Lenalidomide, capsules 5 mg, 10 mg, 15 mg and 25 mg, Revlimid®, November 2008
Public summary document for Lenalidomide, capsules, 5 mg, 10 mg, 15 mg and 25 mg, Revlimid®, November 2008
Page last updated: 24 March 2009
Printable version of Lenalidomide, capsules 5 mg, 10 mg, 15 mg and 25 mg, Revlimid®
(PDF 74 KB)
Public Summary Document
Product: Lenalidomide, capsules 5 mg, 10 mg, 15 mg
and 25 mg, Revlimid®
Sponsor: Celgene Pty Ltd
Date of PBAC Consideration: November 2008
1. Purpose of Application
To request a Section 100 (Highly Specialised Drugs Program) listing
for the treatment of patients with relapsed/refractory multiple
myeloma for whom thalidomide therapy has failed or in whom there is
severe intolerance/toxicity to thalidomide.
Highly Specialised Drugs are medicines for the treatment of chronic
conditions, which, because of their clinical use or other special
features, are restricted to supply to public and private hospitals
having access to appropriate specialist facilities.
2. Background
At its March 2008 meeting, the PBAC rejected a submission to list
lenalidomide for treatment of relapsed/refractory multiple myeloma
based on the quality of the data, the uncertainty of the clinical
claim and the resulting unacceptably high and uncertain
cost-effectiveness ratios. (See also Public Summary Document for
March 2008).
3. Registration Status
Lenalidomide was TGA registered on 20 December 2007 and is
indicated for use in combination with dexamethasone in patients
with multiple myeloma whose disease has progressed after one
therapy.
4. Listing Requested and PBAC’s View
Section 100
Private Hospital Authority Required
Relapsed/refractory multiple myeloma in combination with dexamethasone in a patient
with multiple myeloma who has progressive disease, has received at least 1 prior therapy
(other than thalidomide), has undergone or is ineligible for a primary stem cell transplant
and who has experienced treatment failure after a trial of at least four (4) weeks
of thalidomide at a dose of at least 100 mg daily.
If the dosing requirement for thalidomide cannot be met, the application must state
the reasons why this criterion cannot be satisfied.
Thalidomide treatment failure is defined as:
- confirmed disease progression during or after completion of thalidomide treatment; or
- severe intolerance or toxicity unresponsive to clinically appropriate dose adjustment.
Progressive disease is defined as at least 1 of the following:
a. at least a 25% increase and an absolute increase of at least 5 g per L in serum M protein (monoclonal protein); or
b. at least a 25% increase in 24-hour urinary light chain M protein excretion, and an absolute increase of at least 200 mg per 24 hours; or
c. at least a 25% relative increase and at least a 10% absolute increase in plasma cells in a bone marrow aspirate or on biopsy; or
d. an increase in the size or number of lytic bone lesions (not including compression fractures); or
e. at least a 25% increase in the size of an existing or the development of a new soft tissue plasmacytoma (determined by clinical examination or diagnostic imaging); or
f. development of hypercalcaemia (corrected serum calcium greater than 2.65 mmol per L not attributable to any other cause).
Severe intolerance due to thalidomide is defined as unacceptable somnolence or sedation interfering with activities of daily living. Toxicity from thalidomide is defined as peripheral neuropathy (Grade 2 or greater, interfering with function), drug-related seizures, serious Grade 3 or 4 drug-related dermatological reactions, such as Stevens-Johnson Syndrome, or other Grade 3 or 4 toxicity.
NOTE:
Patients receiving lenalidomide via the PBS must be registered in the RevAccess program.
For PBAC’s view, see Recommendations and Reasons.
5. Clinical Place for the Proposed Therapy
Multiple myeloma is a disorder in which malignant plasma cells
accumulate in the bone marrow and produce immunoglobulin. It is a
rapidly progressing condition for which there is no cure. While
existing treatments for newly diagnosed patients have the potential
to delay disease progression and increase survival, eventually all
patients will experience disease relapse, including those who have
undergone a stem cell transplant. In some patients, their disease
will fail to be controlled by those initial treatment
options.
