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NICE guidance on bortezomib for induction therapy in multiple myeloma before high-dose chemotherapy and autologous stem-cell transplantation
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NICE guidance on bortezomib for induction therapy in multiple myeloma before high-dose chemotherapy and autologous stem-cell transplantation Stem-cell transplantation is the goldstandard treatment for multiple myeloma because it is associated with improved survival. The aim of induction therapy is to enable more people to have stem-cell transplantation successfully. The present standard induction therapy in the UK is the combination of cyclophosphamide, thalidomide, and dexamethasone. Bortezomib has a marketing authorisation for use ‘in combination with dexamethasone, or with dexamethasone and thalidomide for the induction treatment of adult patients with previously untreated multiple myeloma, who are eligible for high-dose chemotherapy with haemopoietic stem-cell transplantation’.1 On April 23, 2014, the National Institute for Health and Care Excellence (NICE) published guidance recommending bortezomib as an acceptable use of UK National Health Service resources within its marketing authorisation.2 Bortezomib was appraised under the single technology appraisal process. The manufacturer of bortezomib (Janssen, UK) submitted an evidence dossier on the clinical and costeffectiveness of the drug.2 This dossier was reviewed by an independent review group—Southampton Health Technology Assessment Centre.3 Committee meetings were attended by patient experts, clinical specialists, and manufacturer representatives. The key clinical-effectiveness evidence was from the open-label Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) and Intergroupe Francophone du Myelome (IFM) randomised controlled trials3 done in patients younger than 65 years with newly diagnosed and untreated www.thelancet.com/oncology Vol 15 May 2014
symptomatic multiple myeloma and measurable disease (serum or urine M protein, or both), who were eligible for autologous stem-cell transplantation. In the PETHEMA trial,3 patients were randomised to receive either bortezomib, thalidomide and dexamethasone or thalidomide and dexamethasone, both of which consisted of six cycles of 28 days, with each cycle including four infusions of bortezomib (1·3 mg/m²) and oral dexamethasone (40 mg), and oral thalidomide (up to 200 mg). Patients who received bortezomib had significant overall responses after induction compared with those receiving thalidomide and dexamethasone (85% vs 61%; p<0·001). This difference in treatment effect in patients achieving an overall response was maintained after transplantation (78% vs 57%; p<0·001).2 Patients receiving bortezomib also had significantly more postinduction and post-transplantation complete response than did those receiving the thalidomide-containing regimen. The IFM trial was an open-label study designed to compare the efficacy and safety of bortezomib plus dexamethasone with vincristine, doxorubicin, and dexamethasone. Treatment with bortezomib and dexamethasone consisted of four 21-day cycles of 1·3 mg/m2 of bortezomib and 40 mg of dexamethasone.4 People in the IFM trial who received bortezomib in combination with dexamethasone had significantly better overall responses after induction compared with those who received vincristine, doxorubicin, and dexamethasone (77% vs 61%; p<0·001); however, this difference was not maintained after stem-cell
transplantation (80% vs 74%; p=0·179). Progression-free survival was longer in patients in the bortezomibcontaining groups of the PETHEMA and IFM trials, but the difference was significant only in the PETHEMA trial (PETHEMA hazard ratio [HR] 0·65, 95% CI 0·45–0·92; p=0·015; IFM 0·88, 0·70–1·11; p value not reported). Median overall survival was not reached in either the PETHEMA trial (HR 0·80, 95% CI 0·48–1·34; p=0·393) or the IFM trial (0·8, 0·54–1·19; p value not reported). The manufacturer attempted to do an indirect comparison based on findings from the PETHEMA, Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA), Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON), IFM, and Medical Research Council (MRC) Myeloma IX trials to present an analysis comparing the bortezomib regimens with cyclophosphamide, thalidomide, and dexamethasone.2 However, the manufacturer stated that an indirect comparison with cyclophosphamide, thalidomide, and dexamethasone was not possible, and bortezomib and dexamethasone could not be compared with a thalidomide-containing regimen. The manufacturer submitted a Markov model evaluating the cost-effectiveness of bortezomib, thalidomide, and dexamethasone compared with thalidomide and dexamethasone. They also compared the cost-effectiveness of bortezomib and dexamethasone with vincristine, doxorubicin and dexamethasone. An assumption was that patients entered the model at the start of their induction therapy and thereafter entered one of three health states: complete response, partial response, or nonresponse. To model long-term survival,
