The Long PD-1 Receptor Binding Kinetics of Nivolumab May Increase Efficacy of Subsequent Therapy in Relapsed and Refractory Multiple Myeloma Patients
Authors: Funt Samuel A. , Page David B. , Cattry Deepika , Lendvai Nikoletta , Hassoun Hani , Landgren Ola , Borrello Ivan M. , Lesokhin Alexander M. 
Published: October 2019

Abstract
Introduction: Programmed cell death-1 (PD-1) signaling suppresses the antigen driven activation of T cells upon interaction with its ligands PD-L1 and PD-L2. The PD-1/PD-L1 axis is thought to mediate the resistance of multiple myeloma to conventional therapy (Tamura 2013; Paiva 2015). Nivolumab, a fully human IgG4 monoclonal PD-1 receptor-blocking antibody, has shown clinical activity in a variety of tumor types. Nivolumab has demonstrated a prolonged receptor binding kinetic lasting >100 days that may lead to an efficacy or toxicity signal in the post-treatment period. We therefore evaluated the response of patients with relapsed or refractory multiple myeloma to additional myeloma therapy received within 3 months of the end of nivolumab administration.
Methods: The preliminary results of an open-label study that treated patients with relapsed or refractory multiple myeloma using a dose escalation design (1 mg/kg and 3 mg/kg) of nivolumab administered every 2 weeks have been reported previously (NCT01592370, Lesokhin et al., ASH 2014). Here we will report responses and safety data using standard criteria to the next line of therapy received immediately after nivolumab.
Results: 8 patients with multiple myeloma from the original open label study were treated at Memorial Sloan Kettering Cancer Center. The disease characteristics and efficacy results are shown in the table. 1 of 8 patients (12.5%) experienced progression while on therapy manifested by development of an isolated plasmacytoma. The patient received radiation and then resumed and completed 97 weeks of therapy with nivolumab. He is currently off therapy without any evidence of disease at 48 weeks after cessation of nivolumab. 3 of 8 patients (37.5%) achieved a partial response to the next line of treatment after nivolumab. 2 of 8 patients (25%) who were exposed and refractory to immunomodulatory drugs (IMiDs) received single-agent, low-dose lenalidomide as the next line of therapy and achieved stable disease lasting approximately 100 days after cessation of nivolumab followed by disease progression. 1 of 8 patients (12.5%) experienced progressive disease despite the next line of therapy, and 1 of 8 patients (12.5%) received an experimental treatment as the next line of therapy and was therefore not evaluable. No new drug-related adverse events occurred in the 3 months after completing treatment with nivolumab. Overall, 6 out of 8 patients derived clinical benefit from post-nivolumab therapy, an unusually high response rate for this population.
Conclusions: In a small cohort of patients with relapsed and refractory multiple myeloma, evaluation of response kinetics after cessation of nivolumab supports the notion that long PD-1 receptor binding kinetics may increase the efficacy of subsequent therapy without added toxicity. Larger studies are needed to confirm and expand our findings.
Table. Patient Characteristics and Efficacy Age Sex ISS Cytogenetics Prior Lines ASCT IMiD E IMiD R Prot E Prot R Best Response to Nivolumab Next Line of Standard Therapy Best Response to Next Line 52 M 1 S 3 Y Y Y Y Y SD Carfilzomib, Cyclophosphamide, Dexamethasone PR 32 M 1 S 3 Y Y Y Y Y SD None* N/A 80 F 1 S 1 N Y N N N SD Lenalidomide PR 52 F 1 I 3 Y Y Y Y N SD Lenalidomide SD 62 M 1 H 1 Y Y N Y N PD Cyclophosphamide, Bortezomib, Dexamethasone PR 58 M 2 S 5 Y Y Y Y Y PD Lenalidomide SD 57 F 1 S 3 Y Y N Y Y PD None^ N/A 59 F 1 S 3 Y Y Y Y Y PD Lenalidomide, Bortezomib, Dexamethasone PD ISS=international staging system; S=standard cytogenetics; I=intermediate cytogenetics; H=high risk cytogenetics; ASCT=autologous stem cell transplant; IMiD E=IMiD exposed; IMiD R=IMiD refractory; Prot E=proteosome exposed; Prot R=proteosome refractory; PD=progressive disease; SD=stable disease; PR=partial response *Patient completed 97 weeks of nivolumab and continues untreated without any evidence of disease at 48 weeks after cessation of therapy ^Patient received treatment on an experimental protocol

Disclosures
Funt: Kite Pharma: Equity Ownership. Off Label Use: Nivolumab is FDA approved for use in patients with metastatic melanoma but not in patients with multiple myeloma. . Page:Celgene: Consultancy. Landgren:Bristol-Myers Squibb: Honoraria; Celgene: Consultancy; BMJ Publishing: Consultancy; Bristol-Myers Squibb: Consultancy; BMJ Publishing: Honoraria; Medscape: Consultancy; Medscape: Honoraria; Celgene: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Honoraria; Onyx: Research Funding; Onyx: Consultancy. Borrello:Celgene: Research Funding. Lesokhin:Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Aduro: Consultancy; Genentech: Research Funding; Efranat: Consultancy.