Isatuximab Demonstrates Activity as Single-Agent in Multiple Myeloma

Joanne Lorraine Blum, MD, PhD

Joshua Richter, MD

The anti-CD38 monoclonal antibody isatuximab (SAR650984) showed promising signs of activity as a single-agent for patients with heavily pretreated relapsed/refractory multiple myeloma, according to updated findings from a phase II study presented at the 2016 ASCO Annual Meeting.

In the open-label, single-arm study, patients treated with isatuximab at ≥10 mg/kg (n = 74) had a median progression-free survival (PFS) of 3.65 months (95% CI, 2.33-5.55) and a median overall survival (OS) of 18.63 months (95% CI, 15.7-not reached). The objective response rate (ORR) was 24.3%, including those with high-risk cytogenetics.

"This progression-free survival for a single-agent in a heavily pretreated population is quite impressive; however, what I think is even more impressive is the overall survival data," said Joshua Richter, MD, a hematologist/oncologist specializing in multiple myeloma at the John Theurer Cancer Center. "The median duration of response ranged from 8.75 to 12.9 months. The median overall survival has not yet been reached for some of the cohorts."

Isatuximab was administered intravenously to 97 total patients who previously received ≥3 prior therapies or were refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Isatuximab was administered at 3 mg/kg every 2 weeks (Q2W; n = 23), 10 mg/kg Q2W for 2 cycles followed by Q4W (n = 25), 10 mg/kg Q2W (n = 24), and 20 mg/kg every week for 4 doses (1 cycle) followed by Q2W (n = 25).

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

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

At the lowest dose of isatuximab, the ORR was 9%. In the 10-mg/kg arms, the ORRs were 20% and 29%, in the Q2W/Q4W and Q2W arms, respectively. In the 10 mg/kg Q2W arm, responses consisted of partial responses (PRs; 4.2%) and very good PRs (VGPR; 25%). In the 20-mg/kg arm, the ORR was 24%, which consisted of PRs (20%) and VGPRs (4%).

At the data cutoff of February 29, 2016, 15% of patients (n = 11) continued to receive treatment, including 5 of 25 in the 20 mg/kg arm. The median duration of follow-up in the 20 mg/kg arm was 14.1 weeks. In the 10 mg/kg arms, median follow-up was 17.1 and 15.8 weeks, in the Q2W/Q4W and Q2W arms, respectively.

"The 20 mg/kg group did not have as long of a follow-up as the 10 mg/kg group," Richter pointed out. "What we see with all therapies in myeloma is that those patients who stay on therapy longer tend to deepen their responses, stable disease become minimal response, which becomes PR, and then PRs become VGPRs."

Responses remained consistent across subgroups of patients treated with the &ge;10 mg/kg doses of isatuximab. The ORR was 46.2% for those age &ge;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%.

"We found the subgroup studies to be quite encouraging," said Richter. "There is an impressive response rate in the classically higher risk groups of elderly patients, poor renal function, and high-risk cytogenetics."

Six patients discontinued therapy due to adverse events (AEs). The most common AEs with isatuximab, which were primarily grade &le;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 (IRR) were experienced by 55% of patients, primarily during the first infusion. Two cases of grade 3/4 IRR occurred, 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.

"The vast majority of infusion-related reactions occurred with the first infusion, no infusion-related reactions were seen after the fourth infusion," said Richter. "Most infusion reactions were grade 1/2, and the median fusion duration is shorter following the first infusion, making this more pragmatic to infuse in the clinic."

A phase I study is exploring isatuximab with carfilzomib for relapsed/refractory multiple myeloma (NCT02332850) and another phase I trial is looking at isatuximab with bortezomib, cyclophosphamide, and dexamethasone for newly diagnosed patients with multiple myeloma (NCT02513186). Additionally, in other settings, a phase I/II study is looking at isatuximab in CD38-positive hematological malignancies (NCT01084252).

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).