Roxanne Nelson, BSN, RN

June 22, 2016

Triplet therapy is the initial preferred treatment for myeloma, and various combinations are used around the world. A new combination, with the recently approved oral agent ixazomib (Ninlaro), can now be added to the options. It offers high responses and manageable toxicity at a reasonable cost, say researchers.

Most of the commonly used triplets involve the proteasome inhibitor bortezomib (Velcade), which "is given subcutaneously but is associated with some degree of peripheral neuropathy and frequent hospital visits," said Meletios A. Dimopoulos, MD, from the National and Kapodistrian University of Athens School of Medicine in Greece. He spoke during a Highlights of the Day session here at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting.

In the United States, the combination of bortezomib, lenalidomide (Revlimid), and dexamethasone (VRd) is often used, whereas in Europe, the combinations of bortezomib, cyclophosphamide, and dexamethasone (CyBorD) and of bortezomib, thalidomide, and dexamethasone (VTD) are often used.

The first oral proteasome inhibitor, ixazomib (Ninlaro), was recently approved for use with lenalidomide and dexamethasone (IRd). This three-agent combination was the first all-oral regimen approved for the treatment of multiple myeloma.

Now another triplet combination — ixazomib, cyclophosphamide, and dexamethasone (ICd) — has shown encouraging clinical results.

The cost of this new regimen compares with others in clinical use, Dr Dimopoulos reported.

ICd costs about $1000 per month and involves one hospital visit, IRd costs about $2000 per month involves one hospital visit, VRd costs about $2000 per month and involves an average of four hospital visits, and CyBorD costs about $1000 per month and involves four hospital visits.

"The take-home message is that ICd is an all oral and effective proteasome-inhibitor-based triple combination," Dr Dimopoulos said. "It is well tolerated, has a reasonable cost, and continuous therapy is feasible and improves quality of response."

New Results With ICd Combination

New results with the ICd combination were reported at the ASCO meeting from a phase 1/2 trial presented by Martha Lacy, MD, from the Mayo Clinic in Rochester, Minnesota, and colleagues.

The study was conducted in 48 newly diagnosed myeloma patients with a median age of 64 years.

Patients received ixazomib 4 mg on days 1, 8, and 15, dexamethasone 40 mg days 1, 8, 15, and 22, and cyclophosphamide 300 or 400 mg/m² on days 1, 8, 15, and 22. Treatment cycles were 28 days. Patients could continue on ixazomib alone after 12 cycles.

Stem cell collection was allowed after four cycles. At 12 months, patients were taken off of the cyclophosphamide and dexamethasone and continued on ixazomib until progression.

The median duration of response was 18.4 months. For patients who remained on study, the depth of response improved over time, Dr Lacy noted.

The overall response rate was 77%, and the overall survival at 12 months was 100%. Progression-free survival at 12 months was 91% for the entire cohort.

A total of 77% of patients experienced grade 3 or higher toxicity, and 71% had grade 3+ hematologic toxicity.

"Only 2% of patients needed a dose reduction of ixazomib," she said. "Importantly, there were no study deaths."

Toxicity, including myelosuppression, was manageable overall, and similar to what has previously been reported with ixazomib. "Neurotoxicity was mild and does not appear to be cumulative," she said.

Well Tolerated, Reasonable Cost

Dr Dimopoulos noted that his own group has been studying the ICd combination. Results from that phase 2 trial were presented last year at the annual meeting of the American Society of Hematology (Abstract 26).

That trial was conducted in an elderly population (median age, 70 years), and the goal was to define a dose of cyclophosphamide in newly diagnosed transplant-ineligible patients.

The results showed promising early response rates in this population, Dr Dimopoulos reported.

The combined complete response and very good partial response was 28% in the group that received cyclophosphamide 300 mg/m² and 21% for those treated with the 400 mg dose. Overall responses were 78% and 65%, respectively, and complete responses were 10% and 9%, respectively.

"Prolonged therapy improved the quality of responses, and lower doses were better tolerated with similar efficacy," said Dr Dimopoulos.

The latest study presented at ASCO included both older and younger patients. Furthermore, he pointed out, patients receiving upfront ixazomib going on to transplant were able to undergo stem cell collection.

Dr Dimopoulos has disclosed no relevant financial relationships. Dr Lacy reports relationship with Celgene.

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract 8002. Presented June 3, 2016.

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