Lenalidomide would provide an alternative option for patients with
relapsed or refractory multiple myeloma.
In the proposed treatment algorithm, patients will be treated with
lenalidomide plus dexamethasone as third line therapy, after
failing thalidomide and one other therapy.
6. Comparator
The submission nominated bortezomib, either as monotherapy or in
combination with dexamethasone as the comparator. This is as
previously advised by the PBAC and is appropriate.
7. Clinical Trials
New trial data were presented in the re-submission. The basis of
the comparison with bortezomib was an indirect comparison of two
lenalidomide plus dexamethasone and dexamethasone only trials
(Study 009 and Study 010) compared with one bortezomib and
dexamethasone trial (APEX) with dexamethasone as the common
comparator, and two supportive bortezomib studies (Jagannath 2006,
Kropff 2005). The previous submission did not present the two
supportive bortezomib studies. The re-submission presented analyses
including longer time to follow-up for the lenalidomide plus
dexamethasone and dexamethasone only trials.
A list of the published trials and studies provided in the
submission is presented below.
| Trial ID / Author | Protocol title/ Publication title | Publication citation |
| Lenalidomide | ||
| Randomised trials | ||
| Study 009 | Knight RD. Lenalidomide (Revlimid). A multicentre, randomized, parallel-group, double-blind, placebo-controlled study of CC-5013 plus dexamethasone versus dexamethasone alone in previously treated subjects with multiple myeloma. September 2005. | Not published |
| Weber DM et al. (Study 009) | Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. | N Engl J Med 2007; 357: 2133-2142. |
| Study 010 | Knight RD. Lenalidomide (Revlimid). A multicentre, randomized, parallel-group, double-blind, placebo-controlled study of CC-5013 plus dexamethasone versus dexamethasone in previously treated subjects with multiple myeloma. September 2005. | Not published |
| Dimopoulos M, et al (Study 010) | Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. | N Engl J Med 2007; 357: 2123-2132. |
| Wang M, et al (Study 009 and Study 010) | Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. | Blood 2008; 112 (12): 4445-4451. |
| Bortezomib | ||
| Randomised trial | ||
| APEX | ||
| Richardson PG et al. (2005) | Bortezomib or high dose dexamethasone for relapsed multiple myeloma. | N Engl J Med 2005; 352(24):2487-2498. |
| Richardson PG et al. (2007) | Extended follow-up of a phase 3 trial relapsed multiple myeloma: final time-to event results of the APEX trial. | Blood 2007; 110 (10): 3557-3560. |
| Richardson PG et al. (2007) | Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma | Br J Haematol. 2007; 137(5):429-35. |
| San-Miguel J-F et al. (2008) | Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. | Leukemia 2008; 22: 842–849. |
| Non-randomised studies | ||
| Jagannath S et al (2006) | Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. | Haematologica 2006; 91:929-934. |
| Kropff M et al. (2005) | Bortezomib in combination with dexamethasone for relapsed multiple myeloma. | Leukemia Research 2005; 29:587-590. |
8. Results of Trials
The key results are summarised in the tables below.
The primary outcome for the direct randomised trials was time to progression.
Results of time to progression across the direct randomised trials
| Study 009 | Study 010 | APEX | ||||
| Len+Dex n = 177 | Dex n = 176 | Len+Dex n = 176 | Dex n = 175 | Bort n = 315 | Dex n = 312 | |
| Median time of follow-up (months) | 17 | 17 | 17 | 17 | 8.3 | 8.3 |
| Median TTP (months) | 11.1 (7.0, NE) | 4.7 (3.9, 5.6) | 11.3 (8.4, NE) | 4.7 (4.6, 5.1) | 6.2 (4.9, 6.9) | 3.5 (2.8, 4.2) |
| HR (95% CI) | 0.35 (0.27, 0.47) | 0.35 (0.27, 0.46) | 0.55 (0.44, 0.69) | |||
| Log-rank test p-value | <0.001 | <0.001 | <0.001 | |||
NE: not estimable, CI: confidence interval, HR: hazard ratio, Len: lenalidomide, Dex:
dexamethasone, Bort: bortezomib.
