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Immune System Dysfunction in Multiple Myeloma

Beth Faiman, PhD, MSN, CNP, AOCN, Nurse Practitioner, Department of Hematologic Oncology, Cleveland Clinic, Cleveland, OH, describes how immune dysfunction may contribute to the progression of multiple myeloma.

Tip Sheet about this topic

Hello, my name is Dr. Beth Faiman. Welcome to the Multiple Myeloma Center for Nurses video: Immune System Dysfunction in Multiple Myeloma.

In this video, we’ll discuss the immune dysfunction associated with multiple myeloma. First, we will review how a healthy immune system works. Then, we’ll look at immune dysfunction in patients with multiple myeloma. Let’s get started.

The immune system provides three main lines of defense against pathogens.1 The first is a set of mechanical, chemical, and biological barriers that protect the body,1 for example, the skin or GI tract where cilia, certain acids, oils, or colonizing microbes remove or block pathogens.2,3 If the first line fails, the second and third lines are activated.1

The second line of defense is the body’s rapid-acting innate immune system.1,2 Innate immunity includes phagocytic cells (such as neutrophils, monocytes, and macrophages), cells that release inflammatory mediators (such as basophils, eosinophils, and mast cells), and natural killer cells.2 Innate immunity is nonspecific and fast acting.2

Innate immunity also plays an important role in activating and alerting the third line of defense, the adaptive immune system, by signaling the formation of cytotoxic T cells.3 The third line of defense, adaptive immunity, is specific and adapts to diverse stimuli.1,2 Adaptive immunity is activated after a few days of pathogen exposure and produces long-lived memory cells.2

Adaptive immunity is orchestrated by T and B cells and their interaction with antigen-presenting cells.2

The B cells mature in the bone marrow and are transformed into plasma cells as part of this immune response.2

Let’s take a closer look at how the adaptive immune system works.

Adaptive immunity relies on the immune cell’s ability to recognize and attach to specific antigens on the surface of infected cells and tumor cells.1,2 The cells responsible for adaptive immunity include B and T cells and antigen-presenting cells.2 Adaptive immunity can be broadly classified into humoral immunity and cell-mediated immunity.2

A humoral response, also called antibody-mediated immunity, relies on antibodies that are produced by plasma cells under the direction of T lymphocytes.2 Lymphocytes and lymphocyte products are involved in adaptive immunity by recognizing substances known as antigens, while antigen-presenting cells display the antigen to lymphocytes and collaborate with them in response to the antigen.2 A cell-mediated response primarily results from T cells activated by antigen-presenting cells.2 Antigen-presenting cells display the antigen to lymphocytes and collaborate with them in response to the antigen.2

A major role of cytotoxic T cells is to destroy virus-infected cells. However, CD8+ cells also play a role in fighting cancer. They protect cells by secreting interferon and tumor necrosis factor, or TNF.4

Now that we have reviewed normal immune function, let’s look at the immune dysregulation that occurs in patients with multiple myeloma.

Multiple myeloma is a clonal B cell malignancy characterized by overproduction of monoclonal protein from dysfunctional plasma cells known as myeloma cells.5

Myeloma cells accumulate in the bone marrow resulting in:

Let’s take a look at how all of these work together to drive the disease.

The main pathophysiological changes in multiple myeloma are abnormalities within the bone marrow microenvironment, bone marrow stromal cells, and cytokine interactions.5 The interaction of myeloma cells within the bone marrow microenvironment involves activation of cytokines, growth factors, and/or adhesion molecules.5

Adhesion molecules mediate interaction between bone marrow stromal cells and myeloma cells resulting in enhanced production of cytokines.5

The cytokines carry out their messenger-like role to promote bone destruction, myeloma cell growth, migration, and drug resistance.5,7

The interaction between bone marrow stromal cells and myeloma cells is also involved in the impairment of osteoclasts, the bone-resorbing cells, and osteoblasts, the bone-forming cells.5

This can cause extensive skeletal destruction, renal impairment, and hypercalcemia.6 The interaction between plasma cells and bone marrow stromal cells may also alter the patient’s immune cells and contribute to failure of immune surveillance.5

Now let’s examine the immune abnormalities seen in patients with multiple myeloma in the context of innate and adaptive immunity.

