Infusion-Related Reactions (IRRs) in the DREAMM-2 Study of Single-Agent Belantamab Mafodotin (Belamaf) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction: IRRs are commonly reported by patients receiving intravenous (IV) treatments for RRMM (Nooka et al. J Oncol Pract 2018); these can be troublesome for patients and can lead to discontinuation of treatment, negatively impacting durability of response. In the Phase II DREAMM-2 study (NCT03525678), single-agent belamaf (GSK2857916), a first-in-class B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate, demonstrated deep and durable responses with a manageable safety profile in patients with heavily pre-treated RRMM (Lonial et al. ASCO 2020; poster 436). As expected with IV biologic agents, IRRs were commonly reported in this study, but were considered self-limited. Here, we report details on IRRs for patients receiving belamaf 2.5 mg/kg (the recommended dose for future clinical development) after 13-months of follow-up.

Methods: In the DREAMM-2 study, patients with RRMM progressing after ≥3 prior therapies, refractory to an immunomodulatory agent and a proteasome inhibitor, and refractory and/or intolerant to an anti-CD38 monoclonal antibody, and who provided informed consent, received single-agent belamaf (2.5 or 3.4 mg/kg IV every 3 weeks) on Day 1 of each cycle until disease progression or unacceptable toxicity. Pre-medication for IRR prophylaxis was not protocol mandated (administered per investigator discretion, if deemed medically appropriate). These events were graded by Common Terminology Criteria for Adverse Events criteria version 4.03 and included the terms: IRR, pyrexia, chills, diarrhea, nausea, asthenia, hypertension, hypotension, lethargy, and tachycardia. Grade 2 IRRs were managed by stopping the infusion, providing medical treatment and continuing the infusion at half the original infusion rate until resolution to Grade ≤1. Grade 3 IRRs were managed by discontinuing the infusion until recovery to Grade ≤1, after which the treatment could only continue (with pre-medication and a longer infusion time) following discussion with the study sponsor; all future infusions were pre-medicated. Patients experiencing Grade 4 IRRs were permanently withdrawn from the study. IRRs were followed until resolution/stabilization.

Results: After 13-months of follow-up, IRRs occurred in 20/95 (21%) patients; most were mild to moderate in severity, with no Grade 4 or 5 events (Grade 1, n=6 [30%]; Grade 2, n=11 [55%]; Grade 3, n=3 [15%]). Pyrexia was reported in 5/20 (25%) patients; chills, diarrhea, and nausea in 2/20 (10%) each; asthenia, hypertension, lethargy, and tachycardia in 1/20 (5%) patients each; and the adverse event term ‘IRR’ was recorded for 16/20 (80%) patients. In most patients (18/20 [90%]), IRRs occurred during Cycle 1, and the incidence of these events declined thereafter (Figure). Of 73/95 (77%) patients without pre-medication at Cycle 1, 12 (16%) experienced an IRR. A total of 22/95 (23%) patients received a pre-medication at Cycle 1; of these, 8 (36%) had an IRR. Among the 20 patients experiencing an IRR, 11 (55%) received ≥1 pre-medication over the course of the study (most commonly: antihistamine, n=6 [30%]; analgesic (paracetamol); n=7 [35%]; steroid, n=6 [30%]). The median time of onset of the first IRR occurrence was at Day 1 (range: 1–22). The median duration of IRRs was 1 day (range: 1–3). Most patients experiencing IRRs (12/20 [60%]) had only one event; 3 (15%) experienced two IRRs and 5 (25%) patients had ≥3 events. Treatment was permanently discontinued due to IRRs in 1 (5%) patient (Grade 3 IRR at first and second infusion); no dose reductions or interruptions/delays occurred due to an IRR. At 13-month follow-up, IRRs were considered recovered/resolved in most (18/20 [90%]) patients (recovered/resolved with sequelae; recovering/resolving, n=1 [5%] each).

Conclusions: As expected with biologic treatments administered via IV infusion, IRRs were reported with belamaf in the DREAMM-2 study. However, IRRs were typically mild-to-moderate in severity and most were considered resolved at 13-month follow-up. Importantly, IRRs resulted in few dose modifications or discontinuations, allowing patients to continue active belamaf treatment, which has been associated with durable responses in patients with RRMM.

Funding: GSK (Study 205678; drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.