Introduction:Lenalidomide (LEN) plus daratumumab (DARA) and dexamethasone (DEX) is a standard-of-care treatment for transplant-ineligible (TNE) newly diagnosed multiple myeloma (NDMM). Iberdomide (IBER) is an oral CELMoD™ agent with superior potency and specificity than LEN; IBER has distinct binding features and binds cereblon with higher affinity leading to more efficient cereblon conformational changes, which results in faster and greater Ikaros/Aiolos degradation and enhanced antitumor and immunostimulatory effects. IberDd has shown notable efficacy and tolerability in TNE NDMM in the ongoing phase 1/2 CC-220-MM-001 trial (NCT02773030). Prior analysis showed that renal impairment (RI) did not influence clinical outcomes in patients (pts) with relapsed/refractory MM (RRMM) treated with IBER+DEX (van de Donk NWCJ, et al. Clin Lymphoma Myeloma Leuk 2022;22(suppl):S191–S192). Here we assess whether RI impacts efficacy, safety, and pharmacokinetics (PK) of IberDd in pts with TNE or transplant-deferred NDMM in Cohort K of CC-220-MM-001.

Methods: Pts with untreated symptomatic NDMM with no planned or ineligible for autologous stem cell transplant were recruited. Pts were randomized 1:1:1 to receive oral IBER (1.0, 1.3, or 1.6 mg) on days (D) 1–21 of each 28-day cycle (C) combined with subcutaneous DARA (1800 mg) on D1, 8, 15, and 22 in C1–2, on D1 and 15 in C3–6, and on D1 in ≥C7, plus weekly DEX (40 mg; 20 mg if >75 years of age). Baseline creatinine clearance (CrCl) was used to stratify pts with no RI (≥90 mL/min), mild RI (60–<90 mL/min), or moderate RI (30–<60 mL/min). ​IBER doses were not modified based on RI. Overall response rate (ORR; primary endpoint), duration of response (DOR), and safety by RI subgroup were assessed. Oral IBER clearance (CL/F) was estimated from an integrated population PK (popPK) model. Logistic regression analyses were performed to investigate the correlation between RI and key efficacy (≥ complete response [CR]) and safety endpoints (dose reductions, neutropenia).

Results: All 75 pts in Cohort K received IberDd; 44 (58.7%) were ≥75 years of age, 42 (56.0%) were male, 6 (8.0%) had plasmacytomas, and 31 (41.3%) had high-risk cytogenetics. Median (range) time since diagnosis was 0.1 (0.0–11.3) years.

At data cutoff (March 3, 2025), median (range) follow-up was 22.3 (0.4–28.5) months; 50 (66.7%) pts remained on therapy and median duration of treatment was 22.4 (0.3–29.0) months. Median number of cycles received was 23.0 (1.0–31.0). Of the 74 pts evaluable for RI analysis, 10 (13.5%) had no RI, 29 (39.2%) had mild RI, and 35 (47.3%) had moderate RI. No differences were observed in median treatment duration across RI subgroups. ORR was 94.6% (all), 90.0% (no RI), 93.1% (mild RI) and 97.1% (moderate RI); ≥CR was 67.6% (all), 80.0% (no RI), 55.2% (mild RI), and 74.3% (moderate RI). Among RI subgroups, MRD-negativity rate at any time was 80.0% (no RI), 48.3% (mild RI), and 71.4% (moderate RI). Median DOR was not reached in any group.

Grade (Gr) 3/4 treatment-emergent adverse events (TEAEs) occurred in 97.3% (all), 100% (no RI), 100% (mild RI), and 94.3% (moderate RI) of pts. Gr 3/4 hematologic TEAEs were observed across all RI groups; Gr 3/4 neutropenia occurred in 78.4% (all), 60.0% (no RI), 75.9% (mild RI), and 85.7% (moderate RI) of pts. Infections, the most common non-hematologic Gr 3/4 TEAE, were also comparable between RI groups (52.7% [all], 50.0% [no RI], 58.6% [mild RI], and 48.6% [moderate RI]). Dose reductions occurred in 47.3% (all), 50.0% (no RI), 58.6% (mild RI), and 37.1% (moderate RI) of pts. Among RI subgroups, median relative dose intensity was 87.9% (no RI), 78.3% (mild RI), and 87.5% (moderate RI).

PopPK analysis showed baseline CrCl and RI category had no impact on oral IBER CL/F. Logistic regression analyses suggested no correlation between baseline CrCl and ≥CR; additionally, no clear trend was observed between baseline CrCl and Gr 3/4 neutropenia (including febrile neutropenia), and TEAEs with ≥1 dose reduction.

Conclusions: Despite the observed numerical differences in ORR and CR between RI subgroups, logistic regression analyses showed no correlation between baseline CrCl and key efficacy and safety endpoints, suggesting that RI does not impact clinical outcomes in pts with TNE NDMM treated with IberDd, and that IBER dose modifications are not required for pts with mild to moderate RI. These data are consistent with previous observations in pts with RRMM receiving IBER+DEX.

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2025
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