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). 

Ninlaro is FDA-approved in combination with the immunomodulatory agent Revlimid® (lenalidomide) plus the steroid dexamethasone, a “triplet” (3-drug) combination known as IRd. For more information about the other drugs in the IRd combination therapy, read these IMF publications: 

• Understanding Dexamethasone in the Treatment of Myeloma  (https://www.myeloma.org/resource-library/understanding-dexamethasone)
• Understanding REVLIMID® (lenalidomide)  (https://www.myeloma.org/resource-library/understanding-revlimid)

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

NCCN Guidelines Recommendation of IPd 

In addition to the FDA-approved IRd combination therapy with Ninlaro, the National Comprehensive Cancer Network (NCCN) classifies the combination of Ninlaro, the immunomodulatory agent Pomalyst® (pomalidomide), and dexamethasone [IPd] as a Category 1 recommended treatment option for previously treated myeloma. For more information about Pomalyst, read the IMF’s publication:

• Understanding POMALYST® (pomalidomide). (https://www.myeloma.org/pomalyst-pomalidomide)

NCCN Category 1 recommendations are based on high-level evidence, such as data from meta-analyses or randomized phase 3 clinical trials, that have received at least 85% agreement from the NCCN panel of experts that the treatment is either superior or highly appropriate. Category 1 represents the most definitive evidence level in NCCN guidelines.

How Does Ninlaro Work?

Ninlaro blocks the activity of enzyme complexes called prote asomes. Both normal cells and cancer cells contain proteasomes, which break down damaged and unwanted proteins into smaller components. If the proteasome is inhibited (stopped), then the damaged and unwanted proteins build up in the myeloma cell’s nucleus and cytoplasm, which cause  it to die. Myeloma cells are more sensitive to proteasome inhibition than normal cells, so the myeloma cells die while normal cells are able to recover

Clinical Trial Experience with Ninlaro

The FDA approval of Ninlaro was based on data from the TOURMALINE-MM1 clinical tria (https://www.myeloma.org/videos/final-analysis-phase-3-tourmaline-mm1-study-investigating-ixazomib-lenalidomide)l, a phase III study of IRd vs. placebo, 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, which is recommended for all myeloma patients taking Rd. Additional medications were used at the treating physician’s discretion to improve treatment tolerability. In 2021, the Journal of Clinical Oncology published the final analysis (https://ascopubs.org/doi/10.1200/JCO.21.00972) of overall survival (OS) in the TOURMALINE-MM1 clinical trial. With a median follow-up of 85 months, median OS was 53.6 months [IRd] vs. 51.6 months [placebo-Rd]. 

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 (https://www.myeloma.org/infoline) or visit clinicaltrials.gov (https://clinicaltrials.gov/) for up-to-date information. 

What Is the Dose and Schedule for Taking Ninlaro?

Discuss Ninlaro-based treatment options with your doctor, especially if you are a patient who can benefit from an all-oral regimen. It is important to note that when a patient is prescribed oral medication, it is crucial to understand the instructions provided by the doctor and to take the medication as directed. For more information, read the IMF’s Tip Card:

• Adherence to  Oral Cancer Therapy.  (https://www.myeloma.org/resource-library/tip-card-adherence)

Treatment with IRd

Your doctor will determine which starting dose and schedule is best for you. If you have liver or kidney dysfunction, your dose of Ninlaro may be lowered. If you require dialysis, discuss the administration of Ninlaro  and the timing of dialysis with your doctor. 

• Each treatment Cycle of IRd is 28 days. 
• Ninlaro is taken orally on days 1, 8, and 15 of each treatment Cycle. 
• Revlimid is taken orally on days 1 through 21 of each treatment Cycle. The recommended starting dose of Revlimid is 25 mg. If necessary, your dose of Revlimid can be lowered by your doctor. 
• Dexamethasone is taken orally on days 1, 8, 15, and 22 of each treatment  Cycle. The recommended starting dose is 40 mg. If necessary, your dose of dexamethasone can be lowered by your doctor.  

Treatment with IPd

Your doctor will determine which starting dose and schedule is best for you. If you have liver or kidney dysfunction, your dose of Ninlaro may be lowered. If you require dialysis, discuss the administration of Ninlaro and the timing of dialysis with your doctor.

• Each treatment Cycle of IPd is usually 28 days. 
• Ninlaro is usually taken orally at 4 mg on days 1, 8, and 15 of each Cycle. In the iPod-790 clinical trial, Ninlaro was given at 3 mg on days 1, 4, 8, 11 of a 21-day Cycle as second-line or third-line treatment for triple-class exposed patients. 
• Pomalyst is taken orally at 4 mg on days 1 through 21. 
• Dexamethasone is taken orally once-weekly on days 1, 8, 15, and 22 of each treatment Cycle. The recommended starting dose is 40 mg. If necessary, your dose of dexamethasone can be lowered by your doctor.

Important Instructions for Taking Ninlaro Safely

Take the IRd combination therapy exactly as your doctor instructs. Before starting therapy with Ninlaro, be sure to tell your myeloma doctor about all of your medical conditions, as well as all medications and supplements that you are taking. Special precautions may be needed if you have diabetes, or issues with your liver or kidneys. 

• Take Ninlaro on an empty stomach, at least 1 hour before or 2 hours after eating. Swallow the Ninlaro capsule with a full glass of water.  Do not crush, chew, or open the Ninlaro capsule.
• Do not take Ninlaro at the same time you take dexamethasone, because dexamethasone should be taken with food and Ninlaro should be taken on an empty stomach. 
• 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 you take more Ninlaro than your doctor has prescribed, or if you experience any new or worsening side effects, alert your doctor immediately or go to the nearest hospital emergency room.

