Multiple Myeloma (MM) Refractory to Lenalidomide: A Systematic Literature Review (SLR) of Randomised Controlled Trials (RCTs)

OBJECTIVES: Lenalidomide is increasingly used in early lines of therapy for patients with MM. Patients treated with lenalidomide, especially in maintenance settings, often experience relapse and become refractory. RCTs in second line and beyond (2L+) feature patients with varying lenalidomide exposure resulting in variable outcomes. Evaluation of 2L+ RCTs focusing on first-line lenalidomide exposure and subsequent impact on outcomes is valuable; understanding the evidence supporting therapies and associated outcomes in 2L+ lenalidomide-refractory patients is vital.

METHODS: An SLR following the PRISMA-P checklist identified RCTs reporting data on patients with lenalidomide-refractory MM. EMBASE, MEDLINE and additional electronic databases were searched (up to December 2021). Records were screened by two independent reviewers; discordance was resolved via discussion. The PICO framework was used to develop literature search strategies in broad populations of patients with relapsed/refractory MM to ensure comprehensive and bias-free searches, with subsequent refinement to solely those studies reporting data on lenalidomide-refractory patients.

RESULTS: In total, 47 studies were identified in patients with relapsed/refractory MM. Patients with lenalidomide-refractory MM were reported in 13 studies: APOLLO; ARROW; ASPIRE; BOSTON; CANDOR; CASTOR; ELOQUENT-3; ENDEAVOR; ICARIA-MM; IKEMA; MM-002; NIMBUS/MM-003; and OPTIMISMM. Median PFS data were reported in 12 studies, whilst 3 reported median OS. Outcomes were highly variable. Median PFS ranged from 1.9 months (high-dose dexamethasone [NIMBUS]) to 15.7 months (carfilzomib and dexamethasone [IKEMA]). Median OS varied from 8 months (high-dose dexamethasone [NIMBUS]) to 29.2 months (carfilzomib and dexamethasone [ENDEAVOR]). Overall response rates were 9% (high-dose dexamethasone [NIMBUS]) to 81% (daratumumab, bortezomib and dexamethasone [CASTOR]).

CONCLUSIONS: Outcomes for lenalidomide-refractory patients with MM remain suboptimal and substantial variability in outcomes was identified: patients receiving monotherapies experienced inferior outcomes than those receiving combination regimens. High unmet need remains for new, more efficacious therapies in this hard-to-treat patient population.