Safety and Tolerability of Magrolimab Combinations in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Safety Run-in Results from a Phase 2 Study
Authors: Paul Barry , Minarík Jirí , Cottini Francesca , Gasparetto Cristina , Khouri Jack , Gandhi Mitul , Hillengass Jens , Levy Moshe , Liedtke Michaela , Manda Sudhir , Sandhu Irwindeep , Sborov Douglas , Spicka Ivan , Usmani Saad Z , Gu Lin , Robeson Michelle , Murphy Michael , Renard Camille , Chen Christine , Pour Luděk 
Published: December 2023

Background
Outcomes remain poor for patients (pts) with RRMM; thus, novel combinations incorporating standard-of-care (SOC) regimens with new drugs possessing unique mechanisms of action and nonoverlapping toxicity are needed. Magrolimab (Magro) is a first-in-class monoclonal immunoglobulin G4 antibody blocking CD47, an antiphagocytic signal overexpressed in cancer cells, including MM, enabling them to evade phagocytosis. In vitro, blocking CD47 resulted in elimination of MM cells, and preclinical data suggested that Magro may synergize with commonly used agents in MM. Reported here are initial safety and tolerability data from 3 safety run-in (SRI) cohorts of our phase 2, open-label, multiarm study (NCT04892446) in which Magro-based combinations were evaluated in pts with RRMM.
Methods
Adult pts with RRMM were eligible if they had received ≥3 prior lines of therapy for MM, including an immunomodulatory drug and a proteasome inhibitor. In the SRI cohorts, pts received Magro in the following combinations: with daratumumab (Magro + D), pomalidomide/dexamethasone (Magro + Pd), or carfilzomib/dexamethasone (Magro + Kd). At the initial dose level tested, Magro was given intravenously as a 1-mg/kg priming dose, followed by a maintenance dose of 30 mg/kg every week during the first 2 cycles and then every 2 weeks starting in cycle 3. All other therapies were administered at standard doses and schedules per clinical guidelines. Dose-limiting toxicities (DLTs) were evaluated throughout cycle 1 (35 days); cycles were 28 days thereafter. Primary end points of the SRI included incidence of adverse events (AEs) and DLTs. Pts were included in the DLT-evaluable population if they met 1 of 2 criteria: (1) experienced a DLT during cycle 1 or (2) completed cycle 1 and received ≥3 Magro infusions and ≥2 (D, d, K) or ≥10 (P) doses of the SOC agents. DLTs were generally defined as grade (gr) ≥3 AEs that worsened from baseline and were at least possibly Magro-related (with a few exceptions, including gr 3 anemia and gr 3 neutropenia resolving within 2 weeks). Dose de-escalation of Magro was planned in the event of &gt;2 DLTs per 6 DLT-evaluable pts.
Results
Of the 25 pts treated in the SRI (Magro + D, n = 9 [6 DLT evaluable]; Magro + Pd, n = 9 [6 DLT evaluable]; Magro + Kd, n = 7 [5 DLT evaluable]), all were treated at the Magro initial dose level. Median (range) age was 59 (55-78) years for Magro + D, 69 (46-79) years for Magro + Pd, and 64 (57-82) years for Magro + Kd. The mean (range) number of prior lines of therapy received was 5.2 (3-9).
Two DLTs were reported: gr 3 febrile neutropenia (Magro + D) and gr 3 dyspnea (Magro + Pd) experienced in a context of probable infusion-related reaction (IRR). No DLTs were reported in the Magro + Kd arm. All pts experienced ≥1 treatment-emergent AE (TEAE); all but 2 experienced ≥1 Magro-related TEAE ( Table 1). The most common Magro-related TEAE observed in each cohort was anemia; other common Magro-related TEAEs were headache (Magro + D), fatigue (Magro + D, Magro + Pd), and thrombocytopenia (Magro + Kd). Magro-related anemia was reported in 13 of 25 pts (gr ≥3, n = 6). There were 3 pts with Magro-related IRRs (all gr 1-2: Magro + Kd, n = 1; Magro + D, n = 2) and 1 pt with a subcutaneous D-related IRR. Gr 3-4 Magro-related TEAEs reported in &gt;1 pt in any cohort were anemia (Magro + D, n = 3; Magro + Pd, n = 2), decreased neutrophil count (Magro + Pd, n = 2), and decreased platelet count (Magro + Pd, n = 2). Serious Magro-related TEAEs occurred in 3 of 9 pts in the Magro + D cohort (febrile neutropenia, a DLT, on day 12; anemia on day 21; bacteremia on day 135), 1 of 9 pts in the Magro + Pd cohort (dyspnea, a DLT, on day 9 followed by febrile neutropenia on day 22 occurring in the same pt), and 1 of 7 pts in the Magro + Kd cohort (pneumonia on day 75). One pt (in the Magro + Pd arm) discontinued treatment due to Magro-related TEAEs reported on day 15 (gr 1 fatigue, gr 3 decreased neutrophil count, gr 3 decreased white blood cell count). No TEAEs leading to death occurred.
Conclusion
Magro demonstrated an acceptable safety profile with minimal additive toxicity when given in combination with SOC regimens for pts with heavily pretreated RRMM.