The phase 2 ISASOCUT study, published in Blood Cancer Journal, evaluated subcutaneous isatuximab delivered through an on-body injector (OBI) within frontline Isa-VRd therapy for multiple myeloma. It met its primary response endpoint: 88% of patients achieved a very good partial response or better at eight months. The OBI completed 99.3% of more than 2,500 injections, a reliable subcutaneous administration.

Following the FDA approval of subcutaneous isatuximab, ISASOCUT provides additional regimen-specific evidence on efficacy, safety and treatment delivery in the frontline transplant-ineligible setting.

Moving From IV to Subcutaneous Delivery

Isa-VRd is an established frontline option for transplant-ineligible patients with newly diagnosed multiple myeloma after the phase 3 IMROZ and BENEFIT trials. CD38 antibody therapy is increasingly common, and because it continues until progression, infusion time and repeated hospital visits add up. Intravenous isatuximab has historically required about 75 minutes per infusion from the third administration onward, though 30-minute infusions have since been evaluated.

A fixed-dose subcutaneous formulation delivered through an OBI has already been studied in relapsed or refractory multiple myeloma. In the randomized phase 3 IRAKLIA trial, subcutaneous isatuximab combined with pomalidomide and dexamethasone was noninferior to intravenous administration for the co-primary endpoints. Infusion-related reactions occurred in 1.5% of patients receiving subcutaneous treatment and 25% of those receiving intravenous treatment.

Study Design

ISASOCUT was a prospective, single-arm phase 2 trial at 23 centers in France. It enrolled 80 patients aged 65 or older with newly diagnosed multiple myeloma who were ineligible for autologous stem cell transplantation, with an ECOG performance status of 0-2 and a Charlson comorbidity index of 1 or lower. Of these, 74 received treatment. Median age was 73 years, 31% were 75 or older, and 36% had high-risk disease by IMS/IMWG consensus genomic criteria.

Patients received a fixed 1,400-mg subcutaneous dose of isatuximab through the OBI, weekly in cycle 1 and twice monthly through cycle 12, plus lenalidomide, dexamethasone, and bortezomib (twice weekly in cycle 1, weekly in cycles 2-12). From cycle 13, patients continued monthly isatuximab plus lenalidomide, without bortezomib or dexamethasone, until progression, unacceptable toxicity, or withdrawal.

The primary endpoint was the rate of very good partial response or better at eight months. Secondary endpoints included measurable residual disease, progression-free survival, event-free survival, and safety.

Responses and Early Survival

Sixty-five of 74 patients (88%) reached a very good partial response or better at eight months, exceeding the prespecified 70% threshold and meeting the primary endpoint.

Key efficacy outcomes included:

Very good partial response or better: 88% at eight months
Complete response or better: 19%
Median time to very good partial response or better: Three months
MRD negativity at 10⁻⁵ sensitivity: 36%
MRD negativity at 10⁻⁶ sensitivity: 28%

Responses were generally consistent across the age and cytogenetic-risk subgroups, but the subgroups were small, which limits conclusions for patients with high-risk genomic features. The MRD rate is close to the 36.6% at 10⁻⁵ reported after six months in IMROZ. Differences in treatment schedules, assessment timing and study populations limit the comparison.

At a median follow-up of 21.2 months, estimated progression-free survival at 14 months was 93.1% and event-free survival was 91.7%. Event-free survival counted permanent treatment discontinuation for any reason, so it also reflects the tolerability of prolonged quadruplet therapy. Only four patients had progressed at data cutoff.

Safety and Injector Performance

Toxicity matched prior experience with Isa-VRd, with frequent severe events: grade 3 or higher adverse events occurred in 92% of patients. Neutropenia was reported in 82% (59% grade 3 or higher), and peripheral neuropathy in 49% (7% grade 3 or higher).

The full regimen was temporarily interrupted in 57% of patients. Bortezomib and dexamethasone were each permanently discontinued in 12%, and lenalidomide in 4%. No patient permanently discontinued isatuximab alone because of an adverse event, and median relative dose intensity for isatuximab was 91.8%.

Infusion-related reactions occurred in 5%, predominantly grade 1. The OBI completed 2,553 of 2,570 injections. Device deficiencies in 12 patients did not substantially affect the completion rate.

What the Injector Adds

The OBI provides standardized, hands-free subcutaneous administration through a needle-shielded system that needs no battery or external power. For patients on prolonged CD38 antibody therapy, shorter administration may reduce time in treatment facilities and simplify repeated visits. Centers managing growing numbers of patients on long-term antibody therapy may also gain workflow advantages.

ISASOCUT did not measure nursing workload, healthcare resource use, patient satisfaction or cost. Preference data come from the separate phase 2 IZALCO study of manual versus OBI administration of subcutaneous isatuximab in relapsed or refractory multiple myeloma, in which 74.5% of patients preferred the OBI and 17% preferred manual injection. Those preferences cannot be assumed to hold for frontline Isa-VRd.

Limitations

ISASOCUT was a single-arm study of 74 patients with no intravenous isatuximab comparator, so it cannot establish equivalent efficacy or safety between routes and was not designed to. The population was relatively fit, which limits generalizability to frailer transplant-ineligible patients. Pharmacokinetic measurements were not collected, and follow-up is too short to assess long-term survival, durability of disease control or sustained MRD negativity.