Paper Details

ABSTRACT

Introduction
Most patients with multiple myeloma (MM) develop lenalidomide (Len) resistance at first relapse. Subsequent use of IMiD-containing triplets have suboptimal outcomes. While T-cell redirecting therapies have gained prominence in early relapse, options are needed for balancing efficacy, toxicity, and de-escalation. Iberdomide is a cereblon E3 ligase modulator (CELMoD) active in IMiD-resistant disease (Lonial et al., Lancet Haematology. 2022). We developed a quadruplet strategy, ReKInDLE [Reinduction with Carfilzomib (K), Iberdomide (Iber), and Daratumumab (Dara;D) for Long-Term Efficacy], to assess the ability of time-limited combination therapy to re-capture MRD-negativity (MRD-) in an IMiD-resistant setting and facilitate de-escalation to oral monotherapy. Secondly, key studies have investigated the effects of CRBN variants on IMiD/CELMoD binding (Chrisochoidou et al., Blood. 2025) and described chr2q/COP9 signalosome deletions at IMiD relapse (Gooding et al., Blood 2022), but genomic determinants of response to CELMoDs are underexplored. We additionally present correlative whole genome sequencing (WGS) to elucidate determinants of resistance.

Methods
This is a single-center, phase II study (NCT05896228) with combination and monotherapy phases. Eligible patients received 1-3 prior lines inclusive of Len. Prior treatment with K and anti-CD38 therapy was allowed if not previously discontinued for toxicity or progression of disease (PD). The primary endpoint was the rate of MRD- (10^-5, NGS) at end of combination therapy. Patients received up to eight 28-day cycles of Iber-DKd: 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) followed by Iber monotherapy for up to 3 years. Baseline 80x WGS of CD138+ marrow tumor (40x germline match) was performed.

Results
The study opened for enrollment on Feb 2, 2024. Median age is 63 (43-77); 16% are Black and 47% are Hispanic/Latino; 31% are high-risk per IMS-IMWG 2025 criteria; 19% have extramedullary MM. Median prior lines is 1 (1-3); 93% are Len-refractory. 28%, 34%, and 47% had received a prior anti-CD38 antibody, K, and autologous stem cell transplantation, respectively.

With median follow-up of 17.5 months, 19 (59.4%) patients remain on monotherapy. Eleven experienced PD; 4 before and 7 after de-escalation to monotherapy. One patient went off treatment for toxicity and one withdrew for social reasons. 19 achieved MRD- (10^-5; 59.4%). The most common grade 3/4 adverse event (AE) was neutropenia (59%) and 7 (22%) patients had a grade 3 infection. No deaths occurred. 18 (56.25%) patients required a dose reduction of Iber during the combination phase, however protocolized dose re-escalation allowed 77% to increase their monotherapy dose. Additional response data, safety, and MRD at 10^-6 will be reported.

Currently, 18 patients have baseline WGS. Eleven (61%) achieved MRD- at 10^-5 and 6/18 (33%) have experienced PD. WGS upgraded IMS-IMWG risk for three patients. One early progressor had t(14;16) with >70k APOBEC SNV and extramedullary disease. Two patients progressed by end of combination: each with chromothripsis and one with IKZF1 Q156K and the other with DDB1 L631F. IKZF1 Q156 is in the degron that interacts with CRBN while the DDB1 variant might disrupt CRL4^CRBN. Three achieved MRD- at 10^-6 and had PD 6, 7, and 11 months after de-escalating to Iber monotherapy. The latter two had focal deletions of COPS8 and COPS7B, components of the COP9 signalosome that maintains CRL4^CRBN, and one had focal deletion of CRBN. Findings are consistent with response driven by combination therapy with clonal regrowth upon de-escalating to Iber monotherapy. For those remaining on monotherapy, three did not achieve MRD- of which one harbored a deletion of COPS7B and COPS8 with a COPS8 L71P. Nine others who achieved MRD- have no such aberrations. Additional baseline and relapse WGS and RNA-seq are in progress and will be presented.

Discussion
Iber-DKd is a novel, effective quadruplet combination which delivers high rates of MRD-negativity in Len-exposed/refractory MM and affords the opportunity for de-escalation to oral monotherapy. WGS reveals discrete resistance variants apart from CRBN aberrations that appear to influence response, suggesting a role for screening in IMiD-resistant scenarios to inform Iber monotherapy.