Perrot, Aurore

7569 Background: MAIA and CEPHEUS trials demonstrated that daratumumab (Dara) with standard of care (SOC) VRd or Rd significantly improved clinical outcomes versus SOC in TIE NDMM. Here we describe efficacy and safety in TIE pts from both trials by age and baseline (BL) frailty using the latest data cuts. Methods: Pts were randomized 1:1 to DRd (n=368) or Rd (n=369) in MAIA and 1:1 to DVRd (n=144) or VRd (n=145) in CEPHEUS. Progression-free survival (PFS), complete response or better (≥CR), overall MRD negativity (neg) at 10 -5 with ≥CR, sustained MRD neg with ≥CR (confirmed MRD neg ≥12 ± 1 months [mo] apart without MRD positivity in between), and safety were assessed by age (<70, 70–<75, or ≥75 years [y]) and BL frailty (assessed by IFM simplified frailty score: 0–1, non-frail; ≥2, frail). Results: Median follow-up was 64.5 mo in MAIA and 76.0 mo in CEPHEUS. In MAIA, 155 (21%) pts were <70 y, 261 (35%) 70–<75 y, and 321 (44%) ≥75 y; 341 (46%) pts were frail, 88.0 % of whom were ≥70 y. In CEPHEUS TIE pts, 70 (24%) pts were <70 y, 133 (46%) 70–<75 y, and 86 (30%) ≥75 y; 83 (29%) pts were frail, 86% of whom were ≥70 y. DRd or DVRd improved PFS, MRD neg rates, sustained MRD neg rates, and ≥CR rates vs Rd or VRd arms across age and frailty subgroups in both trials (Table). Safety was consistent with established individual drug profiles, and adverse event rates were generally comparable across treatment arms and subgroups within both trials. Additional data on patient-specific factors relevant to these subgroups will be presented. Conclusions: Dara-based regimens improved efficacy outcomes across subgroups in MAIA and CEPHEUS trials, reinforcing Dara-based regimens as SOC in TIE NDMM regardless of age or frailty. These data offer clinically relevant insights to help guide treatment selection for TIE pts. Clinical trial information: NCT03652064 ; NCT02252172 . PFS, hazard ratio (95% CI) ≥CR rate, % MRD neg with ≥CR (10 -5 ) rate, % Sustained MRD neg with ≥CR (10 -5 ) rate, % Age/ Frailty status MAIA* CEPHEUS** MAIA* CEPHEUS ** MAIA* CEPHEUS** MAIA* CEPHEUS ** <70 y 0.35 (0.21–0.56) 0.60 (0.31–1.18) 56.4 vs 31.2 85.7 vs 68.6 35.9 vs 11.7 74.3 vs 42.9 25.6 vs 3.9 62.9 vs 28.6 70–<75 y 0.64 (0.45–0.89) 0.60 (0.37–0.99) 56.2 vs 31.3 77.9 vs 69.2 36.2 vs 12.2 55.9 vs 47.7 20.8 vs 5.3 45.6 vs 38.5 ≥75 y 0.59 (0.44–0.79) 0.46 (0.22–0.94) 44.4 vs 28.6 80.5 vs 44.4 26.9 vs 9.9 58.5 vs 26.7 13.8 vs 3.1 43.9 vs 15.6 Frail 0.64 (0.48–0.85) 0.62 (0.32–1.18) 44.8 vs 33.1 72.9 vs 54.3 25.6 vs 13.0 56.3 vs 34.3 15.7 vs 4.1 39.6 vs 17.1 Non-frail 0.48 (0.36–0.64) 0.51 (0.34–0.78) 56.6 vs 27.5 84.4 vs 63.6 37.8 vs 9.5 63.5 vs 41.8 21.4 vs 4.0 54.2 vs 32.7 *MAIA: DRd vs Rd; **CEPHEUS: DVRd vs VRd.

