Talquetamab for treating relapsed and refractory multiple myeloma after 3 or more treatments

Multiple myeloma is an incurable and progressive condition that has a substantial impact on survival and quality of life. Complications of multiple myeloma can be significant, debilitating and painful. The relapsing–remitting nature of the condition has a huge psychological impact, because people are aware that treatment options and life expectancy reduce with each relapse. The patient expert at the committee meeting highlighted the negative impact of frequent relapses of multiple myeloma. They spoke about the anxiety around the availability of treatment options after each relapse. They also spoke about the anxiety around having to take corticosteroids, which are associated with a considerable negative impact on quality of life. The committee recognised the substantial impact that multiple myeloma has on survival and quality of life. It acknowledged the unmet need for more treatments that are effective for people with multiple myeloma who have already had several treatments.

According to the marketing authorisation, people having talquetamab must have had 3 or more treatments including a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 monoclonal antibody. The condition must have also progressed on the last treatment. The company submission provided a comparison with teclistamab, a treatment at fourth line and beyond. Clinical advice to the EAG was that teclistamab is the most relevant comparator for this evaluation, given the company's positioning after 3 or more lines of treatment. The clinical experts at the committee meeting agreed that teclistamab is the most frequently used fourth-line treatment option for relapsed and refractory multiple myeloma and a relevant comparator to talquetamab. But the NHS England Cancer Drugs Fund clinical lead highlighted that most people have pomalidomide plus dexamethasone and daratumumab at fourth line, with teclistamab mostly being used at fifth line. They also noted that the treatment pathway was rapidly evolving and that the data informing treatment use may change as newer treatments are implemented into the pathway. The committee was aware that teclistamab was cost effective compared with pomalidomide plus dexamethasone and that NICE recommended it for use after 3 or more lines of treatment. (See NICE's technology appraisal guidance on teclistamab for treating relapsed and refractory multiple myeloma after 3 or more treatments (TA1015). The committee was also aware that elranatamab is available for treating relapsed and refractory multiple myeloma after 3 or more lines of treatment. But elranatamab is only recommended for use within the Cancer Drugs Fund (see NICE's technology appraisal guidance on elranatamab for treating relapsed and refractory multiple myeloma after 3 or more treatments). So, it cannot be considered a comparator to talquetamab in this appraisal. The committee concluded that teclistamab is the most relevant comparator to talquetamab for this evaluation.

The key clinical-effectiveness evidence for talquetamab came from the MonumenTAL-1 trial. This is an ongoing phase 1 and 2, single-arm, open-label, multicentre study. People in the trial have triple-class-exposed relapsed and refractory multiple myeloma that is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug and 1 anti-CD38 monoclonal antibody. The company presented data for cohort C only (n=154). The company said that it had had clinical advice that the majority (90%) of people in UK clinical practice will have talquetamab once every 2 weeks (cohort C) with 10% having it once weekly (cohort A). It presented data from the September 2024 data cut, with a median follow up of 31.2 months. The overall response rate was 69.5%. Median overall survival was not estimable and median progression-free survival was 11.2 months. The committee was aware that the marketing authorisation allowed talquetamab to be used once weekly or once every 2 weeks. So, it questioned whether the clinical-effectiveness evidence from cohort A was appropriately captured in the company submission, and noted that median progression-free survival was worse for cohort A (7.5 months) than for cohort C. The company said that the once every 2 weeks dosage in cohort C is more convenient and should increase the cost effectiveness. A clinical expert said that approximately 90% of people have the once every 2 weeks dosage in NHS clinical practice because of its convenience over the once weekly dosing regimen. The committee was aware that the company had provided a scenario analysis using a weighted split of 90% for cohort C and 10% for cohort A. It considered that it may be appropriate to model resource use according to 90% of dosing regimens being once every 2 weeks and 10% being once weekly. But the committee was unclear why the clinical efficacy would differ markedly between these 2 dosing regimens. So, it decided that it would also like to see clinical and cost-effectiveness analyses on pooled data. The committee concluded that the clinical-effectiveness evidence for talquetamab from MonumenTAL-1 was appropriate. But it said that it would also like to see results from clinical-effectiveness analyses of all cohort A and cohort C data from MonumenTAL-1 pooled, and the related economic analyses.

