P-320: Iberdomide (IBER) plus dexamethasone (DEX) in patients with relapsed/refractory multiple myeloma (RRMM): a safety analysis from the CC-220-MM-001 trial

Introduction: IBER is a novel, oral cereblon (CRBN) E3 ligase modulator (CELMoD™) with enhanced antimyeloma effects compared with immunomodulatory drugs (IMiDs®). In the phase 1/2 CC-220-MM-001 trial (NCT02773030), IBER+DEX showed meaningful clinical activity (overall response rate 32.2% in Cohort B [dose escalation], 26.2% in Cohort D [dose expansion]) in heavily pretreated RRMM; treatment-emergent adverse events (TEAEs) were mostly hematologic, consistent with the profile of a CRBN-modulating drug. Here we report the safety profile of IBER+DEX in Cohorts B and D.

Methods: Patients (pts) received IBER on days (D) 1–21 at a dose range of 0.3–1.6mg (Cohort B) or at 1.6mg (Cohort D) with weekly DEX (40mg; 20mg if >75 years of age) of each 28-day cycle. Following a dose interruption, the IBER dose may be maintained if neutropenia was the only IBER-related toxicity and granulocyte-colony stimulating factor (G-CSF) was used. Primary endpoints were to determine recommended phase 2 dose (Cohort B) and efficacy (Cohort D); safety was a secondary endpoint. Pharmacokinetics (PK) samples were collected on D8, 15, and 22 in cycles 1–4 and a population PK model was developed to estimate IBER PK exposure, which was correlated with efficacy and safety endpoints to assess exposure–response (ER) relationships.

Results: As of June 2, 2021, 197 pts had received IBER+DEX (90 in Cohort B, 107 in Cohort D). The most frequent grade (Gr) 3/4 TEAEs were neutropenia (38 [42.2%] pts), anemia (24 [26.7%] pts), and infections (23 [25.6%] pts) in Cohort B, and neutropenia (48 [44.9%] pts), anemia (30 [28.0%] pts), and infections (29 [27.1%] pts) in Cohort D. Excluding infections, Gr 3/4 non-hematologic TEAEs were low. Venous thromboembolism occurred in 4 (4.4%) pts in Cohort B and 5 (4.7%) pts in Cohort D. Seventy-four (82.2%) pts in Cohort B and 95 (88.8%) pts in Cohort D experienced at least 1 TEAE related to IBER.
Median onset of neutropenia, anemia, and thrombocytopenia was < 1 mo (both Cohorts); median time to resolution was ≤0.26 mo (Cohort B) and ≤0.46 mo (Cohort D).
TEAEs led to IBER dose interruptions in 47 (52.2%) and 56 (52.3%) pts in Cohorts B and D, and dose reductions in 22 (24.4%) and 20 (18.7%) pts in Cohorts B and D, respectively. Epoetin was used in 15 (16.7%) and 13 (12.1%) pts in Cohorts B and D, and G-CSF was used for neutropenia in 33/44 (75.0%) and 40/66 (60.6%) pts in Cohorts B and D, respectively. TEAEs led to IBER discontinuation in 6 (6.7%) and 5 (4.7%) pts in Cohorts B and D; of these, 3 (3.3%) and 1 (0.9%) pt(s) discontinued due to hematologic TEAEs, respectively.
ER analysis showed that a higher IBER PK exposure was associated with a higher probability and earlier occurrence of Gr ≥3 neutropenia (P < 0.05) and Gr ≥3 thrombocytopenia (P < 0.05).

Conclusions: The all-oral regimen of IBER+DEX showed a tolerable safety profile in pts with RRMM. TEAEs were manageable with dose modifications, dose interruptions, and G-CSF, and few pts discontinued IBER due to TEAEs.