A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients with Relapsed/Refractory Multiple Myeloma

Background: Magrolimab is a humanized monoclonal antibody that blocks the immune checkpoint CD47, a "do not eat me" signal, overexpressed on tumor cells. The binding of magrolimab to CD47 leads to phagocytosis of cancer cells from human solid tumors and hematologic malignancies. The overexpression of CD47 contributes to the pathogenesis of multiple myeloma (MM) and blocking CD47 induces immediate activation of macrophages and elimination of myeloma cells (Sun et al). Hence, a blockade of CD47 with magrolimab may have therapeutic benefit in patients with MM. Combination therapies are more effective than single-agent therapy for both newly diagnosed and relapsed/refractory MM (RRMM). In vitro studies show synergy between magrolimab and daratumumab on MM cell line phagocytosis, and complimentary mechanisms suggest potential enhanced efficacy in other combinations. The current study (NCT04892446) is investigating the efficacy of magrolimab in combination with commonly used myeloma therapies in patients with RRMM. Design and Methods: This phase 2, multi-arm study includes patients aged ≥18 years currently requiring treatment for RRMM; all participants must have received at least 3 previous lines of therapy for MM, including an immunomodulatory drug and a proteasome inhibitor. This study includes 2 phases: a safety run-in cohort and a dose-expansion cohort (Figure 1). The primary objectives of the safety run-in cohort are to evaluate the safety and tolerability of magrolimab in combination with other anticancer therapies using the occurrence of dose-limiting toxicities (DLTs) as the primary endpoint, and to determine the recommended phase 2 dose (RP2D) of magrolimab in the following combinations: magrolimab+daratumumab; magrolimab+pomalidomide+dexamethasone; and magrolimab+bortezomib (maximum of 8 prior cycles in those who previously received bortezomib)+dexamethasone. Dose expansion cohorts will evaluate the efficacy of magrolimab combinations with objective response rate (ORR) as the primary endpoint. Secondary endpoints include duration of response, progression-free survival, and overall survival. Minimal residual disease negativity, biomarker changes from baseline, immune cell signaling alterations, and the mutational profile of plasma cell clones will also be explored. Magrolimab is administered intravenously (IV) with an initial priming dose, followed by a maintenance dose on days 8, 15, 22, and 29 during cycle 1 (35 days) and days 1, 8, 15, and 22 from cycle 2 (28 days) onwards. Daratumumab, pomalidomide, dexamethasone, and bortezomib will be administered according to manufacturer's prescribing information. Dose de-escalation may occur based on DLTs per protocol. Patients will continue treatment until unacceptable toxicity, progressive disease, or patient/investigator choice to discontinue. Planned enrollment is approximately 153 patients. Status: Recruitment is ongoing. Reference: Sun J, Muz B, Alhallak K, Markovic M, Gurley S, Wang Z, Guenthner N, Wasden K, Fiala M, King J, Kohnen D, Salama NN, Vij R, Azab AK. Targeting CD47 as a novel immunotherapy for multiple myeloma. Cancers (Basel). 2020;12(2):305. Figure 1 Figure 1. Disclosures Paul: Amgen Inc.: Speakers Bureau; Bristol Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months; Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees. Liedtke: Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Monge: Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy. Rifkin: Takeda: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Coherus: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Gandhi: Karyopharm Therapeutics: Honoraria; TG Therapeutics: Honoraria; GlaxoSmithKline: Honoraria. Kovacsovics: Janssen Pharmaceuticals: Research Funding; Amgen Inc.: Research Funding; Stemline: Honoraria; Jazz Pharmaceutials: Honoraria; Novartis: Research Funding; AbbVie: Research Funding. Levy: Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker. Siegel: Karyopharm: Honoraria; Celularity: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau; Amgen Inc.: Honoraria; Janssen: Honoraria, Speakers Bureau. Silbermann: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Ncube: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Murphy: Gilead Sciences, Inc.: Current Employment, Current holder of stock options in a privately-held company. Gu: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Rajakumaraswamy: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Chao: Gilead Sciences, Inc.: Current Employment; TigaTx: Membership on an entity's Board of Directors or advisory committees; Stanford University: Patents & Royalties; Hepatx Inc: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Iconovir Bio: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Stanford University Medical School: Membership on an entity's Board of Directors or advisory committees; Foresite capital: Consultancy; Bioverge: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Chimera Bioengineering: Current equity holder in publicly-traded company. Usmani: Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy. OffLabel Disclosure: Magrolimab is an investigational therapy