Draft guidance consultation

Multiple myeloma is an incurable, relapsing and remitting cancer of plasma cells. Relapsed multiple myeloma refers to previously treated myeloma that has progressed. Refractory refers to multiple myeloma that shows no response to treatment or that has progressed on or within 60 days of the last treatment. The patient experts emphasised that multiple myeloma is a highly individual and complex cancer with a wide range of symptoms and variation in severity.They explained that the condition has a large psychological impact because of the constant possibility of relapse and the knowledge that with each relapse, the condition is more difficult to treat and options become more limited. The patient experts explained that the condition can have a large impact on quality of life, affecting all aspects of life for both the individual and their carers. The committee acknowledged that multiple myeloma is a chronic, incurable, highly individual condition, that can have a negative impact on quality of life for people with the condition and their families and carers.

The clinical experts agreed with the EAG's clinical advisers that:

• the treatment pathway, although representative of current NHS practice, is evolving

• most people would have a daratumumab-containing regimen at first line, which is proving to be effective. But the impact of previous daratumumab treatment on overall survival in subsequent lines of treatment is not known.

The clinical-effectiveness evidence for Bel‑Pom‑Dex came from DREAMM-8, an ongoing, phase 3, international, randomised, open-label trial. It was stratified by prior bortezomib, prior anti-CD38 therapy (such as daratumumab) and line of treatment. It included people 18 years or over with relapsed or refractory multiple myeloma, who had 1 or more lines of treatment including a lenalidomide-containing regimen. People in the trial were randomised to have Bel‑Pom‑Dex (n=155) or pomalidomide plus bortezomib and dexamethasone (from now, Pom‑Bor‑Dex; n=147). There was no treatment crossover. The company used data from the full intention-to-treat (ITT) population, who had treatment at second line (53%), third or fourth line (35%) and beyond (12%). The primary outcome was progression-free survival as assessed by an independent review committee that was blind to treatment group allocation.

The committee noted that the average age of people in DREAMM-8 was about 66 years. This was younger than people seen in the NHS, where the average age on diagnosis is usually around 75 years (see section 3.2). The committee noted that about half the population had treatment at later lines than the company's second-line positioning of Bel‑Pom‑Dex. It noted that only about 25% of the population had previously had daratumumab and there were no people of Black African or Caribbean ethnicity. In terms of generalisability of the results, the clinical experts mainly had concerns about the lower proportion having had daratumumab in DREAMM-8 compared with about 50% who would have it in the NHS. The committee questioned the impact of refractoriness to daratumumab on the clinical effectiveness of Bel‑Pom‑Dex. The clinical experts explained that there is no data, but generally, if the condition is refractory, outcomes are worse, but that this would apply to Bel‑Pom‑Dex and any comparator. The committee recalled that the clinical experts suggested that prior belantamab mafodotin treatment would likely not affect the clinical effectiveness of other BCMA agents at later lines of treatment (see section 3.3). This was inconsistent with the clinical experts' suggestion that prior daratumumab would affect the clinical effectiveness of Bel‑Pom‑Dex and other treatments at later lines. The company explained that progression-free survival was consistent for daratumumab-exposed and refractory subgroups compared with the ITT population (see section 3.7).

The company did Bayesian network meta-analyses using Markov chain Monte Carlo simulations to estimate the effectiveness of Bel‑Pom‑Dex compared with the following second-line options in a lenalidomide-exposed population:

• Car‑Dex

• Dar‑Bor‑Dex

• Sel‑Bor‑Dex (when the condition was also refractory to daratumumab).
  
  The company used fixed-effects models in its base case because results were similar across the fixed- and random-effects models. The committee noted that although the point estimates may have been similar, the confidence intervals may have been wider with the random-effects models. The EAG considered that the company's network meta-analyses were at high risk of bias because:

• The populations of the included trials were variable, including different lines of treatment and levels of exposure to lenalidomide and daratumumab.

• The DREAMM-8 data, particularly for overall survival, was immature (see section 3.7).

• There was limited reporting of the trials' baseline characteristics, which made it difficult to assess between-study heterogeneity and the assumptions of transitivity and inconsistency.

• For some comparator trials, the proportional hazards assumption for progression-free and overall survival may not have held.

