Proteasome inhibitors

Myeloma cells generate lots of additional proteins, like M proteins, that aren’t useful to the body. One way to target myeloma cells is to use these extra, “garbage” proteins to kill them. When too much garbage builds up in a cell, it dies. Proteasome inhibitors are a type of drug that prevents proteasomes, the garbage disposal system of the cell, from chewing up excess proteins. The proteins build up and kill the myeloma cells. There are currently three proteasome inhibitors that are used for multiple myeloma (MM) treatment: Velcade (bortezomib), Kyprolis (carfilzomib), and Ninlaro (ixazomib).

Velcade (bortezomib)

Velcade is used in a combination with Revlimid (lenalidomide) and dexamethasone, called VRd, for the initial treatment of patients with multiple myeloma or alone as maintenance treatment to keep the cancer away. Sometimes it is given in combination with cyclophosphamide and dexamethasone (VCd). Velcade can also be used for patients who have received it previously. There are two ways that Velcade can be received: as a shot into the abdomen or thigh (subcutaneously) or as an injection into a vein (intravenously, as an IV injection). Velcade is given twice a week for the first 6 months followed by once-weekly dosing for the next 6 months.

Common side effects with Velcade are nausea, vomiting, diarrhea, constipation, a low number of platelets (increased risk of bleeding, slower blood clotting), fatigue, a low number of red blood cells (anemia), a low number of white blood cells, rash, fever, peripheral neuropathy, and loss of appetite. Additional myeloma drugs taken with Velcade may cause different side effects as well. If you experience side effects with any of your medications, reach out to your oncologist. Many side effects can be treated—or even prevented.

If you experience peripheral neuropathy—the feeling of tingling, numbness, pain, or burning in the hands and feet or weakness in the arms and legs—your doctor may lower your dose or switch to another treatment. Patients who receive Velcade shots are less likely to experience peripheral neuropathy than those who receive IV Velcade. If peripheral neuropathy develops, certain medications can help to decrease neuropathic pain, and many treatment centers may also use vitamins, amino acids, and minerals to help manage pain.

Make sure to stay hydrated while taking Velcade, especially if vomiting, nausea, or diarrhea occurs. Grapefruit and grapefruit juice may interfere with the way the body breaks down Velcade. Talk to your doctor about whether you should continue to consume these foods.

Your doctor may give you medication to prevent shingles, a virus that causes a painful rash. If you are taking diabetes medication, talk to your doctor so your blood glucose can be monitored, as Velcade may have an effect. Also, tell your doctor immediately about any serious side effects, like peripheral neuropathy; low blood pressure; and heart, lung, or liver problems. Rare side effects called posterior reversible encephalopathy syndrome (PRES) and tumor lysis syndrome have been reported with Velcade.

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Kyprolis (carfilzomib)

The MMRF was instrumental in the development of Kyprolis, which is used for patients with relapsed or refractory MM. Relapsed disease means that myeloma is once again detectable, and refractory disease means the myeloma didn’t respond or has stopped responding to a given treatment. Kyprolis is given as an IV infusion on a 4-week schedule (cycle), 2 days in a row for weeks 1-3 and no treatment during week 4, for the first 12 cycles. During cycles 13-18, Kyprolis is given 2 days in a row during weeks 1 and 3, with no treatment during weeks 2 and 4. Kyprolis is given alone, with dexamethasone, or in combination with Revlimid (lenalidomide) and dexamethasone (KRd).

Common side effects with Kyprolis alone are a low number of red blood cells (anemia), tiredness, a low number of platelets, nausea, fever, trouble breathing, diarrhea, headache, cough, and swelling of the lower legs or hands. Peripheral neuropathy tends to occur less frequently than with Velcade and tends to be mild. Serious side effects may include a low number of blood cells (red blood cells, platelets, and white blood cells) and pneumonia. Side effects may be different when Kyprolis is used with dexamethasone and Revlimid.

As with other treatments you’re receiving, talk to your doctor about side effects. Some side effects can be managed or prevented. With Kyprolis treatment, you may receive medicine to prevent shingles.

A recent study comparing Kyprolis and dexamethasone (Kd) against Velcade and dexamethasone (Vd) showed that patients with relapsed disease receiving Kd had better outcomes than those receiving Vd. In a separate study conducted in collaboration with the Multiple Myeloma Research Consortium (MMRC), 20% of patients that could not tolerate or didn’t respond to Velcade responded to Kyprolis.

Before receiving Kyprolis, it’s important to be adequately hydrated. Two days before cycle 1, day 1, your doctor will advise you on the amount of water you will need to drink. A 180-pound patient will need to drink about 10 cups of water to be adequately hydrated before treatment. You will also receive IV fluids prior to the first dose. You may also receive IV fluids following Kyprolis treatment.

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Ninlaro (ixazomib)

As with Kyprolis, the MMRC (the clinical trials arm of the MMRF) helped to advance studies of Ninlaro for its approval and use in MM. Ninlaro is given in combination with Revlimid (lenalidomide) and dexamethasone in people who have received at least one prior treatment for their multiple myeloma. All three drugs are oral (taken by mouth). Ninlaro is taken once a week for 3 weeks of a 4-week cycle. It should be taken at about the same time each day, an hour before or two hours after eating. It should not be taken with dexamethasone, which should be taken with food.

Common side effects that occur with the Ninlaro regimen are diarrhea, constipation, nausea and vomiting, a low number of platelets (a type of blood cell that helps blood clot), peripheral neuropathy, swelling of the hands or feet, and back pain. If you vomit after taking Ninlaro, do not take another dose until it is scheduled. Dose reductions of Ninlaro, Revlimid, and/or dexamethasone can help if you experience certain side effects. Some of the side effects of Ninlaro, Revlimid, and dexamethasone can become severe. Your doctor will monitor your response to your treatment and certain side effects with lab tests.

Talk to your doctor about any side effects you experience. Certain side effects like nausea and vomiting or certain infections can be prevented with prescription drugs. Your doctor may prescribe a medication to help prevent shingles from occurring. Other side effects, like diarrhea and rash, can be treated if they develop.

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