CD38-Targeting Isatuximab Combo Active in Refractory Myeloma

The combination of isatuximab with dexamethasone and pomalidomide had a manageable safety profile and promising clinical activity in patients with relapsed or refractory multiple myeloma, according to a phase Ib study published in Blood.

More than half of patients had disease response, with a median duration of response of about 1.5 years.

“The efficacy and safety observed in this heavily pre-treated population demonstrate that isatuximab may be an effective treatment option for patients with a high burden of disease who have become refractory to lenalidomide and PIs [proteasome inhibitors],” wrote Joseph Mikhael, MD, of City of Hope Cancer Center and the International Myeloma Foundation, and colleagues.

The study included 45 patients who had at least 2 prior lines of therapies, including lenalidomide and a PI; 23 of these patients were included in the dose escalation phase of the study. The drug regimen consisted of isatuximab at 5, 10, or 20 mg/kg every week for 4 weeks followed by every 2 weeks, plus pomalidomide 4 mg and dexamethasone 40 mg in 28-day cycles. Patients had a median of 3 prior therapies, with 91% refractory to their last regimen.

Eight patients were treated at the 5-mg/kg dose of isatuximab, with 1 experiencing a dose-limiting toxicity of grade 4 neutropenia. Six patients received 10 mg/kg, and 1 had a dose-limiting grade 4 neutropenic infection. Finally, 6 patients received 20 mg/kg, and 1 patient experienced a grade 3 confusional state. None of these toxicities led to treatment discontinuation.

Because there was one dose-limiting toxicity at each dose level, the recommended dose of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic modeling.

The median duration of treatment was 9.6 months, and a little less than half of patients (42%) remain on therapy. With a follow-up of 8.6 months, the overall response rate was 62.2%, a rate that the researchers noted “is 2-fold higher than historical observations with pomalidomide/dexamethasone alone.” Ten patients had very good partial responses, one had a complete response, and one had stringent complete response.

Among those patients who received the recommended dose, the overall response rate was 64.5%.

According to the researchers, responses were durable, with a median duration of response of 18.7 months. Data on progression-free and overall survival are still maturing.

Common adverse events included fatigue, upper respiratory infection, infusion reactions, and dyspnea. About 18% of patients had grade 3 or worse treatment-emergent pneumonia. Other common hematologic adverse events included lymphopenia (72.7%) and leukopenia (70.4%).

“Although cross-trial comparisons should be interpreted with caution, the safety profile of isatuximab in combination with pomalidomide/dexamethasone appears to be consistent with the safety profile of the individual drugs, with the exception of neutropenia,” the researchers wrote. “Despite the high incidence of serious TEAEs [treatment-emergent adverse events] with grade ≥ 3 severity (55.6%), and high dose reductions of pomalidomide (75.6%) and dexamethasone (75.6%) caused by TEAEs, definitive treatment discontinuation due to AEs [adverse events] was not very common (4.4%).”