Ninlaro®

What is Ninlaro?

Ninlaro®, also known as ixazomib, is a type of cancer drug called a proteasome inhibitor. Ninlaro is in the same class of drugs as Velcade® (bortezomib, Takeda Oncology) and is made by the same company. It is considered to be a second-generation proteasome inhibitor because it has improved characteristics and activity over Velcade.

Ninlaro is an oral medication.

The Multiple Myeloma Research Consortium (MMRC) has been instrumental in the development of Ninlaro. The MMRC facilitated a clinical trial for newly diagnosed patients with Ninlaro in combination with Revlimid® (lenalidomide, Celgene) and dexamethasone and has initiated 4 additional trials in patients with relapsed or refractory myeloma, residual myeloma, as maintenance therapy following autologous stem cell transplant, and as a treatment for patients with plasma cell leukemia or extramedullary disease.


How is Ninlaro used?

Ninlaro® (ixazomib, Takeda Oncology) is an oral agent approved for use in combination with lenalidomide (Revlimid®, Celgene) and low-dose dexamethasone for patients with multiple myeloma who have received at least one prior therapy.

What types of patients can benefit from Ninlaro?

Ninlaro has been studied in a variety of patients with multiple myeloma including:

  • Patients who received one to three prior therapies
  • Patients who have received three or more prior therapies (heavily pretreated)
  • Patients who were refractory to their previous treatment(s)
  • Patients who previously received high-dose chemotherapy and stem cell transplant
  • Both younger and older patients
  • Patients with reduced liver function (hepatic impairment)
  • Patients with reduced kidney function (renal impairment) and patients on dialysis

Ninlaro has also been evaluated in combination with other myeloma therapies in newly diagnosed patients in early-stage clinical trials. A Phase III trial is evaluating Ninlaro in combination with Revlimid and low-dose dexamethasone in newly diagnosed myeloma.

How does Ninlaro work?

Ninlaro is a proteasome inhibitor. Proteasomes are enzymes found in cells that help the cell break down old or unwanted proteins. These proteins are split into amino acids which can then be recycled to make new proteins. Cancer cells depend on the proteasome to provide this protein metabolism (turnover) function to regulate their growth and survival. Ninlaro disrupts a cancer cells’ ability to survive by blocking the proteasome and disrupting protein metabolism. Myeloma cells may be uniquely sensitive to proteasome inhibitors because they make large amounts of protein (called M-protein) and need this recycling function to survive.

Laboratory and animal studies show that Ninlaro inhibits the growth of myeloma cells, including those that are resistant to Velcade and other anti-myeloma therapies. Ninlaro also induces myeloma cell death (apoptosis)


How is Ninlaro administered?

Ninlaro® (ixazomib, Takeda Oncology) is an oral medication. It is available as 4 mg, 3 mg, and 2.3 mg capsules.

The recommended starting dose of Ninlaro is 4 mg orally once a week on days 1, 8, and 15 of each 4-week cycle along with Revlimid® (lenalidomide, Celgene) and dexamethasone.

  • Patients with moderately or severely reduced liver function (hepatic impairment) will typically receive a lower (3 mg) starting dose of Ninlaro.
  • Patients with severely reduced kidney function (renal impairment) and patients receiving dialysis will also typically receive a 3-mg starting dose of Ninlaro.

Revlimid is taken orally at 25 mg on days 1 to 21 of each cycle and dexamethasone is taken orally at 40 mg on days 1, 8, 15, and 22 of each cycle. In addition, a blood thinner such as aspirin is typically taken along with Revlimid-dexamethasone to reduce the chance of developing a blood clot.

Patients receive Ninlaro, Revlimid, and dexamethasone until their disease progresses or they experience unacceptable side effects.

Ninlaro should be taken with water once a week on the same day and at approximately the same time. It should be taken at least 1 hour before or at least 2 hours after eating, separately from dexamethasone, which should be taken with food.

If you are late in taking a dose of Ninlaro or you miss a dose, take this dose if your next scheduled dose is at least 72 hours (3 days) away. Do not take this dose if your next dose is scheduled within 3 days. Do not take a double dose to make up for a missed dose.

If you vomit after taking Ninlaro, do not take another dose. Wait until your next scheduled dose to resume Ninlaro.


What are Ninlaro side effects?

The most common side effects seen in a clinical study with Ninlaro® (ixazomib, Takeda Oncology) in combination with Revlimid® (lenalidomide, Celgene) and dexamethasone included:

  • Gastrointestinal effects (diarrhea, constipation, nausea, or vomiting)
  • Low platelet count (thrombocytopenia)
  • Peripheral neuropathy
  • Peripheral edema (swelling of the hands or feet)
  • Back pain

In this study, the most common serious side effects included:

  • Low platelet count
  • Diarrhea

Patients have also experienced low numbers of white blood cells known as neutrophils (neutropenia).

Women should avoid becoming pregnant while taking Ninlaro, as it caused fetal harm in animal studies.

How are side effects of Ninlaro managed?

If you experience any new or worsening side effects, contact your health care provider. Most side effects can be managed with supportive care measures, other medications, temporarily stopping treatment, or dose modifications.

Patients who experience low platelet or neutrophil counts may have their next dose of Ninlaro and Revlimid held until their counts go back up. At that point, Revlimid is resumed at a lower dose and the same dose of Ninlaro is taken. Patients experiencing neutropenia may also receive a colony-stimulating factor, a medication to stimulate the production of neutrophils.