The company used a partitioned survival model with 3 health states:

• pre-progression

• post-progression

• death.
  
  The cycle length was 1 week and the time horizon was 40 years. The EAG was broadly satisfied with the company's model structure. It noted that the company discounted costs and quality-adjusted life years (QALYs) in the first year of the model and applied a half-cycle correction to account for mid-cycle transitions in the model. The EAG considered that discounting for costs and benefits was inappropriate in the first year. It also thought that the cycle length was not long enough to apply half-cycle corrections in the model. So, the EAG discounted costs and QALYs from year 2 onward and excluded the half-cycle correction in its base-case model. The EAG also had reservations about several assumptions and the parameter selections used in the economic model (see section 3.4 and sections 3.9 to 3.12). The committee noted that the company's model was similar to previous models used for multiple myeloma. But it considered the EAG's approach to discounting from year 2 onward and the exclusion of the half-cycle correction appropriate. The committee concluded that overall, the model structure was appropriate for decision making.

To estimate long-term overall survival, progression-free survival and time to treatment discontinuation beyond the trial follow-up period, the company fitted parametric models to the MajesTEC-1 individual patient data for teclistamab. The company selected a log-normal model for all 3 outcomes and calibrated it to clinical-expert estimates for these outcomes at 10 and 15 years in line with TA1015. The hazard ratios from the indirect treatment comparison for each outcome were then applied to the calibrated log-normal models for teclistamab. This was done to predict long-term overall survival, progression-free survival and time to treatment discontinuation for talquetamab. Long-term overall survival for talquetamab was then capped to the general population mortality. With differing hazard profiles for overall survival, progression-free survival and time to treatment discontinuation, the EAG noted that the same parametric model did not need to be selected for all 3 outcomes. It highlighted that extrapolating using the log-normal model produces implausible long-term overall-survival estimates. It said that in order to produce plausible overall-survival curves, the company had to force it in to plausibility using clinical-expert estimates. The EAG also said that it did not think that the proportional hazards assumption was compatible with the selected log-normal models. So, the EAG selected the Weibull model which does not need to be adjusted to produce clinically plausible estimates. The committee did not agree with the company's choice of using the log-normal model for overall survival, progression-free survival and time to treatment discontinuation given their different hazard profiles. It also questioned the need to calibrate the log-normal models when there are other parametric models that would not need calibration. The company explained that selecting log-normal models for all 3 outcomes and calibrating them to meet clinical-expert estimates was consistent with the approach accepted by the committee in TA1015. The company further explained that aligning with TA1015 ensures internal and external validity. But the committee was aware that the calibrated log-normal model for progression-free survival and time to treatment discontinuation did not fit the observed Kaplan–Meier curves well despite having mature Kaplan–Meier data. So it thought that the calibrated log-normal model lacked internal validity. The committee was also aware of the availability of individual patient data for both treatments. It said that using the IPTW method in the indirect treatment comparison would allow independent models to be fitted that would not need an assumption of proportional hazards. The committee thought that the EAG's approach using the uncalibrated Weibull model was more appropriate because it had not needed calibration. But it considered that it would prefer to see independent curves modelled rather than applying the indirect treatment comparison hazard ratio. The committee concluded that it would like to see the long-term overall survival, progression-free survival and time to treatment discontinuation extrapolations modelled independently for both teclistamab and talquetamab without calibrating to clinical-expert estimates.

