How do you decide on an appropriate treatment at relapse with so many to choose from?

What factors should you consider when choosing a new treatment?

it's a great question. So essentially, how do we do treatment decisions in relapsed and refractory myeloma? And I'd say that this is an incredibly complex field these days. And this is really, I think, one of the benefits of seeing a myeloma specialist. It's no longer the days where we have one or two treatment options and it doesn't make a difference because neither of them works really well.

These days, we have, a tremendous menu of different treatment options in terms of specific medications. And then when we think about the combinations that we can put these medications together in, it's a huge menu of different options.

And so when we think about treatment options for someone, someone with relapsed refractory myeloma, of course, studies, I mentioned the importance of studies.

And so if there's a good study option, I always encourage a person to participate in that, if it's appropriate.

But aside from that, you know, when we think about different treatment options for myeloma, there's a number of different considerations.

First is long term strategy. So with all these different treatment options that are available, we really need to be smarter about long term strategy in managing a person's myeloma.

And that means not only thinking about what we're going to treat the myeloma with today. Rather, we also need to think about, okay, if the myeloma if the myeloma comes back, you know, a year or two years, five years from now, what do we do then? What comes after that? And even what happens after that and what studies are coming?

CAR-T, transplant, there's really lots of different things that we need to think about. And if we do this strategically from the outset, then that often helps things to go better.

So that's one consideration. And then in terms of making the actual decision about treatment now, there's a number of different things.

So we look at a person's age, we look at other medical problems that they may have.

We look at how functional they are. You know, if somebody is perfectly fit and alive, hitting out, hitting golf balls and, you know, running marathons, or if there's somebody who comes in and they're in a wheelchair because they've had a prior stroke or they have heart trouble or kidney trouble, you can imagine that treating those two people is different.

And then even an individual's goals of care. You know, when we think about goals of care and treating myeloma, we often think about living as long as possible and then quality of life. I want to I want to feel good and I want to live for as long as possible. But when we dig into that a little bit more deeply, people's goals can often be quite different, meaning that often, especially people when they're, you know, in their eighties or nineties and have other medical problems for a lot of those people who are my patients that are goal is not necessarily to live for as long as possible.

Their goal is to not spend a whole lot of time in the clinic. Their goal is to preserve functional status. They don't want to feel sick. They don't want to be in the hospital. They don't want to go to a nursing home. They want to maintain functional status and they want to feel good.

And so goals of care such as those and many others are also a consideration.

How often I want to come to a clinic, whether I want to get, you know, treatments that I get in the clinic or if I want to do things that are all oral at home.

So that's just a small list of many considerations that we have when we think about treating relapsed refractory myeloma. And again, I would use that as a as a point to highlight the fact that it really benefits patients to see myeloma specialist because we go through these calculations all the time in our head, which means that we're very aware of the different options and the pros and cons to all of them.

a very common question, that one that we have to deal with in clinic, unfortunately, quite frequently. A patient that comes back has relapsed or refractory disease that we have to make the choice of the next line of therapy.

it's a process that has to do as much with the art as it has to do with science.

Because even though there's abundant data on how this regimen performed with that regimen before, there's really not a road map for a given patient.

So like my colleagues, we try to look at a few things. First and foremost, efficacy. I mean, patients, particularly patients with relapsed disease, they often need they want to start a new therapy, they want the therapy to work, and oftentimes they need a therapy to work fast because that relapse has come with threatens to their kidney function, with anemia, with fatigue or with pain.

So activity certainly is the first and ranked. But the other things that are important is how frail is that patient? How important is convenience for that patient?

If I have a younger patient with not a lot of comorbidities who can have no problems commuting back and forth to the clinic. You can really pick your three part combination that you think has the greatest activity and imply on that basis as opposed to a frail patient who come in a wheelchair is in the eighties and lives 2 hours away.

Where are you going to lean more towards oral drugs or infusions that are not frequent?

And another factor that is just as important is what the patient has been treated with in the past and in how has the patient responded and how has the patient tolerated it. So if a patient who has substantial neuropathy from prior therapies, you're not going to choose another agent or a combination that has a high rate of the neuropathy or a patient who has, you know, significant low platelets or low neutrophils, you're not going to choose an agent or a combination that has a high risk of neutropenia and of reducing the white blood cell count or reducing reducing the platelets.

And in a little bit in line of what we discuss about refractory in this hour, relapse, you tend to reemploy, redeployed drugs that the patient was exposed to before. As long as the patient responded and tolerated. But you are unlikely to reintroduce a drug that the patient's disease was refractory to in the past.

