Reducing Infusion Times for Isatuximab in Myeloma: Improving Treatment Convenience and Scheduling

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The therapeutic landscape of multiple myeloma (MM) has undergone a remarkable and tectonic change in recent decades, yielding improved outcomes for patients. Monoclonal antibody (mAb)-based therapies are recent additions to the MM treatment landscape, with the regulatory approval of daratumumab, elotuzumab, and isatuximab.1 The clinical efficacy of mAb therapies establishes their significance in MM management for years to come.

Overall, mAb therapy in MM is well-tolerated, with modest and predictable adverse reactions, without the severe toxicities associated with traditional cytotoxic/myelosuppressive agents.2–4 Infusion reactions (IRs) are the most common adverse effects associated with mAb-based treatments.2,3 Mild-to-moderate IRs present with chills, fever, dyspnea, and rash, while more severe and rare IRs include anaphylaxis, severe hypotension, and cardiac dysfunction.3 Current mAb therapy-associated IRs in MM are mostly of grade 1 or 2, manifesting more often with the first, and sometimes, second infusion.4–6 IRs can be managed with pre-/post-infusion medications, including antihistamines, corticosteroids, and acetaminophen.4–6

While treatment discontinuation rates for mAb therapies in MM are low (<1%) across studies, lengthy and/or frequent infusions can impact treatment burden and indirect costs, compared with all-oral regimens.7,8 Strategies that reduce infusion times without compromising clinical efficacy can help improve treatment scheduling, convenience, and adherence.

In our study, we addressed the feasibility of a fixed-volume infusion of isatuximab, used in combination with pomalidomide and dexamethasone, for treatment of patients with relapsed/refractory MM. Incremental increase of the infusion rate is one approach for mitigating IRs, by reducing infusion times.3 In the dose-escalation Part A of this Phase 1b study, patients received isatuximab at 5, 10, or 20 mg/kg in four weekly doses (cycle 1), and every other week thereafter, plus pomalidomide and dexamethasone. Isatuximab was administered via intravenous infusion, initially at 87.5 mg/hour (5 mg/kg cohort) or 175 mg/hour (10 and 20 mg/kg cohorts), with an increase of 50 mg/hour (first infusion) and 100 mg/hour (subsequent infusions) to a maximum of 400 mg/hour, every half hour, in the absence of IRs.

In the Part B expansion cohort, a 250 mL fixed-volume infusion of isatuximab (10 mg/kg) was administered plus pomalidomide and dexamethasone, with the rate increased after the first infusion. The median infusion time decreased from 3.7 hours during the first infusion to 1.85 hours and 1.25 hours (75 minutes) during the second and subsequent infusions, respectively (Figure). The infusion times were shorter after the first infusion than that with weight-based dosing (mg/hour) in Part A (2.9 hours) and in the pivotal Phase 3 ICARIA-MM study (2.8 hours). All IRs were grade 2, occurred during the first infusion, and resolved on the same day. Importantly, the safety and efficacy of the fixed-volume infusion was comparable to that with weight-based dosing; the overall response rate here was 53.2%, while in Part A it was 62.2% and in the isatuximab plus pomalidomide and dexamethasone arm of ICARIA-MM it was 60%.

Administration of isatuximab as fixed-volume decreases the infusion time to 75 minutes by the third infusion

The fixed-volume infusion of isatuximab reduced infusion time by >60 minutes for the second infusion and >90 minutes for the subsequent infusions, compared with weight-based infusion, and are the shortest of any approved anti-CD38 mAb. This infusion method is approved in the US and EU; the isatuximab plus pomalidomide and dexamethasone regimen is approved in more than 40 countries.

 

References

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Saad Usmani

Division Chief, Plasma Cell Disorders; Director, Clinical Research (Hematologic Malignancies), Levine Cancer Institute/Atrium Health