Phase 1 Dose-Escalation Study of Sotatercept (ACE-011) in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma
Authors: Yee Andrew J. , Laubach Jacob P. , Nooka Ajay K. , O'Donnell Elizabeth K. , Weller Edie A. , Couture Nicole R. , Wallace Ellen E. , Burke Jill N. , Harrington Cynthia C. , Puccio-Pick Marie , Laadem Abderrahmane , Sherman Matthew L. , Raje Noopur S. 
Published: October 2019

Abstract
Introduction
Anemia and bone disease are hallmarks of multiple myeloma (MM). Sotatercept (ACE-011) is a novel, first-in-class activin type IIA receptor fusion protein that binds with high affinity to activin A and GDF11, and it acts during late-stage erythropoiesis to increase the production of mature erythrocytes through a mechanism independent of erythropoietin. Sotatercept has shown promising activity in clinical trials for anemia in myelodysplastic syndromes (Komrokji et al., ASH 2014) and in thalassemia (Cappellini et al., EHA 2015). Additionally, we have shown that targeting activin A through an analog of sotatercept reverses osteoblast inhibition and improves MM bone disease in a mouse model (Vallet et al., PNAS 2010). Lenalidomide increases activin A secretion with consequent inhibition of osteoblastogeneis, and this can be abrogated by treatment with an activin A neutralizing antibody (Scullen et al., Leukemia 2013). Sotatercept has been previously studied with melphalan, prednisolone, and thalidomide in MM (Abdulkadyrov et al., Br J Haematol 2014). Based on these findings, we evaluated sotatercept in combination with lenalidomide and dexamethasone in MM (NCT01562405).
Methods
Patient with relapsed and/or refractory MM with at least one prior line of therapy, anemia with hemoglobin <13 g/dL, lytic bone disease, and otherwise adequate organ function were eligible to participate. Sotatercept 10, 15, 30, or 45 mg was given s.c. q28 days along with lenalidomide and weekly dexamethasone on a standard 28 day schedule, with dose escalation following a 3 + 3 design. Sotatercept was held for hemoglobin ≥13 g/dL or for ≥ grade 3 hypertension. Bone mineral density by DEXA was assessed after four cycles. Bisphosphonates were not permitted during the study; prior bisphosphonate therapy was allowed.
Results
Thirteen patients with a median age of 62 years (range 49-77) and a median of 2 prior lines (range 1-5) of therapy have been enrolled to date (July 31, 2015). Median duration of treatment is 8.1 months (range 0.5, 27 months); five patients continue on study. The MTD has not been reached, and the current dosing level is sotatercept 45 mg with lenalidomide 25 mg. Grade 3-4 adverse events included anemia (38%), diarrhea (15%), fatigue (15%), hypophosphatemia (15%), and thrombocytopenia (38%). Grade 3 hypertension occurred in one patient receiving sotatercept 15 mg (hemoglobin at the time, 11.5 g/dL). There was one death on study that was unrelated to treatment. In patients who completed at least two cycles of treatment, there was a significant mean increase in hemoglobin on study of 0.94 g/dL (N = 10, p = 0.0048) from a mean starting hemoglobin 10.27 g/dL (range 8.6, 12.2). Mean maximal increase in hemoglobin was 2.11 g/dL (range 1.1, 4). Bone density by DEXA was assessed after four cycles. In patients who received a cumulative dose of sotatercept over 45 mg (N = 6), total lumbar spine BMD increased by a mean of 2.0% after four cycles; 83% had increase in BMD. ORR for this combination was 60% (CR = 1, VGPR = 1, PR = 4, SD = 4) in patients evaluable for response.
Conclusion
Sotatercept in combination with lenalidomide and dexamethasone is well tolerated with expected toxicities related to lenalidomide in MM. Preliminary data from this ongoing study suggest that sotatercept leads to early increases in both hemoglobin and bone mineral density, and it is the first agent that may address both of these significant causes of morbidity in MM.

Disclosures
Laubach: Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Nooka:Onyx Pharmaceuticals: Consultancy; Spectrum Pharmaceuticals: Consultancy. O'Donnell:Millennium: Consultancy. Puccio-Pick:Celgene Corp.: Employment. Laadem:Celgene Corporation: Employment. Sherman:Acceleron Pharma: Employment. Raje:Acetylon: Research Funding; AstraZeneca: Research Funding; Onyx: Consultancy; Takeda: Consultancy; Eli Lilly: Research Funding; Millenium: Consultancy; Novartis: Consultancy; Amgen: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy.