Draft guidance consultation document.docx

For this evaluation, the company positioned selinexor plus bortezomib and dexamethasone (selinexor combination) as a second-line treatment for people whose condition is refractory (did not respond) to previous treatment with both daratumumab and lenalidomide. The clinical experts agreed with the company's positioning of selinexor combination as a second-line treatment option. They highlighted that most people who cannot have a stem cell transplant would be offered first-line treatment with daratumumab plus lenalidomide and dexamethasone. They said that the relevant comparator at second line is carfilzomib plus dexamethasone because this is the only option available to people whose condition is refractory to both daratumumab and lenalidomide. They explained that different factors would be considered when choosing between carfilzomib and selinexor such as comorbidities, individual preferences and ease of administration. Carfilzomib is associated with cardiac side effects and is administered by intravenous infusion. Selinexor, an oral tablet, is associated with gastrointestinal side effects and bortezomib is a subcutaneous medicine, so takes less time to administer in hospital.

The company also positioned selinexor combination at third line, for people who had 2 previous lines of any treatments. The clinical experts explained that for people who can still have lenalidomide, ixazomib plus lenalidomide and dexamethasone (ixazomib combination) would be the preferred option. But, they considered that at third line, most people's condition would be refractory to lenalidomide. So, they explained that for these people, there are limited treatment options available. One treatment option is panobinostat plus bortezomib and dexamethasone (panobinostat combination). But, they highlighted that because of the toxicity associated with panobinostat, it is not often used. The clinical experts acknowledged the toxicity associated with selinexor but explained that emerging real-world data shows that a dose reduction of selinexor can help reduce gastrointestinal side effects and thrombocytopenia, with potentially the same level of clinical effectiveness. The company explained that Jagannath et al. (2023), a study analysing data from the main clinical trial (BOSTON, see section 3.6) showed that progression-free survival improved with dose reduction. It explained that a reason for this result could be that people continue to have selinexor for longer at the reduced dose. The clinical experts agreed that selinexor provides an option with a different mechanism of action and that there are limited treatments available at third line.

The committee acknowledged that the company's positioning of selinexor combination is narrower than its marketing authorisation. It agreed with the company's positioning at second and third line and concluded that the choice of comparators was appropriate.

The clinical-effectiveness evidence for selinexor combination came from BOSTON, a phase 3, randomised, open-label, multi-national trial. The trial was stratified by previous proteasome inhibitor treatments, number of previous lines of treatment and the Revised International Staging System stage at entry. Adults aged at least 18 years with relapsing or remitting multiple myeloma who had already had 1 to 3 previous lines of treatment were randomised to selinexor combination (n=195) or bortezomib plus dexamethasone (n=207). Seventy-seven people randomised to the bortezomib plus dexamethasone group changed treatment to selinexor combination or selinexor plus dexamethasone after their condition progressed during the trial. The company used data from subgroups that had treatment at second line (49%) and at third line (32%). The remaining population that had treatment at fourth line (19%) was not included in the analyses for this evaluation (see sections 3.3 and 3.4). The primary outcome was progression-free survival assessed by an independent review committee that was blind to treatment group allocation. The committee noted that the average age of people in the subgroups was 67 years at second line and 65 years at third line. This was younger than people seen in the NHS, whose condition is usually diagnosed around 75 years (see section 3.2). The committee also noted that BOSTON was not statistically powered to find differences in outcomes in the subgroups and that the trial comparator is not relevant to the decision problem at second or third line. It noted that many people in the BOSTON subgroups did not have previous treatment with lenalidomide (68%). The committee was aware that most people having second- or third-line treatment in NHS clinical practice would have already had lenalidomide. So, it considered that there may be issues about how representative the population in BOSTON is to people likely to have selinexor combination in NHS clinical practice. These issues may lead to uncertainty in the generalisability of the results.

The company did Bayesian network meta-analyses using Markov chain Monte Carlo simulations to estimate the comparative effectiveness of selinexor combination to:

• carfilzomib plus dexamethasone at second line

• ixazomib combination at third line

• panobinostat combination at third line.

The company presented a partitioned survival model with 3 health states: progression-free (including on and off treatment), progressed, and death. The probability of being in each health state was calculated using extrapolated progression-free survival, overall survival, and time-on-treatment curves. People start the model in the progression-free health state on second-line or third-line treatment. The model included a cycle length of 1 week with a half-cycle correction over a 35-year time horizon. The committee 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 data from BOSTON Kaplan–Meier curves and indirect treatment comparisons. The EAG's base case assumed no overall survival differences between treatments and used bortezomib plus dexamethasone as the baseline overall survival curve. The EAG considered this was justified because the overall survival data from BOSTON is immature and uncertain, and no statistically significant overall survival differences were seen for any of the comparisons. The EAG noted that an overall survival benefit likely includes varying impacts of subsequent treatments on overall survival after disease progression. In addition, clinical advisers to the EAG suggested that after first line, overall survival is likely to be similar regardless of treatments at different lines. The committee considered in principle, that overall survival differences should be modelled. But, because of the lack of evidence, it preferred the EAG's base case in which no differences in overall survival between treatments were modelled, and overall survival relative to bortezomib plus dexamethasone was applied for all treatments.

