Optimizing Maintenance Therapy in Multiple Myeloma

Amrita Krishnan, MD, FACP: Maintenance therapy has now been shown to improve survival in myeloma. We know from the meta-analysis of 3 large trials using lenalidomide maintenance following autologous transplant that with the use of lenalidomide maintenance, you can improve overall survival by a little over 2 years. So, certainly, any patient you have a discussion with…if you tell them, “Yes, I have a therapy that can improve your survival,” clearly, they are in favor of that. Having said that, there certainly are considerations. The risk of second primary malignancies (SPMs) is something that remains under close study, and we recognize that the risk of SPMs is higher in patients who received lenalidomide maintenance compared with those on the placebo arm of those studies. The good news is that those risks of SPMs don’t appear to be increasing. They seem to plateau. And, again, you balance that against the clearly reduced risk of relapse of myeloma in patients who are receiving lenalidomide maintenance.

The question on my mind becomes, though, moving beyond lenalidomide maintenance—is that a strategy of then adding to it, using lenalidomide as your backbone? And that tends to be where most of the newer trials are going. And certainly, we’re very interested in using the daratumumab as an addition to lenalidomide; proteasome inhibitors, especially in patients with high-risk disease, in combination with lenalidomide. And, certainly, most of us, for patients who have high-risk disease, would not be satisfied using just lenalidomide alone as a maintenance strategy. And we really would look to a combination maintenance strategy. And that speaks to the tolerability of using these other drugs now in combination. And the group from Emory has single-institution, phase II data, for example, using RVd as a maintenance strategy in patients with high-risk myeloma and showing a very good PFS, about a little over 80% in patients who have poor-risk disease. So, many of us have adopted that strategy.

There are data using KRd as a consolidation maintenance strategy after autologous transplant, and so we’ve also adopted that strategy. I’ve tended to use that in younger patients. It is more labor intensive but also showing deep sustained responses, including MRD-negative responses in the majority of patients in that trial of KRd plus transplant.

The duration of maintenance therapy remains a challenging question for us, because none of the randomized trials we have address that question. They kept maintenance until disease progression. The only trial that used a sort of abrogated maintenance was the HOVON trial that looked at VTD followed by transplant followed by Velcade for 2 years. But, to me, that trial was really more just because Velcade at that time was given IV, so it was just not feasible to keep patients on Velcade maintenance beyond 2 years. In reality, many of us are keeping patients with subQ Velcade on therapy beyond 2 years. And the lenalidomide maintenance trials kept lenalidomide going, at least in the United States, until disease progression. The French trial shortened lenalidomide. In the recent IFM trial, they gave lenalidomide maintenance just for a year. I think many of us feel that that’s probably too short a duration, and you can see the PFS curves drop down after stopping maintenance. But on the other end of the spectrum, we also recognize that it’s not clear that you need to keep lenalidomide indefinitely. We just don’t know the answer to that. We recognize there are long-term challenges with lenalidomide—diarrhea and fatigue being the common ones that patients notice.

I think the next generation of our trials does need to address that question of stopping maintenance. We need to do it in randomized settings and use our better strategies in terms of disease assessment—and specifically, MRD—now to help us make those decisions. The bar is getting higher and higher. So, for example, a complete remission now may not be enough for us to say stop maintenance. Stringent complete remission is probably also not because it’s really being supplanted by MRD testing. And I think ultimately, what we’re going to see is that as we gain more data in many more trials using MRD as an end point, that then we will be able to use it to help guide decisions about when you can stop maintenance. But we really need more data first.