NICE Recommends Against Daratumumab Combo for Newly Diagnosed Myeloma

The United Kingdom’s National Institute for Health and Care Excellence (NICE) will not recommend daratumumab (Darzalex) plus bortezomib (Velcade), thalidomide, and dexamethasone (VTd) for use as induction and consolidation treatment in adult patients with untreated multiple myeloma, when an autologous stem cell transplant (ASCT) is suitable.¹

Although findings from clinical trials have indicated that patients who receive daratumumab in addition to VTd experience prolonged survival vs those who are given VTd alone, how durable the benefit is and how long patients who receive the regimen will live are open questions. Moreover, this is some uncertainty about how the company modelled treatment after daratumumab.

“The cost-effectiveness estimates are likely higher than what NICE considers acceptable,” according to the appraisal consultation document. “So, daratumumab plus VTd cannot be recommended for use in the National Health Service.”

To reach this decision, the committee reviewed findings from the open-label phase 3 CASSIOPEIA trial (NCT02541383), which enrolled a total of 1085 adult patients with untreated multiple myeloma who were eligible for ASCT and were aged up to 65 years.

Participants were randomized 1:1 to receive either daratumumab plus VTd or VTd alone. Patients in both treatment arms received 4 cycles of induction with these regimens, followed by ASCT and 2 additional cycles of consolidation treatment. The primary outcome of the trial was the proportion of patients who experienced a stringent complete response (sCR) within 100 days post-transplant. Key secondary outcomes comprised overall survival (OS), progression-free survival (PFS) and the proportion of those with minimal residual disease (MRD) negativity.

At a median follow-up of 18.8 months, 28.9% of patients in the investigative arm achieved a sCR following consolidation vs 20.3% of those on the control arm (odds ratio, 1.60; 95% CI, 1.21-2.12). At a median follow-up of 29.2 months, the hazard ratio (HR) for PFS favored the daratumumab arm over the VTd arm, at 0.50 (95% CI, 0.38-0.65). Additionally, at a later data cutoff, where there was a median follow-up of 44.5 months, the HR for OS was 0.52 (95% CI, 0.33-0.85), which again favored the investigative arm.

“The committee concluded that adding daratumumab to VTd improved PFS and OS,” according to the document.

The committee also analyzed a landmark analysis that evaluated the relationship between MRD status and survival. To do this, MRD was examined at 2 timepoints in the trial: after patients completed induction treatment and after they completed consolidation treatment, which was approximately 100 days following ASCT. Using data collected only from patients who were alive at the post-consolidation assessment, the company split the findings by MRD status, which was

negative or positive. HRs for PFS and OS were calculated for each group with respect to those who received the investigative or control regimen. The company used these HRs for those with and without MRD to extrapolate long-term PFS and OS in the economic model.

Results from the censored analysis indicated that the addition of daratumumab to VTd improved PFS and OS, independent of MRD status. Although there is now greater clinical support for the link between MRD negativity and stronger survival outcomes, the committee noted that they would have preferred to see further evidence to support the assertion that MRD status more strongly predicts PFS and OS benefit than SCR.

Regarding safety, the profiles observed between the 2 arms were comparable per the company, although a higher frequency of nausea, neutropenia, thrombocytopenia, lymphopenia, and cough was noted for the daratumumab arm.

At a median follow-up of 18.8 months, any-grade infusion-related reactions were experienced by 35% of patients on the investigative arm. These effects were determined to be manageable, with a low frequency of grade 3 or 4 effects (3.5%) and a low rate of treatment discontinuation (0.6%). Notably, no fatal events were reported.

The committee concluded that the toxicity profile of the daratumumab regimen was acceptable.

Other conclusions included:

• The company’s approach to modelling long-term survival using a landmark analysis is acceptable for decision making.
• The meta-analysis on relationship between MRD and survival is uncertain but has minimal impact on results.
• Patients with MRD negativity would have a CR over time and the company’s definition is acceptable.

Regarding duration of benefit, the committee projected that the treatment effect of daratumumab would likely wane at some point; however, when that would happen remains uncertain. “It is decided that [the committee] had not seen enough evidence to support changing its original conclusion that the treatment effect of daratumumab would likely last 10 years or less after consolidation,” according to the document.

Moreover, the committee noted that maintenance treatment with lenalidomide (Revlimid) has recently become a standard approach for the frontline treatment of patients with multiple myeloma who had undergone transplant. Although the company’s economic model factored in the costs of lenalidomide, it did not incorporate the benefits because no data are available on the use of lenalidomide maintenance following consolidation treatment with daratumumab.

The list price for daratumumab is £4,320 per 1,800-mg vial of solution for injection intended for fixed-dose subcutaneous administration. The agent is also available as a solution for

intravenous infusion, with a list price of £360 per 100-mg vial and £1,440 per 400-mg vial. The list price of bortezomib is £762.38 per 3.5-mg vial, and the list price for thalidomide is £298.48 per 50-mg capsules. A discount for dexamethasone is nationally available with the Commerical Medicines Unit.

“Daratumumab plus [VTd] is more clinically effective than standard care for untreated multiple myeloma when a stem cell transplant is suitable. However, there are several uncertainties and biases in the economic modelling,” the committee concluded. “The committee agreed that the most plausible incremental cost-effectiveness ratios for daratumumab plus [VTd] compared with [VTd] was above the range normally considered to be a cost-effective use of NHS resources. It concluded that daratumumab plus [VTd] could not be recommended for routine use as an option for untreated multiple myeloma when a stem cell transplant is suitable.”

The committee plans to hold another appraisal committee meeting on November 4, 2021, with a goal to publish a final decision by January 12, 2022.

Reference

1. Daratumumab in combination for untreated multiple myeloma when a stem cell transplant is suitable: Appraisal consultation document. National Institute for Health and Care Excellence. 2021. Accessed August 30, 2021. https://bit.ly/3kz8Kww