Multiple myeloma is a disease that for many years we really didn’t have any new agents and were stuck. With the advent of novel agents the first proteasome inhibitor, bortezomib, entered the market and to this day proteasome inhibitors remain a key component in the backbone of treating virtually all myeloma patients, whether they’re newly diagnosed, relapsed, refractory.

The big advance here is that bortezomib, the first proteasome inhibitor, was initially studied intravenously and then the route of administration was changed to subcutaneous. What we learned from that is there is a dramatic decrease in neurotoxicity and GI issues. The next generation proteasome inhibitor that will be the focus of today’s discussion is ixazomib which is marketed under the tradename of Ninlaro. This represents a major advance because it’s an oral proteasome inhibitor and it has a very nice schedule of administration – once a week for three out of four weeks. This has really driven myeloma therapy forward and it’s made it a key component because one of the things that we look for in myeloma patients is not only the route of administration but, honestly, patient convenience. Especially in the current environment it’s often difficult for patients to get to physicians’ offices or clinics to get a bortezomib injection. In this case with the in-case transition, once we know that they’re responding to proteasome inhibition we can give them the oral proteasome inhibitor. With the study, as we’ll review in detail, the visits now become once a month to clinic which greatly increases patient convenience and works well in the current environment.

So proteasome inhibitors are super-important in the treatment of multiple myeloma and remain in the backbone of almost all regimens.

In light of the latest data from the US MM-6 study, what are the benefits of in-class transitioning? When should clinicians do this?

That was really the whole focus of this study. This is one of the first of its kind where there’s an in-class transition and a different route of administration. The backbone of MM-6, as you can see, is any bortezomib based induction. So we were very liberal with the inclusion criteria so that it would represent a real-world population of patients. As we delve deeper into the data you will see that that’s the kind of sample we’ve been accumulating. MM-6 when we started was a bit slow to launch but once people realised that if you were having a nice response or stable disease to the Velcade-based induction that then the transition to the oral proteasome inhibitor with an IMiD and a steroid was actually relatively easy.

The IRd regimen that we’re using has also been published by others and shown to be safe, effective and non-toxic. Those data will be updated at upcoming congresses but clearly MM-6 is showing that the in-class transition is not only feasible but over time the responses continue to deepen because, remember, it’s not a maintenance type of transition but we’re transitioning to ongoing active therapy of the patient’s symptomatic multiple myeloma.

Overall, the patients seem to be tolerating this very well in terms of safety and we’ve presented at EHA some updates on response rates and all of that. But the patients actually seem to be very happy.

Then the last part of the study, which we touched on briefly at EHA and for which analyses are still ongoing, is quality of life. All of that is extraordinarily important in multiple myeloma trials. What’s unique here is that this is one of the early studies to employ actigraphy. So, as everybody knows, the patients were given a device, usually a Garmin-like device, and we monitor their activity for half of each cycle and then we correlate that with what they report. What was surprising to all of us as investigators is that the patients became very, very involved. In data we’ve shown here the compliance rate for actigraphy actually increased over the course of the studies and is well into the 90% or better range. So it showed that in the real world patients truly enjoyed getting involved with the study, the data collection, and looking at compliance and adherence which is always an issue whenever you’re giving an all-oral regimen.

So overall it’s been pretty well accepted by the patients and the data we presented at EHA had a little bit of an early data cut but enrolment continues to actually pick up in pace. I suspect some of that is due to the Coronavirus outbreak but other parts of it are clearly due to the fact that patients really enjoy being involved in their own care.

Considering the latest results from the US MM-6 study, can we really trust in-class transitioning?

That’s probably a bit of an over-broad statement for all diseases but certainly in myeloma and other diseases I think you’ll be able to. Another interesting thing will be the release of oral azacitidine because we know that’s extraordinarily effective in myeloid dysplasia. There is now already an early release of an oral azacitidine molecule and patients seem to be tolerating that one very well also.

So in-class transition, especially where you change a route of administration to something that’s more convenient and likely less toxic, will pick up but, again, it has to be a bit restricted. So you have to find diseases where there is a parenteral formulation and then perhaps an oral formulation or maybe a parenteral formulation which has a much longer half-life making it more convenient and easy for patients.

So I hope in MM-6 US, which will now be broadened to other countries, that we’re making things safer, effective and more convenient for our paitents.

What is the importance of conducting a community-based study? What benefits can this type of study provide to the physician?

When we look at other large myeloma studies that have been done, the majority of them are at academic centres, although some are in advanced community centres that have all of the resources. But when you look at those initial trials answering very specific questions in multiple myeloma, the inclusion and exclusion criteria are often quite tight so you have a highly selected patient population. But a lot of times those results are not generalizable into the real world. What you have to remember is that the vast majority of multiple myeloma patients are actually treated outside the academic settings. When you look at the inclusion criteria and you apply them to our real-world databases such as large myeloma registries, we find about 40% of those patients would be ineligible for clinical trials. So this represents a much better section, a more realistic cross-section, of patients with multiple myeloma and hopefully will help us to design future trials with a bit different inclusion and exclusion criteria. We really want to make clinical trials available to patients and we want to have them have access to state of the art trials close to home. With current Coronavirus and other constraints, travel is often difficult and if we can start to use things such as in-class transition, patient participation with actigraphy and even Zoom meetings, like we’re doing for this, I think it becomes much more important and the results are much more generalizable as we advance the field of myeloma therapeutics.

Data is very, very exciting. It’s still early, we have a lot of work to do for analysis for generalisability and then make sure the actigraphy is clean, get all of our datasets cleaned up and then hopefully submit a manuscript soon that’s peer reviewed so that we can validate all our findings. Studies like MM-6 and in-class transitions in myeloma are also going to be evaluated in other countries, China, for example, and some European countries, to see if this is really workable. We hope to push the field further because in myeloma, clearly, patient convenience and making things safe, effective and non-toxic are key. What people often forget is that myeloma, in effect, becomes a continuous therapy disease so that even if you have a tremendous response to the study we reviewed today there’s likely a role at some point for ongoing maintenance with, hopefully, an all oral regimen. What we hope is to get deeper and deeper responses.

With the advent of minimal disease testing using next gen sequencing and flow cytometry now our goal is really to get people to stringent CRs, maybe even molecular CRs in a minority of patients. Maybe someday this approach will lead to MRD negativity for prolonged periods of time and allow us to interrupt therapy and follow patients. But with myeloma therapy is really a long-term proposition and we want to make it manageable with our patients and we want to keep them engaged.