Andrzej Jakubowiak, MD, PhD: Relapses are unfortunately part of the natural history of the disease. I would like to add a comment that relapses for some of us are not necessarily inevitable. I think it is important to remind ourselves that we made progress in patients who will not be relapsing, and it’s increasing the proportion of these patients. But if relapses are to be expected, they are to be expected earlier in patients with so-called high-risk disease, which is by most of the evaluations based on either cytogenetics or other risk factor assessments. There is a clear connection, regardless of treatment strategy, of having this relapse come earlier for high-risk disease rather than later.

I would like to stress again that this is not inevitable for a given patient, but for a proportion of patients with high-risk versus good-risk disease, those with high-risk disease will have, on average, earlier relapse. But you may still have patients with good-risk disease relapsing relatively early, unexpectedly, because of other factors that you may not know and patients with high-risk factors doing potentially better than expected because those risks are very much just an assumption of potential for relapse.

To just frame it maybe in some form of summary, disease tends to be relapsing…very much later after the first treatment approach, so-called initial therapy, frontline therapy, when this can happen, on average, between 3 and 5 and now possibly even 6 and 7 years and maybe never again. I would like to still be optimistic. And in the next lines of therapy, as we call it, after 2 or 3 more relapses, the duration of those responses may be, in general, shorter. Again, nothing absolute for a given patient, but statistically that’s how it plays out.

We know that we can potentially be having those types of expectations or maybe observation when you start treatment, and then I personally, when I am approaching it and I speak with the patient, am trying to stress that we do know a lot, but our knowledge is not absolute in terms of what will happen with given patients. So I wouldn’t be falling into desperation because of having high-risk disease. We’re always careful with any status of the disease, how things will play out.

The triggers to switching therapy are, to some extent, established and to some extent are viably approached by many of us. And I think if we polled top myeloma specialists, we probably would not get an answer in this regard. I would maybe discuss my philosophy and my approach in the context of what we know. So I am generally not switching therapy if a patient is tolerating treatment, is in response, even if the patient shows signs of early progression of the disease but not necessarily meeting criteria for progression of the disease. Those criteria are established by the International Myeloma Working Group, and they are required for initiation of new treatment—for example, on a clinical trial.

Exceptions are made, of course, but that’s the general rule that I have been applying. Why? In earlier labs where disease, for example, was either absent or 0.1 M spike increases by 0.2 or 0.3, that may be sometimes quick progression. And that period of continued treatment on a prior regimen may not be too long. But I know also from my own experience and from data that are in the literature that sometimes the emergence of progression is essentially a long process, especially in patients with low proliferative disease, which is usually low-risk disease. So they may benefit continuously from this extended treatment. We need to be vigilant. The disease is not emerging in a different way than by observing just myeloma proteins like an M spike in their serum or free light chains, but we also periodically check imaging because sometimes disease may silently present in the form of plasmacytoma. So it is a period of more vigilance and monitoring of the patient.

If the line of progression of disease is crossed, which is well established in International Myeloma Working Group criteria, for the most part, I discuss with the patient a change of therapy to different treatment. There are some who might potentially, at this point, either stop treatment or continue treatment until there is emergence of organ damage, as for newly diagnosed myeloma. And these were old criteria for restarting therapy. Having one of the CRAB criteria—calcium elevation, renal insufficiency, anemia, and bone disease—or other newer criteria right now.

I think for many of us, for me for sure, at this stage when disease is relapsing, it is not good practice and not in the best interest of patients to wait until that point. I think that specific timing of restarting new treatment may be negotiated or moved if the disease is slowly progressing. But in general, when diseases start to progress, I consider new therapy. Now, importantly, 1 component is that sometimes that new therapy can be very different or just slightly different. That’s something that can be potentially discussed in the context of biology of the disease prior to treatments and what is, at any given time, available.

Transcript Edited for Clarity