In both lenalidomide trials, the median time to progression was significantly longer
in the lenalidomide plus dexamethasone arm compared to the dexamethasone only arm.
In the bortezomib trial, the median time to progression was significantly longer in
the bortezomib arm compared to the dexamethasone only arm. The median time to follow-up
in the lenalidomide plus dexamethasone trials (17 months) was longer than in the APEX
trial (8.3 months). Furthermore, patients in the dexamethasone arm of Studies 009
and 010 were not allowed to cross-over until the time of un-blinding (median time
to follow-up 17 months), while patients from the APEX trial were allowed to cross-over
when they experienced disease progression. At the time of measurement, 44% of the
dexamethasone patients in the APEX trial had crossed over to bortezomib treatment.
Taking into account the indirect nature of the comparison, the re-submission stated
that there may be a suggestion, although not statistically demonstrated, that treatment
with lenalidomide plus dexamethasone is associated with a longer time to progression
than bortezomib in patients with relapsed/refractory multiple myeloma. The re-submission
did not perform a proper indirect comparison of the two treatments, and there are
differences in study design (moment when patients were allowed to cross-over to active
treatment) and time of follow-up.
Overall survival was a secondary outcome for the direct randomised trials. The results
for overall survival are presented below.
Overall survival
| Study 009 & Study 010 | APEX | |||
| Len. + Dex. n = 353 | Dex. n = 350 | Bort. n = 315 | Dex. n = 312 | |
| Median time of follow-up | 41 months | 22 months | ||
| Dead n (%) Censored n (%) | 147 (41.6) 206 (58.4) | 173 (49.4) 177 (50.6) | NR | NR |
| OS (months) Median (95% CI) Mean St dev Min, Max | 34.4 (30.0, >41.8) 29.3 0.7 0.2, 41.8 | 30.7 (25.6, 36.7) 26.6 0.9 0, 43.4 | 29.8 (23.2, NE) | 23.7 (18.7, 29.1) |
| HR (95% CI) | 0.77 (0.62, 0.96) | 0.77 (0.61, 0.97) | ||
| Log-rank test p-value | 0.02 | 0.03 | ||
| Indirect comparison len + dex vs. bort | 1.00 (0.73, 1.38) | |||
NR, not reported; CI, confidence interval; HR, hazard ratio; Len, lenalidomide; Dex,
dexamethasone; Bort, bortezomib; NE, not estimable.
In both the lenalidomide and bortezomib trials, the investigational agent produced
statistically significantly higher survival than dexamethasone alone.
The re-submission stated that comparison of these results across treatments suggests
a numerical difference of 4.6 months in the median survival for patients treated with
lenalidomide plus dexamethasone compared with bortezomib. The HR for the investigational
agents relative to dexamethasone does not differ.
During the evaluation an indirect comparison was performed, using the HR from Studies
009 and 010 combined and the HR from the APEX trial. The HR for this indirect comparison
is 1.00 (95%CI: 0.73 to 1.38). The clinical trial reports of Studies 009 and 010 did
not present a definition of a clinical significant difference for overall survival.
The 95% confidence intervals for the indirect comparison overlap with the HR for overall
survival of 0.77 found in both Studies 009 and 010 combined and the APEX trial. The
re-submission, as clarified in the Pre-Sub Committee Response, considered a HR of
0.77 to be statistically significant.
The PBAC noted the advice of the ESC that caution should be taken when interpreting
this indirect comparison because:
a. the overall survival in the dexamethasone arm in the APEX trial was shorter than in Studies 009 and 010,
b. the ability to cross-over in both trials from the dexamethasone arm to the active treatment arm,
c. the time of follow-up was different between the lenalidomide plus dexamethasone trials and the bortezomib trial.