Lancet Oncol 2014 Published Online April 23, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70184-6
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based on patients achieving postinduction responses, the manufacturer extrapolated overall survival data from the MRC Myeloma VII trial (as overall survival data from the PETHEMA and IFM trials were considered immature). The committee agreed that although there was uncertainty in the magnitude of overall survival associated with bortezomib, the drug’s effect on induction response could be associated with improved overall survival. However, the committee also emphasised that no evidence was available to compare the efficacy against cyclophosphamide, thalidomide, and dexamethasone— the standard induction treatment in the UK. The committee requested that the manufacturer undertake a careful comparison using single groups from relevant clinical trials, taking into account differences in trial design and baseline characteristics. The committee also requested that the manufacturer apply post-stem cell-transplantation response rates in the economic model rather than post-induction response rates, and that they explore data from the Alvares and Nordic Myeloma Study Group (NMSG) 5/94 studies to inform overall survival in the economic model.3 At the meeting in February, 2014, the committee considered responses to its preliminary guidance2 from consultees, commentators, the general public, and the manufacturer. In response to the consultation, the manufacturer updated its economic model for both bortezomib regimens to align it more closely to committee’s requests. On the basis of findings from the threshold analysis presented by the manufacturer, the committee
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was persuaded that a comparison of bortezomib, thalidomide, and dexamethasone with thalidomide and dexamethasone was a reasonable basis for its decision-making; this is because the addition of cyclophosphamide would have to add a clinically implausible level of benefit (almost double) before the incremental cost-effectiveness ratio (ICER) for bortezomib, thalidomide, and dexamethasone compared with cyclophosphamide, thalidomide, and dexamethasone increased to greater than £30 000 per qualityadjusted life year (QALY) gained. For the bortezomib and dexamethasone regimen, the committee considered results based on the manufacturer’s indirect comparison with cyclophosphamide, thalidomide, and dexamethasone, and on a direct comparison with vincristine, doxorubicin, and dexamethasone when thalidomide might not be suitable. The committee remained concerned that the modelling was subject to uncertainties, but acknowledged that bortezomib regimens had a clear advantage with respect to induction response, and that a link between improved response and survival was plausible. The committee was aware of the debilitating nature of the disease, particularly in people with clinically aggressive disease, with organ function at risk, or at risk of irreversible renal damage, who would benefit from a fast response associated with treatment with bortezomib. The committee considered and explored a range of ICERs with several studies included in the submissions, and concluded that, on balance, the ICERs for bortezomib, thalidomide, and dexamethasone
compared with thalidomide and dexamethasone, and for bortezomib and dexamethasone compared with cyclophosphamide, thalidomide, and dexamethasone, and with vincristine, doxorubicin, and dexamethasone, were likely to be below £30 000 per QALY gained. NICE issued a final appraisal determination stating the committee’s decision, and stakeholders were given the opportunity to request corrections of factual inaccuracies or to appeal against the Committee’s recommendations. NICE received no appeals or requests for factual amendment, and the final guidance was published on April 23, 2014.
*Christian Griffiths, Raisa Sidhu, Frances Sutcliffe, Andrew Stevens National Institute for Health and Care Excellence, Level 1A City Tower, Piccadilly Plaza, Manchester M1 4BT, UK christian.griffi[email protected] We declare that we have no competing interests. References 1 European Medicines Agency. Bortezomib CHMP public assessment report. June 27, 2013. http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Assessment_ Report_-_Variation/human/000539/ WC500147837.pdf (accessed April 23, 2014). 2 NICE. Multiple myeloma—bortezomib (induction therapy): final appraisal determination. March, 2014. http://guidance. nice.org.uk/TAG/319/FAD (accessed April 23, 2014). 3 Rosinol L, Oriol A, Teruel AI. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood 2012; 120: 1589–96. 4 Harousseau JL, Attal M, Avet-Loiseau H, 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: 4621–29.
