Ninlaro (ixazomib)

In 2015, the U.S. Food and Drug Administration approved NINLARO® (ixazomib) for the treatment of adult patients with myeloma who have received at least 1 prior therapy. Ninlaro is the third proteasome inhibitor approved by the FDA since 2003, and it is the first proteasome inhibitor that is taken orally (by mouth). 

How Does Ninlaro Work?

Ninlaro works by blocking the activity of enzyme complexes called proteasomes. Both normal cells and cancer cells contain proteasomes. These proteasomes break down damaged and unwanted proteins into smaller components. They also carry out the regulated breakdown of undamaged proteins in the cell. This process is necessary for the control of many critical cellular functions. Then, these smaller protein components are used to create new proteins required by the cell. This is important for maintaining balance within the cell and for regulating cell growth.

If the proteasome is stopped (inhibited), then the damaged and unwanted proteins build up in the cell’s nucleus and cytoplasm and cause it to die. Myeloma cells are more sensitive to proteasome inhibition than normal cells. For that reason, the myeloma cells die whereas normal cells are able to recover.

How Is Ninlaro Given?

Ninlaro is indicated in combination with the immunomodulatory agent Revlimid® (lenalidomide) plus the steroid dexamethasone, a “triplet” (3-drug) combination known as IRd. To learn more, read these helpful IMF publications:

• Adherence to Oral Cancer Therapy tip card
• Understanding Dexamethasone in the Treatment of Myeloma
• Understanding REVLIMID® (lenalidomide) capsules

In April 2022, the FDA added a limitation of use for Ninlaro. The FDA stated that it is not recommended in the maintenance setting or in newly diagnosed myeloma in combination with Rd outside of controlled clinical trials. 

Clinical Trial Experience with Ninlaro

A clinical trial is a medical research study with people who volunteer to test scientific approaches to a new treatment or a new combination therapy. Each clinical trial is designed to find better ways to prevent, detect, diagnose, or treat cancer and to answer scientific questions. 

The FDA approval of Ninlaro was based on data from the TOURMALINE-MM1 clinical trial, a phase III study of IRd versus placebo plus Revlimid and dexamethasone [placebo-Rd] in 722 patients with relapsed or refractory myeloma who had received at least 1 prior line of therapy.

Patients who were refractory to prior treatment with Revlimid or proteasome inhibitors were not eligible to participate. Patients in both the IRd study arm and the placebo-Rd study arm were treated until their myeloma progressed or they were unable to tolerate the treatment.

Study patients were given a blood thinner to prevent blood clots. Blood thinners are recommended for all myeloma patients taking Rd. Other medications were given as necessary at the discretion of the treating doctor to improve the patients’ tolerance of the treatment.

In June 2021, the Journal of Clinical Oncology published the final analysis of TOURMALINE-MM1 overall survival (OS) by Dr. Paul G. Richardson and colleagues. With a median follow-up of 85 months, median OS was 53.6 months [IRd] versus 51.6 months [placebo-Rd]. Progression-free survival  (PFS) benefit with IRd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis.

Ninlaro continues to be studied in clinical trials as part of a wide spectrum of combination therapies and across myeloma disease settings. Contact the IMF InfoLine or visit clinicaltrials.gov for up-to-date information. 

What Is the Dose and Schedule for Taking Ninlaro?

Ninlaro is taken orally. It's the patient’s responsibility to take this medication as directed by the treating doctor. The patient must understand instructions provided by the doctor.

• Each treatment cycle is 28 days.
• Ninlaro is taken orally on days 1, 8, and 15 of each treatment cycle. The doctor will determine which starting dose of Ninlaro is best for the patient. The dose may be lowered if the patient has moderate or severe liver or kidney dysfunction. If the patient requires dialysis, the administration of Ninlaro and the timing of dialysis should be discussed with the doctor. 
• Revlimid is taken orally on days 1 through 21 of each treatment cycle. The recommended starting dose of Revlimid is 25 mg. If necessary, the patient's dose of Revlimid can be lowered by the doctor.
• Dexamethasone is taken orally on days 1, 8, 15, and 22 of each treatment cycle. The recommended starting dose of dexamethasone is 40 mg. If necessary, the patient's dose of dexamethasone can be lowered by the doctor.