The re-submission presented updated toxicity data. Although the overall incidence
of adverse events did not differ between lenalidomide plus dexamethasone and bortezomib,
the pattern is different: lenalidomide plus dexamethasone treatment appears to be
associated with more muscle cramps; bortezomib treatment appears to be associated
with significantly more diarrhoea, nausea, peripheral neuropathy, vomiting, pyrexia,
thrombocytopenia, cough, paraesthesia and bone pain.
The incidence of grade 3 or 4 neutropenia (RD 19.4%) and insomnia (RD 2.1%) was significantly
higher among lenalidomide plus dexamethasone treated patients, whereas the incidence
of peripheral neuropathy (RD -7%), thrombocytopenia (RD -15.8%) and anorexia (RD -3.0%)
was significantly higher among bortezomib treated patients.
Lenalidomide plus dexamethasone treatment was associated with higher incidences of
deep-vein thrombosis (7.8% vs. 3.4%), venous thromboembolic events (13.0% vs. 4.0%)
and pulmonary embolism (4.0% vs. 0.9%) than dexamethasone monotherapy. The publication
for bortezomib does not report the incidence of deep vein thrombosis, venous thromboembolic
events and pulmonary embolism associated with that treatment.
There were 12/343 (3.4%) reported cases of Grade 3/4 febrile neutropenia (FN) among
the lenalidomide plus dexamethasone treated patients. The publications for the APEX
trial do not report whether or not FN occurred, but both Jagannath 2006 and Kropff
2005 note no instances of that event.
9. Clinical Claim
The submission described lenalidomide plus dexamethasone as
non-inferior in terms of comparative effectiveness and having a
different safety profile compared to bortezomib.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The re-submission presented a cost analysis. The equi-effective
doses were estimated as lenalidomide 21.9 mg for 21 days per 28 day
cycle over 6.84 months and bortezomib 1.3 mg/m2 of body
surface area on day 1, 2, 8 and 11 of 21 day cycles over 4.39
months (6.37 cycles).
Lenalidomide is co-administered with dexamethasone at 40 mg on days
1 to 4, 9 to 12 and 17 to 20 of each 28 day cycle for the first
four cycles of therapy. From cycle 5 onwards, the schedule for the
dexamethasone dose was reduced to days 1 to 4 of every 28 day cycle
for 6.84 months.
The re-submission assumed for the cost-analysis that dexamethasone
is co-administered in 90% of bortezomib patients at a dose of 40 mg
on the days that bortezomib was infused, for 4.39 months.
The equi-effective doses presented in the re-submission for the
cost analysis were not the doses used in the clinical trials.
The re-submission included the following costs in the
cost-analysis:
- cost of drug treatment (lenalidomide, bortezomib and dexamethasone),
- costs for the treatment of Grade 3/4 adverse events which were significantly different between lenalidomide plus dexamethasone versus bortezomib treatment, and
- the cost of administration of bortezomib infusion.
The re-submission did not use the ITT population for calculating
the response rate. During the evaluation response rates using the
ITT population were used to calculate the average number of
cycles.
11. Estimated PBS Usage and Financial Implications
The incremental financial cost per year to the PBS was estimated in
the re-submission to be less than $10 million in Year 5, compared
with between $30-60 million in the previous submission.
The likely number of patients per year using lenalidomide was
estimated in the re-submission to be less than 10,000 in Year 5.
This number was reduced from the previous submission.
12. Recommendation and Reasons
The PBAC recommended the listing of lenalidomide for the treatment of patients with
relapsed/ refractory multiple myeloma for whom thalidomide therapy has failed or in
whom there is severe intolerance/ toxicity to thalidomide. Listing was recommended
on a cost minimisation basis with bortezomib with the equi-effective doses to be based
on 6 cycles of bortezomib, in line with the submission’s approach.
The Committee accepted the claim of non-inferiority of lenalidomide plus dexamethasone
in terms of comparative effectiveness compared to bortezomib based on the indirect
comparison. The Committee noted that overall survival may possibly favour lenalidomide
with dexamethasone, however there is uncertainty due to the indirect comparison, and
the differences in the trials used for comparison.
