Bankova, Andriyana K.

Abstract Background: MGTA-145, a CXCR2 agonist, has shown promising activity for hematopoietic stem cell (HSC) mobilization with plerixafor in pre-clinical models and healthy volunteers. It has the potential to become the first GCSF free regimen for HSC mobilization/apheresis in preparation for transplant, with fewer side effects, better patient experience and optimal resource utilization. Methods: We conducted a single center phase 2 trial of MGTA-145 + plerixafor for HSC mobilization in patients with multiple myeloma (MM), NCT04552743. Primary endpoint was collection of ≥2 x 10 6 CD34+ cells/kg in up to 2 days of mobilization/apheresis. Secondary endpoints were collection of 4 and 6 x 10 6 CD34+ cells/kg, safety and engraftment. Patients with MM, 18-70 years of age, within 1 year of starting treatment & CrCl > 30 ml/min were eligible. Patients received plerixafor 0.24 mg/kg (0.16 mg/kg if renal dysfunction) SQ, followed 2 hours later by MGTA-145 (0.03 mg/kg) IV over 3-10 minutes and apheresis within 30 minutes. Mobilization and collection were repeated for a second consecutive day if day 1 yield was < 6 x 10 6 CD34+ cells/kg. The study was open-label single arm trial of 15 patients. If 13 or more patients met primary endpoint, an expansion cohort of 10 patients was planned. The trial has 85% power at a 5% one-sided type I error rate. Our analysis is based on aggregated results from total cohort of 25 patients. Results: Median age was 62 years, 52% were female, 24% had ISS stage 3, 57% had high-risk FISH (primarily gain1q). Induction therapy was VRD in 68% (17), daratumumab VRD in 24% (6), CyBorD in 8% (2) patients. Median duration of induction was 4 months (3-6) and median lenalidomide exposure was 5 cycles (1-8), with > VGPR in 88% of patients. (Table 1) Plerixafor 0.24 mg/kg was given in 24 (96%) patients. Median pre-apheresis CD34 count was day 1, 24/uL (3-99) & day 2, 15/uL (5-46). Median total HSC cell yield (CD34+ cells/kg x 10 6) was 5.0 (1.1-16.2), day 1 yield was 3.4 (0.3-16.2) and day 2 yield was 1.9 (0.5-4.6) (Fig1). 88% (n=22) of patients met the primary endpoint of collecting sufficient HSCs in < 2 days of mobilization + apheresis to proceed to transplant, 68% (17) in 1 day (2 x 10 6 CD34+ cells/kg). 3 patients who did not meet primary endpoint successfully collected HSCs with standard GCSF + plerixafor dosing & 2-3 apheresis sessions. Secondary endpoints of 4 and 6 x 10 6 CD34+ cells/kg in < 2 days were met in 68% (17) and 40% (10) patients. MGTA-145+plerixafor was well tolerated. At least 1 treatment emergent AE (TEAE) with MGTA-145 was seen in 60% of patients (grade 1, n= 14, grade 2, n=1). Pain (all grade 1) was most common, seen in 44% (11), with 38% (9) patients experiencing acute onset transient bone pain with MGTA-145 (duration: 7 minutes, range: 3-28). Using the validated Brief Pain Inventory, 56% (14) patients self-reported pain with mobilization vs 40% (10) at baseline. 7/15 patients without baseline pain reported pain with mobilization. An increase for worst pain was seen on mobilization day 1, that returned to the baseline, but no difference for aggregate score of pain severity/interference (linear mixed effects model). At last follow-up, 18 patients have completed transplant with MGTA-145 mobilized graft, with melphalan 200 mg/m 2 in 15 (83%) patients. Median of 3.5 (2.2-8.1) x 10 6 CD34+ cells/kg were infused. All patients have engrafted. Median time to neutrophil engraftment of 12 days (range: 11-15) & platelet engraftment (platelets > 20,000, no transfusion in 7 days) of 17.5 days (15-33) are comparable to historical data (DiPersio et al. 2009). RBC transfusion was needed in 3 (17%) patients. 14 patients have day 100 follow-up, all with durable engraftment. MGTA-145 + plerixafor mobilized grafts had a favorable graft composition. We observed high enrichment for CD90+CD45RA- among CD34+ cells, a CD34 subset of long term engrafting HSCs (median: 36% of CD34+ cells, range 10-66%, N=25). 