Hillengass, Jens

7528 Background: Lenalidomide (Len) maintenance after ASCT has been a standard of care for patients (pts) with MM. Historically, ~30% of pts discontinue Len within 1 year (yr) due to toxicity and there is a need for more effective and better tolerated maintenance strategies. Iber is a potent, oral cereblon E3 ligase modulator under evaluation in the relapsed/refractory and newly diagnosed settings. We report the results of the primary analysis of a Phase II trial of Iber maintenance following upfront ASCT. Methods: Pts ≥ 19 yrs of age with MM, within 1-yr of initiation of induction therapy and in a ≥ partial response (PR) at day 80-110 post-ASCT, were accrued. Iber was administered 1.0 mg orally days 1-21 of a 28-day cycle, continued until progressive disease (PD) or toxicity. Up to 2 dose reductions (0.75 mg/day then 0.6 mg/day) were allowed. Growth factor support was not permitted. Minimal residual disease (MRD) assessment by flow cytometry (10 -5 ) was performed at registration, post-cycle 12 and post-cycle 24. An optimal Simon two-stage design with type I and II errors of 0.1 was chosen to test whether the proportion of pts who are progression-free and on treatment at 1 yr is <60% against the alternative of ≥ 80%. If ≥ 27 out of 38 pts were progression-free (by 2016 IMWG criteria) and on treatment at 1 yr, Iber would be considered to have promising activity. Results: 38 pts (55% males, median age 61 yrs (range: 41-77)) received Iber. R-ISS at diagnosis was stage I (34%), II (39%), III (8%) and unknown (18%), with 34% having high-risk disease per 2025 IMS/IMWG criteria. All pts received triplet or quadruplet induction therapy, with 97% receiving Len and 84% receiving daratumumab. At day 80-110 post-ASCT, all pts had ≥ very good PR, with 22 (58%) ≥ complete response (CR) and 33 (87%) MRD-negative (neg). The median number of administered treatment cycles is 18 (range: 1-45), with 18 (47%) pts having ≥ 1 dose reduction, most commonly due to neutropenia (n=12). The most common grade (gr) 3/4 adverse event was neutropenia (gr 3 (n=19), gr 4 (n=5)). Within yr 1, 29% (11/38) discontinued Iber due to neutropenia (n=5), rash (n=1), infection (n=1), pt choice (n=1), or PD (n=3). After 1 yr, 6 pts discontinued due to neutropenia (n=4) and PD (n=2). While on Iber, 19 pts had deepening of response to stringent CR and 3 pts converted from MRD-positive to MRD-neg. The post-cycle 12 and 24 MRD-neg rates are 85% (23/27) and 100% (14/14), respectively. Conclusions: Iber demonstrated promising activity with dose reductions/discontinuations mainly due to neutropenia. Strategies including lower starting dose, growth factor support and more flexible management of neutropenia may enable more pts to remain on treatment. Longer follow-up will permit evaluation of sustained MRD-negativity and PFS, but overall, these results provide rationale for further exploration of Iber-based post-ASCT maintenance strategies. Clinical trial information: NCT05177536 .

The treatment landscape for multiple myeloma (MM) is evolving rapidly and includes several new options. The management must be tailored to the individual. The NCCN Guidelines for MM provide a framework to base decisions regarding diagnosis, workup, treatment, and follow-up of both newly diagnosed and previously treated relapsed/refractory MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to newly diagnosed MM (NDMM).

