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

ABSTRACT

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.

KEYWORDS:

• Checkpoint inhibitors
• immune checkpoint targeting
• immunomodulation
• lenalidomide
• monoclonal antibodies
• multiple myeloma
• PD-1/PD-L1 blockade
• pembrolizumab

Article Highlights

• Pembrolizumab given in combination with lenalidomide and low-dose dexamethasone will not be approved to treat multiple myeloma in the frontline setting.

• PD-1 dysregulation appears to be a relevant mechanism of tumoral escape in multiple myeloma on the basis of preclinical evidence.

• Pembrolizumab preclinical data clearly suggested a potential therapeutic efficacy of PD-1/PD-L1 blockade in multiple myeloma, particularly if given in combination with immunomodulating agents such as lenalidomide.

• Pembrolizumab monotherapy is ineffective in multiple myeloma. Early trials in combination with lenalidomide suggested a relevant clinical benefit without significant toxicity.

• An interim FDA-required analysis determined that the risks of pembrolizumab plus lenalidomide outweighed the benefits and terminated the study. Additionally, all studies involving anti PD-1/PD-L1 antibodies in combination with immunomodulatory agents were discontinued.

• A deeper analysis of the biological mechanisms involved in PD-1/PD-L1 blockade in multiple myeloma is needed to understand current discrepancies between preclinical and clinical results of PD-1/PD-L1 inhibitors in combination with lenalidomide or other immunomodulatory agents.

Acknowledgments

Medical Writing Support was provided by Norvella Dunwoody, M.S. The author also wants to thank Laura Abril, Gladys Ibarra, Alicia Senin and Cristina Vazquez, and Natalia Saez for their support in the pembrulizumab trials in multiple myeloma.

Declaration of Interest

A Oriol has participated in advisory boards and industry sponsored symposiums for Celgene, Amgen and Janssen. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was institutionally supported by CERCA Programme/Generalitat de Catalunya and the Josep Carreras Foundation.