Proteasome Inhibitors and Multiple Myeloma: What to Know

Medically Reviewed by Melinda Ratini, MS, DO on August 02, 2023
4 min read

For more than a decade, medical providers have treated multiple myeloma (MM) with proteasome inhibitors (PIs). This important drug therapy has helped improve survival rates of people with MM.

Proteasome inhibitors are a type of drug that prevents proteasomes, a kind of “garbage disposal” system inside a cell, from gobbling up (or breaking down) excess proteins.

Normally, when a cell makes excess amounts of proteins, the cell’s proteasome breaks down and eliminates those proteins. If the proteins are allowed to build up, the cell dies.

The same goes for myeloma cells. Myeloma cells also create excessive amounts of proteins, called “M proteins.” They’re considered to be “garbage proteins” because they aren’t useful. If too many extra proteins build up, it kills the myeloma cell.

Proteasome inhibitors treat multiple myeloma by allowing this type of cell death to happen. They stop (or inhibit) the cell’s proteasomes from breaking down excess proteins, which then build up and kill the myeloma cell. Cancer cells typically have higher levels of proteasome activity, compared to normal cells, so they’re more sensitive to PIs.

Three PIs are used to treat multiple myeloma are:

Bortezomib (Velcade). This was approved for treating multiple myeloma in 2003. It has helped improve survival in MM patients. Bortezomib is used both for patients who were recently diagnosed with MM and those whose myeloma has relapsed (come back) or become resistant (hard-to-treat, or “refractory,” MM). It can be used alone as a maintenance treatment to keep myeloma away or combined with other drugs.

Carfilzomib(Kyprolis). Approved in 2012, carfilzomib has a better safety profile than bortezomib. It moves into all tissue types, except those in the brain. (It doesn’t easily cross the blood-brain barrier.) It’s used alone or along with other drugs to treat those whose myeloma has come back or is hard to treat. Carfilzomib is given through an IV to patients who’ve received at least one other type of treatment.

Ixazomib  (Ninlaro). This was approved in 2015 and is the first PI taken orally (by mouth). It’s used along with other medications for myeloma that are returned or become hard to treat. It can be given as first-line therapy (used first) when the patient prefers a pill instead of an IV shot.

The proteasome inhibitors approved to treat MM within the past 2 decades greatly improved outcomes for myeloma patients. Today they’re considered essential to increasing survival rates and quality of life.

All three main PIs used to treat multiple myeloma (MM) are often used along with other drugs or agents.

Bortezomib can be given as a shot in the belly or thigh or injection into a vein (IV injection). It’s typically taken twice weekly for 6 months, then weekly for another 6 months.

Carfilzomib is given as an IV, typically on a 4-week cycle: 2 days in a row for 3 weeks, followed by no treatment for the fourth week.

Ixazomib is the first oral proteasome inhibitor (taken by mouth) approved by the FDA (in 2015). It’s typically taken once a week for 3 weeks of a 4-week cycle.

Proteasome inhibitors are used to treat all stages of MM. All three PIs have been approved by the FDA for treatment of relapsed or refractory MM. (That means the multiple myeloma has come back or it has stopped responding to treatment.) Proteasome inhibitors are especially effective in patients with a poor prognosis (worse expected outcomes).

When combined with other substances, bortezomib can be used for MM patients who are eligible for stem cell transplants.

Over the past decade, proteasome inhibitors have been a mainstay of treatment. Since being approved for treating multiple myeloma, PIs have improved patient outcomes significantly.

Sometimes PIs stop working in myeloma patients after working at first, though it’s not clear what causes this.

All proteasome inhibitors can cause side effects, including:

Drugs used along with PIs also can cause different side effects. Talk with your doctor about these or any other side effects. Many of them can be treated or prevented.

Other side effects:

Bortezomib may increase your risk of getting shingles, so your doctor may have you take an antiviral medication while taking bortezomib.

Carfilzomib has a higher risk of heart problems, so your doctor should look at any risk factors before starting treatment. It’s also linked to kidney toxicity, which makes it more of a risk for patients with chronic kidney disease or people who are older. You can also get liver failure or pneumonia.

Ixazomib is easy to take, both as a single drug and when used in combination therapy. Side effects include those of the other proteasome inhibitors.

Proteasome inhibitors can stop working after a while, and researchers are learning more about that.

Several studies are looking at the safety and effectiveness of new combination treatment plans involving PIs. Two PIs, marizomib and oprozomib, are being studied in combination with other cancer drugs in patients whose myeloma doesn’t respond to other drug therapies.

New drugs that work along with PIs can be used, including isatuximab, which is being studied in combination with proteasome inhibitors to treat myeloma that has come back or unresponsive myeloma.