Isatuximab Shows Promise as a Single Agent for Relapsed Multiple Myeloma

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. These updated phase 2 findings were presented during the 2016 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of over 30,000 oncology professionals in Chicago.

In the open-label, single-arm study, patients treated with isatuximab had a median progression-free survival (PFS) of 3.65 months and a median overall survival (OS) of 18.63 months. The objective response rate (ORR) was 24.3 percent, 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, 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 more than or equal to three prior therapies or were refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs).

The median age of patients enrolled in the study was 62.5 years, and nearly a third had high-risk cytogenetics. The median number of prior therapies was five and the median time since diagnosis was 5.9 years. Over a third of patients had ISS stage 3 disease.

Patients were refractory to single-agent Revlimid (lenalidomide) and Velcade (bortezomib) or the combination of an IMiD and PI. Most patients had received at least one prior stem cell transplant. Nearly all patients were double refractory and approximately 40 percent were quadruple refractory.v Researchers found patients who received smaller doses of treatment, but stayed on it longer had better responses. "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,” said Richter.

The ORR was 46.2 percent for those 70 years of age or older. In the high-risk cytogenetics group, the ORR was 38.1 percent. "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 were nausea, fatigue, cough and pneumonia. Grade 3/4 AEs included anemia, thrombocytopenia, neutropenia and pneumonia.

Infusion-related reactions (IRR) were experienced by 55 percent of patients, primarily during the first infusion. Two cases of grade 3/4 IRR occurred, which resulted in treatment discontinuation.

"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 1 study is exploring isatuximab with Kyprolis (carfilzomib) for relapsed/refractory multiple myeloma and another phase 1 trial is looking at isatuximab with Velcade, Cytoxan (cyclophosphamide) and Maxidex (dexamethasone) for newly diagnosed patients with multiple myeloma.

Additionally, in other settings, a phase 1/2 study is looking at isatuximab in CD38-positive hematological malignancies.