IRd is an option for patients who can benefit from an all-oral combination therapy, especially older patients.

Herpes zoster

All patients taking a proteasome inhibitor, including patients taking IRd, are at an increased risk for the herpes zoster infection, also called “shingles.” All patients taking IRd should receive preventive treatment with an antiviral medication to prevent the herpes zoster infection. This infection caused by the reactivation of the varicella-zoster virus (VZV), the same virus that causes varicella (also called “chickenpox”). When reactivated, the herpes zoster infection frequently affects nerves.

Venous thromboembolism (VTE) 

Patients taking IRd are at an increased risk for venous thromboembolism (VTE) events. VTE is a condition that includes both deep vein thrombosis (DVT) and pulmonary embolism(PE). Risk factors of VTE  include the following:

• infection
• age >75
• cancer
• a history of VTE

All patients taking IRd should receive preventive treatment with a blood thinner (anti-coagulant) to prevent a possible VTE event. Ask your doctor about getting regular physical activity to prevent blood clots.

Important Instructions for Taking Ninlaro Safely

Read these safety instructions carefully BEFORE taking Ninlaro:

• Take the IRd combination therapy exactly as the doctor instructs.
• Take Ninlaro on the same day each week. This is important for efficacy and safety. It will help establish a routine for the patient to remember when to take medication.
• Take Ninlaro at about the same time of day each week.
• Take Ninlaro at least 1 hour before, or at least 2 hours after eating (i.e., on an empty stomach).
• DO NOT take Ninlaro at the same time with dexamethasone, because dexamethasone should be taken with food, and Ninlaro should not be taken with food.
• Store Ninlaro capsules at room temperature in their original packaging. 
• Do not remove the capsule from the packaging until just before taking it.
• Swallow the whole Ninlaro capsule with a full glass of water.
• Do not crush, chew, or open the Ninlaro capsule.
• Avoid direct contact with the contents of the Ninlaro capsule. If you accidentally get powder from inside the capsule on your skin, wash the area well with soap and water. If you get it in your eyes, flush your eyes well with water.
• If a patient misses or delays a dose of Ninlaro, take the dose as long as the next scheduled dose is more than 3 days (72 hours) away. DO NOT take a missed dose of Ninlaro if it is within 3 days (72 hours) of the next scheduled dose.
• If a patient vomits after taking a dose of Ninlaro, DO NOT repeat the dose. Just take the next dose of Ninlaro on the next scheduled day at the usual time.
• If a patient takes more Ninlaro than prescribed, call the doctor immediately or go to the nearest hospital emergency room.
• Patients should tell their doctor about all other medications and supplements that they’re taking before taking a first dose of Ninlaro.
• Patients should tell their doctor about all their medical conditions. Special precautions must be taken with dosing if the patient has liver or kidney dysfunction or diabetes.

Be sure to promptly report any health issues to the doctor who is treating the myeloma patient.

Side Effects of Ninlaro Noted During the TOURMALINE-MM1 Study

A side effect, also called an adverse reaction or adverse event (AE), is an unwanted or unexpected effect caused by a drug. All the side effects experienced by patients in both arms of the TOURMALINE-MM1 clinical trial were recorded for evaluation before the FDA approval of IRd.

The side effects discussed below occurred most commonly among the patients enrolled in the TOURMALINE-MM1 clinical trial, but other, less common side effects occurred as well. Back pain is also common while taking Ninlaro. In addition, serious side effects outside of clinical trials have been reported to the regulatory agencies. Some side effects can be life-threatening if not managed quickly and effectively.  Any changes in health must be promptly reported to the doctor while a patient is being treated with IRd combination therapy.

Thrombocytopenia

Thrombocytopenia is a low number of platelets in the blood. Platelets help blood to clot. Fewer platelets can lead to easier bruising, bleeding, and slower healing. The “normal” level of platelets varies from laboratory to laboratory. For example, at Mayo Clinic the “normal” level is ≥150,000 platelets per microliter of circulating blood. If the platelet count is less than 50,000, bleeding problems could occur. Major bleeding is usually associated with a reduction to less than 10,000.

