Phase 1 first-in-human study of MEDI2228, a BCMA-targeted ADC, in patients with relapsed refractory multiple myeloma.

Dimopoulos, Meletios A.; Migkou, Magdalini; Bhutani, Manisha; Ailawadhi, Sikander; Kalff, Anna; Walcott, Farzana L.; Pore, Nabendu; Brown, Miranda; Wang, Fujun; Cheng, Lily I.; Kagiampakis, Ioannis; Williams, Marna; Kinneer, Krista; Wu, Yuling; Jiang, Yu; Kubiak, Robert J.; Zonder, Jeffrey A.; Larsen, Jeremy; Sirdesai, Shreerang; Yee, Andrew J.

MEDI2228 is an antibody drug conjugate (ADC) comprised of a fully human B-cell maturation antigen (BCMA) antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer. This phase 1 trial evaluated MEDI2228 in patients with relapsed/refractory (R/R) multiple myeloma (MM), who received prior treatment with approved agents from 3 classes of antimyeloma drugs (proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies). Primary endpoint was safety and tolerability; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. A total of 107 patients were treated and the maximum tolerated dose (MTD) was 0.14 mg/kg Q3W. Two patients had dose-limiting toxicities (DLTs; thrombocytopenia; 0.20 mg/kg Q3W). The most frequent treatment-related adverse events were photophobia (43.9%), rash (29.0%), and thrombocytopenia (19.6%). In MTD cohort A (n = 41), the objective response rate (ORR) was 56.1%, with 1 stringent complete response, 9 very good partial responses, and 13 partial responses. ORR was 53.3% in triple refractory patients. In cohort B (n=25), ORR was 32%. Although MEDI2228 demonstrated efficacy in R/R MM, ocular toxicity precluded further development of this drug. KEY POINTS: MEDI2228 is an ADC comprised of a fully human anti-BCMA antibody conjugated to the cytotoxic PBD payload, tesirine. MEDI2228 monotherapy demonstrated efficacy across all dose levels; and responses were observed in patients with triple refractory MM. This study further validates BCMA as a target for ADC-based therapy in MM; ocular toxicity precluded further clinical development.

OCULAR toxicology; ADVERSE health care events; MULTIPLE myeloma; DRUG development; PROTEASOME inhibitors

Leukemia & Lymphoma, 2024, Vol 65, Issue 12, p1789

1042-8194

Academic Journal

10.1080/10428194.2024.2373331