The PBAC accepted that lenalidomide used in combination with dexamethasone has a different
side effect profile from bortezomib. It was observed that the incidence of grade 3
or 4 neutropenia was significantly higher with lenalidomide plus dexamethasone treated
patients, and the incidence of peripheral neuropathy and thrombocytopenia was significantly
higher among bortezomib treated patients.
The Committee considered one of the key uncertainties in the pre-modelling studies
was the average number of bortezomib cycles assumed. The submission assumed 6.37 cycles,
however it was agreed that this was likely an overestimate as the ITT population from
the APEX trial was not used and the assumptions in the methodology overestimated the
number of cycles for partial responders and non-responders. The PBAC supported using
6 cycles of bortezomib, which was calculated using the ITT population in the APEX
trial with the same methodology as presented in the submission.
The other key area of uncertainty in the pre-modelling studies noted by the Committee
was the modification of the response rate to bortezomib, adjusting for response to
combination therapy with dexamethasone. The PBAC agreed that it was reasonable to
adjust the response to encompass combination with dexamethasone as this would more
closely align to the PBS use of bortezomib and accepted the factor of 1.2 presented
in the submission.
The PBAC considered that combination therapy of lenalidomide with bortezomib should
not be allowed on the PBS and noted the sponsor’s agreement to this in the pre-Sub-Committee
response. The Committee advised that the restriction should exclude the combination
treatment of lenalidomide with bortezomib. The PBAC also advised that patients receiving
lenalidomide prior to PBS listing will not be automatically grandfathered. Grandfathering
criteria are to be developed. The Committee also advised that the listing of lenalidomide
should be administered by written authority applications in a similar way to bortezomib.
Recommendation
LENALIDOMIDE, capsule, 5 mg, 10 mg, 15 mg and 25 mg
Restriction:
Section 100 (Highly Specialised Drugs Program)
NOTE:
Any queries concerning the arrangements to prescribe lenalidomide may be directed
to Medicare Australia on 1800 700 270 (hours of operation 8 a.m. to 5 p.m. EST Monday
to Friday).
Prescribing information (including Authority Application forms) is available on the
Medicare Australia website at www.medicareaustralia.gov.au.
Any queries concerning patients who are enrolled on the Lenalidomide Compassionate
program may be directed to Medicare Australia on 1800 700 270 (hours of operation
8 a.m. to 5 p.m. EST Monday to Friday). These patients must demonstrate they met initial
criteria prior to commencing treatment on the compassionate program and also demonstrate
they do not have progressive disease. Baseline and current pathology reports must
be submitted with the initial application.
Applications for authority to prescribe lenalidomide should be forwarded to:
Medicare Australia
Prior Written Approval of Specialised Drugs
Reply Paid 9826
GPO Box 9826
HOBART TAS 7001
Public and private hospital authority required
Initial PBS-subsidised treatment, as monotherapy or in combination with dexamethasone,
of multiple myeloma in a patient who has progressive disease, who has received at
least 1 prior therapy (other than thalidomide), who has undergone or is ineligible
for a primary stem cell transplant and who has experienced treatment failure after
a trial of at least four (4) weeks of thalidomide at a dose of at least 100 mg daily.
If the dosing requirement for thalidomide cannot be met, the application must state
the reasons why this criterion cannot be satisfied.
Thalidomide treatment failure is defined as:
- confirmed disease progression during or within 6 months of discontinuing thalidomide treatment; or
- severe intolerance or toxicity unresponsive to clinically appropriate dose adjustment.
Any queries concerning additional details about treatment failure may be directed
to Medicare Australia on 1800 700 270 (hours of operation 8 a.m. to 5 p.m. EST Monday
to Friday).
Progressive disease is defined as at least 1 of the following:
a. at least a 25% increase and an absolute increase of at least 5 g per L in serum M protein (monoclonal protein); or
b. at least a 25% increase in 24-hour urinary light chain M protein excretion, and an absolute increase of at least 200 mg per 24 hours; or
c. at least a 25% relative increase and at least a 10% absolute increase in plasma cells in a bone marrow aspirate or on biopsy; or
d. an increase in the size or number of lytic bone lesions (not including compression fractures); or
e. at least a 25% increase in the size of an existing or the development of a new soft tissue plasmacytoma (determined by clinical examination or diagnostic imaging); or
f. development of hypercalcaemia (corrected serum calcium greater than 2.65 mmol per L not attributable to any other cause).