Both Ninlaro and Revlimid can cause platelet counts to drop. During treatment with IRd, the platelet count reaches its lowest point on days 14–21 of each 28-day cycle. Yet, it usually recovers to baseline by the beginning of the next cycle. In the TOURMALINE-MM1 clinical trial, 78% of the patients in the IRd arm and 54% of the patients in the placebo-Rd arm had thrombocytopenia. Some of these instances were severe enough to be life-threatening.

Prevention and treatment of thrombocytopenia

The doctor should monitor the patient's complete blood count (CBC) throughout treatment with IRd. Patients should alert their doctor if they experience excessive bruising or bleeding. Management of thrombocytopenia may include holding Ninlaro and Revlimid treatment until the patient's platelet  count recovers and then adjusting the Ninlaro and Revlimid doses. Some patients with persistent low platelet counts may require platelet transfusions.

Diarrhea

In the TOURMALINE-MM1 clinical trial, 42% of the patients in the IRd arm and 36% in the placebo-Rd arm experienced diarrhea. While no patient in the study had diarrhea that was life-threatening, 6% of the cases in the Ninlaro arm and 2% of the cases in the placebo-Rd arm were severe.

Prevention and treatment of diarrhea

The doctor may direct the patient to take medication to control diarrhea. If the patient has diarrhea, alert the doctor and take precautions to prevent dehydration by drinking a sufficient amount of water. The doctor will monitor the patient's electrolytes and correct abnormalities if they’re detected.

Contact the doctor immediately if the patient experiences dizziness, lightheadedness, or fainting. If needed, the doctor may withhold or adjust the patient's doses of Ninlaro and Revlimid, or administer anti-diarrheal medication or intravenous (IV) hydration.

Constipation

The medical definition of constipation is 3 or fewer bowel movements in one week. The stool may be hard, dry, and difficult to pass. The patient may also have stomach cramps and bloating. Not eating and drinking enough fluids and being less active can contribute to the problem.

In the TOURMALINE-MM1 clinical trial, 34% of the patients in the IRd arm and 25% in the placebo-Rd arm experienced constipation. Less than 1% of cases in either arm were considered serious. Sometimes patients cycle back and forth between the discomfort of constipation and diarrhea. Talk to your doctor about strategies to regulate your bowel health.

Prevention and treatment of constipation

• Drink sufficient fluids.
• Try to eat high-fiber foods.
• Try to be active every day, even if you exercise in a chair.Moving your body increases the rhythmic contractions that move food through your intestines.
• Report your constipation to your doctor or nurse.

Nausea and vomiting

Nausea affected 26% and 21% of the patients in the IRd and placebo-Rd arms of the TOURMALINE-MM1 clinical trial, respectively, and vomiting occurred in 22% and 11%, respectively. These episodes were not life-threatening. 

Prevention and treatment of nausea

The doctor will give the patient medication to help prevent nausea and vomiting before each dose of Ninlaro. Precautions should be taken to prevent dehydration caused by vomiting. The patient must drink a sufficient amount of water and other fluids. Contact the doctor immediately if the patient experiences dizziness, lightheadedness, or fainting. The doctor may provide medication to prevent vomiting or IV hydration if required.

Peripheral neuropathy

Peripheral neuropathy (PN) is a serious condition that affects nerves in the hands, feet, lower legs, and/or arms. Symptoms of PN may include a feeling of numbness, tingling, burning, and/or pain. Patients may experience PN from the effects of myeloma itself and/or from treatments for myeloma. For more information, read the IMF’s publication Understanding Peripheral Neuropathy in Myeloma.

If the patient has PN before beginning therapy with Ninlaro, it is important to promptly report any increase in PN discomfort to the treating doctor.

In the TOURMALINE-MM1 clinical trial, 28% of the patients in the IRd arm reported PN, of which 18% was Grade 1. In the placebo-Rd arm, 21% of the patients reported PN, of which 14% was Grade 1. Only 2% of patients in either study arm reported PN that caused severe pain, weakness, or numbness that interfered with the activities of daily living. 

