Treatment Options - Ixazomib (MLN9708)
What is Ixazomib?
Ixazomib (also known as MLN9708) is a type of cancer drug called 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. Ixazomib 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.
Ixazomib is in the same class of drugs as Velcade® (bortezomib) and is made by the same company, Millennium: The Takeda Oncology Company. Ixazomib is considered to be a second-generation proteasome inhibitor because it has improved characteristics and activity over Velcade. . In addition, ixazomib is available as a pill whereas Velcade is only available as an injection (subcutaneous or intravenous).
The Multiple Myeloma Research Consortium is currently facilitating a clinical trial for newly diagnosed patients with ixazomib in combination with Revlimid and dex.
What do we know about ixazomib’s effectiveness in myeloma?
Laboratory and animal studies show that ixazomib inhibits the growth of myeloma cells, including those that are resistant to Velcade and other anti-myeloma therapies. Ixazomib also induces myeloma cell death (apoptosis). Animal studies show that mice receiving MLN9708 live longer than those receiving Velcade.
Preliminary evidence of ixazomib’s effectiveness was seen in a Phase I trial in patients with relapsed and/or refractory myeloma. In this trial, approximately 57 patients, many of whom had received prior Velcade, Revlimid, and Thalomid, and some who had become refractory to these agents, received single-agent ixazomib twice a week for 2 weeks out of a 3-week cycle. Of 46 evaluable patients in this study, 1 patient achieved a complete response, 5 patients achieved a partial response, and 1 patient achieved a minor response. Most side effects were mild or moderate in severity and were manageable. Severe side effects included lowwhite blood cell and platelet counts, fatigue, and rash. Peripheral neuropathy, a side effect sometimes seen with Velcade, was infrequently seen in this study and no severe cases were reported.
Final results of a Phase I study that evaluated single-agent ixazomib given on a weekly schedule in patients with relapsed and/or refractory myeloma suggest that weekly ixazomib dosing may be better tolerated than twice-weekly dosing.
- The study included 60 patients who had received an average of four prior therapies. An overall response rate of 18% was seen among the 50 evaluable patients. The response rate was higher (26%) in patients treated at dose established for further study.
- The most common side effects included low neutrophil and platelet counts and gastrointestinal effects. Peripheral neuropathy was infrequent, and there was only one case of severe neuropathy reported.
In a Phase I/II trial, weekly ixazomib is also being evaluated in combination with standard dose Revlimid and dexamethasone in patients with newly diagnosed myeloma. Preliminary results from 52 patients treated at the highest acceptable dose of ixazomib show a 90% overall response rate, with 58% of subjects achieving a very good response rate or better, including a complete response rate of 23%. Severe side effects were infrequent and included rash, low white blood cell and platelet counts, nausea, diarrhea, back pain, and fatigue. There were few instances of severe peripheral neuropathy (2 patients). Based on these results, a Phase III trial is planned.
How is ixazomib currently being studied in myeloma?
Ixazomib is being evaluated in combination with Revlimid and dexamethasone in two international Phase III clinical trials:
- In relapsed and/or refractory myeloma (TOURMALINE-MM1), which will enroll approximately 703 patients
- In patients with newly diagnosed myeloma (TOURMALINE-MM2), which will enroll approximately 701 patients
Ixazomib is being evaluated in additional clinical trials in relapsed and/or refractory myeloma, in newly diagnosed disease, as maintenance therapy, and in asymptomatic (smoldering) myeloma.
In relapsed and/or refractory disease it is being studied:
- In a Phase II study in combination with dexamethasone in patients with relapsed myeloma that still responds to Velcade.
Ixazomib is being evaluated in the frontline setting:
- In a Phase I/II study in combination with Revlimid and low-dose dexamethasone, which is being facilitated by the Multiple Myeloma Research Consortium (MMRC). Ixazomib is given twice a week in this study, which has completed enrollment.
- In a Phase I/II study in combination with melphalan and prednisone in patients who are not eligible for high-dose chemotherapy and stem cell transplant.
- In a Phase I/II study in combination with cyclophosphamide and dexamethasone, which is set to begin enrollment
- In a Phase I study in combination with dexamethasone in patients with normal renal function and those with severe renal impairment
The combination of ixazomib and Revlimid is being evaluated as maintenance therapy following autologous stem cell transplant in a Phase I study that has completed enrollment.
Ixazomib is also being evaluated in combination with dexamethasone in patients with smoldering myeloma who are at high risk of progressing to symptomatic myeloma. This trial is set to begin enrollment.