Multiple myeloma is a clonal malignancy of plasma cells that is characterized by plasmacytosis in the bone marrow, production of monoclonal proteins, osteolytic bone lesions, renal disease, anemia, hypercalcemia, and immunodeficiency.5

Findings from several studies suggest that patients with MM have significant immune abnormalities. For example, in patients with multiple myeloma, total lymphocyte counts are decreased (this includes decreased mature B cells and functional defects in NKT cells).8-10

With respect to humoral immunity, MM is also associated with hypogammaglobulinemia and immunoparesis. Preclinical evidence and consensus statements suggest that It is possible that several mechanisms may be contributing to immunoparesis in patients with myeloma.11,12

Additionally, a decrease in the complement factor C3b and an increase in myeloid-derived suppressor cells is seen in patients with MM. Each of these effects may play an important role in suppressing the immune system.13

The cycle of disease mechanisms in multiple myeloma can play a key role in the interaction between malignant plasma cells and bone marrow stromal cells.5 In addition, the production of cytokines and growth factors that lead to compromised immune function may also result in decreased immune surveillance.5,13,14

Immune responses may also be inhibited by increased expression of immune checkpoint molecules such as PDL1 disrupting T-cell activation and the presence of myeloid-derived suppressor cells, which are increased in MM patients.15,16

As multiple myeloma progresses, the proliferation of malignant plasma cells is further enhanced by5:

This concludes the Immune System Dysfunction in Multiple Myeloma video. To find out more on this and other topics related to multiple myeloma, please see additional videos and resources on this site.

Here you will also find a number of educational tools, including tip sheets to help you discuss these topics with your patients, answers to common questions, and other downloadable materials.

Thank you.

References:

  1. Doan T, Melvold R, Viselli S, Waltenbaugh C. The need for self recognition. In: Lippincott’s Illustrated Reviews: Immunology. Baltimore, MD: Lippincott Williams and Wilkins; 2008:3-11.
  2. Noonan K. Anatomy and physiology. In: Tariman JD, Faiman B, eds. Multiple Myeloma. A Textbook for Nurses, 2nd Ed. Pittsburgh, PA: Oncology Nursing Society; 2015:11-34.
  3. Murphy K. Janeway’s Immunobiology. 8th Ed. New York, NY: Garland Science; 2011:37-73.
  4. Nauta J. Humoral and cellular immunity. In: Statistics in Clinical Vaccine Trials. Berlin, Germany: Springer-Verlag Berlin Heidelberg; 2011;13-17.
  5. Noonan K. Pathophysiology. In: Tariman JD, Faiman B, eds. Multiple Myeloma. A Textbook for Nurses, 2nd Ed. Pittsburgh, PA: Oncology Nursing Society; 2015:35-52.
  6. Durie BGM. Concise Review of the Disease and Treatment Options: Multiple Myeloma Cancer of the Bone Marrow. North Hollywood, CA: International Myeloma Foundation; 2011.
  7. Munshi NC, et al. Plasma cell neoplasms. N: DeVita VT, et al, eds. Cancer Principles Practice of Oncology. 7th ed. 2005:2155-2188.
  8. Muthu Raja KR, Kubiczkova L, Rihova L, et al. Functionally suppressive CD8 T regulatory cells are increased in patients with multiple myeloma: a cause for immune impairment. PLoS ONE. 2012;7(11):e49446.
  9. Pessoa de Magalhães RJ, Vidriales M-B, Paiva B, et al. Analysis of the immune system of multiple myeloma patients achieving long term disease control by multidimensional flow cytometry. Haematologica. 2013;98(1):79-86.
  10. Dhodapkar MV, Geller MD, Chang DH, et al. A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma. J Exp Med. 2003;197(12):1667-1676
  11. Krakauer RS, Strober W, Waldmann TA. Hypogammaglobulinemia in experimental myeloma: the role of suppressor factors from mononuclear phagotytes. J Immunol. 1977;118(4):1385-1390.
  12. Barlogie B, Alexanian R. Second international workshop on myeloma: advances in biology and therapy of multiple myeloma. Cancer Res. 1989;49:7172-7175.
  13. Zheng MM, Zhang Z, Bemis K, et al. The systemic cytokine environment is permanently altered in multiple myeloma. PLoS ONE. 2013;8(3):e58504.
  14. Ohm JE, Gabrilovich DI, Sempowski GD. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood. 2003;101:4878-4886.
  15. Favalaro J, Liyadipitiya T, Brown R, et al. Myeloid derived suppressor cells are numerically functionally and phenotypically different in patients with multiple myeloma. Leuk Lymphoma. 2014;55(12):2893-2900.
  16. Rosenblatt J, Glotzbecker B, Mills H, et al. PD-1 blockade by CT-011, anto PD-1 antibody, enhances ex-vivo T cell responses to autologous dendritic myeloma fusion vaccine. J Immunother. 2011;34(5):409-418.