A phase 2 trial of abbreviated fixed-duration (Default 4 Cycles) linvoseltamab immuno-consolidation to deepen responses post newly diagnosed multiple myeloma combination therapy for minimal residual disease positivity (the IMMUNOPLANT Study)

Abstract

Abstract Background : Proteosome inhibitor (PI), immunomodulatory drug (IMiD), and anti- CD38-based quadruplet (quad) therapies have revolutionized the treatment of newly diagnosed (ND) multiple myeloma (MM) with unparalleled clinical benefit independent of patients' transplant eligibility. However, approximately 50% of patients do not attain minimal residual disease (MRD) negativity after initial combination therapy. Although high-dose melphalan with autologous stem cell transplant (HDM-ASCT) remains an option for some patients, others prefer a harvest and delayed approach. We were motivated to develop a study using an abbreviated fixed-duration (default 4 cycles) of the bispecific T cell redirecting monoclonal antibody linvoseltamab (Linvo) which targets CD3xBCMA as a strategy to deliver deep and durable responses after combination therapy (i.e. sustained MRD negativity 10-6). Methods :This is a single academic center investigator-sponsored Phase 2 trial in up to 25 evaluable patients with NDMM irrespective of HDM-ASCT eligibility who completed ≥4 cycles of standard triplet/quad-based combination therapy (IMiD and PI and/or anti-CD38). Patients must have attained a very good partial response (VGPR) or better but remain MRD positive by clonoSEQ with adequate organ function. The primary objective is to determine the MRD conversion rate after 4-6 cycles of Linvo. Key secondary objectives include sustained MRD negativity at 6, 12, and 24 -month milestones, progression-free survival, overall survival, and overall safety profile. Patients receive Linvo (28-day cycles) 200mg IV preceded by 2 step-up doses (5/25mg) weekly for cycles (C) 1-3 and every 2 weeks starting with C4 and beyond. After C4, bone marrow MRD is evaluated, and if positive, patients receive C5-6. After C4 or 6, patients return to standard management including maintenance therapy. Prophylaxis includes tocilizumab 8 mg/kg to prevent cytokine release syndrome (CRS) 1 hour prior to first dose, dexamethasone 40/10mg C1 only, and standard anti-microbial prophylaxis, IViG, and thromboembolism prophylaxis. The preplanned Simon 2-stage design stipulates >1 MRD negative response out of 15 patients before proceeding to stage 2. Results : As of July 23, 2025 (data cut-off), 19 patients (median follow up: 3.9 months) were enrolled with a median age of 60 years (range: 40-77) including 26% female; 11% Black, 47% Hispanic; 74% ECOG PS 0, 26% 1; 47% IgG, 21% IgA, 32% light chain only; 32% high-risk FISH (53% standard, 16% unknown). Prior to study entry, median combination cycles was 8 (range: 6-13) and 42% received KRd, 26% D-VRd, 21% D-KRd, 5% DRd, and 5% Isa-VRd. All patients were clonoSEQ MRD positive (84% VGPR; 16% sCR). As of data cut-off, 14 patients completed 4 cycles of Linvo and underwent MRD assessment with 100% (95%CI: 76.8-100%) achieving MRD negativity by both NGS clonoSEQ (10-6) and flow cytometry (10-5) (13 sCR; 1 VGPR). All patients remain alive, with no relapses and all after C4 have initiated lenalidomide-based maintenance therapy per treating physician. All 3 patients who reached the 6-month post Linvo MRD milestone remain MRD negative. Of the 19 patients who received Linvo to date, no patients developed any grade CRS or ICANS. Any grade adverse event (AE) occurred in 84% (74% Linvo related). Any grade related AEs occurring in >1 patient included: upper respiratory infection (3), rash (3), bone pain (2), cough (2), and neutropenia (2). Grade 3 AEs included neutropenia in 1 patient and infection (peritonsillar abscess) in another which was a serious AE (SAE). No other SAEs nor Grade 4 or 5 AEs occurred. Conclusion: Recent randomized studies of quad-therapies have shown unprecedented MRD negative responses (e.g. PERSEUS, ADVANCE, MIDAS) and in turn, HDM-ASCT may not confer further benefit in these patients. Given the recent clinical success of T cell redirecting bispecific antibodies, this study aims to use Linvo as immunoconsolidation for the fraction of patients who remain MRD positive. Thus far, the IMMUNOPLANT study shows that 100% of MRD assessed patients who completed abbreviated fixed-duration (default 4 cycles) of Linvo attained MRD negativity by both NGS clonoSEQ (10-6) and flow cytometry (10-5) and therefore has met its prespecified analysis threshold and continues to enroll in Part 2 (50 patients total). At the Meeting, we will present updated safety and efficacy data including MRD negative rates and durability (clinicaltrials.gov NCT06376526).