Abstract Both the phase 3 MAIA and ALCYONE studies demonstrated significant survival benefit with the addition of daratumumab to standard-of-care Rd (Revlimid [lenalidomide] and dexamethasone; D-Rd) or to VMP (Velcade [bortezomib], melphalan, and prednisone; D-VMP), respectively, vs Rd or VMP alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). Patients with NDMM are highly susceptible to infection; therefore, gaining a greater understanding of infection incidence may help to mitigate future risk. We conducted a pooled analysis of infection incidence, timing, and management strategies from MAIA and ALCYONE. The median (range) age of the pooled population was 72 (40-93) years. Incidence was higher with D-Rd/D-VMP vs Rd/VMP for grade 3/4 (36.9% vs 22.4%) and grade 5 (3.0% vs 1.5%) infections; however, exposure-adjusted incidence rates were generally comparable between groups. Any-grade infections led to the discontinuation of study treatment in ∼2% of patients across treatment groups. Of the timing intervals explored, the highest incidence of grade 3/4 infection occurred within the first 6-month interval of study treatment initiation in both groups. Median time to the first onset of grade 3/4 infections (per Kaplan-Meier estimates) was 83.3 months and not estimable in the D-Rd/D-VMP and Rd/VMP groups, respectively. Although the rates of D-Rd/D-VMP treatment discontinuation due to infection remained low in MAIA and ALCYONE, clinicians should remain vigilant about infections throughout treatment and follow local guidelines and International Myeloma Working Group recommendations to minimize the risk of infection. These trials were registered at www.ClinicalTrials.gov as NCT02252172 (MAIA) and NCT02195479 (ALCYONE).

ABSTRACTObjectivesThis final post hoc analysis evaluated patient‐reported outcomes from the Phase 3 MAIA study of daratumumab, lenalidomide, and dexamethasone (D‐Rd) versus lenalidomide and dexamethasone (Rd) after median 64.5‐month follow‐up in transplant‐ineligible patients with newly diagnosed multiple myeloma (NDMM), including patient subgroups.MethodsKey scales from the EORTC QLQ‐C30 (global health status [GHS], physical functioning, pain, and fatigue) were assessed. Scores were evaluated every 3 months for 1 year, then every 6 months until disease progression.ResultsThe intent‐to‐treat population (n = 737) included 46.3% frail, 35.4% 70 to < 75 years old, and 43.6% ≥ 75 years old. D‐Rd‐treated patients showed improvements from baseline that were sustained over 5 years in the intent‐to‐treat population and across subgroups by age, frailty, and bone lesions. Greater proportions of patients treated with D‐Rd versus Rd achieved minimally important changes for improvement at cycle 36 (year ~3) in GHS (odds ratio, 1.84 [95% CI, 1.16–2.91]), physical functioning (1.93 [1.18–3.14]), pain (1.41 [0.90–2.22]), and fatigue (2.00 [1.24–3.23]). Greater proportions of patients with bone lesions improved with D‐Rd versus Rd on GHS and physical functioning.ConclusionsIn transplant‐ineligible patients with NDMM, D‐Rd improved health‐related quality of life over a 5‐year period versus Rd. Trial Registration: ClinicalTrials.gov: NCT02252172

AbstractObjectivesCluster of differentiation 38 (CD38) is a key target on multiple myeloma (MM) cells. This multi‐centre, Phase 1, single‐agent study (NCT04000282) investigated SAR442085, a novel fragment crystallisable (Fc)‐modified anti‐CD38 monoclonal antibody (mAb), with enhanced affinity towards Fc‐gamma receptor on effector cells in patients with relapsed and/or refractory (RR) MM.MethodsThis study comprised two parts: Part‐A (dose‐escalation involving anti‐CD38 mAb pre‐treated and naïve patients) and Part‐B (dose expansion). Primary endpoints were maximum tolerated dose and recommended Phase 2 dose (RP2D).ResultsThirty‐seven heavily pre‐treated patients were treated in Part A. Part‐B (dose‐expansion) was not studied. Seven dose‐limiting toxicities were reported at DL3, DL5, DL6, and DL7. RP2D was determined to be 5–7·5 mg/kg. Most common treatment‐emergent adverse events were infusion‐related reactions in 70·3% (26/37) patients. Grade ≥3 thrombocytopenia was reported in 48·6% (18/37). Overall response rate was 70% in anti‐CD38 mAb naïve and 4% in anti‐CD38 pre‐treated patients, with a median progression‐free survival of 7·62 (95%CI: 2·858; not calculable) months and 2·79 (95%CI: 1·150; 4·172) months and, respectively.ConclusionsThe efficacy of SAR442085 was promising in anti‐CD38 mAb naïve patients but did not extend to the larger cohort of anti‐CD38 mAb pre‐treated patients. This observation, along with transient high‐grade thrombocytopenia, could potentially limit its clinical use.