www.thelancet.com/oncology Vol 15 May 2014
NICE guidance on bortezomib for induction therapy in multiple myeloma before high-dose chemotherapy and autologous stem-cell transplantation Stem-cell transplantation is the goldstandard treatment for multiple myeloma because it is associated with improved survival. The aim of induction therapy is to enable more people to have stem-cell transplantation successfully. The present standard induction therapy in the UK is the combination of cyclophosphamide, thalidomide, and dexamethasone. Bortezomib has a marketing authorisation for use ‘in combination with dexamethasone, or with dexamethasone and thalidomide for the induction treatment of adult patients with previously untreated multiple myeloma, who are eligible for high-dose chemotherapy with haemopoietic stem-cell transplantation’.1 On April 23, 2014, the National Institute for Health and Care Excellence (NICE) published guidance recommending bortezomib as an acceptable use of UK National Health Service resources within its marketing authorisation.2 Bortezomib was appraised under the single technology appraisal process. The manufacturer of bortezomib (Janssen, UK) submitted an evidence dossier on the clinical and costeffectiveness of the drug.2 This dossier was reviewed by an independent review group—Southampton Health Technology Assessment Centre.3 Committee meetings were attended by patient experts, clinical specialists, and manufacturer representatives. The key clinical-effectiveness evidence was from the open-label Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) and Intergroupe Francophone du Myelome (IFM) randomised controlled trials3 done in patients younger than 65 years with newly diagnosed and untreated www.thelancet.com/oncology Vol 15 May 2014
symptomatic multiple myeloma and measurable disease (serum or urine M protein, or both), who were eligible for autologous stem-cell transplantation. In the PETHEMA trial,3 patients were randomised to receive either bortezomib, thalidomide and dexamethasone or thalidomide and dexamethasone, both of which consisted of six cycles of 28 days, with each cycle including four infusions of bortezomib (1·3 mg/m²) and oral dexamethasone (40 mg), and oral thalidomide (up to 200 mg). Patients who received bortezomib had significant overall responses after induction compared with those receiving thalidomide and dexamethasone (85% vs 61%; p<0·001). This difference in treatment effect in patients achieving an overall response was maintained after transplantation (78% vs 57%; p<0·001).2 Patients receiving bortezomib also had significantly more postinduction and post-transplantation complete response than did those receiving the thalidomide-containing regimen. The IFM trial was an open-label study designed to compare the efficacy and safety of bortezomib plus dexamethasone with vincristine, doxorubicin, and dexamethasone. Treatment with bortezomib and dexamethasone consisted of four 21-day cycles of 1·3 mg/m2 of bortezomib and 40 mg of dexamethasone.4 People in the IFM trial who received bortezomib in combination with dexamethasone had significantly better overall responses after induction compared with those who received vincristine, doxorubicin, and dexamethasone (77% vs 61%; p<0·001); however, this difference was not maintained after stem-cell
transplantation (80% vs 74%; p=0·179). Progression-free survival was longer in patients in the bortezomibcontaining groups of the PETHEMA and IFM trials, but the difference was significant only in the PETHEMA trial (PETHEMA hazard ratio [HR] 0·65, 95% CI 0·45–0·92; p=0·015; IFM 0·88, 0·70–1·11; p value not reported). Median overall survival was not reached in either the PETHEMA trial (HR 0·80, 95% CI 0·48–1·34; p=0·393) or the IFM trial (0·8, 0·54–1·19; p value not reported). The manufacturer attempted to do an indirect comparison based on findings from the PETHEMA, Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA), Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON), IFM, and Medical Research Council (MRC) Myeloma IX trials to present an analysis comparing the bortezomib regimens with cyclophosphamide, thalidomide, and dexamethasone.2 However, the manufacturer stated that an indirect comparison with cyclophosphamide, thalidomide, and dexamethasone was not possible, and bortezomib and dexamethasone could not be compared with a thalidomide-containing regimen. The manufacturer submitted a Markov model evaluating the cost-effectiveness of bortezomib, thalidomide, and dexamethasone compared with thalidomide and dexamethasone. They also compared the cost-effectiveness of bortezomib and dexamethasone with vincristine, doxorubicin and dexamethasone. An assumption was that patients entered the model at the start of their induction therapy and thereafter entered one of three health states: complete response, partial response, or nonresponse. To model long-term survival,
