d log-rank test adjusted for stratification factors: B2-microglobulin, albumin and region
e Within trial mean estimated using KM method
f The p-value should be interpreted with caution given that the stopping boundary was already crossed at the time of the third interim analysis
Statistically significant differences between the VcMP and MP treatment groups in favour of VcMP were observed with all analyses of TTP, whether it was EBMT-assessed or investigator-assessed. Additional sensitivity analyses of TTP were performed in the VISTA trial, and all results were consistent with the primary TTP analysis.
The results for overall survival (OS) in the VISTA trial, the five thalidomide trials, a meta-analysis of the five thalidomide trials and the indirect comparison of the VISTA and thalidomide trials are summarised in the table below:
Results of the outcome, OS in the VISTA trial, the five thalidomide trials, a meta-analysis of the five thalidomide trials and the indirect comparison of the VISTA and thalidomide trials
|Trial ID||Treatment Effect (VcMP versus MP) (95%CI)||Treatment Effect (MPT versus MP) (95% CI)||Indirect (95% CI)|
|OS at 1 year (%)|
|VISTA||OR = 1.81 (1.17, 2.81) RD = 0.07 (0.02, 0.12) RR = 1.09 (1.02, 1.16)||-|
|Facon 2007||-||OR = 1.80 (0.96, 3.38) RD = 0.08 (0.0, 0.16) RR = 1.10 (1.0, 1.22)||OR = 1.01 (0.47, 2.17) RD = -0.01 (-0.10, 0.08) RR = 0.99 (0.88, 1.12)|
|Hulin 2007||-||OR = 1.40 (0.62, 3.13) RD = 0.04 (-0.06, 0.14) RR = 1.05 (0.94, 1.17)||-|
|Palumbo 2008/2006||-||OR=1.02 (0.57, 1.85) RD=0.00 (-0.08, 0.08) RR=1.00(0.91,1.10)||-|
|Gulbrandsen 2008/07||-||OR = 0.84 (0.51, 1.38) RD = -0.03 (-0.12, 0.06) RR = 0.96 (0.86, 1.08)||-|
|Wijermans 2008||-||OR = 0.71 (0.41, 1.25) RD = -0.06 (-0.15, 0.04) RR = 0.93 (0.83, 1.05)||-|
|Pooled (random effects) Test for heterogeneity of OR = p=0.21, I 2 =32.2%||-||) OR=1.04 (0.75,1.44) RD=0.01 (-0.04, 0.06) RR=1.01(0.95, 1.07)||OR=1.74 (1.01, 3.01) RD=0.06 (-0.01, 0.13) RR=1.08 (0.99,1.18)|
|OS at 2 years (%)|
|VISTA||OR = 1.64 (1.17,2.32) RD = 0.10 (0.03,0.16) RR = 1.14 (1.04,1.25)||-||-|
|Facon 2007||-||OR = 1.96 (1.18, 3.26) RD = 0.14 (0.04, 0.24) RR = 1.22 (1.06, 1.41)||OR = 0.837 (0.45, 1.54) RD = -0.04 (-0.16 ,0.08) RR = 0.934 (0.79, 1.11)|
|Hulin 2007||-||OR = 1.57 (0.87, 2.82) RD = 0.10 (-0.03, 0.23) RR = 1.16 (0.95, 1.42)||-|
|Palumbo 2008/2006||-||OR = 1.35 (0.83, 2.19) RD= 0.06 (-0.04, 0.16) RR e =1.09(0.95,1.24)||-|
|Gulbrandsen 2008/07||-||OR = 0.85 (0.55,1.32) RD = -0.04 (-0.14, 0.06) RR = 0.94 (0.81, 1.10)||-|
|Wijermans 2008||-||OR = 1.45 (0.91, 2.33) RD = 0.09 (-0.02, 0.20) RR = 1.15 (0.96, 1.37)||-|
|Pooled (random effects) Test for heterogeneity of OR = p=0.15, I 2 =40.6%||-||OR=1.36 (1.02, 1.81) RD=0.07 (0.01, 0.13) RR=1.11(1.01,1.21)||OR=1.21 (0.77, 1.88) RD=0.03(-0.06, 0.12) RR=1.03(0.90,1.17)|
|OS at 3 years (%)|
|VISTA||OR = 1.77 (1.15, 2.72) RD = 0.13 (0.03, 0.22) RR = 1.22 (1.05, 1.42)||-||-|
|Facon 2007||-||OR = 1.92 (1.21, 3.04) RD = 0.16 (0.05, 0.27) RR = 1.32 (1.09, 1.60)||OR = 0.922 (0.49, 1.73) RD = -0.03 (-0.18, 0.12) RR = 0.924 (0.72, 1.18)|
|Hulin 2007||-||OR = 1.91 (1.09,3 .36) RD = 0.16 (0.02, 0.30) RR = 1.41 (1.04, 1.91)||-|
|Palumbo 2008/2006||-||OR=1.01 (0.65, 1.56) RD=0.00 (-0.10, 0.11) RR=1.00(0.84,1.20)||-|
|Gulbrandsen 2008/07||-||OR = 0.91 (0.6, 1.38) RD = -0.02 (-0.13, 0.08) RR = 0.95 (0.76, 1.19)||-|
|Wijermans 2008||-||OR = 1.30 (0.82, 1.38) RD = 0.06 (-0.05, 0.18) RR = 1.16 (0.90, 1.49)||-|
|Pooled (random effects) Test for heterogeneity of OR = p=0.08, I 2 =52.2%||-||OR=1.31 (0.97, 1.78) RD=0.07 (-0.01, 0.14) RR=1.14 (0.98, 1.32)||OR=1.35 (0.80, 2.29) RD=0.06 (-0.06, 0.18) RR=1.07(0.87 1.32)|
In the VISTA trial a statistically significant difference in overall survival was observed at 1, 2 and 3 years, in favour of bortezomib.
