Paper Details

ABSTRACT

Introduction: Minimal residual disease-negative complete response (MRDneg CR) can be assessed earlier than traditional survival endpoints and is associated with improved clinical outcomes, leading to its endorsement as an accepted early endpoint for accelerated approvals in multiple myeloma. In the phase 3 EXCALIBER-RRMM randomized controlled trial, iberdomide+daratumumab+dexamethasone (IberDd) demonstrated significantly higher MRDneg CR rates vs daratumumab+bortezomib+dexamethasone (DVd). However, head-to-head comparative evidence of IberDd vs other clinically relevant triplet regimens such as carfilzomib-containing regimens is lacking. To assess early efficacy in patients (pts) with RRMM, 2 unanchored matching-adjusted indirect comparisons (MAICs) were conducted to evaluate IberDd vs daratumumab+carfilzomib+dexamethasone (DKd) and isatuximab+carfilzomib+dexamethasone (IsaKd) using MRDneg CR as a validated endpoint.

Methods: Key eligibility criteria were aligned across trials to establish the most comparable analysis populations for each MAIC, where feasible. Individual pt data from the EXCALIBER-RRMM trial (IberDd; Jul 3, 2025 data cutoff; median follow-up 15.9 mo) were then reweighted to match published aggregate baseline characteristics from CANDOR (DKd) and IKEMA (IsaKd) trials. Prespecified covariates included clinician-ranked prognostic factors and potential effect modifiers reported in both trials being compared. Base-case models adjusted for refractoriness to an immunomodulatory drug (IMiD), high-risk cytogenetics, International Staging System disease stage, age, ECOG performance status, number of prior lines of therapy, renal function, prior stem cell transplantation, time since diagnosis, β2-microglobulin, and sex, with the IKEMA MAIC additionally adjusting for lactate dehydrogenase and immunoglobulin G myeloma type (11 covariates for the CANDOR comparison and 13 covariates for the IKEMA comparison). Sensitivity analyses evaluated the inclusion of race and prior IMiD exposure, as well as an alternative definition of refractory status (ie, lenalidomide rather than IMiD refractoriness).

The primary endpoint was MRDneg CR at any time (10⁻⁵ sensitivity), defined as MRDneg CR at any point with ≥12 mo follow-up in EXCALIBER-RRMM, and MRDneg CR at any point during follow-up in CANDOR and IKEMA; MRDneg CR at 12 mo was assessed as an exploratory endpoint. Analyses used the data cut from the closest available follow-up time to minimize potential bias attributable to differences in follow-up time and their impact on MRDneg CR rates, aligning with EXCALIBER-RRMM (CANDOR: 16.9 mo; IKEMA: 20.7 mo).

Comparative treatment effects were estimated as odds ratios (ORs) with 95% CIs. Progression-free survival could not be assessed because corresponding EXCALIBER-RRMM data were unavailable.

Results: The CANDOR trial had broader eligibility criteria than EXCALIBER-RRMM; therefore, no EXCALIBER-RRMM pts were excluded for initial population alignment (N=207 IberDd pts weighted to match N=312 DKd pts). For the IKEMA comparison, EXCALIBER-RRMM pts with prior carfilzomib exposure were excluded to better align the study populations (N=190 IberDd pts weighted to match N=179 IsaKd pts).

After weighting, baseline covariates were well balanced in both MAICs. For the CANDOR comparison, MRDneg CR at any time rates were 13.8% (DKd observed; N=312), 41.1% (IberDd observed; N=207), and 44.5% (IberDd weighted; effective sample size [ESS]=100.3). For the IKEMA comparison, MRDneg CR at any time rates were 20.1% (IsaKd observed; N=179), 42.7% (IberDd observed; N=190), and 51.0% (IberDd weighted; ESS=71.2). IberDd demonstrated significantly higher odds of achieving MRDneg CR at any time vs DKd (MAIC-adjusted OR 5.02; 95% CI, 3.01–8.37) and vs IsaKd (MAIC-adjusted OR 4.14; 95% CI, 2.29–7.47). Findings were consistent and statistically significant across all sensitivity analyses. IberDd was also associated with higher odds of achieving MRDneg CR at 12 mo in exploratory analyses.

Conclusions: IberDd was consistently associated with significantly higher odds of achieving MRDneg CR vs DKd and IsaKd in pts with RRMM across 2 independent unanchored MAICs. Results were robust across primary, sensitivity, and exploratory analyses and support the clinical efficacy of IberDd vs regimens containing an anti-CD38 monoclonal antibody and carfilzomib in RRMM. Furthermore, these results provide comparative evidence in the absence of head-to-head randomized trials.