A phase II multi-arm study of magrolimab combinations in patients with relapsed/refractory multiple myeloma

Figures & data

Infographic: A PDF version of this infographic is available as supplemental material.

Figure 1. Study design.

Magrolimab+bortezomib+dexamethasone may be initiated based on preliminary safety and efficacy data in the magrolimab+carfilzomib+dexamethasone cohort and if initiated, will require only oneprior line of therapy.

^aMagrolimab 1 mg/kg initial priming dose then 15–30 mg/kg.

MM: Multiple myeloma; RP2D: Recommended phase II dose; R/R: Relapsed/refractory.

Table 1. Key eligibility criteria.

Key inclusion criteria
Male or female aged ≥18years
Previous diagnosis of MM based on the IMWG 2016 criteria and currently requiring treatment
Measurable disease, defined as ≥1 of the following: serum M-protein ≥0.5g/dl (≥5g/l), urine M-protein ≥200mg/24h, SFLC assay with involved SFLC level ≥10mg/dl (100mg/l) and abnormal SFLC ratio
ECOG performance status ≤2
Received ≥3 previous lines of therapy, including an IMiD and a PI
Daratumumab arm: CD38^+ MM with no prior anti-CD38 antibody therapy for ≤6 months prior to enrollment; no history of discontinuation of daratumumab due to toxicity
Pomalidomide/dexamethasone arm: no history of pomalidomide discontinuation due to toxicity; prior pomalidomide therapy allowed if PR was achieved with the most recent pomalidomide therapy and pomalidomide-free interval since last dose is ≥6months; no contraindication to dexamethasone
Carfilzomib/dexamethasone arm: no history of discontinuation of carfilzomib due to toxicity; prior PI therapy allowed if PR was achieved with the most recent PI therapy; no contraindication to dexamethasone
Bortezomib/dexamethasone arm: no history of discontinuation of bortezomib due to toxicity; prior PI therapy allowed if PR was achieved with the most recent PI therapy and PI-free interval since last dose is ≥6months; no contraindication to dexamethasone; if initiated, patients only require one prior line of therapy
Key exclusion criteria
Prior treatment with CD47- or SIRPα-targeting agents
MM of immunoglobulin M subtype, Waldenström macroglobulinemia, or MDS
Known amyloidosis, including myeloma complicated by amyloidosis
Plasma cell leukemia or circulating plasma cells ≥2×10^9/l
Solitary bone or extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia
POEMS syndrome
Glucocorticoid therapy within 14days prior to enrollment
Chemotherapy with approved or investigational anticancer therapies within 28 days prior to enrollment
Focal radiation therapy within 7days prior to enrollment; radiation therapy to an extended field involving a significant volume of bone marrow within 21days prior to enrollment
Immunotherapy within 28days prior to enrollment
Autologous SCT <100days prior to enrollment or considered eligible to receive autologous or allogeneic SCT at the time of enrollment

ECOG: Eastern Cooperative Oncology Group; IMiD: Immunomodulatory drug; IMWG: International Myeloma Working Group; MDS: Myelodysplastic syndrome; MM: Multiple myeloma; PI: Proteasome inhibitor; POEMS: Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes; PR: Partial response; SCT: Stem cell transplant; SFLC: Serum free light chain.

Table 2. Dosing regimens.

Drug	Dose level	(Cycle 1 is 35 days; remainder are 28 days)
		Cycle 1	Cycle 2	Cycle 3+
Magrolimab	Starting dose	Priming dose: day 1 Maintenance dose: days 8, 15, 22, 29	Maintenance dose: days 1, 8, 15, 22	Maintenance dose: day 1, 15
Daratumumab^†	16 mg/kg iv. or 1800 mg sc.	Days 8, 15, 22, 29	Days 1, 8, 15, 22	Days 1, 15 for cycles 3 to6; day 1 of cycles 7+
Pomalidomide	4 mg p.o.	Days 1 to 21 daily	Days 1 to 21 daily	Days 1 to 21 daily
Carfilzomib^‡	20/70mg/m^2 iv.	Days 8 (20mg/m^2), 15 (70mg/m^2), 22 (70mg/m^2)	Days 1, 8, 15	Days 1, 8, 15
Bortezomib	1.3mg/m^2 sc./iv.^§	Days 8, 15, 22, 29	Days 1, 8, 15, 22	Days 1, 8, 15, 22^¶
Dexamethasone	40mg p.o.	Days 1, 8, 15, 22, 29^#	Days 1, 8, 15, 22	Days 1, 8, 15, 22^††

† This arm will not receive treatment with dexamethasone.