The submission’s indirect comparisons of overall survival at 2 and 3 years are not statistically significant although they show a favourable trend for VcMP over MPT.
The VcMP treatment arm in the VISTA trial experienced a higher incidence of adverse events during initial therapy (cycles 1-4) for Grade ≥ 3 adverse events and serious adverse events compared with MP, although there were no new adverse events arising as a result of bortezomib added to the MP regimen and no difference in Grade 4 or 5 adverse events and treatment-related discontinuations or deaths between groups. Additionally, adverse events with VcMP appeared to be non-cumulative, improving to a level that was comparable to the MP arm during cycles 5-9.
The indirect comparison between bortezomib and thalidomide using MP as the common reference provided a comparison of the most common adverse events as well as adverse events of Grade 3 or 4 severity reported in both the VISTA and Facon (2007) trials. Facon (2007) provided the most safety information by far for all of the thalidomide trials. Although the overall safety profile was comparable between VcMP vs. MP and MPT vs. MP, the adverse event profile differed with VcMP associated with significantly less anaemia than MP, but more leucopoenia, gastrointestinal adverse events (nausea, diarrhoea and vomiting), dizziness, anorexia and paraesthesia; and MPT associated with more neutropenia, leucopoenia, constipation, somnolence, dizziness and fatigue, and DVT/pulmonary embolism. This evidence was the basis of the submission’s claim that overall adverse events for VcMP were no worse than MPT.
9. Clinical Claim
The submission described bortezomib as being associated with
superior overall survival (OS) compared to MPT therapy showing
statistically significant better overall survival at 1 year for
bortezomib, with a trend towards superiority at 2 and 3
The submission described the safety of bortezomib (VcMP) as being no worse than MPT, but with different profiles.
The submission described bortezomib, in combination with melphalan and/or cyclophosphamide and prednisone as superior in terms of overall effectiveness and equivalent in terms of comparative safety over melphalan and prednisone.
For PBAC's views see the Recommendations and Reasons.
10. Economic Analysis
Given the VISTA data was not yet mature and followup was ongoing,
the submission did not claim advantage for bortezomib over
thalidomide in first-line treatment. Instead, the submission
presented an economic analysis including use of bortezomib either
at frontline in non-transplant eligible patients or from secondline
onwards in relapsed/refractory patients comparing costs based on
once in a lifetime use of bortezomib in the entire proposed and
comparative treatment algorithms for multiple myeloma.
In addition a stepped cost-effectiveness economic evaluation was presented for the comparison of melphalan and prednisone against bortezomib, melphalan and prednisone.
For PBAC's views see the Recommendations and Reasons.
11. Estimated PBS Usage and Financial Implications
The financial savings/year to the PBS was estimated to be < $10
million per year in Year 5, with patient copayments deducted. The
submission’s estimate was a costing of the entire treatment
algorithm, including proportions of patients on subsequent
12. Recommendation and Reasons
The PBAC recommended the listing of bortezomib on the PBS through
the Intravenous Chemotherapy Supply Program (ICSP) for the
first-line treatment of patients with multiple myeloma in
combination with melphalan or cyclophosphamide and corticosteroids
on a cost minimisation basis compared with thalidomide, using the
thalidomide costs accepted by the PBAC in March 2009 for first-line
treatment of multiple myeloma.
The PBAC noted that TGA registration did not include use with cyclophosphamide and only included use with “prednisone”. The PBAC considered that there was a high clinical need for use with cyclophosphamide particularly in patients with renal failure, that the inclusion would be consistent with the relapsed/refractory listing and that additional non-randomised clinical trial data had been provided to support inclusion in the restriction. The PBAC therefore considered that cyclophosphamide should be included in the listing criteria as well as the more generic term “corticosteroid”, as prednisone is little used in Australia. The PBAC also considered that the WHO status of 2 or less was not necessary as it will be removed from the current relapsed/refractory restriction as proposed at the meeting with clinicians on 16 June 2009 and accepted by the PBAC. The PBAC also considered that restriction option 1 proposed in the submission, and sourced from the VISTA trial, should be the preferred PBS listing as this best reflects drug use in clinical practice and is the pattern of use that best compares with comparator thalidomide. The PBAC did not consider continuation criteria to be necessary.