Introduction: ISB 1342 is a humanized CD38xCD3 bispecific T-cell engager using Ichnos proprietary Bispecific Engagement by Antibodies based on the T cell receptor (BEAT ®) platform, designed to simultaneously bind CD38 on multiple myeloma (MM) cells and CD3ε on T cells, to induce tumor killing. This mechanism of action is different from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in MM. ISB 1342 exhibits potent killing of the primary MM cells and MM cell lines with low sensitivity to daratumumab ( Pouleau B. et al. Blood 2023; 142 (3): 260-273). We report here, the updated findings from the weekly dose-escalations of intravenous (IV) and subcutaneous (SC) injections of an ongoing, single-agent phase 1 study (NCT03309111) of ISB 1342 in patients with RRMM. Methods: Adult patients with RRMM that relapsed after or were refractory to prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody; received ISB 1342 on a weekly (QW) schedule by IV or SC injection with a priming dose on the first day in 2 parallel dose-escalation schemas. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation in the QW schedule began at 0.2/0.3 mg/kg priming/treatment dose and followed a “3 + 3” design. The primary study objectives are to determine the maximum tolerated dose (MTD) and select a recommended phase 2 dose (RP2D) of ISB 1342. Secondary objectives includ evaluation of anti-myeloma activity, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of ISB 1342. Results: As of July 18, 2023, based on ongoing clinical database, 39 subjects had received weekly IV infusions of ISB 1342 in 8 dose-escalation groups from 0.2/0.3 mg/kg to 4.0/16.0 mg/kg as priming/treatment dose; and 7 additional subjects had received weekly SC injections at 2.0/8.0 mg/kg. Two different formulations have been tested in SC group. Median number of cycles administered was 2. The majority were male (57%) and white (74%); 13% were Black or African American. The median age was 69 years (range, 54-76) and the median time since diagnosis was 6.6 years (range, 2.8-22.2). The median number of prior anti-myeloma lines of therapy was 6 (range 1-12). Twenty-one (67%) subjects were considered to be triple-class refractory and 18 (48%) penta-drug refractory. Forty-one (89%) subjects experienced treatment-related adverse events (TRAEs) of any grade. Most TRAEs were grade 1-2, including infusion related reactions (37%), cytokine release syndrome (CRS, 34%, all grade 1or 2), anemia (24%), neutropenia (24%), and thrombocytopenia (17%). Five subjects in SC group (71% of SC) had injection site reaction, all grade 1 or 2. Grade 3 or higher TRAEs occurring in more than 5% of subjects were infusion related reaction (no grade 4), anemia (no grade 4), neutropenia, leukopenia. No Grade 5 TRAE was observed. After QW IV infusion, ISB 1342 serum concentration peaked at the end of infusion and then showed bi-exponential decline. ISB 1342 serum exposures increased in a dose linear fashion across the tested IV infusion dose range. The limited PK data after SC injection suggest slow presentation of ISB 1342 into the systemic circulation leading to lower C max and delayed T max relative to IV. Transient increases in serum cytokines were observed within 24 hours after ISB 1342 dosing, including IFNg, TNFa, IL-2, IL-6 and IL-10. Transient increases in T-cell activation were observed by flow cytometry at 24-48 hours after ISB 1342 dosing at 1.0 / 4.0 μg/kg and above, based on increased expression of CD69 on peripheral blood CD4+ and CD8+ T-cell populations (Figure 1). Comparison of the available data from subjects treated at 2 / 8 μg/kg (Cohort 109) indicated reduced T-cell activation following SC compared to IV administration of ISB 1342. The efficacy signals observed in Cohorts 108 and 109 are consistent with the estimates of the lower boundary of the predicted efficacious dose range using a quantitative systems pharmacology (QSP) model based on preclinical data. Updated clinical data, including response rates and safety data, will be present at the meeting. Conclusions: Treatment with ISB 1342 was well tolerated at higher dose levels evaluated. Observed CRS events were moderate. No increased risk of infection has been observed . Updated safety, efficacy, biomarker and PK data will be presented.