‡ Recommended starting dose is 20mg/m² on cycle 1, day 8. If tolerated, escalate dose to 70mg/m² on cycle 1, day 15and thereafter.

§ sc. is preferred over iv., where feasible.

¶ Maximum of 8 cycles in those who previously received bortezomib.

# Administration on day 1 does not occur in the carfilzomib cohort.

†† Those patients in the magrolimab+carfilzomib+dexamethasone group will receive dexamethasone on days 1, 8, 15and 22 from cycle 2 until cycle 9 and days 1, 8and 15 from cycle 10 onward.

iv.: Intravenous; p.o.: Oral; sc.: Subcutaneous.

Figure 2. Schedule of study assessments.

All treatment arms follow the same schedule of assessments. Not exhaustive.

CT: Computed tomography; DAT: Direct antiglobulin test; IMWG: International Myeloma Working Group; MM: Multiple myeloma; PET: Positron emission tomography; PK: Pharmacokinetics.

Table 3. Objectives and end points.

Safety run-in cohort
Primary objectives • To evaluate the safety and tolerability of magrolimab in combination with other anticancer therapies • To determine the RP2D for combination with daratumumab, pomalidomide/dexamethasone, carfilzomib/dexamethasone, and bortezomib/dexamethasone	Primary end points • Incidence of DLTs, AEs, and laboratory abnormalities according to NCI CTCAE v5.0
Dose-expansion cohort
Primary objective • To evaluate the efficacy of magrolimab in combination with other anticancer therapies in patients with relapsed/refractory MM	Primary end points • ORR, defined as the percentage of patients who achieve complete response, stringent complete response, partial response, or very good partial response (IMWG 2016 criteria)
Secondary objectives • To evaluate the safety and tolerability of magrolimab in combination with other anticancer therapies • To investigate the depth of response, DOR, and survival • To evaluate the PK and immunogenicity of magrolimab combination therapy in relapsed/refractory MM	Secondary end points • Incidence of AEs and laboratory abnormalities according to NCI CTCAE v5.0 • DOR (measured from the earliest date of complete response, stringent complete response, partial response, or very good partial response to the earliest date of documented disease progression, relapse, or death from any cause), PFS (measured from the date of the first dose of study treatment to the earliest date of documented relapse, disease progression, or death from any cause), and OS (measured from the date of the first dose of study treatment to the date of death from any cause) (IMWG 2016 criteria) • Magrolimab concentration vs time and measurements of antidrug antibodies against magrolimab
Exploratory objectives • To evaluate the impact of magrolimab combination therapy on: • MRD negativity • Mutation profiles and mutation burden in myeloma cells • Immune effector cell composition and signaling molecules • Prophagocytic/antiphagocytic signal expressed by myeloma cells • Health-related quality of life • Time-to-response	Exploratory end points • MRD negativity rate (IMWG 2016 criteria) • Mutational profile of myeloma cells and the correlation with clinical response • Changes from baseline in biomarkers of immune cell recruitment and signaling molecules • Changes from baseline in known phagocytic regulators in myeloma cells • Change from baseline in FACT-MM questionnaire • Time-to-response (IMWG 2016 criteria)

AE: Adverse event; DLT: Dose-limiting toxicity; DOR: Duration of response; FACT-MM: Functional Assessment of Cancer Therapy – Multiple Myeloma; IMWG: International Myeloma Working Group; MM: Multiple myeloma; MRD: Minimal residual disease; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; PK: Pharmacokinetics; RP2D: Recommended phase II dose.