The PBAC agreed with the ESC that the more informative analysis was the comparison of bortezomib against the thalidomide, melphalan and prednisone (MPT) regimen. The PBAC accepted that the VISTA trial demonstrated that VcMP has greater efficacy than MP but is associated with greater initial toxicity. However, neither arm in this trial included thalidomide. Thus, the indirect comparison between bortezomib (VISTA trial) and thalidomide (meta-analysis of the five thalidomide trials) which sought to demonstrate the claim that bortezomib had greater efficacy than thalidomide was considered to be a more relevant basis of comparison. However, this evidence appeared to be unstable and was not conclusive due to:
1. Differences in the baseline patient (age) and disease characteristics (different ISS categories) across the trials.
2. Differences in the thalidomide dose (ranging from 100mg/day to 400mg/day).
3. Differences in the number of cycles of MPT (6 to 12 cycles).
4. Differences in the use of thalidomide as maintenance therapy (after first-line treatment cessation).
5. Differences in the second-line treatment regimens employed in the trials which may confound the results reported for overall survival as the effectiveness and safety of the second-line regimens are likely to differ.
6. Differences in the primary outcomes of trials.
An indirect comparison constructed during the evaluation comparing bortezomib with thalidomide, using MP as the common reference, has been carried out comparing the VISTA trial with the Facon (2007) trial (the thalidomide trial which is presented in the TGA approved product information). This analysis indicated that there was no statistically significant difference in OS between VcMP and MPT at 1, 2 or 3 years.
The submission presented cost comparison of the proposed (VcMP) versus the comparator treatment algorithms (second and third-line treatment - thalidomide then lenalidomide or vice versa) rather than only the comparator treatment regimen (MPT). The PBAC agreed there were a number of uncertainties with the data used by the submission for second-line treatments. The cost-effectiveness and efficacy of thalidomide when used after bortezomib is unknown and therefore, the estimation of thalidomide costs after bortezomib are also uncertain. In addition, not all treatment options have been included, the rates of drop outs into third-line are likely to be underestimated, patients requiring fourth-line therapy or greater were not included and no Australian data are provided to indicate that the simple guideline approach is realistic in practice.
The PBAC acknowledged the novel approach to the economic analysis using the comparator treatment algorithms. However, the PBAC considered that as there were considerable uncertainties with this analysis as described above and that the adoption of such an approach could have significant implications for the prices of a number of drugs (both increases and decreases). Hence a direct cost-minimisation comparison with thalidomide in the first-line setting was more appropriate.
The PBAC noted that the price requested for bortezomib in the submission is higher than thalidomide for first line treatment of multiple myeloma. The PBAC considered that the clinical trial data presented did not demonstrate superior efficacy of bortezomib over thalidomide in the first-line setting and therefore the higher price requested for bortezomib was not justified.
The PBAC noted the consumer comments concerning bortezomib, some of which expressed a need for bortezomib in combination with lenalidomide or for first-line treatment of patients eligible for SCT.
BORTEZOMIB, powder for injection, 1 mg (solvent required) and 3.5 mg (solvent required)
Extend the current restriction to include:
Restriction: Authority Required
Initial PBS-subsidised treatment of a patient with newly diagnosed symptomatic multiple myeloma in combination with a corticosteroid and melphalan or cyclophosphamide who is ineligible for high dose chemotherapy.
The authority application must be made in writing and must
(1) a completed authority prescription form; and
(2) a completed Multiple Myeloma Authority Application - Supporting Information Form, which includes details of diagnosis and ineligibility for high dose chemotherapy; and
(3) a signed patient acknowledgment.
Maximum quantity: 3 mg
Number of Repeats: 31
Continuing first-line PBS-subsidised treatment of a patient with newly diagnosed symptomatic multiple myeloma, in combination with a corticosteroid and melphalan or cyclophosphamide, who has received an initial authority prescription for bortezomib and who, at the time of application, has demonstrated
no progressive disease; and
has not yet achieved a best confirmed response to bortezomib.Continuing PBS-subsidised supply will not be approved if there is a gap of more than 6 months between the initial application and this application.Further applications for continuing PBS-subsidised bortezomib will not be approved after this application.
Maximum quantity: 3 mg
Number of repeats: 19
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Janssen-Cilag welcomes the PBAC’s recognition of the need for PBS-subsidised access to bortezomib for newly diagnosed multiple myeloma patients who are not eligible for high dose therapy. For several reasons, Janssen-Cilag is unable to proceed with the PBS availability of bortezomib through the ICSP under the circumstances recommended by the PBAC in July 2009. However, since then, Janssen- Cilag has been working collaboratively with the PBAC Secretariat and Pharmaceutical Evaluation Branch to progress a revised proposal for the PBS listing of bortezomib for newly diagnosed multiple myeloma patients who are not eligible for high dose therapy.