• The analyses had not been adjusted for treatment-effect modifiers, specifically prior line of treatment, Eastern Cooperative Oncology Group Performance Status, and International Scoring System stage.

• The analyses had not accounted for the impact of subsequent treatments on overall survival, including whether subsequent treatments in the trials represented NHS practice.

• The company's hazard ratio (HR) for overall survival (HR 0.76; 95% CI 0.62 to 0.93) from the OPTIMISMM trial – the common comparator trial investigating Pom‑Bor‑Dex compared with bortezomib plus dexamethasone (from now, Bor‑Dex) that linked DREAMM-8 to the rest of the network – lacked credibility.
  
  The company explained that it had used the HR of 0.76 because the analysis that generated this result had been adjusted for subsequent treatments. The company explained that the adjustment was methodologically necessary and appropriate, because it accounted for the high rates of unintended crossover of people between the trial groups. The company explained that 79% in the Bor‑Dex group and 68% in the Pom‑Bor‑Dex group had subsequent treatments. More than 66% of people in the Bor‑Dex group had pomalidomide as a subsequent treatment. It explained that this pomalidomide crossover was unique to OPTIMISMM and that adjusting for subsequent treatments may not be appropriate for other trials in the network. The committee noted that OPTIMISMM's publication states that adjustments were made for any subsequent treatments, not only for pomalidomide crossover.
  
  The EAG highlighted that the company's preferred HR was sourced from an unpublished conference presentation. The EAG explained that the HR had been generated from a pre-planned exploratory overall-survival analysis using a Cox proportional hazards model with subsequent treatment as a time-dependent covariate and adjusting for stratification factors. The committee noted that the approach used to adjust for subsequent treatment is not preferred because it is associated with a high risk of bias (Morden et al. 2011). The EAG highlighted that there was a final ITT analysis in a published conference abstract, which reported an unadjusted HR of 0.94 (95% CI 0.77 to 1.15). It highlighted that the company provided limited information about the adjustment applied in OPTIMISMM and its impact on other trials in the network. It explained that the effect of subsequent treatments on overall survival was likely important as shown by the adjusted results being statistically significant, whereas the ITT results were not. It explained that using the unadjusted HR of 0.94 would likely have led to all the HRs in the network meta-analysis being closer to 1, altering the results of the network meta-analysis.
  
  The company could not provide details about the adjustment method used in OPTIMISMM and confirmed that it had not provided a network meta-analysis using the unadjusted HR. It highlighted that adjusted HRs were only used in trials in which there was unintended crossover and explained that there were 2 trials affected, OPTIMISMM and CANDOR (which compared Car‑Dex with daratumumab plus carfilzomib and dexamethasone).
  
  The committee queried whether the group in OPTIMISMM having Bor‑Dex and then pomalidomide represented NHS clinical practice. The clinical experts thought it did. The committee recalled that in the CASTOR trial which compared Dar‑Bor‑Dex with Bor‑Dex, most people had pomalidomide as subsequent treatment, but this had not been adjusted for in its analyses.
  
  The committee noted that subsequent treatments are important in understanding overall survival. It considered that the same approach to subsequent treatments should be applied to all the trials in the network where possible. It acknowledged the importance of OPTIMISMM given that it includes the common treatment linking Bel‑Pom‑Dex with all the comparators in the decision problem. It noted the limited details provided by the company about the adjustment method used in the OPTIMISMM analysis. It would have preferred to see detailed information about the adjustment method used in OPTIMISMM, and where relevant, approaches to subsequent treatment for all other trials in the network. It considered that the unadjusted HR of 0.94 represented NHS clinical practice, and it would prefer to have seen a scenario analysis using this HR. The committee acknowledged the other methodological limitations of the network meta-analyses and noted that the uncertainty of the results would be considered in its decision making.

