Isatuximab Combination Safe, Active for Relapsed, Refractory Myeloma

The combination of the anti-CD38 monoclonal antibody isatuximab with pomalidomide/dexamethasone had an acceptable and manageable safety profile in patients with relapsed or refractory multiple myeloma, according to the results of a phase Ib study (abstract 8007) presented at the 2017 ASCO Annual Meeting (ASCO), held 2–6 in Chicago.

“Adverse events with this combination are generally consistent with the known safety profiles of the individual agents with perhaps a slight increase in grade 3/4 neutropenia that was quite manageable,” said Joseph R. Mikhael, MD, of the Mayo Clinic, Scottsdale, Arizona, who presented the results.

Isatuximab is an anti-CD38 monoclonal antibody with multiple mechanisms of action including a direct apoptosis effect and immunomodulatory effects.

In this phase Ib study, Mikhael and colleagues enrolled patients with relapsed or refractory multiple myeloma who had been treated with two or more prior therapies including lenalidomide and a proteasome inhibitor. Patients received isatuximab at 5 mg/kg, 10 mg/kg, or 20 mg/kg with pomalidomide 4 mg and dexamethasone 40 mg in 28-day cycles.

Mikhael presented results on the first 26 patients, of whom 50% are still undergoing treatment. The median age of patients was 65. Seventy-five percent of patients had undergone a prior autologous stem cell transplant.

The most common treatment-emergent adverse events were fatigue, dyspnea, and infusional-related reactions. Fifty percent of patients reported infusional reactions, but only one was grade 3. The researchers did see a significant amount of grade 3 hematologic toxicity, according to Mikhael. Twenty-one percent of patients had leukopenia; however, there were no discontinuations or withdrawals due to neutropenia.

Three dose-limiting toxicities occurred: a prolonged grade 4 neutropenia at the 5 mg/kg dose, one grade 4 neutropenia infection at the 10 mg/kg dose, and one grade 3 confusional state at the 20 mg/kg dose. None of these dose-limiting toxicities closed any of the cohorts.

The overall response rate was 65.3% in all cohorts combined. At the 10 mg/kg dose-the dose selected for an expansion cohort-the response rate was 74.9%. In patients refractory to lenalidomide the response rate was 60%. Among the five enrolled patients with known high-risk cytogenetics there was one very good partial response, one partial response, and one minimal response. The mean duration of response of 36 weeks with a median time to first response of 4.3 weeks.

Mikhael noted that one differentiating feature of isatuximab is that the median infusion duration for this combination was 3.9 hours for the first infusion and only 2.8 hours for subsequent infusions.

“Those of us who use monoclonal antibodies in clinical practice, this is a particularly important phenomena speaking to the convenience of using this agent,” Mikhael said.