© Todd Buchanan 2017
Attendees at ASH 2017 Photo courtesy of ASH
ATLANTA—Adding ixazomib to lenalidomide as maintenance therapy for newly diagnosed multiple myeloma (MM) patients after upfront autologous stem cell transplant (ASCT) appears promising, according to an update of a phase 2 study.
The oral doublet produced an overall response rate of 90% and an estimated 2-year progression-free survival (PFS) rate of 81%.
The incidence of peripheral neuropathy was mostly limited to grade 1/2 events, and hematologic adverse events were manageable with dose reductions.
Krina K. Patel, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the 2017 ASH Annual Meeting (abstract 437*).
Dr Patel and her colleagues conducted a single-arm, phase 2 study to evaluate the safety and efficacy of adding ixazomib to lenalidomide maintenance in MM patients after ASCT.
“[O]ur phase 2 hypothesis was that ixazomib would provide a safe, more effective, and more convenient alternative maintenance therapy, which would allow better quality of life and improve PFS when combined with lenalidomide,” Dr Patel said.
Study design
Patients had to have received ASCT within 12 months of induction therapy in order to be eligible for the study.
Maintenance therapy was initiated within 60 to 180 days after transplant. It consisted of 28-day cycles of ixazomib at 4 mg on days 1, 8, and 15 and lenalidomide at 10 mg daily on days 1 to 28.
After 3 months, patients’ lenalidomide dose could increase to 15 mg if they tolerated the drug.
Investigators amended the protocol during the first year of the study to reduce the dose of ixazomib to 3 mg.
“Based on other studies at the time,” Dr Patel explained, “they showed increased neutropenia with the higher dose of ixazomib.”
Patient characteristics
The investigators enrolled 64 evaluable patients from December 2012 to June 2015. They had a median age of 60 (range, 39 – 74).
Forty-two patients (66%) were male, and 22 were female.
Thirty-three had ISS stage I disease, 13 had stage II, and 9 had stage III. Fourteen patients (21.8%) had high-risk disease.
At the time of the presentation, 34 patients (52%) remained on therapy. As of September 2017, patients had received a median of 30 cycles of maintenance therapy (range, 1 – 55).
Safety
Forty-eight patients (75%) had neuropathy at enrollment. Most of these patients had received bortezomib-based induction therapy, Dr Patel explained.
Twenty-two patients (34%) had grade 1/2 peripheral neuropathy at last follow-up, and 6 patients (9%) had grade 3.
Baseline neuropathy worsened in 6 patients, and this necessitated dose reductions. One patient had new-onset neuropathy, also requiring dose reduction. And 8 patients had new-onset neuropathy that did not require dose reductions.
“Most of these patients had a break [in therapy] of about 2 to 8 weeks,” Dr Patel noted, “and were able to either go back on a lower dose versus stopping the therapy.”
Three patients had a secondary primary malignancy: 1 with breast ductal carcinoma in situ and 2 with squamous cell carcinoma of the skin.
Other grade 3 adverse events included: anemia (3%), neutropenia (41%), thrombocytopenia (6%), elevated liver enzymes (11%), back pain (3%), constipation (6%), elevated creatinine (1.6%), nausea/vomiting (11%), diarrhea (9%), fatigue (11%), rash (13%), peripheral neuropathy (9%), myalgia (5%), urinary tract infection (5%), and upper respiratory tract infection/pneumonia (36%).
Grade 4 adverse events included neutropenia (5%), thrombocytopenia (8%), and respiratory failure (1.6%).
Thirty patients are off study, 16 due to progressive disease, 3 at the investigator’s discretion, and 11 withdrew their consent.
Eight of the 16 patients who progressed had high-risk disease. Among the 16, the median PFS was 17 months (range, 3 – 43).
Seven patients died with an overall survival of 4 months (n=1), 16 months (n=2), 20 months (n=2), or 48 months (n=2).
Dose reductions
Sixteen patients started ixazomib at a dose of 4 mg, and 48 started at 3 mg.
Fifteen patients had their ixazomib dose reduced to 2.4 mg due to peripheral neuropathy (n=8), neutropenia (n=3), hearing loss (n=2), rash (n=1), or thrombocytopenia (n=1).
Five patients had a second dose reduction to 1.5 mg due to neuropathy (n=3), neutropenia (n=1), or thrombocytopenia (n=1).
Four patients who required a third dose reduction for neuropathy (n=2), neutropenia (n=1), and thrombocytopenia (n=1) went off study.
All patients started lenalidomide at 10 mg for 28 days.
Twenty-four patients required a lenalidomide dose reduction. Fifteen patients stayed at 10 mg but for 21 of 28 days, and 9 patients reduced to 5 mg for 28 days.
Reasons for these reductions were neutropenia (n=12), rash (n=4), thrombocytopenia (n=3), fatigue (n=2), memory impairment (n=1), infection (n=1), and pruritis (n=1).
Five patients required a second dose reduction to 5 mg for 21 of 28 days. Reasons for these reductions were neutropenia (n=2), neuropathy (n=1), thrombocytopenia (n=1), and fatigue (n=1).
“There are about 10 patients who did not have any ixazomib reductions that needed lenalidomide reductions, mostly for the pancytopenia,” Dr Patel noted.
Efficacy
Fifty-six percent of patients achieved a very good partial response, 26% a complete response (CR), 8% a stringent CR, and 10% a partial response.
Twenty-nine patients (45%) experienced an improvement in their best overall response from post-transplant baseline.
The median time to response was 10.1 months. The median duration of response has not yet been reached. Investigators estimated the 4-year duration of response to be 62%.
At a median follow-up of 38.2 months, the median PFS had not yet been reached. Investigators estimated the 2-year PFS to be 81%.
The median PFS for patients with high-risk disease is 21.85 months.
Based on these results, the investigators believe ixazomib-lenalidomide maintenance is safe, feasible, and well-tolerated and should be further explored in phase 3 studies.
Dr Patel has received research funding from and served on an advisory committee for Pfizer. She has consulted for Juno and Celgene.
The study was supported by Takeda Oncology.
* Data in the presentation differ slightly from the abstract.