The Clinical Efficacy of MEDI2228 in Treating Relapsed/Refractory Multiple Myeloma

MEDI2228, an antibody-drug conjugate (ADC) that targets the extracellular domain of human B-cell maturation antigen (BCMA), demonstrated clinical efficacy at all dose levels in treating patients with relapsed/refractory multiple myeloma (RRMM), according to data presented at the virtual American Society of Hematology (ASH) conference.

The researchers explained that the results from a phase 1, first-in-human, open-label, dose-escalation and expansion trial showed that MEDI2228 administered at 0.14 mg/kg every 3 weeks to patients was observed to have a manageable safety profile and an overall response rate (ORR) of 61% in a population with RRMM following heavy pretreatment with proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibody (mAb) therapies.

MEDI2228 can target BCMA, which is expressed on normal plasma cells and malignant plasma cells in MM, with preferential binding to membrane-bound versus circulating soluble BCMA. MEDI2228 consists of a completely human antibody to BCMA, which is site-specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer through a protease-cleavable linker.

Following binding to BCMA, MEDI2228 internalizes and cleaves in the lysosomal compartment. This then releases the active PBD, which can cross-link DNA, resulting in apoptotic cell death.

The study, which evaluated the safety, pharmacokinetics (PK), and clinical activity of MEDI2228 in treating RRMM, included patients who were aged 18 years or older with confirmed RRMM as defined by International Myeloma Working Group consensus criteria. The patients eligible for inclusion also had measurable disease and an Eastern Cooperative Oncology Group performance status of less than or equal to 1.

Following treatment, patients must have progressed with 3 classes of standard-of-care anti-myeloma drugs, including PIs, IMiDs, and mAbs. The calculations for dose escalation in the study were based on the accelerated titration design, using an mTPI-2 algorithm.

Although dose escalation occurred, MEDI2228 was given in dose levels in ascending order, from 0.0125 to 0.025, 0.05, 0.1, and 0.2 mg/kg given intravenously every 3 weeks. Based on the occurrence of dose-limiting toxicities (DLTs), the dose was decreased from 0.2 mg/kg to 0.14 mg/kg.

By May 15, 2020, 82 patients were given MEDI2228 during dose escalation and expansion. All patients had already received therapy with an IMiD, PI, and mAb: lenalidomide (94%), pomalidomide (84%), bortezomib (95%), carfilzomib (79%), and daratumumab (87%). Patients were given between 2 and 11 lines of prior regimens.

At 0.2 mg/kg, 2 patients were observed to have DLTs at grade 3/4 thrombocytopenia, although they did not have bleeding; however, for other dose levels, no DLTs were reported. Among patients observed, the maximum tolerated dose was 0.14 mg/kg administered every 3 weeks.

In the 0.14 mg/kg cohort, treatment-related adverse events (TEAEs) were observed in approximately 20% of patients, including occurrences of photophobia (53.7%), thrombocytopenia (31.7%), rash (29.3%), increased gamma-glutamyltransferase (24.4%), dry eye (19.5%), and pleural effusion (19.5%). However, no reports of keratopathy or visual acuity loss were experienced by the 0.14 mg/kg cohort. At lower-dose levels, the TEAE profiles were similar but with lower incidences than at the 0.14 mg/kg level.

The researchers observed that efficacy was present at all dose levels. In the 0.14 mg/kg cohort, ORR was 61.0%, with 10 (24.4%) very good partial responses (VGPRs), 15 (36.6%) partial responses, and 3 (7.3%) minimal responses. Additionally, 4 of the observed VGPR patients were immunofixation negative. Also, most (90.2%) of the patients in the 0.14 mg/kg cohort had been administered prior to daratumumab, and the median duration of response in this cohort was not reached.

MEDI2228 was found to have linear PK at doses of greater than or equal to 0.05 mg/kg when administered every 3 weeks. The linear PK was found to be minimally affected by the circulating levels of soluble BCMA at baseline.

There was also no difference in BCMA expression by immunohistochemistry in the bone marrow of responders compared with those of nonresponders. In total, 36 patients in the 0.14 mg/kg cohort discontinued treatment due to adverse events, progressive disease, patient decision, investigator decision, or death.

REFERENCE

Myeloma/Amyloidosis: Therapy, excluding Transplantation: Novel Therapies Targeting B Cell Maturation Antigen in Relapsed/Refractory Multiple Myeloma. Poster presented at ASH 2020 Virtual Conference. December 5, 2020.