OBJECTIVES: Though different drug classes have improved outcomes of multiple myeloma (MM) patients, penta-refractory MM (PR-MM) remains difficult to treat. PR-MM describes refractoriness to two PIs, two IMiDs and a CD-38 mAb. Patients with PR-MM have poor prognosis and limited treatment options. Clinical evidence in PR-MM is required for novel treatments to estimate their relative efficacy versus current standard of care for the purposes of HTA.

METHODS: A systematic review was conducted to identify interventional and observational clinical efficacy and safety evidence of 29 treatments used in Europe to treat RRMM (all lines and prior treatments).

RESULTS: Bibliographic database searching and additional handsearching were carried out in February 2023. Following screening, >900 records were eligible for inclusion, representative of 81 prospective, phase 2/3 interventional trials evaluating RRMM. Of these, most RCTs evaluated RRMM previously treated with 1-3 prior lines, while later line therapies were mostly evidenced by single-arm non-RCTs. Six non-RCTs and four observational studies reported inclusion of 11-112 PR-MM participants. The pivotal phase 2b STORM trial of selinexor plus dexamethasone (Sd) was the only interventional trial to fully report baseline demographics and efficacy outcomes for a pre-specified BCLPD-refractory (bortezomib-carfilzomib-lenalidomide-pomalidomide-daratumumab) efficacy population of 83 participants. The other five non-RCTs did not report data separately for PR-MM participants. The four observational studies, one prospective (Europe and USA) and three retrospective (USA-based), evaluated real-world standard of care in later line RRMM. Data reporting was heterogeneous within the observational studies for the PR-MM population; two reported baseline characteristics, all studies reported median OS and PFS data, but not all had associated Kaplan-Meir curves to inform indirect treatment comparisons.

CONCLUSIONS: With the STORM trial being the only interventional study to prospectively report on PR-MM, there is currently a paucity of evidence in PR-MM from a prospective and randomised setting, which brings challenges in conducting robust comparisons for HTA.