Elsevier

Cellular Immunology

Volume 334, December 2018, Pages 87-98
Cellular Immunology

The challenges of checkpoint inhibition in the treatment of multiple myeloma

https://doi.org/10.1016/j.cellimm.2018.10.003Get rights and content

Highlights

  • MM is associated with defects/dysfunction in both innate and adaptive immunity.

  • PD-L1 expression is up-regulated in MM leading to suppression of T cell activity.

  • Checkpoint inhibitors have not displayed significant activity as single agents in MM.

  • The combination of checkpoint inhibitors and IMiDs increases the risk of death in MM.

  • Further studies aimed at characterizing the immune dysregulation in MM are indicated.

Abstract

Despite significant improvements in the overall survival of patients with multiple myeloma (MM) over the past 15 years, the disease remains incurable. Treatment options are limited for patients who have relapsed or are refractory to immunomodulatory drugs (IMiDs), proteasome inhibitors, and monoclonal antibodies. In these patients, immunotherapies such as checkpoint inhibitors, oncolytic vaccines, and chimeric antigen receptor (CAR) T cells provide a potentially effective alternative treatment. While checkpoint inhibitors are effective in prolonging overall survival in some patients with advanced solid cancers and Hodgkin lymphoma, they have not demonstrated significant activity as a single agent in MM. In fact the combination of checkpoint inhibitors with IMiDs was recently found to increase the risk of death in myeloma patients. These challenges highlight the need for a better understanding of immune dysregulation in myeloma patients, and the mechanisms of action of- and resistance to- checkpoint inhibitors. In this review, we summarize immune dysfunction in patients with MM, and review the preclinical and clinical data regarding checkpoint inhibitors in myeloma. We conclude by proposing strategies to improve the efficacy and safety of checkpoint inhibitors in this population.

Section snippets

Multiple myeloma

Multiple Myeloma (MM) is a malignancy that is characterized by the clonal proliferation of terminally differentiated plasma cells within the bone marrow. MM represents 1% of all malignancies and 18% of hematologic malignancies in the United States accounting for an estimated 30,770 new diagnoses and 12,770 deaths in 2018 alone [1]. Classically, MM results in the secretion of a non-functional monoclonal immunoglobulin (Ig) that is produced by the transformed plasma cells. Production of this

Overview of the human immune system

The human immune system consists of two main components: the innate immune system, and the adaptive immune system. Innate immunity serves as the initial defense mechanism against microbial invasion and is characterized by a rapid, nonspecific response to pathogens. The components of the innate immune system include natural anatomic barriers (skin and mucosa), soluble proteins, bioactive small molecules (cytokines and complement components), and several types of myeloid derived leukocytes which

Immune dysfunction in multiple myeloma

As shown in Fig. 1, patients with multiple myeloma show profound defects/dysfunction in both innate and adaptive immunity [56]. The human innate immune system includes natural killer (NK) cells, macrophages, monocytes, neutrophils, eosinophils, and basophils. NK cells recognize and kill myeloma cells by activating receptors including NKG2D, DNAX accessory molecule (DNAM-1 or CD226) and the natural cytotoxicity receptors (NCRs) Np46, Np30, Np44 [57], [58]. NK cells play an important role in

CTLA-4

CTLA-4 is an inhibitory receptor expressed on T cells. The biological role of CTLA-4 is regulation of T cell responses, predominantly during initial activation in the lymph node and the prevention of autoimmunity; this has previously been illustrated by the development of massive lethal lymphoproliferation in CTLA-4 knock-out mice [88], [89]. Recognizing the role of CTLA-4 as a negative regulator of immunity, investigators have shown that antibody blockade of CTLA-4 could result in antitumor

Preclinical studies targeting CTLA4/CD28 and PD-1/PD-L1 pathways

Immunosuppresion is an important characteristic of MM pathology. Reversing this suppression could potentially restore myeloma immunosurveillance and improve disease control. Immune checkpoints are negative immunologic regulators that downregulate the magnitude of immune responses in order to protect the host from autoimmunity or damage from inflammation. This mechanism is frequently subverted by malignant cells, which escape immune surveillance by increasing inhibitory immune checkpoint ligands

Single agent activity

To date, there are no published clinical trials looking at ipilimumab or tremelimumab exclusively in MM patients. Ipilimumab was tested in a phase I trial of 28 patients with relapsed hematologic malignancies after allogenic stem cell transplant. This trial included 1 MM patient who presented with pulmonary plasmacytomas. Overall, 5 of the 22 (23%) patients who received the maximum tolerated dose of ipilimumab (10 mg/kg) had a complete response while another 2 (9%) patients had a partial

Future directions in treatment with immune checkpoint inhibitors

As detailed above, checkpoint inhibitors have proven challenging in the treatment of multiple myeloma. Targeting the CTLA4 and/or PD-1/PD-L1 pathways can re-activate and boost anti-tumor immunity, resulting in disease regression and prolonged survival in solid tumors. However, checkpoint inhibitors have not been effective as a single agent in multiple myeloma patients. Furthermore, current combinations of checkpoint inhibitors with IMiDs have yielded disappointing results and were associated

Conclusions

Multiple myeloma remains an incurable disease. Immunotherapy using checkpoint inhibitors holds great promise in reversing the suppressive anti-myeloma immune response in MM patients. Thus far, the efficacy and safety profile of checkpoint inhibitors have been disappointing in MM. However, a full understanding of the immune defects present in the MM patient is required to appreciate the unique state of immune impairment that this disease entails. With this understanding, new combinations of

Acknowledgements

None.

Competing interests

The authors declare no competing conflicts of interest.

Funding

This work is supported by Duke Cancer Institute Fund, NIH R44CA199767, NIH R01CA197792, and NIH 5T32HL007057-42.

Authors’ contributions

All authors wrote, read, and approved the final manuscript.

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