A Phase 1/2 Study of Carfilzomib, Iberdomide and Dexamethasone (KID) in Patients with Newly Diagnosed Transplant-Eligible Multiple Myeloma

Background:
Iberdomide is a next generation cereblon-E3 ligase modulating agent (CELMoD) that has increased antitumor activity relative to earlier thalidomide analogs (IMiDs). This is due to direct effects on tumor cells and increased immune surveillance. Herein, we report preliminary dose escalation, safety and efficacy data from this ongoing investigator-initiated study of carfilzomib (CFZ), iberdomide, and dexamethasone (DEX) (KID) as induction therapy in patients with transplant-eligible, newly diagnosed multiple myeloma (NDMM).

Methods:
This multicenter trial included a phase 1 dose escalation study to determine the maximum tolerated dose (MTD) of iberdomide in combination with CFZ and DEX, followed by a phase 2 dose expansion study. Key inclusion criteria included NDMM, eligible for autologous stem cell transplantation (ASCT), ECOG performance status 0-2, and ≤1 cycle of prior induction therapy. In phase 1, patients were enrolled in a standard 3+3 design starting with iberdomide 1 mg on D1-21 of C1-4 in combination with CFZ (IV; 20 mg/m² on C1D1; 56 mg/m² C1D8, D15; 56 mg/m² C2-4, D1, 8, 15) and DEX (40 mg or 20 mg if >75 years on C1-4, D1, 8, 15) in 28-day cycles (Figure 1). Iberdomide dose escalation to 1.3 mg and 1.6 mg (maximum dose) occurred in subsequent cohorts based on the absence of dose-limiting toxicities (DLTs). Phase 1 is complete and there is ongoing enrollment in the phase 2 study. The phase 1 primary objective was to determine the safety and tolerability of KID. The phase 2 primary objective is to evaluate the rate of complete remission (CR) + stringent CR (sCR) after 2-4 cycles of KID. Patients could collect stem cells and undergo ASCT after 2-4 cycles of KID at physician’s discretion. Secondary objectives include the overall response rate (ORR) and progression-free survival (PFS).

Results:
At data cutoff (July 14, 2023), there were 13 patients enrolled, which included 11 and 2 patients enrolled in the phase 1 and 2 studies, respectively. Ten patients are on trial, 2 were screen failures, and 1 is in screening. Of the 10 patients on trial, the median age was 66 years (range 46-78), 40% male, 70% white, and 30% had ISS stage II MM. Four unique patients had high-risk cytogenetics, which included 2 patients with t(4;14), 2 with 1q21 duplication, 1 with t(14;16), 1 with del(17p)/monosomy 17, and 1 with TP53 mutation.

In the phase 1 study, 3 patients enrolled at the starting dose level of iberdomide 1 mg. Grade 1-2 TEAEs occurred in all 3 patients, but no DLTs occurred. The next 3 patients were enrolled at the iberdomide dose of 1.3 mg. Grade 1-2 TEAEs occurred in 2 patients (rash and pruritus), but no grade ≥3 TEAEs were observed. Three patients were enrolled into the final dose level of iberdomide 1.6 mg. Grade 1-2 TEAEs occurred in 2 patients, and 2 patients experienced grade 3 TEAEs (rash and neutropenia). As no DLTs occurred, the MTD of iberdomide was determined to be 1.6 mg given in combination with CFZ and DEX.

Patients on trial (n=10; 6 in follow-up and 4 actively receiving treatment) have completed a median of 3 (range 2-4) cycles of KID. Of these patients, 7/10 experienced TEAEs (Table 1). No treatment-related deaths occurred. The most common TEAEs were maculopapular rash (46%), elevated liver function tests (38%), gastrointestinal symptoms (31%), and neutropenia (23%). Grade 3 TEAEs occurred in 2 patients (rash and neutropenia). One patient experienced a SAE of erythema multiforme on two separate occurrences (grade 1 and grade 2), which resolved with drug interruption. In 9 patients with response data available, the best ORR was 100% (CR, 1 [12%]; very good partial response [VGPR], 4 [44%]; partial response [PR], 4 [44%]). Six patients proceeded to ASCT with a median amount of stem cells mobilized of 9.42 x 10⁶ cells/kg (range 4.84-13.53). At 3-months post-ASCT, the ORR was 100% (CR, 3 [50%]; VGPR, 2 [33%]; PR, 1 [17%]). One patient had documented sCR and MRD-negativity at data cutoff. Median PFS was not reached (NR) (95% CI, NR-NR).

Conclusions:
Induction therapy with KID appears safe with the only grade 3 TEAEs reported being rash and neutropenia. In patients who completed treatment, induction cycles with KID did not interfere with stem cell mobilization. Correlative and additional clinical data are being collected and will be presented. Clinical trial information: NCT05199311.