Modakafusp Alfa Exhibits Antitumor Activity, Immune Activation in Myeloma

Modakafusp alfa induced the upregulation of the type 1 interferon gene signature score, and increased CD38 receptor density in CD-38–positive cells.

Modakafusp alfa, an immunocytokine, exhibited antitumor activity and immune activation in patients with relapsed or refractory multiple myeloma treated with 3 prior lines of therapy who were refractory to at least 1 proteasome inhibitor (PI) and at least 1 immunomodulatory drug (IMiD), according to results from a phase 1/2 trial (NCT03215030) published in Blood.¹

Findings from the study showed that among patients with relapsed or refractory multiple myeloma (n = 89), 20 patients achieved a response. Notably, among those treated with 1.5 mg/kg of modakafusp alfa every 4 weeks (n = 30), the overall response rate (ORR) was 43.3% (n = 13, 95% CI, 25.5%-62.6%), with 3 complete responses (CRs), 1 of which was stringent, and 6 very good partial responses (VGPRs). The median time to response (TTR) in the 1.5 mg/kg group was 1.1 months, the median duration of response (DOR) was 15.1 months (95% CI, 7.1-26.1), and the median progression-free survival (PFS) was 5.7 months (95% CI, 1.2-14.0).

Further data revealed among 7 patients treated at the maximum tolerated dose (MTD) of 3 mg/kg every 4 weeks, the ORR was 42.9% (n = 3/7), including 1 CR and 2 VGPRs. Furthermore, this population attained a median DOR of 10.2 months (95% CI, 7.9-not reached [NR]). Additionally, among 4 patients evaluable for minimum residual disease (MRD) at a sensitivity of 10^-5, 1 patient in the 1.5 mg/kg group was reported as having MRD-negative disease at cycle 8.

“Our first-in-human phase 1/2 trial demonstrates that modakafusp alfa is well tolerated at doses that have single-agent activity in patients with heavily pretreated [relapsed/refractory multiple myeloma],” Dan T. Vogl, MD, MSCE, associate professor of Hematology/Oncology and director of the Abramson Cancer Center Clinical Research Unit at the Hospital of the University of Pennsylvania, wrote in the publication with study coinvestigators.¹ “[M]odakafusp alfa is an immunocytokine that delivers interferon α to [CD38-positive] cells, resulting in immune activation and antitumor activity. The immune stimulatory effects of modakafusp alfa, along with its manageable toxicity profile, monthly administration, and distinct CD38 binding epitope, suggest a potential for combination with a wide range of antimyeloma therapies including IMiDs, PIs, anti-CD38 antibodies, and T cell–redirecting therapies.”

In the dose-escalation phase of the study, 56 patients with relapsed/refractory multiple myeloma were given escalating doses of modakafusp alfa intravenously in 21- or 28-day cycles starting from 0.001 mg/kg up to 6 mg/kg. An initial schedule of the investigational agent began with weekly administration for cycles 1 and 2, every 2 weeks for cycles 3 to 6, and every 4 weeks thereafter. Following dose-limiting cytopenias, additional cohorts explored dosing every 2, 3, or 4 weeks.

During dose escalation (n = 50), modakafusp alfa was given as a single agent, with 20 mg of dexamethasone given as a premedication, as well as diphenhydramine and acetaminophen (Tylenol). Initially, 2 expansion cohorts evaluated 0.4 mg/kg every 3 weeks and 1.5 mg/kg every 4 weeks, respectively. Additional expansion cohorts included treatment with dexamethasone to assess its effect on the efficacy and the immunostimulatory effects of modakafusp alfa on patients.

Among all patients enrolled on the study (n = 106), the median age was 64.5 years (range, 34-84). A total of 58.5% of this population was male, 77.4% were White, and the median time since diagnosis was 5.6 months (range, 1.4-22.7). Most patients had an ECOG performance status of 1 or greater (79.2%), had an International Staging System class of II (40.6%), and had a median of 6.5 lines of prior therapy (range, 3-19).

The primary end points of part 1 included treatment emergent adverse effects (TEAEs), dose-limiting toxicities (DLTs), and dose modifications.² For part 2, the primary end point was ORR. Secondary end points included area under the serum concentration-time curve, DOR, TTR, and PFS.

Among all patients, the most common AEs included thrombocytopenia (any-grade: 77.4%; grade 3 or 4: 51.9%), neutropenia (59.4%, 53.8%), leukopenia (54.7%, 39.6%), anemia (50.9%, 29.2%), and lymphopenia (37.7%, 27.4%). In total, 13 (12.3%) patients had serious drug-related AEs, and 13 had AE-related drug discontinuations.

References

1. Vogl DT, Atrash S, Holstein SA, et al. Targeted interferon therapy with modakafusp alfa for relapsed or refractory multiple myeloma. Blood. 2025;145(9):944-955. doi:10.1182/blood.2024026124
2. A study of modakafusp alfa on adult participants with relapsed/​refractory multiple myeloma (iinnovate-1). ClinicalTrials.gov. Updated December 24, 2024. Accessed March 10, 2025. https://tinyurl.com/pb5nyykm