The EAG clinical advisers suggested that the high number of eye-related adverse events with belantamab mafodotin may affect health-related quality of life. They highlighted that eye-related effects can continue even after treatment is stopped. They noted that as part of the marketing authorisation, people would need ophthalmic examinations (such as visual acuity, slit lamp) before each of the first 4 belantamab mafodotin doses (once every 4 weeks), and be continually monitored during treatment as clinically indicated. They considered that this level of monitoring could be burdensome to people with the condition and their carers, and could be a substantial burden on NHS resources. The company explained that despite a higher incidence of eye-related adverse events in the Bel‑Pom‑Dex group, there was no difference in overall health-related quality of life as measured by the EQ-5D-3L between the treatment groups over time in DREAMM-8. The EAG highlighted that the generic EQ-5D-3L may not adequately capture health-related quality-of-life changes. It highlighted that there is a vision 'bolt-on', the EQ-5D-V, which the company had not used (see section 3.19). The clinical experts explained that across belantamab mafodotin clinical trials, the EQ-5D had not shown a detriment to health-related quality of life because of eye-related adverse events. But they explained that with a more sensitive tool such as the Ocular Surface Disease Index, some variation in health-related quality of life may be seen.

The patient expert explained that eye-related adverse events had affected their ability to read and the distance at which they could watch television. But they explained that they are still able to drive according to DVLA standards. They explained that these eye-related adverse events do not cause pain, anxiety or depression, or affect their mobility. They said that the eye-related adverse events are more of an inconvenience, because their lens prescription does not match their spectacles. They explained that their ophthalmologist does not recommend renewing the spectacles while on treatment as there would likely be more changes to their vision. The clinical experts explained that dose changes to reduce eye-related adverse events can help to maintain health-related quality of life.

The committee noted that almost half of the people having belantamab mafodotin in DREAMM-8 had eye-related adverse events (see section 3.8), but that the impact varied. It concluded that eye-related adverse events and their impact should be appropriately captured in the economic model.

The company provided a cohort-based partitioned survival model to estimate the cost effectiveness of Bel‑Pom‑Dex compared with Car‑Dex, Dar‑Bor‑Dex and Sel‑Bor‑Dex. The model included 4 health states: progression free on treatment, progression free off treatment, progressed disease, and death. The probability of being in each health state was calculated using extrapolated progression-free survival, overall survival and time-to-treatment-discontinuation curves, using standard parametric distributions fitted to DREAMM-8 Kaplan–Meier data. People started in the progression-free on-treatment health state at second line. The model included a cycle length of 1 week with no half-cycle correction over a lifetime horizon of 33.9 years. The starting age of 66.1 years in the model was based on DREAMM-8. The committee was aware of the Systemic Anti-Cancer Therapy (SACT) dataset that had collected data on overall survival and treatment duration from clinical practices in England since 2019 for 1 of the comparators, Dar‑Bor‑Dex (see TA897). It considered that the starting age in the model should reflect NHS practice and should be based on the SACT dataset. It concluded that the company's model structure was acceptable for decision making.

In its base case, the company modelled differences in overall survival between treatments based on extrapolated data from DREAMM-8 Kaplan–Meier curves and the indirect treatment comparisons. In the EAG's base case, it assumed no overall-survival differences between treatments and used the company's overall-survival extrapolation for Bel‑Pom‑Dex from DREAMM-8 for all the comparators. The EAG thought that this was justified because the overall-survival data from DREAMM-8 was immature and uncertain. And there were no statistically significant overall-survival differences for Bel‑Pom‑Dex compared with any of the comparators from the network meta-analysis (see section 3.6).The EAG noted that an overall-survival benefit would likely include the varying effects of subsequent treatments on overall survival after disease progression.

The company argued that an overall-survival benefit was plausible. This was because of the improvement seen in the surrogate measures of progression-free survival and minimal residual disease negativity, which was 5 times higher in the Bel‑Pom‑Dex group compared with the Pom‑Bor‑Dex group in DREAMM-8. It explained that a similar trend was seen with Bel‑Bor‑Dex (ID6212), which showed statistically significant differences in overall survival after improvements in progression-free survival and minimal residual disease negativity compared with Dar‑Bor‑Dex. The clinical experts agreed that there is a strong correlation between minimal residual disease negativity and overall-survival benefit but noted that an overall-survival benefit from DREAMM-8 had not yet been shown. One clinical expert noted that OPTIMISMM did not show overall-survival benefit in a lenalidomide-refractory population and emphasised that mature data is needed to ensure that there is a difference in overall survival.

