Phase III Isatuximab Trial Meets Primary Endpoint of Improving PFS in Relapsed/Refractory Myeloma

The phase III ICARIA-MM trial has met its primary endpoint of improving progression-free survival with the combination of pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma compared with pomalidomide and dexamethasone alone.

John Reed, MD, PhD

The phase III ICARIA-MM trial (NCT02990338) has met its primary endpoint of improving progression-free survival (PFS) with the combination of pomalidomide (Pomalyst) and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma compared with pomalidomide and dexamethasone alone.1

“We are excited by these results, which represent significant progress in our ambition to extend the lives of multiple myeloma patients,” said John Reed, MD, PhD, head of Research and Development at Sanofi, the developer of the anti-CD38 agent, in a press release. “We look forward to engaging with regulatory authorities with the goal of bringing this potential new treatment to patients as quickly as possible.”

This is the first randomized phase III study evaluating the efficacy of adding a monoclonal antibody to pomalidomide and dexamethasone for patients with relapsed/refractory disease. Full findings of the study will be presented at an upcoming at a medical meeting and will be included in regulatory submissions to be submitted in 2019, according to Sanofi.

In the multicenter, open-label ICARIA-MM trial, 307 patients with relapsed/refractory multiple myeloma were randomized to receive the triplet regimen of isatuximab, pomalidomide, and low-dose dexamethasone or pomalidomide and dexamethasone alone. Patients previously received ≥2 or more therapies, including at least 2 consecutive cycles of lenalidomide (Revlimid) and a proteasome inhibitor either alone or in combination.

Isatuximab was administered intravenously (IV) at 10 mg/kg once weekly for 4 weeks followed by bi-weekly for 28-day cycles in combination with standard pomalidomide and dexamethasone for the duration of therapy. Treatment was continued until disease progression or unacceptable toxicity. During follow-up, patients who discontinued therapy due to disease progression were followed every 3 months for survival or until the cut-off date, and those who continued prior to progression were followed up every 4 weeks until progression and then every 3 months.

The primary endpoint was PFS; secondary endpoints were safety, overall response rate (ORR), overall survival (OS), time to progression, duration of response, pharmacokinetic profile, immunogenicity, and disease-specific and health-related quality of life.

To be eligible for enrollment, patients must have had measurable disease, received at least 2 prior lines of myeloma therapy, failed treatment with lenalidomide and a proteasome inhibitor, and had progressed on or within 60 days after end of prior therapy before study entry.

Those with primary refractory disease who never achieved a minimal response, free Light Chain measurable disease, had prior therapy with pomalidomide, had any myeloma therapy within 2 weeks before randomization, an ECOG performance status >2, platelets inferior to 75,000 cells per µL if inferior to 50% of bone marrow—nucleated cells are plasma cells, and inferior to 30,000 cells per µL if superior or equal to 50% of bone marrow­–nucleated cells are plasma cells, were excluded for enrollment.

Additionally, patients with absolute neutrophils count inferior to 1000 per µL; a creatinine clearance inferior to 30 mL per min; total bilirubin superior to twice the upper limit of normal (ULN); corrected serum calcium superior to 14 mg per dL; aspartate aminotransferase and/or alanine aminotransferase super to 3 times the ULN; hypersensitivity to immunomodulatory agents, dexamethasone, sucrose histidine, polysorbate 80 or any study therapy components not amenable to premedication with steroids or H2 blockers; or significant cardiac dysfunction were also not permitted to enroll.

Phase II findings with isatuximab were presented at the 2016 ASCO Annual Meeting. In the open-label, single-arm study, patients with heavily pretreated relapsed/refractory myeloma who were treated with isatuximab at ≥10 mg/kg (n = 74) had a median PFS of 3.65 months (95% CI, 2.33-5.55) and a median OS of 18.63 months (95% CI, 15.7-not reached). The ORR was 24.3%, including those with high-risk cytogenetics.

In this trial, isatuximab IV was administered to those who previously received ≥3 prior therapies or were refractory to immunomodulatory agents and proteasome inhibitors. The agent was administered at 3 mg/kg every 2 weeks (n = 23), 10 mg/kg every 2 weeks for 2 cycles followed by every 4 weeks (n = 25), 10 mg/kg every 2 weeks (n = 24), and 20 mg/kg weekly for 4 doses followed by every 2 weeks (n = 25).

The median age of patients enrolled in the study was 62.5 years (range, 38-85), and nearly one-third had high-risk cytogenetics. The median number of prior therapies was 5 and the median time since diagnosis was 5.9 years; more than one-third of patients had International Staging System stage 3 disease (37%).

Patients were refractory to lenalidomide alone (86%) and bortezomib (80%) or the combination of an immunomodulatory agent and proteasome inhibitor (88%). Most patients (89%) had received ≥1 prior stem cell transplant. Nearly all patients were double refractory and approximately 40% were quadruple refractory.

Responses remained consistent across subgroups of patients treated with the ≥10 mg/kg doses of isatuximab. The ORR was 46.2% for those age ≥70 years (n = 13), and in those with a creatinine clearance of <50 mL/min (n = 11), the ORR was 36.4%. In the high-risk cytogenetics group (n = 21), the ORR was 38.1%.

Regarding safety, 6 patients discontinued therapy due to adverse events (AEs). The most common AEs with isatuximab, which were primarily grade ≤2, were nausea (36%), fatigue (34%), cough (34%), and pneumonia (9%). The most common grade 3/4 AEs included anemia (24%), thrombocytopenia (17%), neutropenia (15%), and pneumonia (9%).

Infusion-related reactions (IRRs) were experienced by 55% of patients, primarily during the first infusion; there were 2 cases of grade 3/4 IRR, which resulted in treatment discontinuation. In the 10 mg/kg arm, the first infusion was administered over 3.2 hours, which was reduced to 2.6 hours for subsequent doses. In the 20 mg/kg group, the first infusion was given over 5.3 hours followed by 4.4 hours for subsequent doses.

Isatuximab was previously granted an orphan drug designation in relapsed/refractory multiple myeloma by the FDA in June 2017; the European Medicines Agency also granted the anti-CD38 agent the same status.

Additional phase III studies with isatuximab are ongoing that are exploring the investigational agent in combination with standard therapy for both newly diagnosed and relapsed/refractory patients.


  1. Isatuximab Phase 3 Trial Meets Primary Endpoint of Prolonging Progression Free Survival in Patients With Relapsed/Refractory Multiple Myeloma. Sanofi. Published February 5, 2019. Accessed February 5, 2019.
  2. Richter JR, Martin TG, Vij R, et al. Updated data from a phase II dose finding trial of single agent isatuximab (SAR650984, anti-CD38 mAb) in relapsed/refractory multiple myeloma (RRMM).J Clin Oncol. 2016;34 (suppl; abstr 8005). doi: 10.1200/JCO.2016.34.15_suppl.8005.