(SLB-022) Concordance between blinded independent central review committee and physician-assessed responses: Analyses based on a real-world external control arm in relapsed/refractory multiple myeloma using IMWG data

Background: External control arms (ECAs) derived from real-world (RW) data are increasingly used to contextualize findings from single-arm trials. Such analyses aim to evaluate endpoints that are similar to the reference single-arm trial. Blinded independent central review (BICR) committees are often established for oncology trials to assess best overall response (BOR), while RW studies typically rely on physician-assessed responses. To emulate clinical trial rigor, a BICR committee was implemented in the R5458-ONC-21101 RW data-derived ECA study (NCT05673967) to evaluate BOR using International Myeloma Working Group (IMWG) criteria similar to the LINKER-MM1 trial (NCT03761108).

Objectives: To evaluate concordance between BICR- and physician-assessed BOR in patients with relapsed/refractory multiple myeloma (RRMM).

Methods: A pre-specified concordance analysis compared BOR assessments between the BICR committee and treating physicians for patients with RRMM. RW data were obtained from chart reviews at 15 participating International Myeloma Foundation IMWG sites. The BICR committee, comprised of three multiple myeloma experts blinded to the treating physician assessment, evaluated BOR through consensus voting. Per protocol, the committee reviewed case report forms consisting of data on serum and urine myeloma protein, and free light chain levels; and, where available, bone marrow plasma cell percentage, presence of plasmacytomas, and bone lesion changes. Concordance between BICR- and physician-assessed BOR was evaluated for objective response rate defined as BOR of ≥partial response (PR), ≥very good partial response (VGPR), ≥complete response (CR), and stringent complete response (sCR), with non-evaluable responses excluded from the analysis. Cohen’s kappa (κ) was used to measure agreement, with values >0.6 indicating strong concordance.

Results: Of 279 evaluable lines of therapy from 203 patients, the BOR of ≥PR was 45.2% by BICR assessment and 42.3% by treating physicians (κ=0.622). Concordance improved for BOR of ≥VGPR (22.2% by BICR vs 24.7% by treating physicians; κ=0.731) but was low for BOR of ≥CR (3.9% vs 10.8%; κ=0.508) and sCR (1.1% vs 4.7%; κ=0.364).

Conclusions: BICR- and physician-assessed responses showed strong concordance for BOR of ≥PR and ≥VGPR. However, as expected, lower concordance for ≥CR and sCR was observed, as evaluation of CR and sCR per IMWG criteria requires examination of bone marrow, which is rarely performed in clinical practice. While the reliability of CR and sCR in RW data is less certain, these results suggest that BOR of ≥VGPR or ≥PR may be reliably ascertained in academic settings based on treating physician evaluations for ECAs.