Optimizing Frontline Therapy in Multiple Myeloma

Sagar Lonial, MD, FACP: Allogenic transplant is a modality of treatment in myeloma that I think is not finding a home. We have not done an allogenic transplant on patients for a long period of time now, except in the context of large randomized clinical trials. I think with the explosion of new drugs, new targets, and now CAR [chimeric antigen receptor] T cells on the clinical market, from a trial’s perspective, I think it’s very hard to justify the use of an allogenic transplant for most patients with myeloma across the board.

When we’re talking about the role of autologous transplant, however, I think there’s a lot of question and debate regarding the timing of autologous transplant. Do you do it in first remission? Do you ride out that first remission and use it in the salvage setting, which was a question that was being asked by the IFM/DFCI clinical trial that was published in the New England Journal of Medicine a couple of years ago.

My personal approach is you want to maximize the depth of response at the time of initial diagnosis. And in almost every induction regimen, the use of a transplant deepens the response, even in the IFM study, where people are using the survival data there to say that it doesn’t matter when you do a transplant, a progression-free survival [PFS] is clearly longer in the transplant group and more patients achieve MRD [minimal residual disease] negativity in the transplant group than in the nontransplant group. And if that’s one of our goals, then why withhold therapy that has a chance of putting you into a deeper response?

As we’ve talked about transplant and induction therapy, the next natural place to really kick up our discussion now involves maintenance therapy. And there are now several trials demonstrating clear benefit for maintenance therapy in the posttransplant setting. So, I think in my mind, maintenance has become an established part of the treatment approach. Patients receive induction, consolidation, and then maintenance therapy. And our approach is to use risk-adapted maintenance, meaning that for most patients, we typically will use lenalidomide in the maintenance setting, unless they have high-risk features, in which case we modify the maintenance based on their response. So I think maintenance is clearly an established standard of care for patients in the posttransplant setting.

As we’ve talked about standardizing maintenance therapy across the board, an ongoing question remains: the duration of maintenance therapy. And so we know from the French that 1 year of maintenance therapy in the context of VRd [bortezomib, lenalidomide, dexamethasone] and a transplant yields a progression-free survival of almost 48 months.

From our own internal data set that was presented at ASH [the American Society of Hematology Annual Meeting] in 2017, what we’ve demonstrated is that with continuous lenalidomide maintenance, the PFS is somewhere around 60 months for all patients in aggregate, suggesting you get an extra year of progression-free survival with the use of continuous maintenance. Our approach is to use continuous maintenance except in the context of progression or in the context of intolerance. So if patients can’t tolerate maintenance therapy, if we can get them through that 1 year that the IFM demonstrated was clearly a benefit, then we feel a little bit better. But even there, patients have stopped after 2 years or 3 years because of adverse effects, and you just maximize what you can do and know that you can always come back and use it again down the road.

I think the idea of using depth of response to determine whether or not to start, continue, or discontinue maintenance therapy is a little bit challenging in the absence of symptoms. So if a patient is doing well, they’ve achieved a complete response and you say, “I’m happy. They’ve gotten where I want them to go,” so you stop, and I don’t know the data really support that approach.

On the other hand, taking into account a patient’s symptoms and adverse effects, if they’ve achieved a major response and then they want to stop, that’s a different situation. And I think we should always include patients’ symptoms as we begin to talk about tailoring therapy.