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- What is T-cell Exhaustion in Myeloma?
What is T-cell Exhaustion in Myeloma?
T-cell exhaustion in myeloma happens to all MM parents eventually. The FDA approved, safe and effective standard-of-care therapy plan for all newly diagnosed MM patients is different classes of chemotherapy again and again until MDR aka multi drug resistance.
While many of us may not have understood the phrase “t-cell exhaustion in myeloma” we all know that chemotherapy wears down a person until they succumb to their incurable blood cancer.
Is there any way to enhance a person’s immune system? Is there any way to manage multiple myeloma with less chemotherapy?
What is T-cell Exhaustion in Myeloma?
Do all types of chemotherapy for myeloma potentially exhaust the immune system?
Not all types of chemotherapy for multiple myeloma (MM) have the same degree of impact on the immune system, but most can contribute to T-cell exhaustion or immune suppression in some way. The extent of immune exhaustion depends on the specific drug, dosage, and duration of treatment. Here’s how different classes of MM treatments affect the immune system:
1. Proteasome Inhibitors (e.g., Bortezomib, Carfilzomib, Ixazomib)
- Impact: These drugs can suppress the immune system but also have some immunostimulatory effects.
- T-cell Exhaustion?
- Mixed effect: They can reduce regulatory T cells (Tregs) and enhance cytotoxic T cells in some cases.
- However, long-term use may lead to functional impairment of T cells, increasing the risk of infections.
2. Immunomodulatory Drugs (IMiDs) (e.g., Thalidomide, Lenalidomide, Pomalidomide)
- Impact: These enhance T-cell and NK cell function while inhibiting Tregs.
- T-cell Exhaustion?
- IMiDs boost immune function in early treatment phases.
- Long-term use might lead to immune dysfunction, partly due to chronic stimulation and exhaustion.
3. Alkylating Agents (e.g., Melphalan, Cyclophosphamide)
- Impact: Directly deplete both tumor and normal immune cells.
- T-cell Exhaustion?
- Yes, significantly. These drugs deplete naive and memory T cells, reducing immune surveillance.
- Used in autologous stem cell transplantation (ASCT), leading to prolonged immune suppression.
4. Monoclonal Antibodies (e.g., Daratumumab, Elotuzumab, Isatuximab)
- Impact: Target specific surface proteins on myeloma cells.
- T-cell Exhaustion?
- Daratumumab (anti-CD38) depletes Tregs but may also reduce CD8+ T-cell function over time.
- Elotuzumab (anti-SLAMF7) enhances NK cell activity and has less T-cell exhaustion risk.
5. Corticosteroids (e.g., Dexamethasone, Prednisone)
- Impact: Strongly suppress immune responses.
- T-cell Exhaustion?
- Yes, profoundly. Chronic steroid use reduces T-cell function and increases PD-1 expression (a marker of exhaustion).
6. CAR-T and Bispecific Antibodies (e.g., BCMA-Targeted Therapies)
- Impact: Can induce powerful immune responses but also cause exhaustion.
- T-cell Exhaustion?
- Yes, especially with prolonged antigen exposure.
- CAR-T cells can become exhausted if MM is not fully cleared, leading to loss of function.
Key Takeaways
- Most MM therapies have some potential for immune exhaustion, but the extent varies.
- IMiDs and monoclonal antibodies can enhance immunity initially but may contribute to exhaustion over time.
- Alkylating agents, corticosteroids, and prolonged CAR-T therapy have the highest risk of depleting or exhausting T cells.
- Combination regimens (e.g., bortezomib + lenalidomide + dexamethasone) balance immune activation and suppression but need careful monitoring.
I am a long-term MM survivor. The aggressive SOC therapy plan didn’t work for me and saddled me with a host of long-term and late stage side effects. To my thinking, doing the same thing over and over again expecting a different result is Albert Einstein’s definition of insanity.
Email me at David.PeopleBeatingCancer@gmail.com
David Emerson
- MM Survivor
- MM Cancer Coach
- Director PeopleBeatingCancer
Impacting T-cell fitness in multiple myeloma: potential roles for selinexor and XPO1 inhibitors
Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including
- tumor burden,
- constant immune activation due to chronic disease, age, nutritional status,
- and certain MM treatments such as alkylating agents and proteasome inhibitors.
Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells.
Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate T-cell fitness and potentially optimize overall benefit and clinical outcomes…
T-cell exhaustion in myeloma T-cell exhaustion in myeloma