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Myeloma Immune Dysfunction

Multiple Myeloma Stages
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Could myeloma immune dysfunction be as much of a problem as monoclonal proteins (MM) are? Meaning, could the damage done to the patient’s immune system shorten the MM survivor’s life as much as multiple myeloma is?

I’m just a long-term MM survivor. While I’ve gotten pretty knowledgeable about MM over the years, I would be the first person to say that I am not an oncologist.

Here is my thinking:

  • All forms of conventional oncological therapy cause myeloma immune dysfunction- myeloma patients undergo round after round of toxic therapies weakening their immune systems-
  • There are no immune-boosting conventional therapies given to fix #1 above- IVIG therapy kind of- but IVIG is only immunoglobulin boosting-
  • Conventional myeloma therapy is all about high-dose, aggressive therapies beginning with an ASCT-
  • MM is incurable- forcing each and every patient to undergo round after round of therapy, weakening their immune system more and more until…
  • MM is largely a disease of the over 60 crowd- when the human immune system is at its weakest-

What is Progressive immune dysfunction in multiple myeloma?

1. Reduction of Healthy Immune Cells:

  • Suppression of normal plasma cells: Cancerous plasma cells overpopulate the bone marrow, crowding out normal plasma cells, which decreases the production of healthy antibodies. This leaves the body more vulnerable to infections.
  • Decreased T-cell and B-cell function: The abnormal bone marrow environment also hampers the function and maturation of T-cells and B-cells, both essential for adaptive immunity.

2. Immunosuppressive Tumor Microenvironment:

  • Production of immunosuppressive cytokines: Multiple myeloma cells secrete various cytokines (e.g., interleukin-6), which create a microenvironment that favors tumor growth and dampens immune responses.
  • Expansion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs): These cells are known to inhibit immune responses and are often elevated in MM patients, further contributing to immune suppression.

3. Impaired Antigen Presentation:

  • Multiple myeloma can interfere with the function of dendritic cells, which are responsible for presenting antigens to T-cells and initiating immune responses. This results in a reduced ability to recognize and fight infections and cancer cells.

4. Hypogammaglobulinemia:

  • A characteristic of multiple myeloma is the production of large amounts of abnormal monoclonal proteins (M-proteins), which do not function like normal antibodies. This leads to a deficiency of functional immunoglobulins (antibodies) in the blood, contributing to increased susceptibility to infections.

5. Exhaustion and Dysfunction of T-cells:

  • As the disease progresses, T-cells (particularly CD8+ cytotoxic T-cells) become exhausted, meaning they lose their ability to effectively attack cancer cells and other threats. This contributes to a failure in immune surveillance and control of the cancer.

6. Compromised Innate Immunity:

  • NK (natural killer) cells, which are part of the innate immune system and play a role in attacking cancer cells, often exhibit diminished function in multiple myeloma. This further impairs the body’s ability to mount an effective anti-tumor response.

Consequences of Immune Dysfunction in Multiple Myeloma:

  • Increased susceptibility to infections: Due to reduced antibody production and weakened T-cell responses, infections (particularly bacterial infections) are a major cause of morbidity and mortality in MM patients.
  • Failure of immune surveillance: The immune system is less capable of recognizing and destroying cancer cells, which allows the disease to progress more rapidly.
  • Reduced response to immunotherapies: As the immune dysfunction becomes more severe, it limits the effectiveness of treatments such as immunomodulatory drugs (IMiDs) and immune checkpoint inhibitors.

Clinical Implications:

  • Management of infections becomes critical in MM patients, with frequent monitoring and prophylactic treatments (e.g., antibiotics, antivirals, or immunoglobulin replacement therapy).
  • Therapeutic strategies aimed at restoring immune function are being actively researched. These include CAR T-cell therapy, monoclonal antibodies, and other immunotherapeutic approaches that attempt to bypass or reverse the immune suppression in MM.

In summary, progressive immune dysfunction in multiple myeloma is a complex process involving the suppression of normal immune responses, impaired antibody production, and the creation of an immunosuppressive environment, all of which contribute to disease progression and increased vulnerability to infections.


While research considers infection to be the most common cause of death among myeloma patients, it is difficult to parse the data because both treatment and the disease itself can cause myeloma immune dysfunction.

The solution? Figure out how to boost your immune system regularly and undergo as little chemo as you can.

If you have any questions about myeloma immune dysfunction, email me at David.PeopleBeatingCancer@gmail.com

Thank you,

David Emerson

  • MM Survivor
  • MM Cancer Coach
  • Director PeopleBeatingCancer

Treatment of multiple myeloma: What is the impact on T-cell function?

“Abstract

Treatment of multiple myeloma (MM) has evolved remarkably over the past few decades. Autologous stem cell transplantation, as well as

  • proteasome inhibitors,
  • immunomodulatory drugs,
  • and monoclonal antibodies,

has substantially improved the prognosis of patients with MM. Novel therapies, including:

  • chimeric antigen receptor-T cells,
  • bispecific T-cell engagers,
  • antibody-drug conjugates,
  • histone deacetylase inhibitors,
  • and nuclear export inhibitors,

have provided more options. However, MM remains incurable. T cells are the principal weapons of antitumor immunity, but T cells display a broad spectrum of dysfunctional states during MM.

The promising clinical results of T-cell-directed immunotherapies emphasize the significance of enhancing T-cell function in antimyeloma treatment. This review summarizes the potential effects of these antimyeloma agents on T-cell function and discusses possible optimized strategies for MM management by boosting T-cell immunity.

Conclusion

As more options have been approved, and more agents have made their way through clinical trials, MM treatment has shifted to a promising paradigm. With an increasing understanding of the mechanisms underlying MM, the optimal application and sequencing of existing therapies and their integration into MM management depend on the underlying immune status to some extent.

In this overview, we summarize the effects of the mainstay drugs and novel therapies for MM on T cells (Figures 1 and 2; Table 1) and propose a new therapeutic paradigm integrating the functional status of T cells (Figure 3).

However, T-cell dysfunction is not the only reason for MM escape and treatment failure. Suppressive immune microenvironments and intrinsic tumor mechanisms are also important. CAR-T cell therapy has shown promise for achieving long-term remission with a single infusion and holds the potential to play a vital therapeutic role as ASCT in the future.

Therefore, long-term follow-up and more studies are warranted. In addition, the potential synergies and combination strategies among these agents are not detailed in the review, and further research is required.”

 

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