We just assume that, you know, once the disease becomes refractory to the agent, although this may not be always true, it's safer to go on a different direction, to use another agent on the same class or a different class of agents all together.

really it just comes down to twofold. One is when you're trying to choose a new cocktail for a drug, you want to know your about your myeloma and you want to know about your three things, your body, its co-morbidities, and three, what your goals are. And this is the important part of the conversation with your myeloma specialist.

One is how fast is your myeloma growing? The faster it's growing, the more aggressive of a treatment you need. We always want to do triplet therapy at a minimum for patients who have relapsing disease. But when you're thinking about what that triplet therapy may be, we want to think about have you had prior peripheral neuropathy? Have you had prior allergic reactions to anything?

Have you had thromboembolic disease? We want to try and tailor your triplet therapy to fit you perfectly. That's not going to exacerbate any of your comorbidities as you already have.

And thirdly is what are you willing to do for your treatment? We may easily say you should do this, this and this, but, well, you have a job and you're on the road and you've got things to do and people to see maybe that doesn't fit with your life.

So I think you need to understand what your goals of treatment are. I want to work. I want to do everything possible to make it go away, no matter the cost, whatever that may be. Those are the things we consider.

One needs to understand that while these drugs are very effective and we see good responses in a high proportion of patients, unfortunately none of these treatments by itself are curative.

So we're really the goal of treatment is to get as much benefit from each of the available options we have, such that our patients are living longer, living better and living with good quality of life. So that means that eventually patients who have myeloma will end up using most of these drugs that we talked about in some combination or the other.

So it's our job as doctors and patients to try to use these as smartly as we can so we get the maximal benefit.

So one of the things to consider would be, as I mentioned, you know, what treatments is this patient received before? What's the likelihood of responding to a particular combination based on clinical trial data, based on the patient's own prior drug exposure?

Do they have toxicities or conditions that would preclude significant cardiac disease? Might that mean maybe we don't want to use carfilzomib? Significant neuropathy might mean we don't want to try or want to avoid Velcade.

None of these are absolute contraindications, to be sure, but things that we would be more cautious about. So that's the second factor. The third one, like I said, is convenient.

So an oral drug combination, for instance, has the convenience of patients not needing to come every week or twice a week, sometimes to get infusions and treatments in the doctor's office. If it's low levels of disease slowly progressing, we might want to come up with an all oral regimen that allows patients to spend more time at home and more time doing their regular activities rather than spending time in the hospital.

So that's another consideration. As I mentioned, clinical trials are things like CAR-T cells, more intensive treatments, but may provide a significant treatment free interval because it's a one time treatment. There's no ongoing therapy. So are there clinical trials that a patient might be eligible for with CAR-T cells, or are they eligible for commercial CAR-T cells? That would be another consideration.

And then we touched on a little bit about bispecific antibodies. These hematologic treatments that are becoming available for advanced myeloma, but maybe soon also for earlier lines of treatment would be yet another consideration as well for these patients.

What disease factors are taken into consideration when choosing a treatment?

I guess, one that in myeloma classically we've often considered is cytogenetics or high risk myeloma?

This is basically testing that's done on bone marrow biopsies of bone marrow aspirates. When we do these bone marrow biopsies, we send them for genetic testing where we can find specific mutations, changes in myeloma cells that may predict higher risk disease.

And about 25% or so of patients have one of these genetic changes that indicate perhaps a slightly higher risk than the other 75%.

In those patients, oftentimes, doctors want to be more proactive about treating with more intensive, not more intensive, I should say, more more active combinations of treatments. So that's one consideration. The second for me is what we sometimes refer to as functional high risk.

This means patients may not have the high risk, you know, genetic changes, but the disease behaves like high risk. For instance, they had a good response, but less than 6 to 12 months later, the disease is coming back, which we typically would not expect. So that would be somebody, even in the absence of high risk cytogenetics, we would worry that this is somebody who has high risk for reasons that we don't fully understand. Those patients, we would want to be more cautious about how does the relapse come on?

Is that just like genes and M-spikes slowly creeping up, as in serologic relapse, that gives us more leeway in terms of when to treat, how to treat? Or is this disease that's coming back very symptomatic with bone disease or affecting kidneys or other organs? In those cases you want to be very proactive in starting treatments as quickly as possible, going with our most effective treatments upfront, etc..

So those are, I would say, some of the disease or patient related factors that plays into to how we decide which combinations and treatments to go with.