TA897 · reconsideration_of_cdf_guidance
Only for adults who have had just one previous line of treatment and either: (1) the previous treatment included lenalidomide, or (2) lenalidomide is unsuitable as a second-line treatment. Conditional on company providing it according to the commercial arrangement (simple discount patient access scheme).
Source documents
Interventions
Condition
Comparators
| Name | Type | Established | Committee preferred |
|---|---|---|---|
| bortezomib with dexamethasone | active drug | Yes | Yes |
| carfilzomib with dexamethasone | active drug | Yes | Yes |
| lenalidomide with dexamethasone | active drug | Yes | — |
| carfilzomib with lenalidomide and dexamethasone | active drug | Yes | — |
| bortezomib plus dexamethasone | active drug | Yes | Yes |
| carfilzomib plus dexamethasone | active drug | Yes | Yes |
| lenalidomide combination treatments | active drug | — | — |
Clinical trials
| Trial | Design | Phase | Pivotal |
|---|---|---|---|
| CASTOR | RCT | 3 | Yes |
| ENDEAVOR | RCT | — | — |
Economic model
ICER
Methodological decisions (17)
Whether lenalidomide combination treatments should be included as comparators for second-line treatment. Company submission focused on bortezomib and carfilzomib combinations; lenalidomide combinations not in scope but understood to be used in NHS practice for some patients.
Company: Focus on bortezomib plus dexamethasone and carfilzomib plus dexamethasone as comparators, aligned with NICE scope
Committee: Could not make recommendation for lenalidomide population because no evidence presented, though acknowledged some people would have lenalidomide combinations at second line in NHS
ICER impact: uncertain_direction
Lenalidomide combination treatments were not included as comparators in the scope of this appraisal; no evidence was submitted for lenalidomide
ICER impact: uncertain_direction
Subsequent treatment costs modelled using basket approach based on outdated CASTOR trial data rather than current NHS practice
Company: Applied one-off basket costs based on CASTOR trial; only included 1 subsequent line of treatment
ERG: Noted limitations of company approach
Committee: Subsequent treatment cost assumptions do not reflect current practice; lenalidomide plus dexamethasone likely overestimated; only one subsequent line insufficient
ICER impact: increases
Modelling the costs of subsequent treatments
ICER impact: uncertain_direction
Adjusting for subsequent treatment use in the NHS using IPCW analysis from CASTOR
Company: Used IPCW analysis to estimate adjusted HRs
ERG: Not explicitly stated but noted limitations of adjustment
Committee: IPCW analysis did not accurately adjust for subsequent treatment use in NHS; both adjusted and unadjusted HRs should be considered as bounds of clinical effectiveness
ICER impact: uncertain_direction
Network meta-analysis for comparison with carfilzomib plus dexamethasone using CASTOR and ENDEAVOR second-line subgroups
Company: Performed network meta-analysis using second-line subgroup data
ERG: Agreed with approach
Committee: Network meta-analysis was appropriate for decision making
ICER impact: uncertain_direction
Partitioned survival model with 3 health states versus alternative approaches
Company: Used partitioned survival model with progression-free, progressed disease, and death states
ERG: Agreed with company structure
Committee: Model structure is acceptable
ICER impact: negligible
Interpretation of SACT real-world data compared to CASTOR trial. SACT showed lower overall survival than CASTOR despite younger population characteristics being adjusted for. Committee noted SACT conducted mostly during COVID-19 pandemic with potential excess mortality impact.
Company: Performed matching-adjusted indirect comparison to adjust for baseline characteristics differences between CASTOR and SACT datasets; prognostic factors explored did not explain differences
Committee: SACT likely reflects true NHS experience but has limitations: mostly during COVID-19 pandemic, shorter follow-up, missing key prognostic data. Would prefer to see survival outcomes for people who entered SACT before March 2020.
ICER impact: decreases
Applicability of CASTOR trial results to NHS population given trial was global (16 countries, no English centres), conducted several years ago, and current multiple myeloma pathway significantly different. Previous treatment with bortezomib or daratumumab (both available at first line) and impact on second-line effectiveness.
Committee: Previous treatment with bortezomib or daratumumab at first line not expected to affect second-line effectiveness if used for finite time rather than until progression; gaps between remissions typically several years. CASTOR clinically appropriate for establishing relative effect.
ICER impact: uncertain_direction
Whether SACT real-world data better represents NHS population than CASTOR trial; impact of COVID-19 on survival outcomes
Company: Presented SACT scenarios using Weibull curve fitted to SACT data with relative treatment effects from CASTOR
ERG: Noted SACT data has limitations but supports relative treatment effects from trial
Committee: SACT data better represents NHS clinical practice than CASTOR; larger sample size than trial; preferred for absolute baseline event rates; COVID-19 impact uncertain
ICER impact: uncertain_direction
The effect of COVID-19 on the outcomes in the SACT dataset
ICER impact: uncertain_direction
Choice of parametric function for extrapolating survival curves beyond follow-up period
Company: Initially used various parametric curves; changed to Gompertz curve after technical engagement
ERG: Recommended using Gompertz curve
Committee: Gompertz curve was appropriate for extrapolating survival, allowing curves to diverge over time but may overestimate benefit of daratumumab
ICER impact: uncertain_direction
Whether relative treatment effects observed in CASTOR would hold when daratumumab plus bortezomib and dexamethasone used outside clinical trial setting
Company: Applied HRs from randomised trial to real-world data
ERG: Aligned with company approach
Committee: Likely that relative effect would hold in clinical practice but uncertainties remain
ICER impact: uncertain_direction
Adjusting the relative treatment effect from CASTOR to account for use of subsequent treatments not available in the NHS
Company: Not specified
ERG: Not specified
Committee: The adjusted and unadjusted HRs reflected the higher and lower bounds of clinical effectiveness
ICER impact: uncertain_direction
Adjustment for subsequent treatments not available in NHS. CASTOR trial showed 30% of people had daratumumab as subsequent treatment, but company adjusted analysis estimated 27% of second-line bortezomib plus dexamethasone group would have fourth-line daratumumab monotherapy. Committee believed most people progressing to fourth line without prior CD38 therapy would have daratumumab monotherapy.
Company: 27% of bortezomib plus dexamethasone group would receive fourth-line daratumumab monotherapy
Committee: Most people progressing to fourth line who had not had CD38 targeted therapy before would have fourth-line daratumumab monotherapy
ICER impact: increases
Whether subsequent daratumumab costs and clinical estimates are aligned in modelling
Company: Included fourth-line daratumumab costs and clinical estimates but misalignment between proportions
ERG: Noted the misalignment
Committee: Higher proportion of bortezomib plus dexamethasone patients had daratumumab costs modelled than were included in clinical estimates; biases cost-effectiveness estimates in favour of daratumumab
ICER impact: increases
Source of health-state utility values and whether low-level adverse events captured
Company: Used EQ-5D data from ENDEAVOR trial; applied disutilities based on grade 3 and 4 adverse events only
ERG: Not explicitly stated
Committee: Utility values from ENDEAVOR acceptable; grade 1 and 2 adverse events not included but more frequent in bortezomib plus dexamethasone arm; likely small underestimate of impact on quality of life
ICER impact: decreases
Evidence gaps
Commercial arrangement
Special considerations
Cross-references