The company explained that it had provided a scenario analysis in its submission in which overall survival was extrapolated assuming a surrogacy between progression-free survival and overall-survival outcomes. HRs (reflecting the surrogacy between progression-free survival and overall survival) for each comparator were applied to the progression-free survival curve of each comparator to estimate overall survival for each comparator. A Bel‑Pom‑Dex progression-free survival curve was used as the baseline treatment curve. The EAG noted that the overall-survival estimates for both Bel‑Pom‑Dex and Pom‑Bor‑Dex were above the estimates from DREAMM-8 at 12 and 24 months, and so lacked face validity. The EAG reiterated the additional issue of the methodological limitations of the network meta-analysis (see section 3.6), which would not be resolved with more mature overall-survival data from DREAMM-8.

The committee considered that the company's scenario analysis did not reduce the uncertainty about the overall-survival benefit. It agreed with the EAG that there would likely still be uncertainties in the relative estimates of Bel‑Pom‑Dex compared with the relevant comparators because of the methodological limitations of the network meta-analysis. It acknowledged the strong correlation between minimal residual disease negativity and overall survival, but agreed that a strong correlation alone is not sufficient to assume surrogacy. It considered that there was high uncertainty about the size and direction of the overall-survival benefit of Bel‑Pom‑Dex compared with Car‑Dex, Dar‑Bor‑Dex and Sel‑Bor‑Dex. To address the uncertainty in the relative estimates of overall survival, it would also have preferred to see scenario analyses using matching-adjusted indirect comparisons (MAIC) for all the comparators. And it reiterated that it would have preferred to see a scenario analysis using estimates from the network meta-analysis that included the published HR of 0.94 from OPTIMISMM (see section 3.6).

The committee recalled the issue of generalisability of the population of DREAMM-8 to the company's target population in the NHS, in terms of being younger and only 53% having treatment at second line (see section 3.5). For the base case, it would have preferred to see an analysis in which the overall-survival data from SACT for Dar‑Bor‑Dex was used to estimate the absolute baseline curve, with the relative effects of the comparators applied from the network meta-analysis. The committee considered that neither the company's modelling of overall survival nor the EAG's assumption of no differential overall-survival benefit were aligned with its preferred assumptions. It had serious concerns about the credibility of the company's estimates of long-term overall survival and recalled that no overall-survival benefit for Bel‑Pom‑Dex over its comparators had been shown (see section 3.7). So, in the absence of evidence of differential overall survival and concerns about the company's overall-survival modelling, it preferred to apply the EAG's base case that assumed no difference in overall survival among the treatments.

The summary of product characteristics states that belantamab mafodotin should be given in a 4-week cycle, starting at 2.5 mg/kg once in cycle 1 and then decreased to 1.9 mg/kg once every 4 weeks from cycle 2 until progression or unacceptable toxicity. Clinicians may increase the time between doses from 8 weeks up to 6 months to reduce eye-related adverse events. It was aware that there are restrictions on funding for breaks in treatment. The Cancer Drugs Fund lead confirmed that the treatment break policy for adverse events is normally 6 weeks, but may extend to up to 3 months for immunotherapy. They explained that should Bel‑Pom‑Dex be recommended, a treatment-interruption break of up to 6 months would be allowed. The clinical experts explained that in the compassionate-use programme for belantamab mafodotin, most treatment interruptions were less than 6 months. They agreed a threshold of 6 months would be adequate. The committee concluded that a 6-month treatment interruption should be allowed for eye-related adverse events with belantamab mafodotin.

In its base case, the company assumed the acquisition cost of pomalidomide would be reduced because of the availability of generic alternatives. The company considers that the assumed percentage reduction is confidential and so it cannot be reported here. The Cancer Drugs Fund lead advised that it is likely that the cost of pomalidomide would be higher than that assumed by the company. They explained that the price should be available before the marketing authorisation for Bel‑Pom‑Dex has been granted. After the committee meeting, the price of pomalidomide through the Medicines Procurement and Supply Chain framework became available. These prices are commercial in confidence and cannot be reported here. The EAG provided revised confidential cost-effectiveness estimates using the updated price for pomalidomide. The committee acknowledged that there may be variation in the acquisition price of generic pomalidomide. It concluded that the price of pomalidomide should reflect prices that are available to the NHS at the time of writing, and preferred to use the revised cost-effectiveness estimates provided by the EAG.

