Iberdomide Alone or in Combination with Dexamethasone for the Treatment of Intermediate- or High-Risk Smoldering Multiple Myeloma (SMM)

Background: Improved risk stratification models in conjunction with effective and less toxic therapeutic options have shifted the standard approach to high-risk smoldering myeloma (SMM) in recent years. Randomized data has shown a progression free survival (PFS) benefit with lenalidomide for patients with high-risk SMM.[1, 2] Iberdomide (CC-220) is a novel CELMoD (cereblon E3 ligase modulator) shown to have increased potency and improved safety profile as compared to IMIDs in relapsed myeloma. We are investigating the efficacy and safety of iberdomide in the treatment of intermediate and high-risk SMM.

Methods: This is a single center phase 2 study with a safety run-in. Eligible patients must have intermediate or high-risk smoldering myeloma by the Mayo 2018 criteria diagnosed in the past 5 years.[3] Following the safety run-in, patients are randomized 1:1 to iberdomide at the determined dose with or without dexamethasone weekly for the first four cycles. Patients will be treated for two years total or until unacceptable toxicity or disease progression per IMWG response criteria. Primary endpoint is overall response rate (ORR); secondary endpoints include PFS, TTP, OS, grade 3-4 events, and collection of 3.5 x 106 CD34 cells/kg. Correlative studies are concurrently being done to assess MRD, QOL, and pharmacodynamic effects of iberdomide on immune cells using CyTOF and single cell RNA sequencing.

Results: There were no dose limiting toxicities during the safety run-in, though given recurrent issues with neutropenia, it was decided to proceed to the randomized phase at recommended dose of 1.3 mg instead of 1.6 mg. Twenty patients have been enrolled to date. The median patient age is 65.5 (49-83); M 55%/F 45%; 20% black. The median number of completed cycles is 10.2 (1-24). Fourteen patients remain on treatment, 3 are in follow up, 2 withdrew consent (1 patient preference, 1 due to adverse events), and 1 patient progressed to MM while on treatment. The ORR for evaluable patients (n=19) is 79%, and for patients who completed at least 4 cycles of therapy (n=13), the ORR is 84.6%. For the 5 patients who have completed at least one cycle but less than 4 cycles, 3 patients have already achieved 50% tumor reduction with a median decrease in paraprotein of 62.5%. Five patients have been randomized to the dexamethasone arm to date with an ORR 80%. The majority of TEAEs in both arms were grade 1-2 with the most common being diarrhea (35.0%), rash (40.0%), nausea (25.0%), and fatigue (20.0%). Six patients were diagnosed with COVID-19 while on study. One patient had grade 3 thrombocytopenia and two patients had recurrent grade 3-4 neutropenia both initially on iberdomide 1.6 mg monotherapy, and were managed successfully with dose reductions and G-CSF. One patient on 1.6 mg dosing was diagnosed with cryptococcal meningitis while on cycle 22 of treatment. Grade 1-2 TEAEs limited to the dexamethasone arm include headache, abdominal cramping, dyspepsia, and insomnia reported in 10-15% of patients. Eleven patients have undergone stem cell collection with one patient failing to collect adequately.

Conclusion: Iberdomide has shown promising efficacy in both intermediate and high-risk SMM with an ORR of 79% in all patients and 85% in patients who have completed at least 4 cycles of therapy with limited grade 3-4 non-hematologic AEs. While high rates of tumor regression have been described with more aggressive therapies (i.e. SCT, BsAbs) in SMM, whether novel CELMoDs can achieve deep and durable responses with improved tolerance is not known. Updated enrollment, efficacy and safety data will be presented at the meeting.

References
1. Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, et al. Randomized Trial of Lenalidomide Versus Observation in Smoldering Multiple Myeloma. J Clin Oncol. 2019:JCO1901740. doi: 10.1200/JCO.19.01740.
2. Mateos M, Hernandez JM, Giraldo P, de la Rubia J, de Arriba F, Lopez Corral L, et al. Sustained overall survival benefit with lenalidomide plus dexamethasone versus no treatment in patients with smoldering myeloma at high risk of progression to myeloma: long term analysis. Blood. 2016;128(22):3308-008.
3. Lakshman A, Rajkumar SV, Buadi FK, Binder M, Gertz MA, Lacy MQ, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 2018;8(6):59. doi: 10.1038/s41408-018-0077-4.