If the platelet or neutrophil counts fall again, both Ninlaro and Revlimid are again withheld until the counts go up. Then, Ninlaro is resumed at a lower dose and Revlimid is resumed at its most recent dose. For any subsequent instances of low platelet or neutrophil counts, any dosing modifications will alternate between Revlimid and Ninlaro.

Patients who experience side effects such as rash, peripheral neuropathy, or other severe toxicities may also have their next dose of Ninlaro and Revlimid held until the symptoms improve. When dosing is resumed, one agent may be administered at a lower dose, depending on the side effect seen. Ninlaro-Revlimid-dexamethasone may be stopped in cases of life-threatening or disabling side effects.


What have Ninlaro clinical trials shown?

Ninlaro® (ixazomib, Takeda Oncology) has been evaluated alone and in combination with other myeloma agents in both relapsed and/or refractory multiple myeloma and newly diagnosed disease.

Relapsed and/or Refractory Multiple Myeloma

The approval of Ninlaro was based on results from the Phase III TOURMALINE-MM1 trial, which included patients with relapsed and/or refractory multiple myeloma who had received one to three prior therapies. In this trial 722 patients received Ninlaro in combination with Revlimid® (lenalidomide, Celgene) and low-dose dexamethasone (IRd) or Revlimid-low-dose dexamethasone alone (Rd).

On average, patients receiving IRd lived significantly longer without their disease worsening compared to patients receiving Rd (20.6 months vs. 14.7 months).

  • Responses lasted longer when Ninlaro was added (20.5 months vs.15 months with Rd).
  • The overall response rate was higher with IRd compared with Rd (78% vs. 72%) and the complete response rate was also higher (12% and 7%, respectively).
  • Patients in this study continue to be followed for survival and safety outcomes.
  • IRd is listed as one of several preferred regimens for relapsed and/or refractory myeloma in current treatment guidelines.

In two Phase I trials, single-agent Ninlaro has been shown to provide clinical meaningful responses in patients with relapsed and/or refractory myeloma when given once or twice a week.

  • With weekly dosing, 27% of patients treated at the maximum tolerated dose achieved a partial response (PR). Patients in this study had received an average of 6 previous therapies and nearly three-quarters no longer responded to their last therapy.
  • Weekly dosing of Ninlaro appeared to be better tolerated than twice-weekly dosing.

In a small Phase II study in patients with relapsed myeloma, dexamethasone was shown to enhance the activity of weekly Ninlaro when added in instances where there was limited or lack of response to Ninlaro alone.

Based on the results of these early studies, Ninlaro alone or in combination with dexamethasone is listed as a preferred treatment option for relapsed and/or refractory in myeloma treatment guidelines.

Newly Diagnosed Multiple Myeloma

Ninlaro given weekly or twice-weekly has also been evaluated in combination with Revlimid-dex in Phase I/II trials in patients with newly diagnosed myeloma.

  • Results of the combination trial with weekly Ninlaro show a 92% overall response rate, with 58% of patients achieving a very good partial response rate or better, including a complete response (CR)/stringent CR rate of 27%.
    • The most common side effects were nausea, vomiting, rash, fatigue, and peripheral neuropathy.
    • Severe side effects were infrequent and the most common included rash, low white blood cell and platelet counts, gastrointestinal effects, and fatigue. There were few instances of severe peripheral neuropathy (6% of patients).
  • Following initial therapy with Ninlaro and Revlimid-dex, continuing maintenance therapy with Ninlaro alone was tolerable and improved responses and contributed to durable responses lasting over 2 years on average.
  • Preliminary results of a combination trial with Revlimid-dex and twice-weekly Ninlaro facilitated by the Multiple Myeloma Research Consortium (MMRC) also show a high overall response rate (95%), but higher rates of severe side effects and dose reductions were seen.
  • Ninlaro in combination with Revlimid-dex is listed as a treatment option for initial therapy in both transplant-eligible and -ineligible patients.

Ninlaro has also been evaluated in combination with cyclophosphamide and dexamethasone in a small Phase II trial in newly diagnosed patients who were not eligible for transplant.

  • Two doses of cyclophosphamide were evaluated (300 mg/m2 and 400 mg/m2).
  • The overall response rate in both dosing groups combined was 71%, including 9% complete responses.
  • Side effects, including serious adverse events, increased with the higher cyclophosphamide dose.

How is Ninlaro currently being studied in myeloma?

Ninlaro is being evaluated in clinical trials in the United States in relapsed and/or refractory myeloma, in newly diagnosed disease, and as maintenance therapy.

Ninlaro is being evaluated in several Phase III trials, including:

  • In combination with Revlimid-low-dose dex in an international clinical trial in patients with newly diagnosed myeloma (TOURMALINE-MM2) that has enrolled over 700 patients.
  • As maintenance therapy in patients who have achieved a partial response or better to their initial therapy and who have not undergone autologous stem cell transplantation (ASCT)
  • As maintenance therapy in patients who have achieved a partial response or better to their initial therapy and who have undergone ASCT, which has completed enrollment.

Interested in learning more about Ninlaro clinical trials? Talk to an MMRF Patient Support Nurse to learn more or use our clinical trials finder:

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