Background and Significance: Lenalidomide (LEN) maintenance after autologous stem cell transplant (ASCT) therapy extends disease control in multiple myeloma (McCarthy PL, et al. NEJM 2012). The GRIFFIN trial showed that adding IV daratumumab (DARA) to pre-ASCT induction and post-ASCT maintenance improves stringent CR (sCR) and Minimal Residual Disease (MRD)-negative rates compared to standard therapy (Voorhees PM, et al, Blood 2020). The PERSEUS study confirmed these findings with the addition of SQ DARA to standard induction and maintenance therapy improving progression free survival (PFS) (Sonneveld P, et al, NEJM 2023). The ongoing SWOG S1803 trial is studying LEN +/- DARA as post-ASCT maintenance (Clinicaltrials.gov identifier NCT04071457). These studies will likely establish LEN+DARA as the new standard for post-ASCT maintenance. Iberdomide (IBER) is an oral cereblon modulator (CELMoD) which, like LEN, targets the cereblon component of the ubiquitin E3 ligase complex. Preclinical data showed enhanced tumoricidal and immune stimulatory effects compared to LEN, clinically supported by studies with IBER and IBER+DARA inducing responses in patients (pts) with LEN-resistant, relapsed myeloma (van de Donk N , et al. ASH 2020, abstr 724; Lonial S, et al. ASH 2022, abstr 1918). On this basis, the EMN26 trial is evaluating IBER as single agent post-ASCT maintenance following Imid and PI induction (Gay F, et al. EHA 2024 abstr 958).

The IBEX trial, described herein, is a Phase II trial designed to evaluate the combination of IBER and subcutaneous DARA (IBER+DARA(SC)) as maintenance therapy in myeloma pts who remain MRD(+) following ASCT.

Study Design and Methods:

The primary objective is to assess the efficacy of post-ASCT IBER+DARA(SC) maintenance as reflected by capacity to induce MRD(-) responses using the commercially available ClonoSEQ assay with a 10-5 sensitivity. The primary endpoint is the proportion of pts reaching MRD(-) status by 12 months. Secondary objectives include assessing sustained MRD(-) status, PFS, Overall Survival (OS), response rate, safety and quality of life (QoL). Safety will be assessed by reporting the frequency of adverse events according to CTCAE 5.0 criteria, and QoL will be measured using EORTC-QLQ-C30 and EQ-5D-5L surveys. The sample size was determined based on the primary objective, using a phase 2 single-stage single-arm design, assuming a null hypothesis MRD(-) conversion rate of 10% (p0 = 0.1) and the alternative hypothesis should improve this rate by 15% (p1 = 0.25) based on the results of the IFM2009 (Attal M, et al. NEJM 2017) and GRIFFIN trials. This requires 55 evaluable patients to achieve 90% power at a 2-sided 10% level, with 60 patients enrolled to account for a 5% to 8% dropout rate. We anticipate up to 6 sites to enroll the required pts over a period of 12 months. Karmanos is currently open and enrolling with 2 additional sites in the process of activation.

Key eligibility:

Pts have been treated with a DARA-containing induction regimen with at least a partial response; completed ASCT 90-150 days prior to registration, without any post-ASCT therapy or progression and resolution of prior therapy-related toxicity to </=Grade 1 ; MRD(+) disease as measured by the ClonoSEQ assay (sensitivity of 10-5) and a trackable clone OR measurable disease post-ASCT (M-protein ≥ 0.5 g/dL and/or abnormal free light chain ratio with involved serum free light chain of ≥ 10 mg/dL); ECOG Performance Status </= 2 and adequate bone marrow, hepatic, and renal function; agrees to contraception if females of childbearing potential (FCBP) or males with FCBP partner.

Treatment:

IBER will be dosed at 1mg daily on days 1-21 out of 28-day cycle for 3 cycles, with the option to increase to 1.3mg after cycle 3 to minimize the likelihood of early dose reductions and/or interruptions due to myelosuppression. Subcutaneous DARA is weekly for cycles 1-2, every other week for cycles 3-6, then monthly thereafter, following the DARA schedule currently being used in the S1803 trial. Patients will be treated for up to 2 years on this study (26 cycles of therapy).

This study is registered with ClinicalTrials.gov: ID NCT06107738

Disclosures

Kin:Regeneron: Consultancy; Sanofi: Consultancy. Zonder:BMS, Janssen, RLL: Research Funding; BMS (employment of spouse): Current Employment; Regeneron: Consultancy. Cole:Genentech: Consultancy, Ended employment in the past 24 months; GSK: Consultancy, Current Employment, Honoraria; Abbive: Consultancy, Ended employment in the past 24 months, Honoraria; Janssen: Ended employment in the past 24 months, Honoraria; Pfizer: Ended employment in the past 24 months, Honoraria; Sanofi: Ended employment in the past 24 months, Honoraria; Binding Site: Current Employment, Speakers Bureau. Deol:Kite, a Gilead Company: Consultancy; Janssen: Consultancy; Adicet Biotherapeutics: Consultancy. Balasubramanian:Kura Oncology: Research Funding; Alexion AstraZeneca: Speakers Bureau.

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2024
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