CD38-Targeting Isatuximab Combo Active in Refractory Myeloma

Researchers tested the combination of isatuximab with dexamethasone and pomalidomide in patients with relapsed or refractory multiple 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%).”