In its base case, the company used different approaches to estimate medication use for belantamab mafodotin compared with the other treatment options. It used individual patient data (IPD) from DREAMM-8 to estimate doses of belantamab mafodotin. For all other medicines including pomalidomide and dexamethasone, the company based medication use on the summary of product characteristics and a constant RDI to capture dose modifications, sourced from the publications of key trials. The company explained that it had used the IPD data for belantamab mafodotin to account for its unique time-varying dose delays. It explained that this was not done for other medicines because their RDIs were high (ranging from 92% to almost 100%) compared with belantamab mafodotin, the RDI of which was much lower. The EAG agreed that using IPD provided a more accurate estimate of costs for belantamab mafodotin and would be the preferred approach for all treatments. But it considered a consistent approach should have been adopted across all treatments. So, it provided a scenario analysis in which RDI-based costs were used for all treatments. This analysis showed that the total cost of belantamab mafodotin increased considerably (the company considers the exact figure to be confidential and so it cannot be reported here). The committee acknowledged the company's concerns about using the RDI for belantamab mafodotin and understood its rationale for preferring the IPD. It noted that the company had access to IPD for pomalidomide, bortezomib and dexamethasone from DREAMM-8, and also Dar‑Bor‑Dex from ID6212. The committee would have preferred to see a scenario analysis in which all available IPD was used to estimate medication use and costs to provide reassurance on the consistency of the RDI-based costs for the comparators.

In its base case, the company included a one-off cost for up to 2 lines of subsequent treatments following disease progression after second-line treatment. It assumed that people would stay on subsequent treatments for a median of 9 months, in line with the median overall survival for multiple myeloma at third line and beyond shown in Kumar et al. (2012). It assumed that the same proportion of people would start third-line (81%) and fourth-line (34%) treatment based on Raab et al. (2019). The committee questioned the validity of these studies, given their age and that the treatment pathway for multiple myeloma has progressed with many more options now being available. The company used the average proportions of subsequent treatment options provided by 3 clinical experts to inform the distribution of subsequent treatments. At third line, included options were Sel‑Bor‑Dex (63.3% to 66.7%) and Pan‑Bor‑Dex (33.3% to 100%). At fourth line, included options in order of preference were Pom‑Dex (81.1% to 83.3%), daratumumab monotherapy (16.7%) and Pan‑Bor‑Dex (2.1% to 2.2%). The EAG thought that the company's approach to modelling subsequent treatments was acceptable. The committee recalled that the company had stated that it was unlikely daratumumab monotherapy would be used at fourth line, and that other BCMA agents such as teclistamab may be used (see section 3.2). It had concerns about the old studies used to inform the modelling of subsequent treatments. It considered that data collected from SACT may better reflect subsequent treatments used in the NHS. It would have preferred to see scenario analyses in which SACT data was used to inform the modelling of subsequent treatments and teclistamab was included as a fourth-line option.

In its base case, the company assumed that people having Bel‑Pom‑Dex would be seen by an ophthalmologist for only the first 4 treatment cycles as per the summary of product characteristics, at a resource use per model cycle of 0.33. The company thought that this was likely to be an overestimate given that dose delays are common and so people would likely see an ophthalmologist fewer than 4 times over the first 4 treatment cycles (see section 3.7). The Cancer Drugs Fund lead explained that the ophthalmic monitoring needed for belantamab mafodotin would likely be burdensome for ophthalmology departments in the NHS, which have long waiting lists. They explained that delays in implementation would be likely. They highlighted that everyone must have an ophthalmic eye exam before each of the first 4 doses of belantamab mafodotin, and subsequent monitoring in the event of eye-related adverse events. They explained that the mechanism of delivery of this monitoring service and method of communication between ophthalmology departments or community services and oncologists were unclear. The clinical experts highlighted that about 30 to 40 hospitals took part in the compassionate-use scheme for belantamab mafodotin, and so hospitals have a pathway in place for eye examinations. The company explained that between 2018 and 2024, over 100 NHS sites administered belantamab mafodotin in different settings. It is exploring the option of supporting people through access to community-based ophthalmology at the point of recommendation.

