EHA 2017: Ixazomib Plus Lenalidomide/Dexamethasone in Newly Diagnosed Multiple Myeloma With No Stem Cell Transplant, Followed by Maintenance Ixazomib
Data from two phase I/II clinical trials evaluating ixazomib (Ninlaro) in patients with newly diagnosed multiple myeloma was presented at the 2017 European Hematology Association (EHA) Annual Meeting (Abstracts S408, S780). Both studies evaluated ixazomib plus lenalidomide (Revlimid) and dexamethasone in newly diagnosed patients with multiple myeloma who did not undergo stem cell transplant, followed by maintenance with single-agent ixazomib. Ixazomib is currently not approved for the treatment of newly diagnosed multiple myeloma or in the maintenance setting.
“Despite recent progress, multiple myeloma remains a rare, devastating, and incurable hematologic cancer.… These phase I/II data demonstrate the potential use of ixazomib in combination with lenalidomide/dexamethasone in newly diagnosed multiple myeloma and as a single-agent maintenance therapy, which resulted in patients achieving deepening responses with continual use of the treatment. Ixazomib’s efficacy and safety profile—coupled with its administration as a completely oral regimen—potentially can reduce some logistical burdens, and help patients be able to sustain a multiple myeloma therapy,” said Jesus Gomez Navarro, MD, Vice President, Head of Oncology Clinical Research and Development, Takeda.
Weekly Regimen
In this phase I/II study (Abstract S408), patients with newly diagnosed multiple myeloma received weekly oral ixazomib (1.68–3.95 mg/m2 in phase I and 4.0 mg in phase II) plus lenalidomide and dexamethasone for up to 12 28-day induction cycles. Of the 65 enrolled patients, 42 continued on study treatment without withdrawing early for stem cell transplant. After initial therapy, 25 patients went on to receive weekly, single-agent ixazomib at the last tolerated dose given during induction until disease progression or unacceptable toxicity.
Key findings, presented by Shaji Kumar, MD, of the Mayo Clinic, include:
- Patients who did not undergo stem cell transplant and were treated with ixazomib plus lenalidomide and dexamethasone at induction achieved high response rates.
- At a median follow-up of 55.2 months, the confirmed overall response rate was 80%; the complete plus very good partial response rate was 63%; and the complete response rate was 32%.
- Of the patients who achieved complete or stringent complete response and were evaluated for minimal residual disease, 6 of 7 (86%) were minimal residual disease–negative.
- Median progression-free survival was 29.4 months.
- Median overall survival was not reached at a median follow-up of 55.2 months; the 4-year landmark overall survival estimate was 82%.
- After completing 12 cycles of induction therapy with lenalidomide and dexamethasone, 25 patients went on to receive maintenance single-agent ixazomib.
- Increased depth of response occurred in a number of patients who received maintenance therapy with single-agent ixazomib; 32% of patients improved their response during maintenance.
- A total of 86% of patients had grade > 3 adverse events and 52% of patients had serious adverse events. The most common grade > 3 adverse events were neutropenia, thrombocytopenia, diarrhea, back pain, vomiting, rashes, eruptions and exanthems, peripheral neuropathy, and nausea. Among the two patients who died on study, one death was considered to be treatment-related and was due to respiratory syncytial viral pneumonia.
- The occurrence of the most common grade > 3 adverse events and adverse drug reactions, which included neutropenia, thrombocytopenia, back pain and rashes, and eruptions and exanthems, was confined almost exclusively to the induction period.
- Less toxicity was reported during the maintenance vs induction periods.
“Based on an increasing body of evidence that long-term therapy may improve clinical outcomes, this phase I/II trial focused on continuous treatment of patients with newly diagnosed multiple myeloma,” said Dr. Kumar. “The trial evaluated patients who received weekly ixazomib plus lenalidomide and dexamethasone as an induction regimen followed by maintenance with single-agent ixazomib. Data showed that patients had deep responses on single-agent therapy and median progression-free survival of more than 2 years. We remain committed to gathering additional data on ixazomib in this investigational, maintenance setting.”
Twice-Weekly Regimen
This phase I/II study (Abstract S780) evaluated twice-weekly oral ixazomib (3.0 or 3.7 mg) plus lenalidomide and dexamethasone for up to 16 21-day cycles followed by maintenance therapy with single-agent twice weekly ixazomib (at the last tolerated dose). Of the 64 patients enrolled, 41 continued on study treatment without early withdrawal for stem cell transplant.
Key findings, which were presented by Deborah Berg, Senior Scientific Director, Oncology Clinical Research, Takeda, on behalf of Paul Richardson, MD, of the Dana-Farber Cancer Institute, included:
- In patients who did not undergo stem cell transplant, initial treatment with twice-weekly ixazomib plus lenalidomide and dexamethasone was associated with deep responses.
- At median follow-up of 47 months, the overall response rate was 92%, the complete plus very good partial response rate was 69%, and the complete response rate was 31%.
- Of the patients who achieved complete or stringent complete response and were evaluated for minimal residual disease, 8 of 9 (89%) were minimal residual disease–negative.
- Median progression-free survival for patients was 24.9 months and median overall survival was not estimable; 3-year landmark overall survival estimate was 86%.
- After completing induction therapy, 18 patients went on to receive maintenance with twice-weekly single-agent ixazomib.
- Patients on maintenance therapy received a median of 31.5 treatment cycles.
- 22% patients improved their responses during maintenance.
- A total of 85% of patients had grade > 3 adverse events, and 54% of patients had serious adverse events. The most common grade >3 adverse events included rash, eruptions and exanthems, hyperglycemia, peripheral neuropathy, peripheral edema, thrombocytopenia, and neutropenia. There was one on-study treatment-related death due to cardiorespiratory arrest.
- 44% of patients who received maintenance therapy had an onset of a grade > 3 adverse event and adverse drug reactions in cycle 17 or beyond. The most common grade > 3 adverse events and adverse drug reactions were hyperglycemia, rashes, eruptions and exanthems, diarrhea, vomiting, peripheral neuropathy, nausea, and neutropenia.
“The addition of ixazomib—a first-in-class oral proteasome inhibitor—to doublet therapy has been shown to substantially improve efficacy in newly diagnosed multiple myeloma patients,” said Dr. Richardson. “In this phase I/II trial in newly diagnosed multiple myeloma, ixazomib plus lenalidomide and dexamethasone resulted not only in high quality of responses using a twice–a-week schedule, but also in an encouraging deepening of responses over time in patients who did not receive a stem cell transplant. In addition, impressive durable clinical benefit was seen as patients went on to receive maintenance therapy with single-agent ixazomib after successful induction/remission therapy using this all-oral approach.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
