Low conversion rates to minimal residual disease (MRD) negativity despite improved IMWG responses with lenalidomide-isatuximab maintenance after autologous stem cell transplant (ASCT) in multiple myeloma.

Abstract Introduction: Doublet maintenance regimens of lenalidomide and CD38 MoAb may facilitate the eradication of MM cells, especially in patients with persistent bone marrow (BM) MRD, thereby achieving long-term disease-free survival. Elimination of MRD disease after ASCT (EMAT) is a single-center, investigator-initiated, phase II clinical trial investigating the role of isatuximab and lenalidomide maintenance in patients with persistent BM MRD following ASCT (NCT05690984). Methods: Key eligibility criteria included patients with persistent BM MRD following upfront ASCT (performed within one year of diagnosis).Patients could receive either a triplet or quadruplet induction regimen. The study treatment included lenalidomide at 15 mg daily for 21 days, every 28-day cycle, for cycles 1-12, along with isatuximab at 10 mg/kg weekly (cycle 1), then every 2 weeks, every 28-day cycle, for cycles 2-12. The primary endpoint was the proportion of patients achieving MRD negativity at a sensitivity of 10-5, measured by clonoSEQ next-generation sequencing assay at the end of 12 cycles of treatment. Secondary endpoints included augmentation of post-ASCT IMWG response, progression-free survival (PFS), and patient-reported outcomes (PRO) as assessed by the EORTC QLQ-C30 questionnaire. Key exploratory endpoints included characterizing tumor microenvironment changes with study treatment using single-cell RNA sequencing (scRNA-seq) of paired BM samples from selected patients at study enrollment and exit. The data cuff was May 31st, 2025. Results: A total of 26 patients are included in this analysis. The median age was 65 years (range 42-75), with 39% (n=10) females and 19% (n=5) Black. All patients had an ECOG performance status of 0-1. High-risk cytogenetics were present in 50% (n = 12) of patients at baseline. The majority (67%) received a CD38 MoAb during induction, and 58% (n=14) achieved a ≥VGPR following ASCT. As of data cutoff, 14 patients completed study treatment, and one patient (7%) had MRD conversion to negativity. Augmentation of IMWG response at 6 months was observed in 6 of 11 evaluable patients (55%; 95% CI, 35.9%, 74.3%), with 1 patient upgrading from VGPR to sCR, 4 from PR to VGPR, and 1 from SD to VGPR. The 12-month PFS was 83% (95% CI, 55.9%, 94.3%). Two patients who experienced disease progression received commercial BCMA-directed CAR T-cell therapy. At 6 months of treatment, overall quality of life remained stable, with fatigue and constipation being the most worsened symptoms, while social functioning improved notably compared to baseline. Grade 3/4 treatment-emergent AEs (TEAEs) occurring in ≥5% of patients included lymphopenia (31%), hypertension (27%), neutropenia (15%), diarrhea (3.8%), infections (3.8%), respiratory disorders (3.8%), and back pain (3.8%). Serious TEAEs occurred in 19 patients (73.1%), most commonly lymphopenia (31%). Two patients developed a second primary cancer during therapy (papillary thyroid cancer[n=1], and prostate cancer[n=1]). No TEAEs resulted in study treatment discontinuation or death. Correlative phenotypic studies by flow cytometry revealed a decrease in CD4 T cells and NKT cells in the bone marrow of patients when compared to healthy control. In addition, we observed an increase in PD-1 expression on CD4 T cells and PD-L1 on plasma cells and bone marrow macrophages. Single-cell RNA sequencing of paired bone marrow samples collected at study entry and exit is underway and will be updated at the meeting. Conclusions: More than half of the patients showed an improvement in IMWG response, with doublet maintenance of lenalidomide and CD38 MoAb in patients with persistent MRD following ASCT in this patient population, which was enriched for high-risk disease and predominantly received a quadruplet CD38 MoAb-based induction regimen. There is thus significant potential for continued exploration of novel approaches, including CAR T-cell therapy and bispecific antibodies, to further enhance responses in patients with persistent MRD.