Special Precautions When Taking Ninlaro

If possible, have a conversation with your doctor before you begin treatment with Ninlaro about any and all special precautions and possible side effects that may be relevant to you. If your treatment with Ninlaro has started already, be sure to promptly report to your doctor any changes in your health, such as new or worsening signs or symptoms. 

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 those in the trial had thrombocytopenia severe enough for it to be life-threatening. Your doctor should monitor your complete blood count (CBC) throughout your treatment with IRd. You must alert your doctor if you experience excessive bruising or bleeding. 

Management of thrombocytopenia may include holding your treatment with Ninlaro and Revlimid until your platelet count recovers, then adjusting your doses of Ninlaro and Revlimid. 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. 

Your doctor may direct you to take medication to control diarrhea. If you have diarrhea, alert your doctor and take precautions to prevent dehydration by drinking a sufficient amount of water. Your doctor will monitor your electrolytes and correct abnormalities if they’re detected. Contact your doctor immediately if you get dizzy or lightheaded, or experience fainting. If needed, your doctor may withhold or adjust your 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. You 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. Promptly report your constipation to your healthcare team. Try to drink sufficient fluids and eat high-fiber foods. Also, attempt 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. 

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. Vomiting occurred in 22% and 11%, respectively. These episodes were not life-threatening. 

If you vomit after taking a dose of Ninlaro, DO NOT repeat the dose. Promptly alert your doctor, who may instruct you to take your next dose of Ninlaro as scheduled. Your doctor will give you medication to help prevent nausea and vomiting before each dose of Ninlaro. Precautions should be taken to prevent dehydration caused by vomiting. You must drink a sufficient amount of water and other fluids. Contact your doctor immediately if you get dizzy or lightheaded, or experience fainting. You may be given medication to prevent vomiting or IV hydration if required.

Peripheral edema 

Edema is an abnormal accumulation of excess fluid under the skin in the spaces within tissues. There are several potential causes, including longterm use of anti-inflammatory medications such as dexamethasone. Peripheral edema can cause swelling in the ankles, feet, and legs. If you have swelling in one leg only, you must alert your doctor immediately, as this might signal the presence of a blood clot. 

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. 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. Your doctor may modify your dose of dexamethasone.  

If your edema is severe, your doctor may modify your dose of Ninlaro. 

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. Also, 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. Promptly alert your doctor if you experience a new or worsening skin rash. It may be possible to manage and reverse your skin rash, but it may be necessary to withhold IRd until the rash resolves and then resume at an adjusted dose, or your regimen may be 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 your eyes and/or pain in your right upper-stomach area. Your doctor will monitor your liver enzymes with regular blood tests while you are being treated with IRd. If you have moderate to severe liver impairment, your dose of Ninlaro should be reduced.

Embryo-fetal toxicity 

Embryo-fetal toxicity is an exposure of an embryo or a fetus to a toxic substance. Based on animal studies, Ninlaro can cause 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. You should not become pregnant or breastfeed while taking Ninlaro. 

Possible Common Side Effects of Ninlaro

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 prior to 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. 

Neutropenia 

Neutropenia is a reduced level of neutrophils, a type of white blood cell (WBC). Neutrophils make up about 60% of WBCs. Neutrophils fight infection caused by bacteria or fungi. Fever is the most common sign of neutropenia.

If you have a fever, you must get immediate medical attention. Your neutrophil count will be monitored while you receive treatment with Ninlaro. If your doctor determines that the level of your neutrophils is low, your doses of Ninlaro may be decreased or interrupted. You may also receive medication to increase your WBC production.

Peripheral neuropathy

Peripheral neuropathy (PN) (https://www.myeloma.org/what-is-peripheral-neuropathy) 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 Neuropathy in Myeloma.  (https://www.myeloma.org/resource-library/understanding-neuropathy-myeloma)

If you have PN before beginning therapy with Ninlaro, it is important that you promptly report to your treating doctor any increase in your PN discomfort. 

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.

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

Herpes zoster infection 

Herpes zoster (“shingles”) is caused by the reactivation of the varicellazoster virus (VZV), the same virus that causes varicella (“chickenpox”). All patients taking a proteasome inhibitor are at an increased risk for the herpes zoster infection. All patients taking Ninlaro should receive preventive treatment with antiviral medication. Your doctor will instruct you whether or not to continue taking an antiviral medication after your last dose of Ninlaro. 

Venous thromboembolism (VTE) 

Patients taking IRd are at an increased risk for VTE events. VTE is a condition that includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Risk factors include infection, age > 75, cancer, and 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. 

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 blurred vision, dry eye, and conjunctivitis (pinkeye), 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. Eye disorders are readily detectable. That's why reporting and seeking medical attention for them can and should be done as soon as you experience a problem. Members of your healthcare team may provide supportive care or refer you to an eye specialist.

Additional Information

Ninlaro support programs Takeda Oncology, the company that developed Ninlaro, has established the website here2assist.com (https://www.here2assist.com/) to connect you with a case manager who will help you to understand your insurance coverage, check your eligibility for financial assistance, and ensure that your specialty pharmacy fills and ships your prescription of Ninlaro. Continued support of your treatment journey is available in English and over 200 other languages. Call 1.844.817.6468 from Monday through Friday, 8 a.m. to 8 p.m. (Eastern).