What are some therapies being used in the maintenance setting? Can maintenance therapy be adapted to risk status?

What are some therapies being used in the maintenance setting? Can maintenance therapy be adapted to risk status?

So when we talk about maintenance therapy we are referring specifically to the treatments that are given after transplant. Autologous stem cell transplant.

After all that work of going through the induction and the transplant and all the successes that hopefully have happened at that point, I always say we're knocking this thing down. We want to figure out how we can keep a lid on it.

And so that's the approach to maintenance is keep a lid on that myeloma cell, whatever it is that went wrong, that caused it to grow, enjoyed this remission and let that be as durable as possible.

Now, historically, we have always done lenalidomide maintenance. That's been our go to and that is founded on very good rigorous, research that showed us that doing something was better than doing nothing after a transplant.

So you can look at studies that say, let's just do observation and maintenance, really was a way to show that by doing something, you had more, improved progression free survival and eventually data that went back and looked at all those studies again and said, and we're letting people live longer for having do it, done it. So maintenance is an important part of the entire treatment approach, particularly after transplant,

So, lenalidomide maintenance has been kind of the queen on her throne all this time.

If you will. And it's good. But could we make it better? And is it the right approach for everybody?

It is up till now been the right approach for everybody. We thought. We thought doing something for everybody was worth it. We've wondered along the years if if lenalidomide maintenance by itself was enough because it's a good drug.

We have lots of good drugs out there and perhaps doing more than just one medicine would do kind of a better one two punch on myeloma to keep that lid on a little tighter.

And so, recent data has told us that perhaps doing two drugs together in particular the Auriga trial, which showed us that lenalidomide with daratumumab maintenance, the Cd38 monoclonal antibody when compared to doing just lenalidomide maintenance, did much better if these patients had much more likely, were much more likely to achieve an MRD negative, state, which we think is going to translate into much prolonged progression free survival as well.

So we now know from that trial and several others that have incorporated in doublet maintenance in it, the Perseus trial, for example, that two drugs are possible and it's looking like two drugs are successful. Now this is a do as I say, not as I do sometimes situation, because I'm not sure that everybody across the board needs two drugs.

There are lots of patients out there that have standard risk myeloma, and perhaps they only need lenalidomide maintenance.

Now, it's worthwhile to mention that not all high risk patients are included in a lot of clinical trials, they only represent 15% of all myeloma patients. And so I'm not sure we still know what the right approach is for maintenance for high risk patients.

But what we know from lots of trials is perhaps that just doing one drug is not going to be enough.

So there's lots of interest in doing something more. Combine lenalidomide maintenance with something else. There's been data out there of carfilzomib as an example, Daratumumab as an example. We think that two drugs and a little bit is that is based on some older data that thought that a proteasome inhibitor wasn't particularly important for patients with the 4;14 translocation.

With that kind of brought us to the point to say if patients have higher risk disease, which tells us it's a more aggressive type, we probably need to be more aggressive with our approach just the same. So I think for the meantime, single agent lenalidomide maintenance has a really good history, is very effective. But we probably need to start thinking with more recent data about how we can help our patients with high risk disease and recognize that doing more might be better for them.

What are some unanswered questions about maintenance therapy?

Maintenance, where we really go down on the intensity of treatments. And there's a couple of different choices for maintenance as well. Some of these trials have shown that perhaps using both daratumumab or isatuximab and lenalidomide, that is a two drug maintenance without steroids, without the proteasome inhibitor,

Bortezomib or carfilzomib is one approach. So that's using two drugs as maintenance. Both isatuximab or daratumumab and lenalidomide.

But there's also potential for patients who have done very well to maybe just do one of the two drugs. Like lenalidomide alone. There are currently ongoing studies that are trying to answer this question.

Does everybody need both drugs for maintenance or only one drug? And how might we choose that based on patient characteristics or responses, etc..

But that would be yet another discussion of saying do we do maintenance with one drug or two drugs? Obviously two drugs may give you deeper responses, but on the other hand may also come with more side effects, more opportunity cost.

By that I mean you have to come in more often, spend more time in the doctor's office while your myeloma is under good control.

So there's not a clear single answer for a given patient, but it is something that I would encourage patients to discuss with their doctors, to pros and cons of what maintenance to use. What are the side effects?

How often do you need to come in? How often do you need to be monitored? And then the last question we don't know the answer yet exactly is, how long to continue the maintenance. Do we stop at one year, two years, three years, five years? Continue indefinitely?

Can we use things like MRD testing, good response assessments to decide when might be the optimal time to stop some of the maintenance?

Either if you're doing two drugs, maybe stop one of the two drugs, or potentially even both drugs.

Again, there are ongoing trials that hopefully will give us some answers about the optimal duration as well. So those I think would be the key challenges as we go forward is to say which are the patients who would benefit mostly from transplant, which patients benefit more from two drug versus one drug maintenance?

And what is the optimal duration of maintenance?

Is there any data on doing single agent daratumumab as maintenance therapy?

There is some data about looking at single agent daratumumab. We have some information looking at doing single agent dara versus doing observation, for example.

Daratumumab is a great option for maintenance, but the option is because it's such a great, easily well-tolerated medication.

There's a suppose a little bit of inconvenience of needing to come in once a month, for example, to get the injection, but heck, maybe, perhaps your energy's better.

Or maybe, perhaps your bowels and your GI function is different than that of lenalidomide maintenance. So there is data to support its use. A lot of the use, however, that we're seeing more now is to do it in doublet and then drop one and continue on with the other. But I'll tell you, I've lots of patients who want to drop the lenalidomide and not the daratumumab, but there are certainly precedents for using daratumumab maintenance.

The questions that are going to arise, however, is this the right thing to do with patients who've already had daratumumab as part of their induction, and should they continue on with it after the fact? Or should we be introducing it with patients who've never had daratumumab and use it as part of their maintenance after the fact?

And I think the jury's still a little bit out on that, although most of the data is pointing us to say that drug is so good, we should probably be using it at all these different time points in the newly diagnosed journey.

Is there any concern with becoming refractory to daratumumab? And if so, could it potentially be used again in the future?

I think that's a concern with all drugs. We know that at least today, our approach to myeloma therapies is to use these drugs until they either patients either develop unacceptable toxicity, intolerable toxicity, quality of life changes, or it stops working.

So I think for today, where we're heading is, is yes, where we are going to develop refractoriness

But maybe that's okay because we have so many other opportunities.

There's some trials out there that are helping us maybe wonder if we can kind of bring these drugs back to life with new combinations with T-cell engagers, for example. And so perhaps they're not completely losing all their juice. Maybe that's something we could look at using again in the future.

But yes, there is a concern about developing refractoriness, but for the great benefit of keeping the disease under control for the meantime.