The committee recalled that about 50% of people in DREAMM-8 experienced eye-related adverse events (see section 3.8). It was aware that the company had included a one-off cost for keratopathy, blurred vision and dry eyes using incidence rates from DREAMM-8. The EAG highlighted that the proportion of people having grade 3 eye-related adverse events in the model was lower than that reported in DREAMM-8. It noted that the cost for the eye-related adverse event included 1 hospitalisation. It considered this cost to be plausible given that a change in treatment for eye-related adverse events would be to stop or reduce the dose of belantamab mafodotin and allow the adverse event to resolve, possibly with some ointments. The committee considered that there was uncertainty about whether the cost of eye-related adverse events had been adequately accounted for in the model because it had not included continued monitoring until resolution of eye-related adverse events. So, the cost of monitoring with belantamab mafodotin was likely to be underestimated. It concluded that the base case should include the cost of monitoring eye-related adverse events using hospital-based ophthalmology services, with a scenario analysis using the community-based ophthalmology services proposed by the company.

In its base case, the company assumed wastage on 100% of administrations including tablets, and no vial sharing. In its base case, the EAG considered that wastage of tablets (pomalidomide, selinexor and dexamethasone) should be excluded. This is because these medicines come in tablet sizes that allow reductions from the recommended dose; so doses can be lowered without wastage. The company agreed that it was plausible that there may be no wastage of tablets. The EAG explained that its clinical advisers suggested that there would likely be some vial sharing, although the extent of sharing is unknown. The clinical experts explained that while measures are taken to give treatment to people having the same medicines on the same day to maximise vial sharing, there is still some wastage. The committee concluded that no vial sharing should be included in the base case given the lack of information on its extent in clinical practice. It concluded that wastage of tablets should be excluded because they will likely be re-used in future cycles. The committee noted that the EAG's base case included both these assumptions.

In its base case, the company used EQ‑5D‑3L data from DREAMM-8 to derive health-state utilities. It assumed that health-related quality of life in the 'progression-free on-treatment' health state varied by treatment. For all comparators, it assumed that the utility value for the 'progression-free on-treatment' health state was the same as the utility value from the Pom‑Bor‑Dex group in DREAMM-8. The company used a higher utility value for the Bel‑Pom‑Dex group than the comparators for the 'progression-free on-treatment' health state. For the 'progression-free off-treatment' health state, the company used the pooled 'progression-free on-treatment' utility value and applied it to all treatments. For the 'progressed-disease' health state, the company used the pooled utility value from the Pom‑Bor‑Dex group and Bel‑Pom‑Dex group in DREAMM‑8 and applied it to all treatments. The company considers the values to be confidential and so they cannot be reported here.

The EAG thought it implausible for belantamab mafodotin to have a higher 'progression-free on-treatment' utility value than its comparators given the eye-related adverse events, likely not captured by the generic EQ-5D-3L (see section 3.8). It also thought that the pooled 'progression-free off-treatment' and 'progressed-disease' utility values were not appropriate because they included data from the Pom‑Bor‑Dex group, which was not a relevant comparator. The EAG noted that the DREAMM-8 data comprised a population in which only 53% had treatment at second line. So, the EAG preferred to use the company's scenario that applied utility values from one of the comparators, Dar‑Bor‑Dex (see TA897). The EAG noted that these utility values were derived from a fully second-line population, and applied them to all treatments. For the 'progression-free on and off-treatment' health states it applied a utility value of 0.737, and for the 'progressed-disease' health state it applied a value of 0.665, which it noted was similar to the value derived from DREAMM-8.

