Multiple myeloma is a cancer of plasma cells, a type of white blood cell in the bone marrow that produces antibodies. In this disease, abnormal plasma cells proliferate uncontrollably, producing large quantities of nonfunctional proteins and crowding out healthy blood cells. A significant advancement in managing this condition has been the development of proteasome inhibitors. These drugs are a form of targeted therapy, designed to interfere with specific molecules involved in cancer cell growth and survival.
The Role of Proteasomes in Myeloma Cells
Every cell contains proteasomes, which function as a disposal and recycling system. Their primary job is to break down proteins that are damaged, misfolded, or no longer needed. This quality-control process is fundamental for maintaining cellular health by ensuring only functional proteins are present. By degrading unwanted proteins into smaller components, the proteasome helps maintain protein balance.
This process is particularly active in multiple myeloma cells. These cancerous cells are characterized by rapid growth and the production of enormous quantities of abnormal proteins. This high level of protein synthesis places immense stress on the cell, generating a large volume of defective proteins that must be cleared. As a result, myeloma cells become highly dependent on their proteasomes to prevent the buildup of these toxic byproducts.
This reliance is much greater in myeloma cells than in normal, healthy cells. Any disruption to the proteasome’s ability to clear defective proteins can be catastrophic for the myeloma cell. This dependency creates a specific vulnerability that makes the proteasome an ideal therapeutic target.
Mechanism of Proteasome Inhibition
Proteasome inhibitors work by blocking the enzymatic activity of these cellular recycling centers. The drugs bind to specific active sites within the proteasome, shutting down its ability to break down proteins. When inhibited, the proteasome can no longer perform its housekeeping function, leading to a rapid accumulation of misfolded proteins inside the myeloma cell.
This buildup of intracellular proteins triggers intense cellular stress, particularly within the endoplasmic reticulum where proteins are made. The accumulation of unfolded proteins initiates a signaling cascade known as the unfolded protein response (UPR). While the UPR is initially protective, its prolonged activation shifts its function from promoting survival to initiating cell death.
The toxic accumulation of proteins ultimately pushes the myeloma cell to undergo apoptosis, or programmed cell death. This is a controlled self-destruction sequence that eliminates the damaged cell without triggering a broad inflammatory response. Because myeloma cells are more reliant on proteasome function than healthy cells, they are more sensitive to this inhibition, creating a therapeutic window to target the cancer.
Common Proteasome Inhibitors and Administration
The first drug in this class was bortezomib (Velcade®), approved in 2003. It is administered as either a subcutaneous (under the skin) injection or an intravenous (IV) infusion.
Carfilzomib (Kyprolis®), a second-generation inhibitor approved in 2012, binds irreversibly to the proteasome for sustained inhibition. It is administered exclusively as an IV infusion, typically given over 10 to 30 minutes. Carfilzomib is often used for patients whose disease has relapsed or is resistant to other treatments.
Ixazomib (Ninlaro®), approved in 2015, is the first oral proteasome inhibitor. This capsule allows for at-home administration and is taken once a week for three weeks, followed by a one-week rest period in a 28-day cycle. This oral option has provided an important alternative for managing multiple myeloma.
Managing Side Effects
Treatment with proteasome inhibitors is associated with a range of side effects that require careful management to maintain a patient’s quality of life.
Peripheral Neuropathy
A common side effect is peripheral neuropathy, nerve damage that causes tingling, numbness, or pain in the hands and feet. Management includes adjusting the drug’s dose or frequency. Switching from intravenous to subcutaneous bortezomib is also an option, as it carries a lower risk of neuropathy.
Gastrointestinal Issues and Fatigue
Gastrointestinal issues are frequently reported. Common symptoms include:
- Nausea
- Vomiting
- Diarrhea
- Constipation
These can be controlled with supportive medications, hydration, and dietary adjustments. Fatigue is another prevalent side effect, which can be managed by balancing rest with light activity.
Hematologic Side Effects
These drugs can cause hematologic side effects, affecting blood cell counts. Thrombocytopenia, a low platelet count, increases the risk of bruising and bleeding. Regular blood tests are used to monitor counts, and treatment schedules may be adjusted to allow them to recover. Antiviral medication may also be prescribed with bortezomib to prevent shingles reactivation.
Integration into Treatment Regimens
Proteasome inhibitors are rarely used alone, instead forming the backbone of combination therapies. This multi-pronged approach has been shown to produce deeper and more durable responses than single-agent therapy and can help overcome or prevent the development of drug resistance.
They are frequently combined with immunomodulatory drugs (IMiDs), like lenalidomide, and a corticosteroid like dexamethasone. This creates synergy: the proteasome inhibitor disrupts protein disposal, the IMiD modulates the immune system, and the corticosteroid provides anti-inflammatory and anti-cancer activity. This strategy targets multiple survival pathways in myeloma cells.
This combination approach is reflected in acronyms for common regimens. For example, the “VRd” regimen consists of bortezomib (Velcade®), lenalidomide (Revlimid®), and dexamethasone. Another common regimen, “KRd,” combines carfilzomib (Kyprolis®) with lenalidomide and dexamethasone. These triplet therapies are standard treatments for both newly diagnosed and relapsed patients.