OPTIMISMM trial for refractory multiple myeloma

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Published: 3 Jun 2018
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Dr Paul Richardson - Dana Farber Cancer Institue, Boston, USA

Prof Richardson speaks with ecancer at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting about the OPTIMISMM trial assessing the triplet combination of pomalidomide, bortezomib and dexamethasone compared to bortezomib and dexamethasone alone in relapsed/refractory multiple myeloma.

He describes the doses and patient cohort involved in the trial, all of whom had been previously exposed to lenalidomide, and notes significant improvement in response rate and PFS among patients with only one prior line of therapy.

Prof Richardson describes the increase in neutropenia among patients as largely manageable, and that overall survival data is maturing.

ecancer's filming has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

ecancer's filming has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

The excitement around the OPTIMISMM trial was built on the fact that it’s a very large phase III study comparing the triplet of pomalidomide, bortezomib and dexamethasone to a control group of bortezomib and dexamethasone in one to three prior therapies. It builds on the synergy that we have come to recognise between proteasome inhibitors and IMiDs that is well established with RVD; carfilzomib, lenalidomide and dexamethasone; ixazomib, lenalidomide and dexamethasone. And combinations with pomalidomide using proteasome inhibitors are now widely used in US practice, particularly in the relapsed setting. The goal of this study, however, was in a very organised fashion to explore what actually the benefit might be of the three drug combination over the two in the context of lenalidomide exposure. So the goal here was to ensure that all patients were lenalidomide exposed and after lenalidomide treatment had run out of its benefit for each patient they would then come on to this trial to further clarify exactly what the benefit of the three drugs versus the two would be in such a setting.

So this was an international study run across multiple countries, multiple centres, and basically in this context we looked at one to three prior regimens. 70% of the patients were truly lenalidomide refractory, the remaining 30% had been lenalidomide exposed but were not truly refractory at the time of coming on to treatment. What was particularly promising in terms of the results we saw a PFS difference overall by intent to treat that was approximately 4½ months in favour of the three drugs over the two. But what was particularly striking was in the patients who had had one prior therapy and were in first relapse the PFS difference was quite remarkable at over 10 months. It was 20 months versus around 11 for the control group. That’s important because it tells us that the clinical benefit from the triplet was quite significant in that group of patients. It also, of course, was broadly significant across all groups of patients but particularly in those folks.

An important part of the trial to share with everyone is that continuous therapy was part of the study design for both arms. So there wasn’t a pre-specified conclusion to treatment, what there was was eight cycles of PVD, eight cycles of bortezomib and dexamethasone and then after cycle nine a maintenance strategy followed. So, as a result of that, these are very real world type results in showing a benefit in favour of the three drugs over the two.

It’s worth mentioning that the response rate overall for the three drugs was about 82% but in the patients who had had one prior therapy it was actually north of 90% and that was encouraging with high quality responses seen as well. In terms of tolerability, generally speaking the combinations were well tolerated in both arms. It’s fair to say there was more neutropenia encountered with the pomalidomide bortezomib and dexamethasone, as you would expect, but the rate of febrile neutropenia was actually lower, just 3%, so generally manageable. There was also slightly more peripheral neuropathy for the three drugs over the two but, having said that, that too was generally manageable and there were certainly no significant adverse events that were unexpected or particularly unusual. In that regard it’s worth noting that rates of thromboembolism for both arms were very low. So that was all encouraging in terms of the tolerability profile but the efficacy data, obviously, were our focus of this first presentation of this information because obviously the primary endpoint had been met.

And when can we expect overall survival? What’s the timeline here?

That’s a great question. The overall survival data is probably going to take a while to mature because, as you know, now thank goodness in myeloma we have multiple regimens that we can use for patients in relapse and so we’re in a position to really derive benefit for each successive line of therapy that’s needed for any particular patient. So in that context survival data may take a while to mature. Having said that, the PFS difference is quite striking so one would expect to see a survival difference potentially become more apparent in a few years.

It’s important to mention that other endpoints included quality of life, duration of response and a variety of surrogates. Those analyses are all ongoing.

Just to double-check, was there any cross-over between the arms?

No, there wasn’t. Both arms were stratified by risk factors and cytogenetics, ISS data and so forth and number of prior therapies. What we saw was that in fact in the three drug group there was a consistent benefit across all subgroups pre-specified in the study. Obviously when the patient relapsed on the control arm, bortezomib and dexamethasone, they could have access to whatever was best therapy available and in our own patients, and we were the lead enroller in the United States, for our patients obviously we offered pomalidomide based therapy, typically, upon the recurrence of disease and the need to treat.

It just reflects another very important phase III trial in a very particular space which is those patients in whom lenalidomide treatment has run out of benefit. I emphasise that because, in fact, in the same area the phase III trials that have been largely done have been very important and very informative but it’s important for everyone to know they don’t necessarily include a large number of lenalidomide exposed or refractory patients. This is the first of its kind in that regard.