Cost-Effectiveness of Newly Emerging Regimens for Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Autologous Stem Cell Transplantation (ASCT) Compared with the Current Standards of Care in EU5

Background: Lenalidomide and low-dose dexamethasone (Rd)-based therapies are widely used in the USA, while both Rd and bortezomib, melphalan, and prednisone (VMP) are used in Europe as first-line treatments (Txs) for patients (pts) ineligible to receive ASCT (Moreau P, et al. Ann Oncol. 2017;28:52-61). Of these, only Rd has the advantage of being an oral therapy which stimulates the immune system, is non-stem cell toxic, and has demonstrated both progression-free survival (PFS) and overall survival (OS) advantages compared with melphalan, prednisone and thalidomide (MPT). Rd is generally well tolerated, enabling pts to benefit from continuous therapy in contrast to the fixed duration employed for VMP. Newer regimens, such as the quadruplet daratumumab (Dara) in combination with VMP, have shown improved PFS vs VMP in the ALCYONE study, however, are yet to demonstrate an OS benefit (Mateos MV, et al. N Engl J Med. 2018;378:518-28). No study has compared VMP + Dara with Rd. Although clinical considerations are important in Tx decisions, combination regimens involving newer agents tend to add costs and require demonstration of significant added value to be considered cost-effective, especially given their potential impact on health system budgets. This analysis assessed the cost-effectiveness of Rd vs VMP, and compared these regimens with VMP + Dara, as first-line therapy for NDMM pts ineligible for ASCT from the perspective of the national health services (NHSs) of EU5 countries.

Methods: A partitioned survival model was developed to model PFS and OS over a lifetime horizon. PFS and OS parametric functions for Rd were derived using published real-world Kaplan-Meier curves. A network meta-analysis was conducted to derive hazard ratios (HRs) for Rd vs VMP + Dara and vs VMP. In the absence of OS data for VMP + Dara, any advantages in survival are unknown. For the purposes of this analysis, a conservative estimate of OS equivalency compared with Rd was used, yet a range of values are possible. Drug acquisition costs were sourced from national drug price databases. Resource utilization costs were sourced from UK NHS reference costs and converted to EU5 country costs using producer price indices published by OECD; an average of all EU5 country costs was used. EQ-5D utilities for pre- and post-progression disease states were taken from Ramsenthaler C, et al. BMC Cancer. 2016;16:427. Disutilities for regimens requiring subcutaneous injections and intravenous infusions were applied (Stopeck A, et al. J Med Econ. 2012;15:712-23).

Results: The base case analysis produced a total number of 3.17, 2.23, and 3.12 quality-adjusted life years (QALYs) for Rd, VMP, and VMP + Dara, respectively. The incremental cost-effectiveness ratio (ICER) for Rd vs VMP was EUR 43,030/QALY, indicating that Rd is cost-effective vs VMP at a willingness-to-pay threshold of EUR 50,000/QALY. Rd dominates VMP + Dara, having a greater gain in QALYs at lower cost. The ICER for VMP + Dara vs VMP was EUR 202,903, well above any acceptable cost-effectiveness threshold in Europe.

Discussion: Achieving durable remission while minimizing toxicities in first-line Tx is an important Tx goal, as it has a bearing on the subsequent Tx journey both from an outcome and cost perspective. Individual country pharmacoeconomic assessments have shown Rd is cost-effective vs VMP (SMC No 1096/15, 2015; AWMSG advice 2116, July 2016; Usmani SZ, et al. J Med Econ. 2016;19:243-58), and a recent cost impact analysis suggested substantial cost savings with Rd use relative to VMP + Dara at first-line Tx (Jackson G, et al. HemaSphere 2018;2:PS1429). Limited clinical data and experience with VMP + Dara mean that estimates of long-term clinical outcomes (e.g. OS) associated with this regimen and costs of managing adverse events are not fully known and may not accurately reflect outcomes in clinical practice. In contrast, PFS and OS benefits for Rd vs MPT have been demonstrated (Facon T, et. al Blood. 2018;131:301-10), and an indirect Tx comparison reported statistically significant PFS and OS benefits for Rd vs VMP (Weisel K, et al. Leuk Lymphoma. 2017;58:153-61). As additional regimens are evaluated to assess clinical benefits over current standards of care, cost-effectiveness analyses are warranted to help define their place in the management of NDMM. For example, it may be interesting to compare Rd and Rd-based triplet regimens with VMP + Dara once relevant clinical data become available.