The company had explained that despite a higher incidence of eye-related adverse events in the Bel‑Pom‑Dex group, there was no difference in overall health-related quality of life as measured by the EQ-5D-3L between the treatment groups over time in DREAMM-8 (see section 3.8). The company explained that it modelled a treatment-specific progression-free on-treatment utility because of a statistically significant coefficient in the linear regression utility model. The committee acknowledged this but highlighted that there was no interaction term between Bel‑Pom‑Dex and the progression-free health state. It explained that the interaction term would be necessary to claim that quality of life is different with a given treatment in a given state. It noted that the company had also fitted a simpler model that did not assume a difference by treatment, and this had an objectively better fit to the data (judged by quasi-likelihood under the independence model criterion). The committee queried whether it would be plausible to have a better health-related quality of life by only having Bel‑Pom‑Dex compared with other treatments, before experiencing longer progression-free survival. The clinical experts explained that based on DREAMM-8, people had a deeper response on Bel‑Pom‑Dex given every 10 to 12 weeks compared with Pom‑Bor‑Dex that was given more frequently, and so a better health-related quality of life was plausible. But, they acknowledged that although belantamab mafodotin has limited side effects, issues of eye-related adverse events may affect health-related quality of life. The committee was aware that the company had also presented a scenario using DREAMM-8 pooled values in which no differential effect of treatment on health-state utilities was applied. It considered that there was not strong evidence to justify applying a higher 'progression-free on-treatment' health-state utility value for belantamab mafodotin than its comparators. It concluded that it preferred the EAG's approach that used the same utilities derived from a wholly second-line population, regardless of treatment.

In its base case, the company includedgrade 3+ treatment-emergent adverse events that occurred in at least 5% of people in DREAMM-8 and respective trials for the comparators. For non-eye-related adverse events, it applied a one-off disutility in the first cycle of the model. For eye-related adverse events, the company included keratopathy, blurred vision and dry eyes event rates per model cycle. These eye-related adverse events only affected people having belantamab mafodotin and the company assumed that any disutility was already captured in the generic EQ-5D-3L (see section 3.8). The committee noted that the company had applied a disutility for eye-related adverse events for the evaluation of Bel‑Bor‑Dex (ID6212). The committee recalled the discussion around the responsiveness of the EQ-5D-3L in assessing the impact of eye-related adverse events on health-related quality of life, and the availability of the vision bolt-on, EQ-5D-V. The vision bolt-on asks respondents to describe their vision on a scale of 'no problems', 'some problems' or 'extreme problems'. Based on feedback from the patient expert, the committee considered that the EQ-5D-3L in DREAMM-8 would have likely captured the impact of eye-related adverse events on health-related quality of life, given the frequency of assessments. But, it recalled the clinical experts' suggestion that other vision-specific assessment tools may better capture changes in health-related quality of life (see section 3.9). It considered that the extent to which the EQ-5D-3L captures the impact of vision loss on quality of life is uncertain. The committee preferred to use the same health-state utility values irrespective of treatment (see section 3.18). It noted that disutility was applied to non-eye-related adverse events. It would have preferred to see a scenario in which the disutility of eye-related adverse events had also been applied.

The committee noted that neither the company's nor the EAG's base case included all its preferred assumptions, which were:

• to use the starting age based on the SACT dataset (see section 3.10)

• for overall-survival benefit, to use the overall-survival data from SACT for Dar‑Bor‑Dex to estimate the absolute baseline curve, with the relative effects of the comparators applied from an updated network meta-analysis that addresses the methodological issues highlighted (in particular, the approach used for subsequent treatments; see sections 3.6 and 3.11)

• to model a maximum dose interruption interval of 6 months for belantamab mafodotin (see section 3.12)

• to use the acquisition cost of pomalidomide from the Medicines Procurement and Supply Chain framework (see section 3.13)

• to include the cost of monitoring eye-related adverse events using hospital-based ophthalmology services (see section 3.16)

• to assume no vial sharing (see section 3.17)

• to exclude wastage of tablets (see section 3.17)

• to apply the EAG's approach that used the same utilities derived from a wholly second-line population, regardless of treatment (see section 3.18).

NICE's manual on health technology evaluations notes that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. But it will also take into account other aspects including uncaptured health benefits. The committee noted the high level of uncertainty, specifically related to the:

• generalisability of the population of DREAMM-8 to the company's target population in the NHS, in terms of:

  • the trial population being younger

  • there being no one of Black African or Caribbean ethnicity

  • only 53% of people having treatment at second line

  • only 25% of people having daratumumab-refractory multiple myeloma (see section 3.5)

• indirect treatment comparisons and their methodological limitations (see section 3.6)

• clinical effectiveness of belantamab mafodotin (see sections 3.7 and 3.8)

• credibility of HRs derived from the network meta-analyses, particularly for overall survival and its impact on assumptions of overall-survival benefit (see sections 3.6 and 3.11)

• estimation of medication use and related drug costs for all treatments (see section 3.14)

• modelling of subsequent treatments (see section 3.15)

• cost of monitoring eye-related adverse events for belantamab mafodotin (see section 3.16).
  