Background HPN217 is a B Cell Maturation Antigen (BCMA)-targeting tri-specific T cell engager (TCE). HPN217 contains three binding domains including anti-BCMA for MM cell binding, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. HPN217 is a small (~50 kDa) globular protein, designed to increase the therapeutic window by minimizing off-target toxicities and cytokine release syndrome (CRS). HPN217 is under investigation in patients (pts) with heavily pretreated relapsed/refractory MM (RRMM). Methods This study is designed to assess the safety, pharmacology and early clinical activity of HPN217 using fixed and step-dose (prime dose followed by target doses) regimens in dose escalation cohorts along with expansion of selected regimens for further evaluation. Pts with RRMM who have received at least 3 prior therapies including a proteasome inhibitor, an immunomodulatory drug, and CD38-targeted therapy are eligible. Prior exposure to a BCMA-targeting agent is permitted. Primary objectives include evaluation of safety, tolerability, pharmacokinetics (PK), and determination of the Recommended Phase 2 Dose(s) (RP2D). Secondary objectives include preliminary efficacy. HPN217 is administered IV once weekly or once every 2 weeks. Adverse events (AEs) are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS) and ICANS. Clinical activity is assessed per IMWG Response Criteria. Results Dose escalation has been completed. 97 pts were enrolled across 15 dose escalation cohorts and expansion of 3 regimens with the highest target dose levels from dose escalation (12mg weekly; 24mg every 2 weeks; 24mg weekly for 1 cycle followed by 24mg every 2 weeks). As of 26 June 2023, across all cohorts, 94 pts were treated and had received a median (range) of 6 (2-19) prior lines of treatment (62% penta-exposed, 17% BCMA-targeted therapy, 68% prior transplantation). Median age was 70 (38-85) years. 36 pts (38%) remain on treatment. The most common (≥25%) treatment-emergent adverse events (TEAEs) across all cohorts and in the 12mg and 24mg cohorts are summarized in Table 1. Dose limiting toxicities (DLTs) of reversible transaminitis (Gr 3, n=1; Gr 4, n=1) in 2 pts at 2.86 mg fixed dose during dose escalation informed the choice of 2.15 mg as priming dose in the highest step dose cohorts; a maximum tolerated dose (MTD) has not been reached in step dose cohorts. All CRS events were grade 1-2 except one event of grade 3 CRS at 24 mg. Grade 1 ICANS was reported in 2 pts. Responses were observed at doses ≥ 2.15 mg. Among the 12mg and 24mg cohorts, 55% (22/40) of efficacy-evaluable pts currently have had a confirmed response (PR or better) including 2 pts with prior BCMA directed CAR-T cell therapy; disease assessments for recently enrolled patients are pending. Among pts with a response, 73% (16/22) have had a confirmed response of VGPR or better. Across all dose levels, the median time on treatment for pts with a confirmed response was 40 weeks (range 8.3-114 weeks), including 9 patients on treatment for over 12 months, with data maturing to include longer follow-up on patients recently enrolled. HPN217 exhibited linear and dose proportional PK across all dose groups with a median half-life of 68 hours (range 26-197 hours). Transient cytokine increases were higher with the initial/priming dose compared to subsequent/target doses. Conclusions Dose escalation of HPN217, a novel half-life extended BCMA-targeting T-cell engager, has been completed; the MTD was not reached in step dose cohorts. The 12mg and 24mg target doses are well tolerated with manageable adverse event profiles similar to those at lower dose levels and are associated with robust and durable clinical responses. Additional follow up of recently enrolled pts in 12 mg and 24 mg cohorts will inform the choice of the RP2D(s), and complete data on all pts enrolled will be presented. NCT04184050

Autologous stem cell transplantation (ASCT) has been a backbone of therapy for newly diagnosed patients with multiple myeloma eligible for high-dose therapy for decades. Survival outcomes have continued to improve over time, in part because of the incorporation of highly effective induction regimens prior to ASCT as well as post-ASCT maintenance therapy. Randomized phase III clinical trials have helped establish lenalidomide maintenance as a standard of care. However, as nearly all patients will eventually experience disease relapse, there continues to be significant interest in developing novel maintenance strategies to improve upon lenalidomide maintenance. In this review, we summarize the available evidence for the use of immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies as post-ASCT maintenance therapies as well as discuss future directions and unanswered questions in the field.