The company included the cost of subsequent treatments by using a weighted average of these treatments in BOSTON and adjusted for treatments which are available in the NHS. The EAG considered that the subsequent treatments modelled by the company do not reflect NHS practice. For example, the company assumed that 56% of people who had ixazomib combination would have lenalidomide and dexamethasone, whereas clinical advice to the EAG suggested no one would have this subsequent treatment. The EAG instead used market share data provided by the company, and assumptions based on the NHS treatment pathway and adjusted for the proportion of people from BOSTON having subsequent treatments (80%). The clinical experts explained that there is significant attrition with each line of treatment. They noted that the average age of diagnosis is 75 to 80 years, and that some studies suggest that at fourth and fifth line, only about 20% of people remain on treatment. The committee recalled the younger cohort included in BOSTON and considered that, by using data from this study, the proportion of people continuing on subsequent treatments may be overestimated. The clinical experts explained that after third line, multiple myeloma is likely to be refractory to lenalidomide and people are more likely to have pomalidomide plus dexamethasone. They considered that there would be no significant differences in subsequent treatments after third line based on whether people had selinexor combination or panobinostat combination. The committee was aware that subsequent treatment assumptions were a key driver of costs and cost effectiveness in the model, particularly when assuming no overall survival benefits between treatments (see section 3.12). The committee acknowledged that the EAG's distributions of subsequent treatments excluded treatments that were not relevant to NHS clinical practice. However, it considered that these distributions, particularly after third line, did not reflect the opinion of the clinical experts. It concluded that it would have preferred to have seen subsequent treatments modelled more accurately based on the treatment pathway seen in NHS clinical practice.

In the company's base case, Grade 3+ treatment-emergent adverse events that occurred in at least 5% of people in BOSTON were modelled as weekly rates for the duration on therapy. The impacts of the adverse events on quality of life were also modelled as a weekly disutility. The company assumed that all adverse events are managed in primary and secondary care. In its base case, the EAG modelled adverse events as a one-off event in cycle 1 in line with previous multiple myeloma technology appraisals and assumed that adverse events are managed in secondary care. The clinical experts explained that adverse events are generally managed in secondary care. If side effects are not manageable, treatment is stopped. They considered that adverse events are likely to become less frequent over time with improved management and dose reduction, if appropriate. The committee considered that modelling a one-off event does not consider the distribution of adverse events over the duration on treatment and does not capture the long-term impact on quality of life. It acknowledged that the company's approach using cumulative adverse event rates divided to provide weekly event rates assumes constant incidence of adverse events over time, which was not appropriate and benefits treatments with shorter estimated progression-free survival such as selinexor. The committee concluded that the approach of modelling adverse events as a one-off event in cycle 1 was the best option.

In its base case, the company used EQ‑5D‑5L data from BOSTON for health state utilities mapped to the EQ‑5D‑3L using the algorithm published in Hernandez -Alava et al. (2020). It applied pooled utilities from trial arms and assumed that health-related quality of life did not depend on treatment, lines of treatment or differences in treatment-emergent adverse event profiles. The company also provided a scenario analysis using utility values from Hatswell et al. (2019), a source used in other multiple myeloma technology appraisals. In its base case, the EAG used EQ‑5D‑5L data from BOSTON and line of treatment as a covariate. The clinical experts noted the small difference in utilities between the progression-free survival and progressed health states in BOSTON, whereas a larger difference was shown using the Hatswell et al. (2019)'s data. The company explained that often in trials, utilities for the progressed health state are based on an assessment at 1 timepoint shortly after disease progression. The clinical experts explained that disease-related and non-disease-related comorbidities increase over time. It is clinically plausible that over time and with later lines of treatment, the impact on health-related quality of life will be greater. The committee acknowledged the likely overestimation of the utility for the progressed health state but considered that it preferred to use the trial utility value data by line of treatment. It considered that the EAG's base-case approach for health state utilities was more appropriate for decision making.

The committee's preferred assumptions were in line with that of the EAG's base case, which were:

• using the results of the network meta-analyses for the second-line comparison with carfilzomib plus dexamethasone, and the third-line comparison with panobinostat combination (see section 3.7)

• using the results of the unanchored matching-adjusted indirect comparison for the third-line comparison with ixazomib combination (see section 3.7)

• using independently fitted models for extrapolations of progression-free survival, overall survival and time on treatment (see section 3.10)

• using baseline curves of bortezomib plus dexamethasone for comparator extrapolations (see section 3.11)

• assuming no difference in overall survival between treatments and using bortezomib plus dexamethasone as baseline for overall survival for all treatments (see section 3.12)

• using EAG distributions of subsequent treatments (see section 3.13)

• modelling of adverse events and associated disutility as a one-off event in cycle 1 (see section 3.14)

• modelling health state utilities by line of treatment (see section 3.15).

NICE's health technology evaluations manual notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the incremental cost-effectiveness ratio (ICER). The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. NICE's health technology evaluations manual also states that decisions about the acceptability of the technology will consider aspects that relate to uncaptured benefits and non-health factors. The committee recalled the statements from the clinical and patient experts on the significant unmet need for effective and safe treatments at later lines in the treatment pathway. It also noted that selinexor has a novel mechanism of action and, as an oral treatment, would be easily administered and fit into the existing care pathway. The committee acknowledged the high unmet need for novel treatments especially at later lines in the treatment pathway. But, it also noted the high levels of uncertainty (see section 3.16). So, the committee concluded that an acceptable ICER would be below £20,000 per quality-adjusted life year (QALY) gained.

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

The clinical experts considered that selinexor combination provided an alternative treatment option with a novel mechanism of action. The company highlighted some uncaptured benefits, including the impact on carer health-related quality of life. The committee considered there may be benefits uncaptured in the economic modelling. For example, the value of an additional oral treatment option, particularly at second line, whose ease of administration and adverse effect profile may make it more acceptable than existing options. The committee also acknowledged that there would be an increasing number of people whose condition is refractory to lenalidomide and daratumumab. It concluded that selinexor combination provided an alternative treatment option with a novel mechanism of action.

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