Randomized Phase 2 Dose Optimization Trial of Modakafusp Alfa in Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Atrash Shebli , Holstein Sarah A. , Mian Hira , Dimopoulos Meletios A. , Schjesvold Fredrik , Popat Rakesh , Shah Nishi , Gatt Moshe E , Gocke Christian B. , Frenzel Laurent , Touzeau Cyrille , Beksac Meral , Manier Salomon , Magen Hila , Travis Patrick M. , Nadeem Omar , Suryanarayan Kaveri , Li Shuli , Parot Xavier , Vogl Dan T. 
Published: December 2024

Modakafusp alfa is a first-in-class immunocytokine directing interferon-α to CD38-positive cells. In our previously reported phase 1/2 trial, the maximum tolerated dose of modakafusp alfa in patients with RRMM was 3 mg/kg every 4 weeks (q4w). In a cohort of 30 patients treated with single-agent modakafusp alfa 1.5 mg/kg q4w, the overall response rate (ORR) was 43% and median duration of response was 12.5 months; toxicities were primarily hematologic (Vogl DT, et al. Blood. 2022:140(Suppl 1):1357-59). Here, we describe the results of a non-comparative randomized phase 2 dose optimization study evaluating modakafusp alfa at the fixed-dose equivalents of 3.0 mg/kg and 1.5 mg/kg q4w (NCT03215030).

Patients with triple-class refractory RRMM (refractory to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible if they had progressed on their last line of therapy. Patients were randomized to receive modakafusp alfa q4w at 240 mg or 120 mg intravenously over 1 hour, with corticosteroid use limited to dexamethasone 20 mg as premedication with each dose of modakafusp alfa. The primary endpoint was ORR. No formal statistical comparison between the two doses was planned.

In total, 146 patients (71 patients in the 120 mg cohort and 75 in the 240 mg cohort) were accrued over 57 global sites and started treatment between Jun 2022 and Sep 2023. The data cutoff date for this final analysis was Feb 9, 2024. The median number of prior lines of therapy received was 6 (range, 3-17) in the 120 mg cohort and 6 (range, 3-15) in the 240 mg cohort. Rates of exposure to prior anti-B cell maturation antigen therapy were 48% and 43%, respectively. At a median follow-up of 7.3 months, the ORR was 32% (95% confidence interval [CI], 22-45%) in the 120 mg cohort and 41% (95% CI, 29-52%) in the 240 mg cohort, with median progression-free survival of 4.1 and 5.3 months, and median duration of response of not estimable and 9.2 months, respectively. In the combined cohort of 146 patients, ORR was 29% in patients exposed to an anti-B-cell maturation agent (BCMA), and 44% in non-anti-BCMA-exposed patients. Rates of grade 3 or higher adverse events (AEs) were 90% in the 120 mg cohort and 96% in the 240 mg cohort, with the majority of AEs being hematologic (grade 3-4 hematologic AE rates: 86% and 92%, respectively). Grade 3 and 4 thrombocytopenia were observed in 28% and 27% of patients in the 120 mg cohort, and 32% and 29% of patients in the 240 mg cohort, respectively. Grade 3 and 4 neutropenia were observed in 35% and 21% of patients in the 120 mg cohort, and 45% and 23% of patients in the 240 mg cohort, respectively. Rates of serious AEs were 39% in the 120 mg cohort and 44% in the 240 mg cohort. Rates of grade 3-4 infections were 21% and 15%, respectively. Infusion-related reactions (IRRs) were observed in 25% of patients in the 120 mg cohort, and 16% of patients in the 240 mg cohort, with rates of grade 3 IRRs of 3% in each cohort. Three patients (4%) died on study in the 120 mg cohort, and 5 patients (7%) died on study in the 240 mg cohort.

Our results confirm the efficacy of single-agent modakafusp alfa in patients with RRMM. The 240 mg dose appears to have resulted in both a higher ORR and higher rates of toxicity, which were primarily hematologic.