MK-4002, a B-cell maturation antigen-targeting T-cell engager, in relapsed or refractory multiple myeloma: a...

The optimal treatment strategy for relapsed or refractory multiple myeloma remains unclear. This first-in-human study aimed to evaluate the safety, preliminary activity, and pharmacokinetics of the trispecific B-cell maturation antigen-targeting T-cell engager MK-4002 in relapsed or refractory multiple myeloma.

This open-label, phase 1 study was conducted at 12 sites (hospitals and cancer centres) in France, Spain, and the USA. Participants were aged 18 years or older, had relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status score of 0 to 2, and had received at least three previous therapies. Participants received MK-4002 at doses from 0·005 mg to 24 mg intravenously weekly or every 2 weeks following a dose escalation design. One participant was enrolled per dose level, starting at 0·005 mg. Once an adverse event of grade 2 or worse or a dose-limiting toxicity was observed, the study transitioned to a 3 + 3 dose escalation phase. Initially, dose escalation occurred in fixed-dose cohorts (target dose weekly on day 1 of each cycle). Once a grade 2 or worse cytokine release syndrome event occurred, step-up dosing began (treatment initiated with at least one priming dose on day 1 of cycle 1 followed by the target dose weekly or every 2 weeks). Dose escalation continued until the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), or both, were identified. Expansion cohorts of up to 15 participants were added to assess regimens and schedules at dose levels considered safe by the Cohort Review Committee. Primary endpoints were safety; MTD, RP2D, or both; and pharmacokinetics. The key secondary endpoint was overall response rate (ORR) per International Myeloma Working Group criteria. Safety was analysed in all participants who received at least one dose of MK-4002. ORR was analysed in all participants who received at least one dose of MK-4002 and had at least one postbaseline disease assessment. This study is registered with ClinicalTrials.gov (NCT04184050) and is ongoing but closed to recruitment.

Between April 21, 2020, and June 28, 2023, 97 participants were enrolled and treated across 17 fixed-dose, stepped-dose, and dose-expansion cohorts. Median age was 69 years (IQR 61-74); 50 participants (52%) were male and 47 (48%) female. Median time since diagnosis was 6·8 years (IQR 4·2-9·9), and participants had received a median of six (IQR 4-8) previous lines of therapy. Median time from first dose to data cutoff was 27·1 months (IQR 15·7-34·3). Dose-limiting toxicities occurred in six participants. The MTD for the fixed dose was established as 2·15 mg and was not reached in the stepped-dose cohorts. Adverse events occurred in 97 participants (100%); 77 (79%) had grade 3 or worse events. The most common grade 3 or worse adverse events were anaemia (33 participants [34%]), neutrophil count decreased (22 participants [23%]), and neutropenia (18 participants [19%]). Serious adverse events occurred in 56 participants (58%). One participant (1%) died due to treatment-related traumatic subdural haematoma. Cytokine release syndrome occurred in 29 participants (30%): grade 1-2 occurred in 27 participants, and grade 3 occurred in two participants (both after a 24 mg dose). MK-4002 exhibited dose-proportional pharmacokinetics with a median half-life of 68 h (range 52-76). ORR was 41% (95% CI 22-61) in the 2·15-6 mg dose group (nine of 27 participants had a very good partial response or better), 63% (38-84) in the 12 mg group (ten of 19 participants had a very good partial response or better), and 48% (31-67) in the 24 mg dose group (12 of 33 participants had a very good partial response or better). Taking safety and activity results together, a target dose of 12 mg was identified as the preliminary RP2D.

MK-4002 had manageable safety and clinical activity at doses of 2·15 mg or higher in participants with heavily pretreated relapsed or refractory multiple myeloma. Optimal safety and activity were observed at 12 mg, supporting further clinical evaluation of this dose.

Harpoon Therapeutics, a subsidiary of Merck & Co, Rahway, NJ, USA.