Multiple myeloma is a cancer that begins in plasma cells, a type of white blood cell found in the bone marrow. These abnormal plasma cells multiply uncontrollably, accumulating in the bone marrow and interfering with the production of healthy blood cells. This proliferation can lead to complications such as anemia, increased infection risk, and bone damage. Proteasome inhibitors represent a targeted class of medications that have significantly improved outcomes for individuals living with this condition.
The Proteasome’s Function in Myeloma Cells
Within every cell, large protein complexes known as proteasomes act as a cellular recycling center, breaking down and removing damaged or unneeded proteins. This process is fundamental for cellular balance. Unwanted proteins are tagged with a small protein called ubiquitin, signaling them for degradation by the proteasome through the ubiquitin-proteasome pathway.
Myeloma cells are characterized by their rapid growth and the excessive production of abnormal proteins. This high rate of protein synthesis burdens the proteasome system, as these cells heavily depend on it to process and dispose of proteins. This heightened reliance on the proteasome makes myeloma cells uniquely vulnerable to treatments that disrupt this pathway.
How Proteasome Inhibitors Work
Proteasome inhibitors block the proteasome’s activity. When the proteasome is inhibited, the myeloma cell’s ability to clear out misfolded and excess proteins is severely impaired. This leads to a rapid accumulation of these abnormal proteins within the cell.
The buildup of these proteins triggers a state of cellular distress, known as endoplasmic reticulum (ER) stress. This stress activates a series of internal signals that ultimately prompt the myeloma cell to undergo programmed cell death, or apoptosis. This mechanism preferentially targets cancerous myeloma cells over healthy cells because myeloma cells produce proteins at a much higher rate and are therefore more sensitive to the disruption of their protein disposal system.
Specific Proteasome Inhibitors and Administration
Several proteasome inhibitors are approved for treating multiple myeloma. Bortezomib was the first drug in this class and is commonly administered as a subcutaneous injection or an intravenous infusion. It inhibits the proteasome’s active sites.
Carfilzomib is a next-generation proteasome inhibitor. It is given as an intravenous infusion and works by irreversibly inhibiting the proteasome. This irreversible binding can be effective against myeloma cells that have developed resistance to bortezomib.
Ixazomib is the first oral proteasome inhibitor available for multiple myeloma. Patients take this medication as a pill, typically once a week. Its oral formulation offers convenience and a favorable safety profile, making it a valuable option, including for patients who may have developed resistance to other proteasome inhibitors.
Managing Side Effects of Treatment
Proteasome inhibitors can cause various side effects, and managing them is an important part of patient care. A common neurological side effect is peripheral neuropathy, which can cause numbness, tingling, or pain in the hands and feet. Patients should communicate any such symptoms to their healthcare team, as dose adjustments or changes in treatment frequency can often help alleviate this issue.
Gastrointestinal issues include nausea, vomiting, diarrhea, constipation, and decreased appetite. Hematological effects, such as thrombocytopenia (low platelet counts) and anemia (low red blood cell counts), can also occur. Fatigue and generalized weakness are also common during treatment.
Specific proteasome inhibitors can have unique side effect profiles; for example, carfilzomib has been linked to a higher risk of heart problems like hypertension and kidney damage. Bortezomib may increase the risk of shingles, so patients receiving it are often prescribed antiviral medication to prevent this. Close monitoring and proactive management, in discussion with a healthcare provider, are important for addressing these effects.
Use in Combination Treatment Regimens
Proteasome inhibitors are rarely used alone; they are most often combined with other medications in multi-drug regimens to maximize effectiveness. This approach allows for a broader attack on myeloma cells through different biological pathways.
Common combinations include proteasome inhibitors with immunomodulatory agents, such as lenalidomide or pomalidomide, and corticosteroids like dexamethasone. These multi-drug regimens are widely used in various stages of treatment. They serve as initial (induction) therapy for newly diagnosed patients, aiming to reduce tumor burden. Proteasome inhibitors also play a significant role in managing relapsed or refractory multiple myeloma, where the disease has returned or no longer responds to previous therapies.