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Targeting CD38, Isatuximab Produces Impressive Responses in Relapsed or Refractory Multiple Myeloma

August 2016 Vol 9, Special Issue: Payers' Perspectives in Oncology - Multiple Myeloma

Interim results from a phase 1b study indicate that the investigational monoclonal antibody isatuximab, in combination with lenalidomide and dexamethasone, achieves responses in >50% of patients with relapsed or refractory multiple myeloma, including those with disease refractory to immunomodulatory drugs (IMiDs).

Based on these positive findings, a global phase 3 clinical trial will be initiated soon, said Ravi Vij, MBBS, MD, MBA, Professor of Medicine, Oncol­ogy Division, Washington University School of Medicine, St Louis, MO, who presented the study at ASCO 2016.

Isatuximab is a humanized immunoglobulin G1 monoclonal antibody that targets the CD38 protein and has multiple modes of action. It exhibits tumor-killing activity through direct engagement with the tumor cell and promotes immunomodulation. Preclinical data have demonstrated that the anti–multiple myeloma activity of isa­tuximab was enhanced with the addition of lenalidomide.

This trial explored the dose levels of isatuximab. Previously, data were presented for cohorts receiving 3 mg/kg, 5 mg/kg, and 10 mg/kg of isatuximab every other week. Based on pharmacokinetic modeling, 2 new dosing schedules (ie, expansion cohorts) of isatuximab were added—10 mg/kg weekly followed by every other week (median, 12 weeks) and 20 mg/kg weekly and every other week thereafter (median, 10 weeks). Lenalidomide 25 mg was given on days 1 to 21 of a 28-day cycle, and dexamethasone 40 mg was given on days 1, 8, 15, and 22.

Dr Vij presented data from 3 of the cohorts, a group that received 10 mg/kg of isatuximab (N = 24) and the 2 dose-expansion cohorts, for a total of 46 patients.

All patients had received ≥2 previous treatments. The patients in the 10-mg/kg dosing cohorts received a median of 4 previous lines of therapy; the patients in the 20-mg/kg cohort received a median of 6.5 previous lines of therapy. Nearly all of the patients received previous stem-cell transplantation.

In each dosing group, 66% to 100% of the patients had disease refractory to IMiDs. “This represents probably one of the most heavily pretreated and lenalidomide-exposed groups that has been reported with an anti-CD38 antibody in combination with lenalidomide and dexamethasone,” noted Dr Vij.

Study Results

In all, 16 of the 50 patients who enrolled in the study remain in the study: 34 patients discontinued treatment, 24 because of disease progression. The median duration of dosing varied from 10.1 weeks in the group receiving isa­tuximab 20 mg to 35.9 weeks in the group receiving 10 mg/kg weekly and every other week thereafter. The cohort that received 20 mg/kg of isatuximab had the shortest duration (median, 14.7 weeks) of follow-up compared with 29.1 weeks and 31.5 weeks in the 10-mg/kg groups.

There were 7 deaths in the expansion cohorts, 5 as a result of disease progression.

The cohort receiving 10 mg/kg of isatuximab every 2 weeks had the longest follow-up, and had an objective response rate (ORR) of 63%. The other 2 expansion cohorts were more heavily pretreated, with a response rate of 50% each. The ORR for the entire expansion set was 57%. The median duration of response was 7.6 months. The depth of response was improved with longer treatment, said Dr Vij.

Among the 39 patients with disease refractory to IMiDs, the ORR was 54%, which was consistent across all 3 dosing groups.

Most toxicities were grade 1 or 2, with the most common being diarrhea, fatigue, pyrexia, upper respiratory infection, dyspnea, and nausea. The drugs used in combination “did not seem to add to the toxicity profile,” said Dr Vij. Infusion-related reactions, mostly grade 1 or 2, occurred in 60% of the patients, predominantly during the first infusion.

Potential Cure?

Based on the findings, the investi­gators recommend proceeding with 10-mg/kg isatuximab weekly followed by 10 mg/kg every other week for future combination studies.

Rafael Fonseca, MD, Deputy Director, Mayo Clinic Cancer Center, Scotts­dale, AZ, said that CD38-targeted monoclonal antibodies in combination regimens “is likely the part of the path to cure in patients with multiple myeloma” as first-line therapy. “We need to decide which agents, and in which order, this is best used…and should they be combined with other immune enhancers, potentially even other monoclonal antibodies,” Dr Fonseca said. Last year, the first anti-CD38 monoclonal antibody, daratumumab (Darzalex) was approved by the FDA for this patient population.

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Last modified: August 30, 2021