Oral combination of ixazomib and thalidomide shows promising results in RRMM

An oral PI-IMID regimen has shown ‘promising’ effectiveness and tolerability in patients with relapsed/refractory multiple myeloma (RRMM) and could be a more affordable option, an Australian study shows.

Victorian researchers investigated the efficacy and tolerability of continuous ixazomib-thalidomide dexamethasone (ITd: 4 mg, day 1, 8, 15; 100 mg daily; and 40 mg weekly).

A total of 39 patients with RRMM  with one to three prior lines of therapy were enrolled across two hospitals in in Victoria and South Australia.

The all-oral combination of ITd resulted in an ORR of 56.4% with a Clinical Benefit Rate of 71.8%

Lead investigator Professor Andrew Spencer, Head of the Malignant Haematology and Stem Cell Transplantation Service at The Alfred Hospital, said that while the response rate was ‘modest’ the the most interesting aspect of the protocol was the durability of the response

“The median duration of the response was about 18 months, which is pretty good for multiple myeloma. It’s also relatively easy utilise because it’s an oral combination and we had quite a number of older and rural patients who went on to the study because it suited them not to be coming in to hospital to for subcutaneous or IV therapy.”

Another reason to explore the combination is cost, he said.

The alternative oral proteasome inhibitor combination is ixazomib with lenalidomide and it appears exceedingly unlikely that will ever be reimbursed in Australia by the PBAC, Professor Spencer tells the limbic.

“And there are a lot of other jurisdictions where the cost would be prohibitive, so if you combine ixazomib with a fairly cheap drug like thalidomide it provides an alternative in those areas where high cost combinations can’t be made available”.

Patients received a median of 11 cycles of therapy and six patients (15%) remained on therapy at the time of final analysis. The median progression-free survival was 13.8 months [95% confidence interval (CI) 82–222] and median overall survival was not reached. The median time to best response and duration of response was 3.7 months (95% CI 28–105) and 18.4 months (95% CI 102–310) respectively.

Despite the continuous therapy approach, tolerability and safety were maintained with Grade 3/4 non-haematological adverse events seen in 21% of patients. Meanwhile 49% required thalidomide dose reductions and 41% were taken off the IMID altogether, mainly for peripheral neuropathy.

While being a recognised side-effect of both thalidomide and ixazomib, Professor Spencer said peripheral neuropathy was manageable with ITd therapy with careful observation and early dose reductions.

“Most people will over time develop neuropathy, sensory neuropathy in the feet and potentially in the hands, which is related to the accumulated dose of thalidomide. So in the initial phase we would dose reduce. But we had a very low threshold for stopping thalidomide once people had achieved disease control if they had emerging neuropathy – because we were happy to continue people on ongoing therapy either with ixazomib and dexamethasone or in some cases just the ixazomib alone.”

The study also showed that prior IMID exposure was associated with a lower ORR (40% vs 73.7% p=0.03) with similar outcomes in patients with with prior proteasome inhibitor exposure.

“The landscape is changing all the time,” said Professor Spencer, responding to the question of who would benefit most from the combination.

“We’re going to see more use of lenalidomide in frontline therapy and one of the emerging problems in myeloma is what to do with people who have had and failed lenalidomide. A lot of the trials that are opening now are looking at that population and as evidenced here the response rate is lower if you’re refractory to IMIDs.”

“Nevertheless the response rate was still 40+ % so that’s not too bad – it’s comparable to some other studies looking at lenalidomide refractory disease with other agents, so it’s got efficacy in a meaningful subset of patients.”

The findings are published in the British Journal of Haematology 


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