EHA 2018: Results of the OPTIMISMM trial

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Published: 15 Jun 2018
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Prof Paul Richardson - Dana-Farber Cancer Institute, Boston, USA

Professor Paul Richardson discusses at EHA 2018, the results from the recent OPTIMISMM trial in patients with relapsed or refractory multiple myeloma. He talks around the main findings from the trial, subsets of interest and the anticipated impact of these result on clinical practice.

Professor Richardson goes on to discuss his opinion on future novel agents which show promise in the treatment of patients with multiple myeloma.

 

The OPTIMISMM study was designed as very much a real-world phase III trial to explore a platform of three drugs in one to three prior therapies or with patients with relapsed refractory myeloma who’d had one to three prior treatments. And when I say real world it’s real world in the sense that in the up-front setting now, lenalidomide-based therapy is used as part of induction remission treatment, and as part of maintenance, and so there’s a real need for understanding when patients have run out of benefit from lenalidomide, when lenalidomide, for want of a better term, has failed them, what are best options after that? And this trial therefore was designed to test in patients who’d all been lenalidomide exposed, indeed 70% were in fact lenalidomide refractory, how the three-drug combination of pomalidomide, bortezomib and dexamethasone performed. Now the standard of care in one to three prior lines of therapy has, until recently, been bortezomib and dexamethasone for IMiD refractory patients, so in that context the control arm was for bortezomib and dexamethasone and the experimental arm was pomalidomide, bortezomib and dex. Now the three-drug platform had been built out of a carefully run phase I/II effort in which we’d shown that the combination of pomalidomide, bortezomib and dexamethasone was well tolerated, quite active, and established a dosing schedule, which was basically pomalidomide at 4mg, two weeks on, one week off, and  bortezomib days 1, 4, 8 and 11, standard dosing of 1.3mg/m2 with dexamethasone given on the day of bortezomib and the day after, at 20mg per day for patients under the age of 75 and 10mg per day for those over the age of 75.


So trial was a 1:1 randomised study, we randomised approximately 570 patients and in that context patients were stratified by age, number of prior therapies and by ISS categorisation at study entry. What’s important to share with listeners is that the treatment arm was basically continuous in both arms. In other words, what I mean by that is that after eight to nine cycles of induction remission treatment in both arms, then maintenance followed. And that’s important because in some randomised phase III trials in this setting there’s been a fixed duration of treatment in the control arm in particular, which again doesn’t really reflect real-world practice. Continuous therapy in myeloma has now become an established approach in controlling disease. So in that regard, the study had a maintenance phase in both groups.
So that was the design of the trial, and we opened the study in around 2013, completed it in about three years and it was an international study across multiple countries including the United States, Canada, most of Europe, Israel and other countries as well around the globe. Now importantly, we were able to show in this real-world setting, therefore, that there was a highly significant advantage to the three drugs over the two in terms of its progression-free survival benefit with an early look by protocol amendment, because we were concerned that the endpoint was being reached relatively quickly by virtue of other studies. We actually amended so we could look early. We found with an early look that the control arm was performing as expected with a median progression free survival of about seven months and the experimental arm enjoyed about a four month difference in favour of the three drugs at approximately twelve months. So that was the important primary endpoint.


So what was impressive about the one line of prior therapy group was there we saw a progression free survival advantage of around ten months, which was quite striking, and the hazard ratio with that was 0.54. So we were pleased with that result.


What was also noteworthy in that group is that the response rate was high, at over 90% PR or better. Overall for the trial, 82% of the patients on the three-drug platform responded, whereas about 60% responded for the control group. So we therefore had met our primary endpoint, the data are too immature for survival at this point. I think the important other aspect was safety and in that regard no new side effect signals were seen that were unexpected, and generally speaking treatment in both arms was well tolerated. We saw slightly more thromboembolic events with the three-drug combination, but again with appropriate thromboprophylaxis, that was manageable. We did see more neutropenia for the three drugs, but only in a small subset of patients, around 3%, did we see febrile neutropenia. And in that setting there were no infectious deaths, so that’s an important safety parameter to be aware of. So, generally speaking, a well-tolerated platform with clear evidence of clinical benefit.


How will this affect clinical practice?


The benefit in clinical practice is going to be along the lines that now we have patients receiving lenalidomide-based induction and maintenance, what then, when lenalidomide fails the patient, is the best choice? And what we know is that pomalidomide can engender a response, even in lenalidomide failure, but most importantly, when you combine it with bortezomib the quality of responses and the clinical benefit seen is very impressive.  So I think this then becomes a very encouraging option for patients in first relapse and beyond.


Were there any subgroups of particular interest?


That’s a great question. I think that first and foremost in all the pre-specified subgroup analyses the clinical benefit was consistent and sustained. What was impressive was that in the high-risk group, of which there are around 20% per arm defined by cytogenetics, the clinical benefit was there and it was very similar to the group overall. Age, for example, we had patients as old as their mid-eighties in the trial; they did just as well in the older group as the group overall, which is encouraging. Similarly patients with some degree of renal dysfunction did well as well. And I think what’s most important is in those patients who are lenalidomide refractory, the clinical benefit was also apparent. Not just lenalidomide exposed but also lenalidomide refractory.


What is next for the management of patients with multiple myeloma?


There’s an awful lot actually. I mean there’s a lot of immunotherapeutic approaches using monoclonal antibodies, using next-generation immunomodulatory drugs, next-generation proteasome inhibitors, and of course there’s the excitement and promise around CAR T therapy, albeit early in the development phase at the moment. I think what OPTIMISMM provides is a very nice combination strategy that’s a bridge to these next steps, and it does so in a way in which it’s truly a value proposition, because obviously the monoclonal antibodies, in particular daratumumab, are very exciting, but when you think of a combination platform that you might want to use, this particular platform provides something, I think, very realistic and attainable. And that was our goal with the trial, was to say can we provide the community with a realistic, accessible platform for most countries, that they can then benefit from? And then these exciting new agents can be reasonably added too.