Abstract
Introduction Advances in newly diagnosed multiple myeloma (MM) have resulted in high rates of MRD- negativity independent of transplant status. However, most patients eventually relapse while on lenalidomide-based maintenance therapy. The ubiquitous use of this immunomodulatory imide drug (IMiD) in frontline and maintenance settings leads to early IMiD resistance in most patients. While T-cell redirecting therapies are gaining prominence in the early relapse setting (i.e., following lenalidomide resistance; 1-3 prior lines), more options are needed in this space for balancing efficacy and toxicity as well as to provide avenues for de-escalation. In this context, Iberdomide is a potent cereblon E3 ligase modulator (CELMoD) with demonstrated activity in IMiD-resistant disease (Lonial et al., Lancet Haematology. 2022).
We were motivated to develop a quadruplet reinduction strategy for early relapsed MM: ReKInDLE (Reinduction with Carfilzomib (K), Iberdomide (Iber), and Daratumumab (Dara) for Long-Term Efficacy).
Methods This is a single-center, phase II study (NCT05896228) of Iber with a combination phase and a monotherapy phase. Eligible patients have ECOG PS 0-2 and have received 1-3 prior lines of therapy inclusive of lenalidomide. Prior treatment with K and CD38-directed therapy is allowed if they were not discontinued for toxicity or disease progression.
The primary endpoint is the rate of MRD-negativity (10-5, NGS) at end of combination therapy. Key secondary endpoints include safety and tolerability (CTCAE v5), overall response rate, duration of response, progression-free; event-free; and overall survival (PFS, EFS, OS), and annual rate of MRD-negativity. For the combination phase, patients receive up to eight 28-day cycles of Iber (1mg oral 21/28 days), Dara [1800mg SC days 1, 8, 15, and 22 (C1-2), days 1 and 15 (C3-6), day 1 (C7-8)], K (20/56 mg/m2 IV, days 1, 8, and 15) and dexamethasone (d; 40mg C1-4 and 20 mg C5-8; on days of parenteral therapy). Patients with a response of ≥SD may de-escalate to Iber monotherapy (1mg 21/28 days) for up to 3 years.
The two-stage design stipulated treatment of 15 patients and if 10-5MRD-negativity is achieved by at least one, the study continued to full accrual (n=30).
Results The study opened for enrollment on February 2, 2024 and as of July 20, 2025, the study is fully enrolled. Median age is 63 (44-77); 17% are Black and 53% are Hispanic/Latino; 33% are high-risk per IMWG 2025 criteria; 17% have extramedullary disease. Median prior lines of therapy is 1 (1-3); 93% are lenalidomide-refractory. 27% had received a prior anti-CD38 antibody, 30% had received prior K, and 47% had prior autologous stem cell transplantation.
As of the data cutoff, 12 patients (40%) have had an MRD assessment on combination therapy and 8 have MRD-negative (10-5) CR & PET-negativity (66.7%; 95% CI 34.9-90.1%). Of 26 response evaluable patients, 10 achieved ≥CR (38%) and 9 VGPR (35%); ORR (92.3%). 27 patients (90%) remain on treatment; 1 patient experienced extramedullary disease progression, 1 patient went off treatment for toxicity, and 1 withdrew consent for social reasons. 8 patients (27%) have so far de-escalated to Iber monotherapy with longest total duration of treatment 17 months. Hematologic AEs were relatively common. Grade 3 or greater events included neutropenia (50%), lymphocytopenia (40%), leukopenia (23%), thrombocytopenia (10%), and anemia (3%) but were manageable with growth factor support and/or iber dose-reduction, as needed. 6 Serious (S)AE occurred including 3 lung infections and 1 incidence each of febrile neutropenia, presyncope, and myocardial infarction, for which the latter patient was taken off-treatment. There were no deaths in the study.
Discussion IberKDd is a novel, effective quadruplet combination-therapy which delivers high rates of MRD-negativity (~2/3 of patients) in early relapse/refractory MM. Updated data and MRD at 10-6 will be presented at the meeting. This quadruplet reinduction strategy adds another treatment alternative in the early relapse setting (i.e., following lenalidomide resistance; 1-3 prior lines) where parenteral (SC or IV) T-cell redirecting therapies are gaining increased prominence. IberKDd is safe with a manageable toxicity profile, and it affords the opportunity for de-escalation to oral monotherapy; decreasing the burden of continuous parenteral therapy which is common in this setting of MM.