Severe intolerance due to thalidomide is defined as unacceptable somnolence or sedation
interfering with activities of daily living.
Toxicity from thalidomide is defined as peripheral neuropathy (Grade 2 or greater,
interfering with function), drug-related seizures, serious Grade 3 or 4 drug-related
dermatological reactions, such as Stevens-Johnson Syndrome, or other Grade 3 or 4
toxicity.
Lenalidomide will only be subsidised for patients with multiple myeloma who are not
receiving concomitant PBS-subsidised bortezomib.
The authority application must be made in writing and must include:
1. a completed authority prescription form; and
2. a completed Multiple Myeloma Authority Application – Supporting Information Form,
which includes details of prior treatments including name(s) of drug(s) and date of
most recent treatment cycle and record of prior stem cell transplant or ineligibility
for prior stem cell transplant; details of thalidomide treatment failure; and details
of the basis of the diagnosis of progressive disease.
To enable confirmation by Medicare Australia of eligibility, current diagnostic reports
of the following are required:
(a) the level of serum monoclonal protein; and
(b) if Bence-Jones proteinuria is present, the results of 24-hour urinary light chain
M protein excretion..
If neither serum M protein or urine Bence-Jones protein are present in measurable
quantities, additional diagnostic reports are required, including:
(c) bone marrow aspirate and trephine; and
(d) if present, the size and location of lytic bone lesions (not including compression
fractures); or
(e) if present, the size and location of all soft tissue plasmacytomas by clinical
or radiographic examination i.e. MRI or CT-scan; or
(f) if present, the level of hypercalcaemia, corrected for albumin concentration;
or
(g) if present, the serum free light chain levels..
Results for (a) and (b) should be provided for all patients. Where the patient has
oligo-secretory or non-secretory multiple myeloma, (c) must be provided and if relevant
(d), (e) or (f). In patients with oligo-secretory or non-secretory multiple myeloma
with free light chain assays, (g) must be provided. Where 1 or more results cannot
be provided, the application must state the reason(s) these cannot be provided; and
3. duration of thalidomide and daily dose prescribed; and
4. a signed patient acknowledgement.
NOTE:
Patients receiving lenalidomide via the PBS must be registered in the RevAccess program.
Public and private hospital authority required
Continuing PBS-subsidised treatment, as monotherapy or in combination with dexamethasone,
of multiple myeloma in a patient who has previously been issued with an authority
prescription for lenalidomide and who does not have progressive disease.
Progressive disease is defined as at least 1 of the following:
a. at least a 25% increase and an absolute increase of at least 5 g per L in serum
M protein (monoclonal protein); or
b. at least a 25% increase in 24-hour urinary light chain M protein excretion, and
an absolute increase of at least 200 mg per 24 hours; or
c. at least a 25% relative increase and at least a 10% absolute increase in plasma
cells in a bone marrow aspirate or on biopsy; or
d. an increase in the size or number of lytic bone lesions (not including compression
fractures); or
e. at least a 25% increase in the size of an existing or the development of a new
soft tissue plasmacytoma (determined by clinical examination or diagnostic imaging);
or
f. development of hypercalcaemia (corrected serum calcium greater than 2.65 mmol per
L not attributable to any other cause).
Authority applications for continuing treatment may be made by telephone to Medicare
Australia on 1800 700 270 (hours of operation 8 a.m. to 5 p.m. EST Monday to Friday).
Pack size: 21
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
Celgene welcomes the recommendation of the PBAC for the listing of
Revlimid in relapsed/refractory multiple myeloma. The Sponsor
considers that the recent approval for the same indication by the
National Institute of Clinical Excellence in England and Wales
further supports the position adopted by the PBAC.
