Impact of Maintenance Therapy in Multiple Myeloma

Keith Stewart, MB, ChB: Talking about length of treatment now, which also has of course economic implications, what’s the impact of maintenance therapy in your practice, Rafael?

Rafael Fonseca, MD: I think we’re, at this moment, in a situation where maintenance is a standard of care. A few years ago, we were debating this. We sometimes had long conversations with patients. I think unless there’s a contraindication, the results of the meta-analysis from the 3 large trials of maintenance would suggest that lenalidomide maintenance is a standard of care for suitable candidates, post-stem cell transplant.

Keith Stewart, MB, ChB: What are the benefits of maintenance?

Rafael Fonseca, MD: So the differences are, I think the data are solid, for lack of a better word, in PFS [progression-free survival]. So you’re talking about 53 versus 23 months of progression-free survival with maintenance. There was an analysis on overall survival improvement of about 2.5 years. I think that’s a little bit less stable because of the number of patients who are out there in that portion of the curve. But the benefits are undoubtedly there. One of the key aspects, I heard this yesterday and I really like the concept, I think for the long-term survival of myeloma, the time to the first relapse is probably one of the most important variables. And that’s why you cannot hold back. You have to put the best team right from the get-go, get your best drugs aligned, and try to maximize that time. Because, as you go through the subsequent lines of therapy, you see that they get shorter and shorter. I call it….

Keith Stewart, MB, ChB: Yes, and there’s attrition, too.

Rafael Fonseca, MD: And that’s another important factor. If you go through one line of therapy, you may not make it to the next. We have data of our own. We presented that last year at EHA [the European Hematology Association] and are submitting the paper, 50% per line of therapy for the transplant-ineligible, a little bit less for the transplant-eligible. But others report 50%.

Keith Stewart, MB, ChB: So 50% never benefit....

Rafael Fonseca, MD: Never make it to the next line. If someone says A + B is better than A, a reasonable hand in the audience would say, wait a minute, you should try A followed by B. A reasonable hypothesis, but it needs to be tested because there may not be time for B to be used.

Keith Stewart, MB, ChB: Putting your societal economic hat on again, do you treat with maintenance indefinitely or do you see that there’s an endpoint where the cost-benefit ratio starts to diminish?

Rafael Fonseca, MD: The short answer is we don’t know. I always make my decisions based on what I think is best for the patient, and I let others decide what’s good from payers’ or society perspective. I think there’s a reasonable argument to be made that time-limited [therapy] may be sufficient. I am hopeful that in the near future, as we bring in MRD [minimal residual disease] testing, that we’ll be able to truncate therapy at the time when we think there’s a sustained MRD-negative status that would allow the patients to be spared the toxicity of maintenance.

Keith Stewart, MB, ChB: What’s your own practice, do you keep people on forever or do you stop after a while?

Rafael Fonseca, MD: I keep them for as long as they tolerate until there is disease progression.

Andrzej Jakubowiak, MD, PhD: Same here. I want to get a sort of patient perspective, although I’m a doctor so I interact with my patients and kind of try to get into their shoes. Some of the points we made earlier—get a good response, treat long so there are good responses achieved—are eventually rewarded with 2 important things the patient experiences. Number 1) If they do achieve and probability is now 60% or something like that, the disease is not detectable and they go into long-term maintenance therapy, there is this sense of comfort that maybe the disease is really gone and maybe never comes back. “Maybe I am cured.” And we know that this is achievable. That’s number 1. And the second is that they actually are, at this stage of the phase, enjoying normal life on maintenance, and that’s all that they have and almost no or minimal toxicities.

Keith Stewart, MB, ChB: Do you treat indefinitely or do you stop?

Andrzej Jakubowiak, MD, PhD: I do, indefinitely. But because we have such a high pool of patients who achieve this long-standing remission, we are more and more scratching our heads, are we doing the right thing by keeping these patients indefinitely? So in my opinion, our frontier now is to try using new tools, MRD, they have to be refined, to tell the patient are you interested in exploring whether we can stop? And I can tell you, they are all interested.

Keith Stewart, MB, ChB: Let’s go to you, Mary, because I’ve kind of lost my train of thought there. What are patients saying to you about continuous therapy? Are they comforted by that? Do you feel like they’d rather come off treatment?

Mary E. DeRome: I think that any patient would prefer to come off treatment, as long as their disease is stable and kept under control. We hear from a lot of patients that toxicity is an issue, especially with lenalidomide maintenance. There’s many patients who can’t tolerate that very well. And we know from patient surveys that the question of maintenance is very much on their minds. The question is which drug is the best for maintenance and how long should they be on it? And as we’ve discussed, there really isn’t any hard and fast answer for that yet.

Keith Stewart, MB, ChB: What is the best drug for maintenance?

Rafael Fonseca, MD: From what we know right now, it’s lenalidomide. There’s a recent phase 3 trial, the TOURMALINE-MM3 trial that addressed whether ixazomib, an oral proteasome inhibitor, was better than placebo, and it was, but the magnitude of the benefit was not there to suggest that it should be used as a single agent. However, we use it in combination with lenalidomide for high-risk patients. I think there’s very interesting studies going on with daratumumab. But as of now, it’s lenalidomide that’s standard.

Keith Stewart, MB, ChB: Andrzej, same with you?

Andrzej Jakubowiak, MD, PhD: Yes, as a standard of care we use mostly, with few exceptions, lenalidomide. But I would put maybe a little bit of a twist into this comment and practice. We’ve determined that we need to treat patients for a long time because they have a better outcome. And we have younger patients who have transplants. They got 4 or 5, maybe 6 induction regimens, then they go on to transplant, and they are then treated with a single agent, which is we know is not as active as doublets or triplets. We need to explore what we do for these patients, no question.

Keith Stewart, MB, ChB: In my own practice, I don’t have many people taking single-agent Revlimid. I’ve tended to be adding a second drug, ixazomib, or even bortezomib. I’m looking for depth of response at the same time.

Rafael Fonseca, MD: In the maintenance setting?

Keith Stewart, MB, ChB: Yes. It used to just be high-risk but now I’ve started doing it for everybody, basically. A lot of these trials are based on progression-free survival. And just very briefly, before we run out of time here, is that enough, Rafael or Mary, to justify the expense? Do we need to see overall survival before you recommend payment for these medications? Maybe we’ll start with you, Mary. Do we need overall survival or is PFS enough?

Mary E. DeRome: Overall survival would be preferable. But sometimes it can take so long to gather that data, so I think that many people are really hoping that MRD will soon become an established practice in the myeloma field. Because that will really help, I think, in determining what overall….

Keith Stewart, MB, ChB: When to stop.

Mary E. DeRome: When to stop, exactly.

Keith Stewart, MB, ChB: Any last thoughts, Rafael?

Rafael Fonseca, MD: It’s all about trade-offs. If you want solid overall survival, but you’re going to deny the drug for many years for patients, I’d rather go with the potential that PFS has consistently shown improvement in overall survival across the board in most myeloma trials, and I think that should be used. But I’m like Mary, I think MRD is going to shorten the time to decision making.

Keith Stewart, MB, ChB: We did just see one, pretty spectacular example, where that did not happen.

Rafael Fonseca, MD: Right.

Keith Stewart, MB, ChB: With venetoclax.

Rafael Fonseca, MD: But we don’t talk about the benefits of the ones that we have already treated. When you actually look at the numbers, I think the benefit has far outweighed the risk, given the challenges with the recent clinical trial.

Keith Stewart, MB, ChB: Very good. Thank you.
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