Some people in MonumenTAL-1 and MajesTEC-1 had subsequent treatments not routinely available in the NHS. To account for this, the company adjusted the overall-survival hazard ratio by removing the effects of these treatments using the 2-stage approach as per NICE Decision Support Unit's Technical Support Document 16. The company included subsequent teclistamab after talquetamab but excluded subsequent talquetamab after teclistamab in its base case. The company also provided a scenario analysis with people having subsequent talquetamab after initial teclistamab and subsequent teclistamab after initial talquetamab. The EAG thought that the company's base-case approach was not equitable and did not allow for a fair comparison of talquetamab with teclistamab. The EAG highlighted that this approach affects both costs and QALYs and favours the talquetamab arm. To allow for a fair comparison, the EAG included both talquetamab and teclistamab as subsequent treatments after initial treatment. The clinical experts at the committee meeting highlighted that if talquetamab is recommended, some people will start talquetamab or teclistamab and then have the other treatment after disease progression. Whether to have treatment with talquetamab or teclistamab first would be a decision between people with multiple myeloma and their healthcare practitioner. The committee noted the lack of detail in the company submission on how it adjusted for subsequent treatments not available in the NHS. It also noted that the company only used the Weibull model when adjusting for subsequent treatments using the 2-stage adjustment approach. The committee considered that other parametric distributions could have been explored in scenario analyses. The committee concluded that the costs and benefits of both subsequent talquetamab and subsequent teclistamab following initial treatment should be modelled. It said that this is because this reflects how they would be used in NHS clinical practice. The committee also concluded that it would like the company to provide a more detailed explanation of overall methods used to adjust for subsequent treatments not available in the NHS. It also concluded that it would like to see analyses using parametric models, other than the Weibull model, when adjusting for subsequent treatments using the 2-stage adjustment approach.

People in MonumenTAL-1 and MajesTEC-1 could have intravenous immunoglobulin (IVIg) to prevent or treat infections. In the company's base-case analysis, IVIg use was modelled as a one-off cost in the first cycle in the talquetamab and teclistamab arms. This was in line with the observed IVIg use in the respective clinical trials. (The proportion of people having IVIg are considered confidential and cannot be reported here). The company assumed 9 doses of IVIg in both treatment arms, which aligns with TA1015. The company highlighted that because of the mechanism of action of talquetamab, people having it have less severe infections compared with teclistamab and need less IVIg. The EAG thought that modelling IVIg use as a one-off cost underestimates IVIg costs in favour of talquetamab. This is because it does not account for IVIg use by people having subsequent talquetamab and teclistamab after disease progression on the initial treatment. So the EAG included IVIg costs associated with subsequent talquetamab and teclistamab in its base case. It based the proportion of IVIg use for subsequent talquetamab and teclistamab on the observed IVIg use in the respective clinical trials. (These figures are considered confidential and cannot be reported here.) The EAG assumed 6 doses of IVIg for subsequent talquetamab and 9 doses of IVIg for subsequent teclistamab. The committee heard from the clinical experts that there is a considerable difference in the use of IVIg between talquetamab and teclistamab treatments in clinical practice. This is likely because there are fewer infections associated with talquetamab because of its novel mechanism of action compared with teclistamab. The experts agreed that the proportions used in the company's base case are broadly reflective of NHS practice. The clinical experts also agreed that people having subsequent talquetamab and teclistamab would also need IVIg. The committee concluded that the proportion of IVIg use in the talquetamab arm based on MonumenTAL-1 and in the teclistamab arm based on MajesTEC-1 is appropriate. It also concluded that IVIg use should be modelled for subsequent talquetamab and teclistamab treatments.

In its base case, the company applied a one-off utility decrement in the first cycle of the model for grade 3 or higher treatment-related adverse events which happened for at least 5% of people who had talquetamab or teclistamab. A higher utility decrement was applied in the teclistamab arm compared with the talquetamab arm because teclistamab was associated with more grade 3 or higher treatment-related adverse events. The EAG considered that including a utility decrement for adverse events may lead to double counting. This is because the effect of adverse events on health-related quality of life was likely captured in the patient-reported outcomes data collected in the trial, which was used to estimate the health-state utility values in the model. So the EAG excluded modelling the utility decrement for adverse events separately to the health-state utility values. The committee heard from the patient experts that talquetamab is associated with altered taste in the first few months of starting talquetamab, which may result in subsequent weight loss. But the patient and clinical experts explained that these side effects are manageable, with weight loss being managed with dietitian support. A patient expert also highlighted that other treatments have more profound side effects, particularly fatigue and gastrointestinal side effects which impact day-to-day life. The committee considered that altered taste and subsequent weight loss is likely to impact quality of life. But it noted that this had not been accounted for in the utility decrement applied for adverse events in the talquetamab arm because changes in taste are not classed as a grade 3 or 4 adverse event. The committee concluded that it would like the company to provide more explicit modelling of adverse-event disutilities and include the impact of altered taste and associated weight loss in the adverse-event disutility for talquetamab.

