A critical evaluation of pembrolizumab in addition to lenalidomide and dexamethasone for the treatment of multiple myeloma

Introduction: Several modalities of immunotherapy have proved successful in multiple myeloma, including immunomodulatory agents, monoclonal antibodies directed to plasma cell surface antigens and chimeric antigen receptor T cells. The PD-1 pathway is implicated in the progression of multiple myeloma. Several properties of lenalidomide are potentially synergistic with PD-1/PD-L1 blockade. Areas covered: Preclinical data related to anti-PD-1/PD-L1 antibodies and the results of early clinical trials of pembrolizumab single-agent and in combination with lenalidomide and dexamethasone are discussed. Despite promising preliminary data, the pivotal phase III trial evaluating lenalidomide and dexamethasone in combination with pembrolizumab in patients with newly diagnosed multiple myeloma presented unexpected safety findings and was discontinued. Differences with previous results and the findings of other trials involving pomalidomide as an immunomodulatory agent or nivolumab as anti-PD-1 antibody are discussed. Expert opinion: Disappointing efficacy outcomes of the combination of checkpoint blockade antibodies and immunomodulating agents in multiple myeloma along with toxicity issues make the combination unattractive in comparison with available alternatives. It is essential to critically review preclinical and clinical datha to understand the pitfalls of lenalidomide with pembrolizumab and similar combinations in multiple myeloma to gain insight on the future role of anti-PD-1 agents in emerging therapeutic scenarios.