Janis C. Kelly

December 17, 2014

SAN FRANCISCO — The first all-oral regimen for the treatment multiple myeloma could be on the way to the clinic, according to early data presented here at the American Society of Hematology 56th Annual Meeting.

In a phase 2 study, treatment-naïve multiple myeloma patients who responded to induction therapy with ixazomib (Millennium Pharmaceuticals), lenalidomide, and dexamethasone received single-agent ixazomib maintenance therapy. In half the patients, responses were maintained for more than 2 years, and in 33% of those, responses improved during the maintenance period, reported lead researcher Shaji Kumar, MD, from the Mayo Clinic in Rochester, Minnesota.

"The results support the efficacy of an all-oral regimen that can add to the convenience without affecting efficacy," Dr Kumar told Medscape Medical News.

The triple combination of a proteasome inhibitor, an immunomodulator, and a steroid is active in treatment-naïve multiple myeloma patients. For patients who respond to induction therapy, long-term maintenance might be an alternative to autologous stem cell transplantation (ASCT) if the regimen is convenient and tolerable, according to Dr Kumar.

Concern About the Data

The trial involved 50 patients 18 years and older who had measurable disease and no peripheral neuropathy worse than grade 2. All patients received induction chemotherapy with ixazomib 4.0 mg on days 1, 8, 15, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg on days 1, 8, 15, 22 for up to twelve 28-day induction cycles. As maintenance therapy, patients received the last dose of ixazomib tolerated during induction therapy on days 1, 8, and 15 of every cycle. Patients who were eligible for ASCT could discontinue the study protocol after six cycles.

The primary end point was the complete response (CR) plus very good partial response (VGPR) rate, assessed with International Myeloma Working Group (IMWG) criteria.

Of the 50 patients, 29 discontinued the protocol during induction, including 14 who underwent ASCT. Six of the withdrawals were related to adverse events.

The remaining 21 patients received ixazomib for at least 13 cycles (median, 27 cycles, including induction and maintenance). Median treatment duration was 26.6 months, and mean ixazomib dose during the maintenance period was 3.6 mg per week.

At the time of the analysis, 11 of the 21 patients were still receiving maintenance ixazomib. Dr Kumar reported a CR in 17 of the 49 evaluable patients and a VGPR or better in 29 patients (59%).

Responses were rapid and improved over time. Median time to first response was less than 1 month, and median time to best response was 7.46 months. Seven patients improved during maintenance; two patients with a VGPR achieved a near CR, three patients with a VGPR achieved a CR, one patient with a VGPR achieved a stringent CR, and one patient with a CR achieved a stringent CR.

Median duration of response at the time of the analysis was 26.5 months.

"The efficacy and tolerability are the key findings, said Dr Kumar. "I was surprised at the increasing depth with treatment, with minimal added toxicity."

The phase 2 results supported an ongoing phase 3 trial, in which maintenance ixazomib is being compared with placebo (NCT02181413), according to the researchers.

However, another hematologic oncologist was more cautious about the phase 2 results.

"These data are interesting but will need to be confirmed in a larger study," said Philip L. McCarthy, MD, from the Roswell Park Cancer Institute in Buffalo, New York.

He noted that the study shrunk in size over time. "The number of patients studied was 50, of which 14 went on to have ASCT, six stopped due to adverse events, four due to patient withdrawal, and five for unknown reasons. So there were 21 patients who received maintenance after induction. The number of cycles of maintenance was three to 20 and, including induction, 15 to 32 cycles. The median number of maintenance cycles was 15, which is just over a year. And three patients had serious adverse events on study (14%)," Dr McCarthy explained.

He also raised a concern about the placebo-controlled phase 3 trial. He pointed out that transplant-ineligible multiple myeloma patients have been shown to have improved progression-free survival with lenalidomide maintenance (N Engl J Med. 2012;366:1759-1769). "Thus, a phase 3 trial comparing ixazomib with placebo would be problematic for multiple myeloma patients who have access to lenalidomide," he observed.

The study was funded by Millennium/Takeda Pharmaceuticals. Dr Kumar reports financial ties with industry, including Millennium. Dr McCarthy reports financial ties with Celgene, the manufacturer of lenalidomide, and several other companies.

American Society of Hematology (ASH) 56th Annual Meeting: Abstract 82. Presented December 7, 2014.

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