NICE's manual on health technology evaluations notes that, above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per 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:

• the limited clinical-effectiveness evidence provided from cohort A of MonumenTAL-1 (see section 3.3)

• the indirect treatment comparison hazard ratio for overall survival (see sections 3.4 to 3.7)

• the modelling of long-term overall survival, progression-free survival and time to treatment discontinuation extrapolations for both talquetamab and teclistamab (see section 3.9)

• the lack of detail on how subsequent treatments not available in the NHS were adjusted for (see section 3.10)

• not taking into account adverse-event disutility for altered taste and associated weight loss with talquetamab treatment (see section 3.12).
  
  The committee concluded that given the considerable uncertainties and based on the evidence and analysis it had seen at the first committee meeting, an acceptable ICER would be around £20,000 per QALY gained.

Because of confidential commercial arrangements for talquetamab and some of the comparators, the exact cost-effectiveness results are confidential and cannot be reported here.

The committee's preferred assumptions included:

• including in the model the costs and benefits of using subsequent talquetamab and subsequent teclistamab after initial treatment (see section 3.10)

• the proportions having IVIg use in the talquetamab arm being based on MonumenTAL-1 data and in the teclistamab arm being based on MajesTEC-1 data (see section 3.11)

• IVIg use being modelled for subsequent talquetamab and teclistamab treatments (see section 3.11)

• discounting for costs and QALYs from the second year of the model (see section 3.8)

• the exclusion of half-cycle correction of costs and QALYs in the economic model (see section 3.8).
  
  Because of the uncertainties in the clinical-effectiveness evidence and in the economic model the committee could not determine the most likely cost-effectiveness estimates for talquetamab compared with teclistamab. So, the committee requested that the company provide the following:

• the clinical-effectiveness results for talquetamab using analyses of all data from cohort A and cohort C from MonumenTAL-1 pooled, and related economic analyses (see section 3.3)

• indirect treatment comparisons for the clinical effectiveness of talquetamab using all data from cohort A and cohort C from MonumenTAL-1 pooled (see sections 3.4 to 3.7)

• a survival analysis censoring for deaths related to COVID-19 (see section 3.7)

• long-term overall survival, progression-free survival and time to treatment discontinuation extrapolations modelled independently for each outcome for both the teclistamab and talquetamab arms without applying a calibration to clinical-expert estimates (see section 3.9)

• a more detailed explanation of overall methods used to adjust for subsequent treatments not available in the NHS (see section 3.10)

• analyses using parametric models other than the Weibull model when adjusting for subsequent treatments using the 2-stage adjustment approach (see section 3.10)

• inclusion of the impact of altered taste and associated weight loss in the adverse-event disutility for talquetamab (see section 3.12).

A professional-organisation submission noted that there is an increased incidence of multiple myeloma and development of more severe disease in African and African-Caribbean people. People with more severe multiple myeloma are more likely to need further lines of treatment because it is associated with an increased risk of relapse with prior lines of treatment. Race is a protected characteristic under the Equality Act 2010. A patient organisation also said that as with all treatments the costs incurred by hospital visits and time off work will have a more significant impact on people with lower incomes. The committee considered that its recommendations do not restrict access to treatment for some people over others. So, the committee agreed that these were not potential equality issues in this evaluation. The committee did not identify any other equality issues.

The clinical-effectiveness evidence for talquetamab is uncertain because of uncertainties in the indirect comparison results for overall survival compared with teclistamab. There are also uncertainties in the economic model. The committee considered that the cost-effectiveness estimates presented by the company and the EAG were highly uncertain. The committee decided that, given its preferred assumptions, and based on the analysis it had seen, it could not determine the most likely cost-effectiveness estimates for talquetamab. Given the uncertainty, the committee would like to see additional analyses (see section 3.15). So, talquetamab should not be used.