Lancet Oncol 2014 Published Online April 23, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70184-6
563
News
based on patients achieving postinduction responses, the manufacturer extrapolated overall survival data from the MRC Myeloma VII trial (as overall survival data from the PETHEMA and IFM trials were considered immature). The committee agreed that although there was uncertainty in the magnitude of overall survival associated with bortezomib, the drug’s effect on induction response could be associated with improved overall survival. However, the committee also emphasised that no evidence was available to compare the efficacy against cyclophosphamide, thalidomide, and dexamethasone— the standard induction treatment in the UK. The committee requested that the manufacturer undertake a careful comparison using single groups from relevant clinical trials, taking into account differences in trial design and baseline characteristics. The committee also requested that the manufacturer apply post-stem cell-transplantation response rates in the economic model rather than post-induction response rates, and that they explore data from the Alvares and Nordic Myeloma Study Group (NMSG) 5/94 studies to inform overall survival in the economic model.3 At the meeting in February, 2014, the committee considered responses to its preliminary guidance2 from consultees, commentators, the general public, and the manufacturer. In response to the consultation, the manufacturer updated its economic model for both bortezomib regimens to align it more closely to committee’s requests. On the basis of findings from the threshold analysis presented by the manufacturer, the committee
564
was persuaded that a comparison of bortezomib, thalidomide, and dexamethasone with thalidomide and dexamethasone was a reasonable basis for its decision-making; this is because the addition of cyclophosphamide would have to add a clinically implausible level of benefit (almost double) before the incremental cost-effectiveness ratio (ICER) for bortezomib, thalidomide, and dexamethasone compared with cyclophosphamide, thalidomide, and dexamethasone increased to greater than £30 000 per qualityadjusted life year (QALY) gained. For the bortezomib and dexamethasone regimen, the committee considered results based on the manufacturer’s indirect comparison with cyclophosphamide, thalidomide, and dexamethasone, and on a direct comparison with vincristine, doxorubicin, and dexamethasone when thalidomide might not be suitable. The committee remained concerned that the modelling was subject to uncertainties, but acknowledged that bortezomib regimens had a clear advantage with respect to induction response, and that a link between improved response and survival was plausible. The committee was aware of the debilitating nature of the disease, particularly in people with clinically aggressive disease, with organ function at risk, or at risk of irreversible renal damage, who would benefit from a fast response associated with treatment with bortezomib. The committee considered and explored a range of ICERs with several studies included in the submissions, and concluded that, on balance, the ICERs for bortezomib, thalidomide, and dexamethasone
compared with thalidomide and dexamethasone, and for bortezomib and dexamethasone compared with cyclophosphamide, thalidomide, and dexamethasone, and with vincristine, doxorubicin, and dexamethasone, were likely to be below £30 000 per QALY gained. NICE issued a final appraisal determination stating the committee’s decision, and stakeholders were given the opportunity to request corrections of factual inaccuracies or to appeal against the Committee’s recommendations. NICE received no appeals or requests for factual amendment, and the final guidance was published on April 23, 2014.
*Christian Griffiths, Raisa Sidhu, Frances Sutcliffe, Andrew Stevens National Institute for Health and Care Excellence, Level 1A City Tower, Piccadilly Plaza, Manchester M1 4BT, UK christian.griffi[email protected] We declare that we have no competing interests. References 1 European Medicines Agency. Bortezomib CHMP public assessment report. June 27, 2013. http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Assessment_ Report_-_Variation/human/000539/ WC500147837.pdf (accessed April 23, 2014). 2 NICE. Multiple myeloma—bortezomib (induction therapy): final appraisal determination. March, 2014. http://guidance. nice.org.uk/TAG/319/FAD (accessed April 23, 2014). 3 Rosinol L, Oriol A, Teruel AI. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood 2012; 120: 1589–96. 4 Harousseau JL, Attal M, Avet-Loiseau H, 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: 4621–29.
www.thelancet.com/oncology Vol 15 May 2014