OA-41: Iberdomide, bortezomib, and dexamethasone (IberVd) in transplant-ineligible newly diagnosed multiple myeloma (NDMM): results from the CC-220-MM-001 trial

Introduction: In patients (pts) with transplant-ineligible (TNE) NDMM, the immunomodulatory drug (IMiD®) lenalidomide forms a standard of care in combination with bortezomib (BORT) and dexamethasone (DEX). Iberdomide (IBER) is a novel, potent oral cereblon E3 ligase modulator (CELMoD™) with increased tumoricidal activity and immune-modulatory effects compared with IMiD agents. IBER has shown preclinical synergistic activity in combination with BORT, and IberVd has shown promising preliminary efficacy and safety in pts with relapsed/refractory MM in the ongoing phase 1/2 CC-220-MM-001 trial (NCT02773030). Here we report results from the dose-expansion cohort of IberVd in pts with TNE NDMM.

Methods: Eligible pts had untreated symptomatic NDMM, no autologous stem cell transplant planned, nor ineligibility due to age or comorbidities. Oral IBER was given on days (D) 1–14 of each 21-d cycle in Cycle (C)1–8 and D1–21 of each 28-d cycle in ≥C9 in combination with subcutaneous BORT (starting at 1.3mg/m2) on D1, 4, 8, and 11 of each 21-d cycle and oral DEX on D1, 2, 4, 5, 8, 9, 11, and 12 of each 21-d cycle in C1–8, and weekly in ≥C9 (20 or 10mg if >75 y of age in C1–8; 40 or 20mg if >75 y in ≥C9). Endpoints included preliminary efficacy and safety, pharmacokinetics, and minimal residual disease assessment.

Results: As of March 3, 2023, 18 pts received IberVd (1 pt 1.0mg; 17 pts 1.6mg). Median age was 77.5 (57–84) y and 11 (61.1%) pts had high-risk cytogenetics. Median follow-up was 10.5 mo. Median treatment (Tx) duration was 48.4 (3.0–65.0) wk; 14 (77.8%) pts continued on Tx. Two pts withdrew from the study before completing a Tx cycle (1 lost to follow-up, 1 consent withdrawal); no pts withdrew due to IBER-related Tx-emergent adverse events (TEAEs).
Grade (Gr) 3–4 TEAEs occurred in 70.6% pts; most common were neutropenia (17.6%) and infections (17.6%, including pneumonia [11.8%]). Two (11.8%) pts had Gr 3–4 peripheral neuropathy. Occurrence of other Gr 3–4 TEAEs was low. Eleven (64.7%) and 6 (35.3%) pts had IBER dose interruptions and reductions due to TEAEs, respectively.
Overall response rate in the intention-to-treat population was 88.9% (95% CI, 65.3–98.6) with 4 stringent complete responses, 5 complete responses (CR), 5 very good partial responses (VGPR), and 2 partial responses; 2 pts were not evaluable. Overall, 9 (50.0%) pts achieved ≥CR, and 14 (77.8%) pts achieved ≥VGPR. Median time to response was 3.1 (3.0–17.0) wk; 68.6% of pts responded in < 6 wk.
Pharmacodynamic data showed that IBER Tx led to robust substrate degradation (median >50% decrease) and immune stimulation (177% median increase in T-cell proliferation) when combined with Vd.

Conclusions: IberVd showed high efficacy with deep, ongoing responses in this cohort of mostly older pts with TNE NDMM. The safety profile was manageable with no new safety signals, and no pts discontinued due to AEs. These data support further assessment of IBER combinations in the frontline setting.