Prevention and treatment of peripheral neuropathy

The best approach to treating PN is to prevent it from occurring or worsening. By promptly reporting any signs of numbness or tingling to the doctor, the patient can avoid potentially painful or disabling neuropathy.

Peripheral edema

Edema is an abnormal accumulation of excess fluid under the skin in the interstitial spaces within the tissues. Peripheral edema is accumulation of fluid that causes swelling in the ankles, feet, and legs. If there is swelling in only one leg, alert the doctor immediately. This type of swelling may signal the presence of a blood clot.

Peripheral edema can be a side effect of long-term use of anti-inflammatory medications (such as dexamethasone), which increase fluid pressure from sodium and water retention, and thereby upset the balance of inflow and drainage of interstitial fluid. Peripheral edema can also result from other causes.

In the TOURMALINE-MM1 clinical trial, peripheral edema affected 25% of the patients in the IRd arm and 18% of the patients in the placebo-Rd arm. The majority of the cases were mild and none were life-threatening.

Prevention and treatment of peripheral edema

Patients should be evaluated for underlying causes of peripheral edema and provided supportive care, as necessary. A reduction in dietary salt intake may be required. The dose of dexamethasone may be modified. If the edema is severe, the dose of Ninlaro should also be adjusted.

Rash

In the TOURMALINE-MM1 clinical trial, rash was reported in 19% of the patients in the IRd arm and 11% of the patients in the placebo-Rd arm. The majority of these cases were mild, and fewer than 1% of the patients in either arm discontinued one or more of the three drugs because of a skin reaction. However, rash can be a serious concern, as a rash may be mild initially and then escalate in severity. Drug rashes vary in severity from mild redness with tiny bumps over a small area to peeling of the entire skin. Rashes may appear suddenly within minutes after a person takes a drug, or they may be delayed for hours or days.

Prevention and treatment of rash

Promptly alert the doctor if the patient experiences a new or worsening skin rash. It may be possible to manage and reverse the skin rash, but it may be necessary to withhold myeloma treatment regimen until the rash resolves and then resume at an adjusted dose, or the regimen maybe discontinued.

Liver toxicity (hepatotoxicity)

In the TOURMALINE-MM1 clinical trial, drug-induced liver damage was reported in 6% of the patients in the IRd arm and 5% of the patients in the placebo-Rd arm. Signs of liver toxicity include yellowing of your skin or the whites of eyes and/or pain in the right upper-stomach area.

Prevention and treatment of hepatotoxicity

The doctor will monitor the patient's liver enzymes with regular blood tests while being treated with IRd. If the patient has moderate to severe liver impairment, the dose of Ninlaro should be reduced.

Eye disorders

In the TOURMALINE-MM1 clinical trial, eye disorders of different types were reported in 26% of the patients in the IRd arm and 16% of the patients in the placebo-Rd arm. The most common disorders were the following:

• blurred vision
• dry eye
• conjunctivitis (pinkeye), which is an inflammation of the thin, clear tissue that lies over the white part of the eye.

More serious eye disorders occurred in 2% of the patients in the IRd arm, and 1% of the patients in the placebo-Rd arm.

Prevention and treatment of eye disorders

Eye disorders are readily detectable, so reporting and seeking medical attention for them can and should be done as soon as the patient experiences a problem. Members of the healthcare team may provide supportive care or refer the patient to an eye specialist.

Embryo-fetal toxicity

Embryo-fetal toxicity is the result of exposure of an embryo or a fetus to a toxic substance. Based on animal studies, Ninlaro can cause fetal harm when administered to a pregnant female.

Prevention of embryo-fetal harm

Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during treatment with Ninlaro and for 90 days following the final dose. Patients and their partners should not conceive or become pregnant nor breastfeed while taking Ninlaro. 

Additional Information

Here2Assist

Takeda Oncology is committed to helping you get access to Ninlaro whenever possible. Here2Assist offers comprehensive programs that can help with coverage, financial, and educational resource needs.