Isatuximab Short-Duration Fixed-Volume Infusion Combination Therapy for Relapsed/Refractory Multiple Myeloma: Final Results of a Phase 1b Feasibility/Safety Study

Background: Isatuximab (Isa), in combination with pomalidomide (P) plus dexamethasone (d), is approved in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult patients with RRMM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. The simplified method of a fixed volume used to reduce infusion duration of Isa, a CD38 monoclonal antibody, was previously confirmed to be feasible and safe in the primary analysis.

Aims: To evaluate the efficacy and safety of a fixed-volume infusion of Isa in combination with Pd in relapsed/refractory multiple myeloma (RRMM).

Methods: This open-label, multicenter, two-part, Phase 1b study (NCT02283775), enrolled RRMM patients aged ≥18 years, who had received ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor, and who demonstrated disease progression. Part A was an Isa dose-escalation study. In Part B, Isa (10 mg/kg) was administered as a fixed infusion volume of 250 mL (mL/h infusion rate) with standard doses of Pd. The primary endpoint for Part B was the incidence of Grade ≥3 infusion reactions (IRs) during the first 6 Isa infusions (patients treated for ≥2 cycles). Secondary endpoints included duration of infusion, safety, efficacy, and immunogenicity.

Results: Of 47 patients enrolled and treated in Part B, 22 (47%) remained on treatment at data cut-off. Prior to study entry, 23 (49%) and 11 (23%) patients had received P and carfilzomib, respectively; all patients with prior P exposure were refractory to P. Seven (15%) and 9 (19%) patients, respectively, had received prior daratumumab (Dara) and elotuzumab. All patients with prior Dara exposure were refractory to Dara; none of the patients received Dara as last regimen. The overall median duration of exposure was 36.9 weeks (range 1–77) and number of cycles was 9 (median; range 1–19). IRs were reported in 19/47 (40%) patients, all Grade 2 in severity (no Grade ≥3), and occurred only during the first infusion. Median duration of the first, second and ≥3 infusions were 3.7, 1.8 and 1.2 hours, respectively. All patients experienced ≥1 treatment-emergent adverse event (TEAE). Safety data are summarized in the Table. The most common non-hematologic TEAEs were fatigue (64%), IRs (40%), cough (40%), and upper respiratory tract infection (40%); 6 patients (13%) died within 30 days of their final study treatment. The overall response rate (ORR) was 53% in all patients (56% in response evaluable population) and 60% in those without prior Dara. In 6 patients evaluable for response who had prior Dara exposure, 1 had partial response, 2 had minimal response, and 3 had stable disease. The ORR in patients with prior P treatment and those without prior P or Dara was 52% (12/23) and 56% (13/23), respectively. Median time to first response was 0.95 months (range 0.9–3.4). At a median duration of 9.9 months follow-up (range 0–17.3), median duration of response (DOR), progression free survival (PFS), and overall survival (OS) were not reached. Six- and 12-month probability of PFS were 65% (95% CI: 49–77%) and 56% (95% CI: 40–69%), respectively, and 6- and 12-month OS were 84% (95% CI: 70–92%) and 71% (95% CI: 54–82%), respectively.

Conclusions: Efficacy and safety findings observed in the current study were consistent with the data from the Isa-Pd infusion schedule reported in the pivotal Phase 3 ICARIA study. Measurements of response were robust, with the median DOR not reached. There were no Grade ≥3 IRs, and no further IRs observed after ≥2 infusions, despite the increased infusion rate and shorter infusion duration of the second and subsequent infusions. These results confirm the safety, efficacy and feasibility of Isa administered by a fixed infusion volume method.