Multiple myeloma (MM) cells upregulate MHC class I antigens which serve as ligands to inhibitory Killer Immunoglobulin-like Receptors (KIR) as a means of evading natural killer (NK) cell immunity. IPH2101 is a human, IgG4 monoclonal antibody against common inhibitory KIR that prevents KIR-ligand interaction and augments NK cell cytotoxicity against MM. A prior, single-agent, phase I study of IPH2101 demonstrated acceptable safety and tolerability with 34% of heavily pretreated patients achieving disease stabilization. Lenalidomide expands and activates NK cells, thus, pairing this agent with IPH2101 may represent a novel, steroid-free therapeutic option. Our preclinical data suggest that IPH2101 and lenalidomide combine to enhance NK cell function against MM. Herein, interim results of a phase I clinical trial of IPH2101 and lenalidomide are presented.
A 3+3 design includes dose escalation over 4 planned cohorts: Cohort 1 = IPH2101 0.2mg/kg & lenalidomide 10mg, Cohort 2 = IPH2101 0.2mg/kg & lenalidomide 25mg, Cohort 3 = IPH2101 1mg/kg & lenalidomide 25mg, Cohort 4 = IPH2101 2mg/kg & lenalidomide 25mg. A 6-patient extension cohort is planned at the maximally tolerated dose. Lenalidomide is administered orally days 1–21 and IPH2101 is given intravenously on day 1 of a 28-day cycle for 4 cycles. Responding patients may continue therapy for 4 additional cycles and are maintained on lenalidomide alone thereafter. The primary objective of the study is to determine the safety and tolerability of IPH2101 and lenalidomide with secondary endpoints including: response rate, progression-free survival, pharmacodynamics, pharmacokinetics, and biologic correlates. Adult patients with relapsed MM following one or two lines of prior therapy are eligible to participate. Prior exposure to lenalidomide is allowed; however, patients must not have been resistant to, or intolerant of, lenalidomide. Patients must have measurable disease, ECOG performance status 0–2, and adequate organ function and bone marrow reserve. Thromboprophylaxis is mandatory for all patients.
To date, n=13 patients have been enrolled in the first 3 cohorts who have received a median number of 4 cycles of therapy to date (range 1–8). Adverse events have been generally low grade and self-limited. Two potential dose-limiting toxicities (DLT) have been observed (cohort 1 and cohort 3). Both patients experienced grade 3 infusion reactions associated with pyrexia and transient, grade 4 leucopenia following cycle 1, day 1 treatment. Clinical cytokine release syndrome was observed, and high levels of IFN-gamma, IL-6, TNF-alpha, and MIP-1beta were documented. Infusion reactions were treated with supportive care, including intravenous fluids and anti-pyretics; steroids were not administered. Leucopenia resolved without intervention, and both patients were subsequently treated in cycle 2 without recurrence of DLT. Both patients appear to have disproportionally greater KIR binding of IPH2101 on T cells relative to NK cells. Cohort 1 was expanded to n=6 patients without recurrence and expansion of cohort 3 is ongoing. An amendment is now included for pre-medication of patients with an anti-pyretic and anti-histamine prior to dosing. Co-administration of lenalidomide does not appear to alter the IPH2101 pharmacodynamic profile observed in the prior, single-agent phase I study. To date, responses include: 1 (unconfirmed) complete response, 3 partial responses, 2 minor responses and 1 stable disease.
In addition to direct anti-MM effects, lenalidomide promotes NK cell activation, and IPH2101 prevents inhibitory signaling to augment NK cell immunity against MM. Results suggest the combination has activity with manageable toxicity in relapsed MM. At present, ongoing unconfirmed complete response has been > 12 months and ongoing partial responses have been > 18 months, > 8 months, and > 1 month in duration. This combination may represent the first steroid-free, “dual immunotherapy” for MM and further development is justified.
Benson:Innate Pharma: Research Funding. Off Label Use: Lenalidomide without dexamethasone, IPH2101 not FDA approved yet. Zerbib:Innate Pharma: Employment. Andre:Innate Pharma: Employment.
Asterisk with author names denotes non-ASH members.