Treating Multiple Myeloma at Second Relapse and Beyond

Sagar Lonial, MD, FACP: Once you get past first relapse, then the question becomes, What do you have left, and how do you use available agents? And in my personal view, we don’t back off in terms of what we’re trying to do to maximize depth of response. So I think it’s important to remember that your goals are probably relatively similar, unless a patient does not have a good performance status. So if they’ve become frail through the course of their disease treatment or they’ve got other comorbidities that really limit your ability to push them, then you back off. But in general, I think about second or subsequent relapse the same way I think about first. Our goal is to hit them with combination therapy and try to eradicate as much of the disease as we can.

When we talk about second relapse and beyond, I think what you really look at is what are the drugs that they’ve had and what are the drugs that they haven’t had, and this is where I begin to incorporate the old-fashioned drugs, like alkylating agents—cyclophosphamide, DCEP [dexamethasone, cyclophosphamide, etoposide, cisplatin]—based combinations. We don’t use DVd [daratumumab, bortezomib, dexamethasone] as much because it’s tough to get an older, frailer patient through that in the second or third relapse situation, but certainly DCEP. And then trying to reuse antibodies or other drugs that we’ve used in the first and second lines to try to maximize depth and response. What our goal really is in that situation is to try to get them to a clinical trial where we can expose them to something different [from what] their myeloma has seen before. And that can include a novel antibody, it can include a CAR [chimeric antigen receptor] T cell, it can include an MCL-1 [myeloid cell leukemia-1] inhibitor, and it can include a BCL-2 [B-cell lymphoma-2] inhibitor. Many, many new drug classes that are available.

I think as we begin to evaluate what are really the areas where we need additional research and additional therapeutic approaches, there are 2 big areas that come to mind. For me, the first is patients who present with high-risk disease, particularly mutations of P53. We may not even get to second- or third-line therapy because there they crash and burn very quickly. Often 20% to 25% of patients will die within the first 2 years. That is the problem we struggle with in patients with true high-risk myeloma. So that to me represents a huge unmet medical need.

The second area is patients beyond second or third relapse where the available agents are no longer effective and we need to cobble together things to try to get them back into remission. And that’s where agents like CAR T cells or other immune approaches really have helped us to overcome some diseases with patients, but not all of them.

As we think about what’s coming in the next few years for patients with myeloma, and for the doctors who take care of these patients with myeloma, I think we’re going to see an explosion not only in immune-based therapies but really begin to understand how to use some of the mutation data we’re getting from newly diagnosed myeloma trials like CoMMpass or other trials along those roads.

I think that that’s really important because we’ve learned from other cancers that targeting mutations can be effective, but in myeloma, I’m not so sure that targeting a single mutation alone will be sufficient. So partnering it with other drugs will be an important part of what we try to do. And in my mind, a really interesting research question is to try to get patients to low-level disease burden where they’re just barely [minimal residual disease]—positive, look at those cells—which are going to be the troublemakers down the road—and try to figure out how to eradicate that very small clone as opposed to the 5, 6, 7, or 8 clones that are present when a patient received a new diagnosis or first relapsed. That really represents the future in figuring out genetically how to get to that small residual disease clone, which is a challenge, but I think that’s what we’re going to be facing.