  So, the committee concluded that an acceptable ICER would be around £20,000 per QALY.

The committee recalled that people with multiple myeloma and clinicians would welcome the option of having Bel‑Pom‑Dex at later lines (see section 3.4). It noted that there were many areas of uncertainty (see section 3.21) and would like to see clarification on:

• the adjustment method undertaken in OPTIMISMM and where relevant, approaches to subsequent treatment for all other trials in the network (see section 3.6)

• the evidence of clinical effectiveness of Bel‑Pom‑Dex in the company's target second-line population (see section 3.7)

• the impact of dose modifications (reductions, delays or interruptions because of eye-related adverse events) of belantamab mafodotin on its clinical effectiveness (see sections 3.7 and 3.8)

• the company's statement that it is exploring the option of supporting people with access to community-based ophthalmology at the point of recommendation (see section 3.16).
  
  The committee also requested the following analyses:

• network meta-analyses using data specific to the company's target second-line population (see section 3.7)

• analyses including Kaplan–Meier plots comparing progression-free survival in people having Bel‑Pom‑Dex treatment at 8 and 12 weekly intervals, to assess the impact of dose interruptions (see section 3.8)

• a base-case analysis using overall-survival data from SACT for Dar‑Bor‑Dex to estimate the absolute baseline curve, with the relative effects of the comparators applied from an updated network meta-analysis that addresses the methodological issues highlighted; in particular, the approach used for subsequent treatments (see sections 3.6 and 3.11)

• a scenario analysis using the unadjusted overall-survival HR of 0.94 from OPTIMISMM in the network meta-analysis (see sections 3.6 and 3.11)

• a scenario analysis in which all available IPD is used to estimate medication use and costs for all treatments (see section 3.14)

• a scenario analysis in which SACT data is used to inform the modelling of subsequent treatments (see section 3.15)

• scenario analyses in which teclistamab is included as a fourth-line option for subsequent treatments (see section 3.15)

• a base-case analysis that includes the cost of monitoring eye-related adverse events using hospital-based ophthalmology services (see section 3.16)

• a scenario analysis in which the cost of monitoring eye-related adverse events is provided using the community-based ophthalmology services as proposed by the company (see section 3.16)

• a scenario analysis in which the disutility of eye-related adverse events is applied (see section 3.19).

The committee considered the cost effectiveness of Bel‑Pom‑Dex compared with Car‑Dex, Dar‑Bor‑Dex and Sel‑Bor‑Dex at second line. It concluded that because of the uncertainties in the economic model and clinical evidence, it was not possible to determine the most likely cost-effectiveness estimates for Bel‑Pom‑Dex.

The recommendations apply equally to all people with relapsed or refractory multiple myeloma. The clinical experts noted that multiple myeloma is common in men, elderly people, and people from Black African and Caribbean ethnic groups. The committee noted that its recommendations apply equally, regardless of sex, age or ethnicity. It concluded that the difference in prevalence did not represent an equality issue in this evaluation.

The committee considered whether there were any uncaptured benefits of Bel‑Pom‑Dex. It acknowledged that Bel‑Pom‑Dex provided a different mechanism of action earlier in the treatment pathway and has longer dose intervals, which may be more convenient for people. But, it noted that the eye-related adverse events and the related monitoring may reduce this benefit. And it considered that these benefits were captured in the economic model. So, the committee concluded that all additional benefits of Bel‑Pom‑Dex had already been taken into account.

NICE's advice about conditions with a high degree of severity did not apply.

Because of the uncertainties in the economic model and clinical evidence, it was not possible to determine the most likely cost-effectiveness estimates for Bel‑Pom‑Dex. So, it could not be recommended for routine commissioning in the NHS for treating multiple myeloma in adults who have had at least 1 treatment including lenalidomide.