74% (17 of 23) grafts were minimal residual disease negative with next generation flow cytometry. Conclusions: This is the first study to evaluate the novel G-CSF-free regimen of MGTA-145 + plerixafor for HSC cell mobilization & collection for hematologic malignancies. The study cohort was representative of transplant eligible patients with MM, with 88% patients meeting the primary endpoint. The regimen was well tolerated. Patients achieved timely & durable engraftment. Our data support further development of this regimen for rapid HSC mobilization. Figure 1 Figure 1. Disclosures Sidana: Janssen: Consultancy, Research Funding; Allogene: Research Funding; Magenta Therapeutics: Consultancy, Research Funding; BMS: Consultancy. Kumar: Bluebird Bio: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Antengene: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Roche-Genentech: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding. Arai: Magenta Therapeutics: Research Funding. Meyer: Indee, Jura: Consultancy; Orca Biosystems: Research Funding; GigaImmune: Current holder of stock options in a privately-held company; Triursus Therapeutics: Current holder of stock options in a privately-held company. Rezvani: US Department of Justice: Consultancy; Kaleido: Other: One-time scientific advisory board; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding. Weng: Kite Pharma: Research Funding. Frank: Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Allogene Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Shiraz: Kite Pharma-Gilead: Research Funding. Girgenti: Magenta Therapeutics: Current Employment. Goncalves: Magenta Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Schmelmer: Magenta Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Davis: Magenta Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Shizuru: Jasper Therapeutics, Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Chair of scientific advisory board; Forty seven Inc: Other: Inventor on a patent licenses by Forty Seven. Forty seven was acquired by Gilead in 2020. Miklos: Pharmacyclics: Patents & Royalties; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees.

8023 Background: MGTA-145 (GroβT), a CXCR2 agonist, has shown promising activity for HSC mobilization with plerixafor in pre-clinical models and healthy volunteers. Methods: This phase 2 single center study evaluates HSC mobilization with MGTA-145 + plerixafor and same day apheresis in patients with multiple myeloma. Patients received plerixafor 0.24 mg/kg (0.16 mg/kg if renal dysfunction) SQ, followed 2 hours later by MGTA-145 (0.03 mg/kg) IV over 3-10 minutes and apheresis within 30 minutes. Mobilization was repeated for a second day if day 1 yield was < 6 x 106 CD34+ cells/kg. This interim analysis reports on mobilization in 10 patients (of 25 planned), including safety cohort of first 6 patients completing transplant. Primary endpoint is collection of 2 x 106 CD34+ cells/kg. Results: Median age was 63 years (range: 46-68), 50% were female, 22% had ISS stage 3 & 50% had high-risk FISH. Induction therapy was VRD in 7 and daratumumab + VRD in 3 patients; median induction duration: 4 months (3-6) & median lenalidomide exposure: 6 cycles (4-6), with > VGPR in 70%. Median total stem cell yield (CD34+ cells/kg x 106) was 7.1 (3-16.2), day 1 yield was 5.4 (1.1-16.2) & yield per apheresis session was 4 (1.1-16.2). 100% of patients met the primary endpoint of collecting sufficient HSCs in < 2 days of mobilization + apheresis to proceed to transplant (2 x 106 CD34+ cells/kg). Secondary endpoints of 4 and 6 x 106 CD34+ cells/kg in < 2 days were met in 90% & 80% patients. 30% patients underwent 1 apheresis, while 70% underwent 2 sessions. MGTA-145 was well tolerated. At least 1 adverse event (AE) was seen in 90% of patients, 20% had grade 2 AEs (anemia, hypokalemia) and 20% had grade 3 AEs (worsening of baseline grade 3 anemia; hypocalcemia); all resolved. Acute & transient bone pain was seen in 40% of patients (back-2, hip-1, sternum-1), all grade 1, all on day 1, & resolved without intervention after 6 minutes (3-10). All 6 patients in the safety cohort have completed transplant with melphalan 200 mg/m2. Median of 4.1 (3.4-5.6) x 106 CD34+ cells/kg were infused. All patients have engrafted timely (DiPersio Blood 2009); median time to neutrophil engraftment: 12 days (11-13) & platelet engraftment: 17 days (16-19). Apheresis graft analysis is available in these 6 patients. Grafts with MGTA-145+plerixafor showed high enrichment for CD90+CD45RA- among CD34+ cells, a CD34 subset of long term engrafting HSCs (median: 31% of CD34+ cells, 27-52), higher than seen with G-CSF (6%, Goncalves TCT 2021). 67% of grafts were minimal residual disease negative with next generation flow cytometry. Conclusions: This is the first study to evaluate the novel regimen of MGTA-145 + plerixafor for same day stem cell mobilization & collection in myeloma/hematologic malignancies, with 100% efficacy in interim analysis and the first to demonstrate successful engraftment in patients with cells collected with this GCSF free regimen. Clinical trial information: NCT04552743.