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 >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 >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.
OffLabel Disclosure:
Paul:Janssen: Membership on an entity's Board of Directors or advisory committees. Minarík:Amgen: Consultancy, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Support for attending meetings and/or travel; Bristol Myers Squibb: Consultancy, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Takeda: Consultancy, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Celgene: Consultancy, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; GSK: Consultancy, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Janssen: Consultancy, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Cottini:The Dedham Group: Consultancy. Gasparetto:Karyopharm: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Khouri:GPCR Therapeutics: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Gandhi:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Membership on an entity's Board of Directors or advisory committees. Hillengass:Targeted Oncology: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; ESMO Florida: Other: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Beigene: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Amgen: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Prothena: Consultancy; Janssen: Consultancy, Other: DSMB; OncLive: Consultancy; Axxess Network: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy; Skyline: Consultancy; GSK: Consultancy, Research Funding; Angitia: Consultancy. Levy:Sellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Bristol Meyer Squibb: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; AZ: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Liedtke:Abbvie: Other: Grants or contracts; Allogene: Other: Grants or contracts; Caelum: Other: Grants or contracts; Janssen: Other: Grants or contracts; Participation on a Data Safety Monitoring Board or Advisory Board; Seagen: Other: Grants or contracts; Adaptive: Other: Participation on a Data Safety Monitoring Board or Advisory Board; Kite: Other: Participation on a Data Safety Monitoring Board or Advisory Board; BMS: Other: Grants or contracts; Participation on a Data Safety Monitoring Board or Advisory Board. Manda:Genmab: Current holder of stock options in a privately-held company. Sandhu:Gilead/Kite: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Forus: Honoraria. Sborov:Arcellx: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; BinayTara Foundation: Other: Support for attending meetings and/or travel; Adaptive Biotech: Other: Payment for an educational seminar; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Spicka:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Support for attending meetings and/or travel events; Celgene: Consultancy, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Support for attending meetings and/or travel events; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Support for attending meetings and/or travel events; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Support for attending meetings and/or travel events; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Support for attending meetings and/or travel events; Sanofi: Consultancy, Other: Received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Participation on a Data Safety Monitoring Board or Advisory Board; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Usmani:Novartis: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Moderna: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; K36 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; SkylineDX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TeneoBio: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Research Funding; EdoPharma: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; SecuraBio: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Gu:Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Robeson:Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Owns stock options for a publicly-traded company. Murphy:Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Renard:Alphabet: Other: Owns stock or stock options in a publicly-traded company; Gilead Sciences, Inc.: Current Employment, Other: Owns stock or stock options in a publicly-traded company. Chen:Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Beigene: Membership on an entity's Board of Directors or advisory committees, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events; Bristol Myers Squibb: Other: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events.
Magrolimab is a first-in-class monoclonal IgG4 antibody blocking CD47, an antiphagocytic signal overexpressed in cancer cells
This feature is available to Subscribers Only
Sign In or Create an Account Close Modal