Abstract CT214: An immune-therapeutic salvage strategy for ‘functional’ high-risk (FHR) multiple myeloma (MM) incorporating iberdomide, isatuximab, and dexamethasone: The IBIS Study AMaRC 20-01

Abstract Background: Functional high-risk (FHR) MM patients, identified by progressive disease (PD) ≤12 months from commencement of 1st-line therapy (1L), were shown in a landmark survival analysis from the Australian and New Zealand Myeloma and Related Diseases Registry to have a median overall survival of 16.9 compared to 78.2 months for those progressing >12 months (p<0.001). Methods: The Australasian Myeloma Research Consortium (AMaRC) IBIS study (ACTRN12621001037897) combines the novel CELMOD iberdomide (IB) with CD38 monoclonal antibody isatuximab (IS) and dexamethasone (DEX) as salvage for 50 FHR patients relapsing ≤18 months of initiation of 1L. IB 1.6mg PO on day (D) 1-21, IS 10mg/kg IV D1, 8, 15, 22 of cycle 1 and fortnightly thereafter and DEX 40mg D1, 8, 15, 22 (20mg, age>70 years) of each 28-day cycle until PD. Primary objective is to establish, after 12 cycles, the overall response rate (ORR) and safety. We present the first planned interim analysis of the initial 10+ evaluable patients, defined as those having either ≥12 months of follow-up or those who withdrew from study earlier. Results: As of 13DEC2024, 16/40 enrolled participants are evaluable - 56% males, median age 64.0 years (range 44.5-81.7), 2/16 (12.5%) were R-ISS III at diagnosis; 31.2%, 43.8%, 25% with 0, 1 or 2 high-risk chromosomal abnormalities respectively, as per EMN2023 criteria. All patients had received PI-IMID 1L (85.7% VRd, 6% VRD-selinexor, 6% VRD-chemotherapy), 1/16 autologous stem cell transplant; 9/16 primary refractory to 1L and 7/16 relapsed after initial response to 1L, of these 5/7 (71.4%) had achieved ≥partial response (PR) prior to relapse. Median time from initiation of 1L to start of IBIS salvage was 5.3 months (range, 1.6-17.3). Regarding the primary endpoint, 13/16 achieved a best response ≥PR within the first 12 months, ORR 81.3% (95%CrI 56.0-93.1%). Posterior probability that the true ORR rate >40% is 99.9% and thus protocol-specific proof of concept (POC) criteria were met. Response was rapid, 75% (12/16) achieving ≥PR by end of cycle 3. At time of analysis 9/16 remain alive and progression-free, 7/16 have confirmed PD with 3 myeloma-related deaths. Survival and PFS analyses are planned once all patients remaining on study have 24 months follow-up.There were 19 reported serious adverse events: 13/19 infections (2/13 febrile neutropenia, 7/13 respiratory tract, 3/13 urinary tract, 1/13 unknown), and one case of squamous cell carcinoma. Conclusion: In this first planned interim analysis of IBIS, IB-IS-DEX was well tolerated, achieved early disease control and demonstrated promising efficacy, fulfilling POC criteria in FHR-MM, a highly adverse-risk subgroup of MM associated with resistance to therapy and dismal survival outcomes. Acknowledgements: Funding + drug support from Bristol Myers Squibb (iberdomide) & Sanofi (isatuximab). Citation Format: Sueh-li Lim, John Reynolds, Wojt Janowski, Hang Quach, Philip Campbell, Georgia McCaughan, Nicole Wong Doo, Sophie Hyesuk Lee, Philip Wong, Nina Byard, Khoa Le, An Nguyen, Andrew Spencer. An immune-therapeutic salvage strategy for ‘functional’ high-risk (FHR) multiple myeloma (MM) incorporating iberdomide, isatuximab, and dexamethasone: The IBIS Study AMaRC 20-01 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT214.